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1.  Decision making in critically ill patients with hematologic malignancy. 
Western Journal of Medicine  1991;155(5):488-493.
Hematologic neoplasms that were previously considered fatal are now potentially curable with techniques such as bone marrow transplantation. Such therapies also carry significant morbidity and mortality. With the increasing application of these therapies, a growing number of physicians are using medical decision making regarding critical care for these patients. The process by which ethical decisions are reached for these critically ill patients may be baffling because of several factors: rapidly evolving treatments, uncertain probabilities of the cure of the malignant disorder, the relatively young age of many of these patients, and the poor prognosis with critical illness. I discuss a process to reach acceptable decisions, providing a case example of the application of the process. This process is derived from the ethical principles that drive decision making in general medicine and attempts to maximize patients' autonomy. It involves a consideration of accurate information regarding the disease process and the prognosis, a clear delineation of the goals of the medical care, and communication with patients. Appropriate, ethical, and consistent decisions regarding the critical care of patients with hematologic malignancy can be reached when these considerations are addressed.
PMCID: PMC1003059  PMID: 1815387
2.  Cross-section perimeter is a suitable parameter to describe the effects of different baffle geometries in shaken microtiter plates 
Biotechnological screening processes are performed since more than 8 decades in small scale shaken bioreactors like shake flasks or microtiter plates. One of the major issues of such reactors is the sufficient oxygen supply of suspended microorganisms. Oxygen transfer into the bulk liquid can in general be increased by introducing suitable baffles at the reactor wall. However, a comprehensive and systematic characterization of baffled shaken bioreactors has never been carried out so far. Baffles often differ in number, size and shape. The exact geometry of baffles in glass lab ware like shake flasks is very difficult to reproduce from piece to piece due to the hard to control flow behavior of molten glass during manufacturing. Thus, reproducibility of the maximum oxygen transfer capacity in such baffled shake flasks is hardly given.
As a first step to systematically elucidate the general effect of different baffle geometries on shaken bioreactor performance, the maximum oxygen transfer capacity (OTRmax) in baffled 48-well microtiter plates as shaken model reactor was characterized. This type of bioreactor made of plastic material was chosen, as the exact geometry of the baffles can be fabricated by highly reproducible laser cutting. As a result, thirty different geometries were investigated regarding their maximum oxygen transfer capacity (OTRmax) and liquid distribution during shaking. The relative perimeter of the cross-section area as new fundamental geometric key parameter is introduced. An empirical correlation for the OTRmax as function of the relative perimeter, shaking frequency and filling volume is derived. For the first time, this correlation allows a systematic description of the maximum oxygen transfer capacity in baffled microtiter plates.
Calculated and experimentally determined OTRmax values agree within ± 30% accuracy. Furthermore, undesired out-of-phase operating conditions can be identified by using the relative perimeter as key parameter. Finally, an optimum well geometry characterized by an increased perimeter of 10% compared to the unbaffled round geometry is identified. This study may also assist to comprehensively describe and optimize the baffles of shake flasks in future.
PMCID: PMC4107583  PMID: 25093039
Shaken bioreactors; Maximum oxygen transfer capacity (OTRmax); Degree of baffling; Relative perimeter; Out-of-phase phenomena
3.  Death from airways obstruction: accuracy of certification in Northern Ireland. 
Thorax  1996;51(3):293-297.
BACKGROUND: Studies of mortality from asthma and chronic obstructive pulmonary disease (COPD) have relied on death certification or registration for case finding. The aim of this study was to determine the accuracy of death certification and registration in asthma and COPD. METHODS: All death certificates in Northern Ireland for 1987 where asthma or COPD (defined as International Classification of Diseases 9th Revision (ICD9) 490, 491, 492, 496) were listed in part I or part II were identified. The following certificates were then selected for further investigation: those mentioning asthma for all ages, those mentioning COPD for ages less than 56 years, and a 50% sample of those mentioning COPD aged 56-75 years. For these selected deaths the general practitioners' case notes, hospital records, and necropsy findings were reviewed. Questionnaires detailing the clinical history and circumstances of death were completed by the general practitioner by post and by a close relative or associate of the deceased (doctor administered) if, after initial investigation, the death was likely to be due to COPD or asthma. A panel of two respiratory physicians reviewed each death and, using clinical diagnostic criteria, assessed the accuracy of the registered cause of death. RESULTS: Of 50 registered asthma deaths 43 were confirmed as being due to asthma. In nine registered deaths from COPD in cases aged less than 56 years one was confirmed as COPD, two as asthma, and six as other respiratory conditions. Of 105 registered deaths from COPD in cases aged 56-75, 42 were confirmed as COPD, 27 as asthma, eight as other respiratory conditions, and 28 as other causes. Although few errors in registration were found, 21% of certificates mentioning asthma and 38% of certificates mentioning COPD but not asthma in part I were subject to variable application of the classification rules by the registering officers. For all deaths under 75 years of age in Northern Ireland in 1987 where either asthma or COPD was mentioned anywhere on the death certificate, the estimated sensitivity and specificity of the registered cause of death in predicting the "true" cause of death were 29% and 98.6% for asthma and 69% and 70% for COPD. CONCLUSIONS: In a population of subjects where asthma or COPD was mentioned anywhere on the death certificate, the registered cause of death is a relatively poor indicator of the "true" cause of death for both asthma and COPD. Variation occurred in the application of death classification rules by registration officers. Many deaths certified and registered as COPD could have been called asthma using current standards of clinical diagnosis. In studies investigating risk factors for deaths from asthma, case finding should consider deaths registered as COPD.
PMCID: PMC1090642  PMID: 8779134
4.  Self expandable stents for relief of venous baffle obstruction after the Mustard operation 
Heart  1998;79(3):230-233.
Objective—Obstruction of the venous pathways after Mustard repair for transposition of the great arteries is associated with an increased risk of arrhythmia and sudden death. The purpose of this study was to assess the effectiveness of the largest (tracheal 22 × 40 mm) Wallstents in treating baffle obstructions.
Design—Retrospective analysis of patients with stented venous pathways.
Subjects—Eleven patients with baffle obstruction after Mustard repair for transposition of the great arteries.
Interventions—Stenoses were dilated with an 18 or 20 mm balloon. However, recoil was noticed in 11 patients: immediately (n = 7) or on repeat angiography (n = 4). Eighteen stents were implanted (mean (SD)) 18 (3.3) years postoperatively. After dilatation a tracheal Wallstent (11.5 F) was deployed.
Main outcome measures—Relief of obstruction, haemodynamic improvement.
Results—In the inferior vena cava, 10 stents were deployed in seven baffle obstructions with an increase in diameter from 9.8 (2.4) mm to 16.5 (1.4) mm (p < 0.01) and a mean (SD) pressure gradient decrease from 5.1 (3.6) mm Hg to 1.4 (2.0) mm Hg; in the superior vena cava, eight stents were implanted increasing the diameter from 9.1 (3.7) mm to 15.6 (3.8) mm (p < 0.001) with a decrease in mean pressure gradient from 5.1 (2.7) mm Hg to 1.9 (1.5) mm Hg. No complications were experienced during implantation. No anticoagulation was prescribed. During follow up (1.7 (0.6) years; range, 0.9-2.6) no problems were noted; five patients were re-catheterised without change in measurements. There was no evidence of peal formation in any of the stents.
Conclusion—It is concluded that Wallstents are safe, easy to use, and effective in relieving baffle obstruction. Anticoagulation does not seem neccessary.

 Keywords: Mustard procedure;  venous baffle obstruction;  stent
PMCID: PMC1728618  PMID: 9602654
5.  Accuracy of death certificates in bronchial asthma. Accuracy of certification procedures during the confidential inquiry by the British Thoracic Association. A subcommittee of the BTA Research Committee. 
Thorax  1984;39(7):505-509.
The Research Committee of the British Thoracic Association conducted a confidential inquiry into death from asthma in adults aged 15-64 years resident in the West Midland and Mersey Regions during 1979. Death certificates recording the word asthma were received for 153 persons. The International Classification of Diseases code for the cause of death was obtained from the Office of Population Censuses and Surveys. Information about the patients, their illness, and their death was obtained by interviews, questionnaires, and inspection of patients' records. A panel of three physicians assisted by a pathologist assessed the clinical and, where applicable, the necropsy findings to ascertain whether bronchial asthma was the true cause of death. Of 147 assessable patients, 89 were considered by the panel to have died from asthma. In 77 of these cases the death certificates were correctly coded, whereas in 12 (13%) death was considered to have been wrongly attributed to another cause (falsely negative). Twenty four deaths on the other hand were considered to have been wrongly attributed to asthma (falsely positive). From this it appears that the total number of 101 certificates recording death from asthma represents a net overestimate of 13%. Accuracy was highest in the youngest age group. There were few discrepancies between the assessment of the panel and certified cause of death when a necropsy had been performed. The most common error (17% of all certificates) was failure to follow the procedure advised for completion of death certificates. This usually occurred when patients suffered from two or more conditions, or when death was sudden and necropsy was not performed.
PMCID: PMC459850  PMID: 6463930
6.  The Relationship between Asthma and Depression in Primary Care Patients: A Historical Cohort and Nested Case Control Study 
PLoS ONE  2011;6(6):e20750.
Background and Objectives
Asthma and depression are common health problems in primary care. Evidence of a relationship between asthma and depression is conflicting. Objectives: to determine 1. The incidence rate and incidence rate ratio of depression in primary care patients with asthma compared to those without asthma, and 2. The standardized mortality ratio of depressed compared to non-depressed patients with asthma.
A historical cohort and nested case control study using data derived from the United Kingdom General Practice Research Database. Participants: 11,275 incident cases of asthma recorded between 1/1/95 and 31/12/96 age, sex and practice matched with non-cases from the database (ratio 1∶1) and followed up through the database for 10 years. 1,660 cases were matched by date of asthma diagnosis with 1,660 controls. Main outcome measures: number of cases diagnosed with depression, the number of deaths over the study period.
The rate of depression in patients with asthma was 22.4/1,000 person years and without asthma 13.8 /1,000 person years. The incident rate ratio (adjusted for age, sex, practice, diabetes, cardiovascular disease, cerebrovascular disease, smoking) was 1.59 (95% CI 1.48–1.71). The increased rate of depression was not associated with asthma severity or oral corticosteroid use. It was associated with the number of consultations (odds ratio per visit 1.09; 95% CI 1.07–1.11). The age and sex adjusted standardized mortality ratio for depressed patients with asthma was 1.87 (95% CI: 1.54–2.27).
Asthma is associated with depression. This was not related to asthma severity or oral corticosteroid use but was related to service use. This suggests that a diagnosis of depression is related to health seeking behavior in patients with asthma. There is an increased mortality rate in depressed patients with asthma. The cause of this needs further exploration. Consideration should be given to case-finding for depression in this population.
PMCID: PMC3115938  PMID: 21698276
7.  Childhood asthma surveillance using administrative data: Consistency between medical billing and hospital discharge diagnoses 
The absence of ongoing surveillance for childhood asthma in Montreal, Quebec, prompted the present investigation to assess the validity and practicality of administrative databases as a foundation for surveillance.
To explore the consistency between cases of asthma identified through physician billings compared with hospital discharge summaries.
Rates of service use for asthma in 1998 among Montreal children aged one, four and eight years were estimated. Correspondence between the two databases (physician billing claims versus medical billing claims) were explored during three different time periods: the first day of hospitalization, during the entire hospital stay, and during the hospital stay plus a one-day margin before admission and after discharge (‘hospital stay ± 1 day’).
During 1998, 7.6% of Montreal children consulted a physician for asthma at least once and 0.6% were hospitalized with a principal diagnosis of asthma. There were no contemporaneous physician billings for asthma ‘in hospital’ during hospital stay ± 1 day for 22% of hospitalizations in which asthma was the primary diagnosis recorded at discharge. Conversely, among children with a physician billing for asthma ‘in hospital’, 66% were found to have a contemporaneous in-hospital record of a stay for ‘asthma’.
Both databases of hospital and medical billing claims are useful for estimating rates of hospitalization for asthma in children. The potential for diagnostic imprecision is of concern, especially if capturing the exact number of uses is more important than establishing patterns of use.
PMCID: PMC2677950  PMID: 18551199
Administrative data; Childhood asthma; Hospital admissions; Medical visits; Surveillance
8.  A retrospective cross-sectional study of risk factors and clinical spectrum of children admitted to hospital with pandemic H1N1 influenza as compared to influenza A 
BMJ Open  2012;2(2):e000310.
To compare risk factors for severe disease as measured by admission to hospital and intensive care unit (ICU) and other clinical outcomes in children with pandemic H1N1 (pH1N1) versus those with seasonal influenza.
Retrospective analysis of children admitted to hospital with pH1N1 versus seasonal influenza A.
Canadian tertiary referral children's hospital.
All laboratory-identified cases of pH1N1 in children younger than 18 years admitted to hospital in 2009 (n=176) and all seasonal influenza A cases admitted to hospital from influenza seasons 2004–2005 to 2008–2009 (n=200). Children with onset of symptoms more than 3 days after admission were excluded.
Primary and secondary outcome measures
Primary outcomes include admission to hospital and ICU and need for mechanical ventilation. Secondary outcomes include length of stay in hospital and duration of supplemental oxygen requirement.
Children admitted with pH1N1 were older than seasonal influenza A admissions (hospital admission: 6.5 vs 3.3 years, p<0.01; ICU admission: 7.3 vs 3.6 years, p=0.02). Children hospitalised with pH1N1 were more likely to have a pre-existing diagnosis of asthma (15% vs 5%, p<0.01); however, there was no difference in the severity of pre-existing asthma between the two groups. After controlling for obesity, asthma (OR 4.59, 95% CI 1.42 to 14.81) and age ≥5 years (OR 2.87, 95% CI 1.60 to 5.16) were more common risk factors in admitted children with pH1N1. Asthma was a significant predictor of the need for intensive care in patients with pH1N1 (OR 4.56, 95% CI 1.16 to 17.89) but not in patients with seasonal influenza A.
While most pH1N1 cases presented with classic influenza-like symptoms, risk factors for severe pH1N1 disease differed from seasonal influenza A. Older age and asthma were associated with increased admission to hospital and ICU for children with pH1N1.
Article summary
Article focus
Young age and underlying medical conditions have traditionally been considered risk factors for severe influenza in children.
Children admitted with pH1N1 influenza are more likely to have asthma; however, the impact of asthma severity is unknown.
Key messages
The presence of asthma and increased age, but not severity of asthma, were more common risk factors for hospitalisation with severe H1N1 influenza than with seasonal influenza A.
These results suggest that in future pandemics, certain high-risk groups may be more adversely affected than expected with seasonal influenza.
Treatment of pH1N1 influenza with oseltamivir did not appear to be associated with differing outcomes or severity of disease.
Strengths and limitations of this study
The strength of this study is that it compares a large number of children admitted with microbiologically confirmed pH1N1 to those admitted over 5 years with seasonal influenza A. For each admitted child with suspected asthma, at least two physicians reviewed the case to confirm a diagnosis of pre-existing asthma and to grade the asthma as mild, moderate or severe.
The main limitations of this study include its retrospective design, single-centre site, the inability to calculate population-based rates and that the number of admitted patients with asthma, particularly to ICU, was small.
PMCID: PMC3307038  PMID: 22411932
9.  Dynamic contrast-enhanced magnetic resonance imaging: fundamentals and application to the evaluation of the peripheral perfusion 
The ability to ascertain information pertaining to peripheral perfusion through the analysis of tissues’ temporal reaction to the inflow of contrast agent (CA) was first recognized in the early 1990’s. Similar to other functional magnetic resonance imaging (MRI) techniques such as arterial spin labeling (ASL) and blood oxygen level-dependent (BOLD) MRI, dynamic contrast-enhanced MRI (DCE-MRI) was at first restricted to studies of the brain. Over the last two decades the spectrum of ailments, which have been studied with DCE-MRI, has been extensively broadened and has come to include pathologies of the heart notably infarction, stroke and further cerebral afflictions, a wide range of neoplasms with an emphasis on antiangiogenic treatment and early detection, as well as investigations of the peripheral vascular and musculoskeletal systems.
Applications to peripheral perfusion
DCE-MRI possesses an unparalleled capacity to quantitatively measure not only perfusion but also other diverse microvascular parameters such as vessel permeability and fluid volume fractions. More over the method is capable of not only assessing blood flowing through an organ, but in contrast to other noninvasive methods, the actual tissue perfusion. These unique features have recently found growing application in the study of the peripheral vascular system and most notably in the diagnosis and treatment of peripheral arterial occlusive disease (PAOD).
Review outline
The first part of this review will elucidate the fundamentals of data acquisition and interpretation of DCE-MRI, two areas that often remain baffling to the clinical and investigating physician because of their complexity. The second part will discuss developments and exciting perspectives of DCE-MRI regarding the assessment of perfusion in the extremities. Emerging clinical applications of DCE-MRI will be reviewed with a special focus on investigation of physiology and pathophysiology of the microvascular and vascular systems of the extremities.
PMCID: PMC3996240  PMID: 24834412
Magnetic resonance imaging (MRI); dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI); peripheral artery disease
10.  Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: Executive summary 
With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there are more adults with CHD than children. This population has many unique issues and needs. They have distinctive forms of heart failure, and their cardiac disease can be associated with pulmonary hypertension, thromboemboli, complex arrhythmias and sudden death. Medical aspects that need to be considered relate to the long-term and multisystemic effects of single-ventricle physiology, cyanosis, systemic right ventricles, complex intracardiac baffles and failing subpulmonary right ventricles. Since the 2001 Canadian Cardiovascular Society Consensus Conference report on the management of adults with CHD, there have been significant advances in the understanding of the late outcomes, genetics, medical therapy and interventional approaches in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. The present executive summary is a brief overview of the new guidelines and includes the recommendations for interventions. The complete document consists of four manuscripts that are published online in the present issue of The Canadian Journal of Cardiology, including sections on genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy and contraception risks, and follow-up requirements. The complete document and references can also be found at or
PMCID: PMC2851468  PMID: 20352134
Adult congenital heart disease; Congenital heart disease; Consensus; Guidelines; Surgery
11.  Canadian Cardiovascular Society 2009 Consensus Conference on the management of adults with congenital heart disease: Complex congenital cardiac lesions 
The Canadian Journal of Cardiology  2010;26(3):e98-e117.
With advances in pediatric cardiology and cardiac surgery, the population of adults with congenital heart disease (CHD) has increased. In the current era, there are more adults with CHD than children. This population has many unique issues and needs. They have distinctive forms of heart failure and their cardiac disease can be associated with pulmonary hypertension, thromboemboli, complex arrhythmias and sudden death. Medical aspects that need to be considered relate to the long-term and multisystemic effects of single ventricle physiology, cyanosis, systemic right ventricles, complex intracardiac baffles and failing subpulmonary right ventricles. Since the 2001 Canadian Cardiovascular Society Consensus Conference report on the management of adults with CHD, there have been significant advances in the field of adult CHD. Therefore, new clinical guidelines have been written by Canadian adult CHD physicians in collaboration with an international panel of experts in the field. Part III of the guidelines includes recommendations for the care of patients with complete transposition of the great arteries, congenitally corrected transposition of the great arteries, Fontan operations and single ventricles, Eisenmenger’s syndrome, and cyanotic heart disease. Topics addressed include genetics, clinical outcomes, recommended diagnostic workup, surgical and interventional options, treatment of arrhythmias, assessment of pregnancy risk and follow-up requirements. The complete document consists of four manuscripts, which are published online in the present issue of The Canadian Journal of Cardiology. The complete document and references can also be found at or
PMCID: PMC2851473  PMID: 20352139
Adult congenital heart disease; Complete transposition of the great arteries; Congenital heart disease; Congenitally corrected transposition of the great arteries; Cyanotic heart disease; Eisenmenger’s syndrome; Fontan operation; Guidelines; Single ventricle
12.  Mutation of the BiP/GRP78 gene causes axon outgrowth and fasciculation defects in the thalamocortical connections of the mammalian forebrain 
Proper development of axonal connections is essential for brain function. A forward genetic screen for mice with defects in thalamocortical development previously isolated a mutant called baffled. Here we describe the axonal defects of baffled in further detail and identify a point mutation in the Hspa5 gene, encoding the endoplasmic reticulum chaperone BiP/GRP78. This hypomorphic mutation of BiP disrupts proper development of the thalamocortical axon projection and other forebrain axon tracts, as well as cortical lamination. In baffled mutant brains, a reduced number of thalamic axons innervate the cortex by the time of birth. Thalamocortical and corticothalamic axons are delayed, overfasciculated, and disorganized along their pathway through the ventral telencephalon. Furthermore, dissociated mutant neurons show reduced axon extension in vitro. Together, these findings demonstrate a sensitive requirement for the ER chaperone BiP/GRP78 during axon outgrowth and pathfinding in the developing mammalian brain.
PMCID: PMC3515720  PMID: 22821687
brain development; axon guidance; cortical lamination; corticothalamic axons; chaperone; Hspa5; mouse; ENU mutant; protein misfolding; UPR; endoplasmic reticulum; heat shock protein
13.  Pacemaker laser lead extraction and reimplantation of dual-chamber implantable cardioverter defibrillator via Mustard baffle in complete transposition of great arteries 
We present a case of a complicated lead extraction and reimplantation of an implantable cardioverter defibrillator (ICD) in a young woman with complete transposition of great arteries (CTGA), a cyanotic congenital heart defect in which the aorta and the pulmonary trunk are transposed. The malformation results in two parallel circulations, whereby the left ventricle is attached to the pulmonary trunk and the right ventricle is attached to the aorta. Survival depends on the mixing of these two circulations at the level of the atria or ventricles or great arteries. Balloon atrial septostomy and creation of an intra-atrial baffle are procedures that increase atrial mixing, increase systemic oxygenation, and hence improve survival. With the improved survival of patients with CTGA, there is an increasing need for permanent pacemakers (PPMs) and ICDs for rhythm disturbances. These leads and/or devices are often inserted when the patients are very young and need to be replaced or explanted in adulthood due to device or lead malfunction, device-associated infection, or generator replacement or upgrades. These procedures are often complicated by the patients' complex anatomy and/or shunts. We describe a patient with CTGA who had an intra-atrial baffle and a nonfunctioning dual-chamber PPM. The lead was extracted via the baffle and the old PPM was upgraded to an ICD. Such descriptions are rare.
PMCID: PMC2900978  PMID: 20671822
14.  Individualized Computer-Based Surgical Planning Addressing Pulmonary Arteriovenous Malformations in Single-Ventricle Patients with Interrupted Inferior Vena Cava and Azygous Continuation 
Single-ventricle patients with interrupted inferior vena cava (IVC) can develop pulmonary arterio-venous malformations due to abnormal hepatic flow distribution (HFD). However, preoperatively determining the hepatic baffle design that optimizes HFD is far from trivial. In this study, we combine virtual surgery and numerical simulations to identify potential surgical strategies for patients with interrupted IVC.
Five patients with interrupted IVC and severe PAVMs were enrolled. Their in vivo anatomies were reconstructed from MRI (n=4) and CT (n=1), and alternate virtual-surgery options (intra/extra-cardiac, Y-grafts, hepato-to-azygous and azygous-to-hepatic shunts) were generated for each. HFD was assessed for all options using a fully validated computational flow solver.
For patients with a single superior vena cava (SVC, n=3), intra/extra-cardiac connections proved dangerous, as even a small left or right offset led to a highly preferential HFD to the associated lung. Best results were obtained with either a Y-graft spanning the Kawashima to split the flow, or hepato-to-azygous shunts to promote mixing. For patients with bilateral SVCs (n=2), results depended on the balance between the left and right superior inflows. When those were equal, connecting the hepatic baffle between the SVCs performed well, but other options should be pursued otherwise.
This study demonstrates how virtual-surgery environments can benefit the clinical community, especially for rare and complex cases such as single-ventricle patients with interrupted IVC. Furthermore, the sensitivity of the optimal baffle design to the superior inflows underscores the need to characterize both pre-operative anatomy and flows to identify the best suited option.
PMCID: PMC3078987  PMID: 21334010
Congenital heart defects; Single-ventricle; Heterotaxy; Fontan; Computational fluid dynamics (CFD)
15.  Giant Coronary Artery Aneurysm Following Takeuchi Repair for Anomalous Left Coronary Artery from the Pulmonary Artery 
The American journal of cardiology  2013;113(1):10.1016/j.amjcard.2013.08.056.
A 33 year old woman with anomalous left coronary artery arising from the pulmonary artery status post Takeuchi repair at age 7 presented for evaluation. The Takeuchi procedure creates an aortopulmonary window and an intrapulmonary tunnel that baffles the left coronary artery to the aorta. A mediastinal mass was identified as a giant aneurysm of the left coronary artery resulting in compression of the pulmonary artery and left upper pulmonary vein. The patient underwent open repair with patch closure at the aortic entrance of the left coronary Takeuchi repair and resection and evacuation of the aneurysm. A saphenous vein graft to the left anterior descending was performed. Postoperative echocardiography demonstrated normal left ventricular function. This is the first reported case of giant aneurysm formation following Takeuchi repair. Reported complications include the development of pulmonary artery stenosis at the intrapulmonary baffle, baffle leak, decreased left ventricular function, and mitral regurgitation. In conclusion, late complications of the Takeuchi procedure are common, underscoring the importance of lifelong follow-up at a center with experience in treating coronary anomalies.
PMCID: PMC3865212  PMID: 24169018
congenital heart disease; coronary anomaly; aneurysm
16.  561 Distribution of Asthma Mortality in Various Districts of Salvador, Brazil 
Brazil still does not have a national program to combat asthma. Isolated initiatives have been developed in a non-standardized fashion. The Program for Control of Asthma in Bahia (ProAR) was established in Salvador, Bahia, in 2003, aiming for the control of the most severe cases.
To analyze time trends in mortality from asthma and its distribution in the districts of Salvador (2000–2009) and to correlate mortality rates with social indicators.
Observational study of deaths from asthma registered by the National Database of Mortality according to ICD-10. Mortality rates were calculated per 100,000 inhabitants and analyzed by simple linear regression. The distribution of mortality for asthma in the period was mapped into the 12 health districts of Salvador. The correlation of the number of deaths in Salvador with GDP per capita, HDI and Index Gini was evaluated.
The average asthma mortality in Salvador between 2000 and 2009 was 1.542/100.000 inhabitants, with a declining trend (R2 = 0.539, b = –11.1, P = 0.016). Deaths occurred more frequently in women than men (66% vs 34%). Asthma mortality rates were higher in subjects > 35 years. There was a reduction at ages younger than 1 year, 5 to 14 years, 25 to 34 years, and 45 to 54 years with a sharp decline between 55 and 64 (–8.14/100,000). The mortality rate (19.68/100,000 inhabitants in 2009) was higher for individuals > 75 years. The highest mortality rates were noted in more populated and poorer areas with less infrastructure and access to health services. It was observed that 78% of the deaths occurred in hospitals or health facilities. Deaths rates for asthma correlated directly with the district Gini index (rho = 0.400, P = 0.505) and inversely with HDI (rho = –0.300, P = 0.624), though not statistically significant.
Asthma mortality in Salvador is concentrated in the poorest areas with less infrastructure and access to health services, most commonly affecting women and the elderly. There was a reduction in mortality during the study period, possibly related to interventions for asthma control in the municipality. Mortality from asthma behaves differently in each district of the city.
PMCID: PMC3513127
17.  Recurrent Pneumonia and a Normal Heart: Late Complication after Repair of Hemianomalous Pulmonary Venous Drainage—A Cautionary Tale 
Case Reports in Medicine  2010;2010:930589.
Hemianomalous pulmonary venous drainage with intact atrial septum is a rare congenital anomaly and reports of its surgical repair and the long-term complications related to the correction are only infrequently encountered in the literature. We report the case of a patient with hemianomalous pulmonary venous drainage and intact atrial septum who underwent surgical repair using a pericardial baffle and creation of an “atrial septal defect” aged 15 years. Dyspnoea and recurrent chest infections started 7 months after surgery when he was seen by a respiratory physician without cardiac followup. He presented again aged 28 years with a recurrent pneumonia investigated over 6 weeks and heart pronounced normal from examination and echocardiography. Correct diagnosis was made in Grown Up Congenital Heart (GUCH) clinic stimulating review of data and catheterisation with pulmonary artery angiography which confirmed it. We feel that this case highlights the importance of specialist care and followup for GUCH patients.
PMCID: PMC2836177  PMID: 20224656
18.  Electronic health record-based assessment of oral corticosteroid use in a population of primary care patients with asthma: an observational study 
Oral corticosteroid prescriptions are often used in clinical studies as an indicator of asthma exacerbations. However, there is rarely the ability to link a prescription to its associated diagnosis. The objective of this study was to characterize patterns of oral corticosteroid prescription orders for asthma patients using an electronic health record database, which links each prescription order to the diagnosis assigned at the time the order was placed.
This was a retrospective cohort study of the electronic health records of asthma patients enrolled in the Geisinger Health System from January 1, 2001 to August 23, 2010. Eligible patients were 12–85 years old, had a primary care physician in the Geisinger Health System, and had asthma. Each oral corticosteroid order was classified as being prescribed for an asthma-related or non-asthma-related condition based on the associated diagnosis. Asthma-related oral corticosteroid use was classified as either chronic or acute. In patient-level analyses, we determined the number of asthma patients with asthma-related and non-asthma-related prescription orders and the number of patients with acute versus chronic use. Prescription-level analyses ascertained the percentages of oral corticosteroid prescription orders that were for asthma-related and non-asthma-related conditions.
Among the 21,199 asthma patients identified in the electronic health record database, 15,017 (70.8%) had an oral corticosteroid prescription order. Many patients (N = 6,827; 45.5%) had prescription orders for both asthma-related and non-asthma-related conditions, but some had prescription orders exclusively for asthma-related (N = 3,450; 23.0%) or non-asthma-related conditions (N = 4,740; 31.6%). Among the patients receiving a prescription order, most (87.5%) could be classified as acute users. A total of 60,355 oral corticosteroid prescription orders were placed for the asthma patients in this study—31,397 (52.0%) for non-asthma-related conditions, 24,487 (40.6%) for asthma-related conditions, and 4,471 (7.4%) for both asthma-related and non-asthma-related conditions.
Oral corticosteroid prescriptions for asthma patients are frequently ordered for conditions unrelated to asthma. A prescription for oral corticosteroids may be an unreliable marker of asthma exacerbations in retrospective studies utilizing administrative claims data. Investigators should consider co-morbid conditions for which oral corticosteroid use may also be indicated and/or different criteria for assessing oral corticosteroid use for asthma.
PMCID: PMC3846655  PMID: 23924393
Oral corticosteroids; Asthma; Anti-asthmatic agents; Retrospective studies; Therapeutic use; Managed care programs; Cross-sectional studies
19.  Fecal Excretion of Soluble Magnesium by Humans 
Western Journal of Medicine  1983;139(5):655-656.
To test the hypothesis that fecal magnesium excretion is related to fecal volume, fecal specimens were collected from healthy persons who drank 32 single doses of poorly absorbed carbohydrate (mannitol, lactulose or raffinose): the concentration of Mg++ (Y) in fecal water (X) was linearly and inversely related to fecal volume—that is, Y = 42−0.03 X. In contrast, after drinking magnesium sulfate, the concentration of Mg++ in fecal water rose and, except after the lowest ingested dose of 10 mmol, the points relating Mg++ concentration and fecal volume were outside the upper 95% confidence limit of the linear regression line. These findings could be useful when physicians are analyzing stool specimens for supportive evidence of magnesium misuse in baffling cases of diarrhea.
PMCID: PMC1010963  PMID: 6659489
20.  Physician based surveillance system for occupational respiratory diseases: the experience of PROPULSE, Québec, Canada. 
OBJECTIVE: To evaluate the feasibility of implementing a physician based surveillance system of occupational respiratory diseases (PROPULSE) in Québec with regard to physician participation rate, characteristics of reported cases, and comparison with official statistics from the Workers' Compensation Board (WCB). METHODS: All chest physicians and allergists in Québec were asked to report suspected new cases of occupational respiratory diseases, on a monthly basis, between October 1992 and September 1993. For each case, personal information was collected and the physician's opinion on whether the condition was related to work was categorised as highly likely, likely, and unlikely. RESULTS: Of the 161 physicians initially approached, 68% participated. Physicians rated 48% of suspected cases as highly likely, 29% as likely, and 20% as unlikely. The most often reported diagnosis was asthma (63%), followed by diseases related to asbestos (16%). Silicosis was less frequent (5%) but it was reported for six workers under 40 of whom five were involved in sandblasting activities. The high proportion of cases of asthma probably reflects the increasing importance of this disease but may also reflect the different patterns of reporting among physicians with different expertise. The distribution of cases by diagnostic category is quite different between the PROPULSE system and that of the WCB (annual mean number of compensated cases during a four year period). Asthma and allergic alveolitis are more frequent in PROPULSE, reactive airways dysfunction syndrome are about the same in both systems, and other diseases are more frequent among compensated cases. The most frequent sensitising agents reported for asthma were the same in both systems (isocyanates, flour, and wood dust). 15% of the PROPULSE cases were not covered by the WCB, and therefore would not be found in the board's official statistics. CONCLUSIONS: A physician based reporting procedure can be implemented as part of a surveillance system to supplement data from other sources and thus provide a better understanding of the occurrence of occupational respiratory diseases.
PMCID: PMC1128702  PMID: 9166134
21.  Neurobehavioral toxicity. 
A growing number of agents are known to perturb one or more of the interconnected processes of the central nervous system. At the same time, there is an increase in the incidence of neurobehavioral disorders that are confronting clinicians with baffling symptoms and presentations that seem uncommon. Fundamental to the assessment of the environmental-relatedness of the syndromes is a work and exposure history, including information different from that routinely obtained in the clinical setting. Exposure examples are described to suggest the scope of inquiry necessary to differentiate neurotoxic syndromes from nonneurotoxic illness.
PMCID: PMC2640554  PMID: 10745641
22.  Preterm Birth and Childhood Wheezing Disorders: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(1):e1001596.
In a systematic review and meta-analysis, Jasper Been and colleagues investigate the association between preterm birth and the development of wheezing disorders in childhood.
Please see later in the article for the Editors' Summary
Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth.
Methods and Findings
Two reviewers independently searched seven online databases for contemporaneous (1 January 1995–23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated “dose–response” associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations.
We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57–1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29–1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61–3.44; adjusted: OR 2.81, 95% CI 2.55–3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population-attributable risk of preterm birth for childhood wheezing disorders was ≥3.1%.
Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding.
There is compelling evidence that preterm birth—particularly very preterm birth—increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions.
Review Registration
PROSPERO CRD42013004965
Please see later in the article for the Editors' Summary
Editors' Summary
Most pregnancies last around 40 weeks, but worldwide, more than 11% of babies are born before 37 weeks of gestation (the period during which a baby develops in its mother's womb). Preterm birth is a major cause of infant death—more than 1 million babies die annually from preterm birth complications—and the number of preterm births is increasing globally. Multiple pregnancies, infections, and chronic (long-term) maternal conditions such as diabetes can all cause premature birth, but the cause of many preterm births is unknown. The most obvious immediate complication that is associated with preterm birth is respiratory distress syndrome. This breathing problem, which is more common in early preterm babies than in near-term babies, occurs because the lungs of premature babies are structurally immature and lack pulmonary surfactant, a unique mixture of lipids and proteins that coats the inner lining of the lungs and helps to prevent the collapse of the small air sacs in the lungs that absorb oxygen from the air. Consequently, preterm babies often need help with their breathing and oxygen supplementation.
Why Was This Study Done?
Improvements in the management of prematurity mean that more preterm babies survive today than in the past. However, accumulating evidence suggests that early life events are involved in the subsequent development of non-communicable diseases (non-infectious chronic diseases). Given the increasing burden of preterm birth, a better understanding of the long-term effects of preterm birth is essential. Here, the researchers investigate the risks of asthma and wheezing disorders in children who are born preterm by undertaking a systematic review (a study that uses predefined criteria to identify all the research on a given topic) and a meta-analysis (a statistical method for combining the results of several studies). Asthma is a chronic condition that is caused by inflammation of the airways. In people with asthma, the airways can react very strongly to allergens such as animal fur and to irritants such as cigarette smoke. Exercise, cold air, and infections can also trigger asthma attacks, which can sometimes be fatal. The symptoms of asthma include wheezing (a high-pitched whistling sound during breathing), coughing, chest tightness, and shortness of breath. Asthma cannot be cured, but drugs can relieve its symptoms and prevent acute asthma attacks.
What Did the Researchers Do and Find?
The researchers identified 30 studies undertaken between 1995 and the present (a time span chosen to allow for recent changes in the management of prematurity) that investigated the association between preterm birth and asthma/wheezing disorders in more than 1.5 million children. Across the studies, 13.7% of preterm babies developed asthma/wheezing disorders during childhood, compared to only 8.3% of babies born at term. Thus, the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.71 times higher than the risk of term babies developing these conditions (an unadjusted odds ratio [OR] of 1.71). In analyses that allowed for confounding factors—other factors that affect the risk of developing asthma/wheezing disorders such as maternal smoking—the risk of preterm babies developing asthma or a wheezing disorder during childhood was 1.46 times higher than that of babies born at term (an adjusted OR of 1.46). Notably, compared to children born at term, children born very early (before 32 weeks of gestation) had about three times the risk of developing asthma/wheezing disorders in unadjusted and adjusted analyses. Finally, the population-attributable risk of preterm birth for childhood wheezing disorders was more than 3.1%. That is, if no preterm births had occurred, there would have been more than a 3.1% reduction in childhood wheezing disorders.
What Do These Findings Mean?
These findings strongly suggest that preterm birth increases the risk of asthma and wheezing disorders during childhood and that the risk of asthma/wheezing disorders increases as the degree of prematurity increases. The accuracy of these findings may be affected, however, by residual confounding. That is, preterm children may share other, unknown characteristics that increase their risk of developing asthma/wheezing disorders. Moreover, the generalizability of these findings is limited by the lack of data from low- and middle-income countries. However, given the projected global increases in children surviving preterm births, these findings highlight the need to undertake research into the mechanisms underlying the association between preterm birth and asthma/wheezing disorders and the need to develop appropriate preventative and therapeutic measures.
Additional Information
Please access these websites via the online version of this summary at
The March of Dimes, a nonprofit organization for pregnancy and baby health, provides information on preterm birth (in English and Spanish)
Nemours, another nonprofit organization for child health, also provides information (in English and Spanish) on premature babies and on asthma (including personal stories)
The UK National Health Service Choices website provides information about premature labor and birth and a real story about having a preterm baby; it provides information about asthma in children (including real stories)
The MedlinePlus Encyclopedia has pages on preterm birth, asthma, asthma in children, and wheezing (in English and Spanish); MedlinePlus provides links to further information on premature birth, asthma, and asthma in children (in English and Spanish)
PMCID: PMC3904844  PMID: 24492409
23.  Increased morbidity and mortality related to asthma among asthmatic patients who use major tranquillisers. 
BMJ : British Medical Journal  1996;312(7023):79-82.
OBJECTIVE--To assess the potentially increased risk of death or near death from asthma in asthmatic patients with psychosis. DESIGN--Case-control study. SETTING--The computerised health databases of the Canadian province of Saskatchewan. SUBJECTS--131 cases of death or near death from asthma identified within a cohort of asthmatic patients; 3930 matched non-cases. EXPOSURE AND OUTCOME MEASURES--The exposure of interest was the use of major tranquillisers in the period before an outcome event. Outcomes included death or near death from asthma. RESULTS--Crude analyses showed that asthmatic patients who had used major tranquillisers in the previous 12 months were at a 3.2 (95% confidence interval 1.4 to 7.5) times greater risk of death or near death from asthma than asthmatic patients who did not use major tranquillisers. Past users of major tranquillisers who had recently discontinued use were at a particularly high risk (relative risk 6.6; 2.5 to 17.6). Adjustment for use of antiasthma drugs and other confounders abolished this excess risk. CONCLUSIONS--Asthmatic patients who use major tranquillisers seem to be at an increased risk of death or near death from asthma. Physicians treating asthmatic patients with a history of use of major tranquillisers should exercise greater caution with regard to management of such patients.
PMCID: PMC2349744  PMID: 8555932
24.  Asthma in the United States: burden and current theories. 
Environmental Health Perspectives  2002;110(Suppl 4):557-560.
Asthma has emerged as a major public health problem in the United States over the past 20 years. Currently, nearly 15 million Americans have asthma, including almost 5 million children. The number of asthma cases has more than doubled since 1980. Approximately 5,500 persons die from asthma each year, and rates have increased over the past 20 years. Rates of death, hospitalization, and emergency department visits are 2-3 times higher among African Americans than among white Americans. The costs of asthma have also increased to 12.7 billion dollars in 1998. Both lifestyle and environmental hypotheses have been invoked to explain the increase in asthma prevalence. Several studies have examined the relationship of obesity and asthma and found associations suggesting that obesity predisposes to the development of asthma. Some studies have found that day care attendance and having older siblings protect against the development of asthma. This observation has led investigators to hypothesize that increased exposure to microbial agents might protect against asthma (the hygiene hypothesis). Environmental exposures found to predispose to asthma include house dust mite allergen and environmental tobacco smoke. Although current knowledge does not permit definitive conclusions about the causes of asthma onset, better adherence to current recommendations for medical therapy and environmental management of asthma would reduce the burden of this disease.
PMCID: PMC1241205  PMID: 12194886
25.  Microbial and immunological investigations and remedial action after an outbreak of humidifier fever 
ABSTRACT Humidifier fever (Monday sickness) occuring in office staff in a factory processing rayon presented as pyrexia with a polyuria and leucocytosis on the first day back to work after a break during the winter half of the year. Chest radiographs showed no abnormalities but pulmonary function tests indicated mild airways obstruction in the affected group as a whole. Respirable dust samples taken on a Monday when 11 cases occured were not pyrogenic, indicating that a mechanism other than direct pyrogen activity produced the pyrexia. Efforts were then directed to determining an immunological basis for the episodes. In particular, Thermoactinomyces vulgaris, previously held responsible for humidifier fever, was studied. During the episode of 11 cases, the number of viable airborne spores of this organism was far higher than on Mondays when no cases occured. In a second episode of nine cases, however, the airborne viable count was of the same order as non-episode Mondays.
Extracts of T vulgaris produced lines of precipitation in gel diffusion studies with roughly half the office staff sera tested, but no correlation was observed between precipitin line formation and disease. A similar proportion of normal sera reacted against this extract. Extracts of dust lying on the topside surface of the suspended ceiling above the office, however, produced precipitin lines with sera from 16/18 affected individuals and 2/18 non-affected individuals (p < 0·001) as did extracts of humidifier material.
Extensive microbial analysis failed to detect any one fungus or bacterium that produced antigens capable of reacting with positive serum, but extracts of amoebae correlated absolutely with humidifier material and ceiling dust extract in gel diffusion studies. A reaction of identity observed between the amoebae and ceiling dust extracts showed the presence of identical antigens. In similar studies the high degree of cross reactivity with antigens and sera from Spanish and Swedish outbreaks was obtained, which suggested a common antigen source in humidifier fever.
That these antigens were produced by microbial development on rayon fibre could be shown by incubating rayon dust from the factory atmosphere with sterile water and testing with sera from affected individuals. Bales of rayon entering the factory did not have this potential to develop antigens, indicating microbial contamination after handling and processing. The initial source of contamination was considered to be the humidifier disseminating microbial spores and cysts throughout the factory and on to the suspended ceiling above the office. These were capable of secondary development on settled rayon fly under wet conditions, and evidence for this was obtained. Remedial action included cleaning the humidifier, modifying the baffle plates, running water to waste, and installing a prefilter. Dust was eliminated from the office area, and new accommodation, including the building of an office block detached from the main factory, was arranged for the office workers. So far no further cases have been reported.
PMCID: PMC1008645  PMID: 6768379

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