Author
Andre Mattman
Other affiliations: Family Research Institute, St. Paul's Hospital, Vancouver General Hospital ...read more
Bio: Andre Mattman is an academic researcher from University of British Columbia. The author has contributed to research in topics: Population & Medicine. The author has an hindex of 23, co-authored 90 publications receiving 2389 citations. Previous affiliations of Andre Mattman include Family Research Institute & St. Paul's Hospital.
Topics: Population, Medicine, Mitochondrial disease, Heteroplasmy, Subclass
Papers published on a yearly basis
Papers
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TL;DR: COX15 is established as an additional cause, along with SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated COX deficiency, and results suggest that reduced availability of heme A stalls the assembly of COX.
Abstract: Deficiencies in the activity of cytochrome c oxidase (COX), the terminal enzyme in the respiratory chain, are a frequent cause of autosomal recessive mitochondrial disease in infants. These patients are clinically and genetically heterogeneous, and all defects so far identified in this group have been found in genes coding for accessory proteins that play important roles in the assembly of the COX holoenzyme complex. Many patients, however, remain without a molecular diagnosis. We have used a panel of retroviral vectors expressing human COX assembly factors in these patients to identify the molecular basis for the COX deficiency by functional complementation. Here we show that overexpression of COX15, a protein involved in the synthesis of heme A, the heme prosthetic group for COX, can functionally complement the isolated COX deficiency in fibroblasts from a patient with fatal, infantile hypertrophic cardiomyopathy. Mutation analysis of COX15 in the patient identified a missense mutation (C700T) on one allele, changing a conserved arginine to tryptophan (R217W), and a splice-site mutation in intron 3 on the other allele (C447-3G), resulting in a deletion of exon 4. This splicing error introduces a frameshift and a premature stop codon, resulting in an unstable mRNA and, likely, a null allele. Mitochondrial heme A content was reduced in the patient's heart and fibroblast mitochondria, and levels of heme O were increased in the patient's heart. COX activity and the total amount of fully assembled enzyme were reduced by 50%–70% in patient fibroblasts. Expression of COX15 increased heme A content and rescued COX activity. These results suggest that reduced availability of heme A stalls the assembly of COX. This study establishes COX15 as an additional cause, along with SCO2, of fatal infantile, hypertrophic cardiomyopathy associated with isolated COX deficiency.
281 citations
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Family Research Institute1, University of British Columbia2, Simon Fraser University3, King Saud bin Abdulaziz University for Health Sciences4, University of Zurich5, University of Alberta6, University of Edinburgh7, National Research Council8, Arabian Gulf University9, University of Lausanne10, University of Texas at Austin11, Aristotle University of Thessaloniki12, Radboud University Nijmegen13
TL;DR: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%.
Abstract: BackgroundWhole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level. MethodsTo uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient’s clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes. ResultsWe performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 prob...
231 citations
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TL;DR: It is demonstrated that the human SCO proteins have non-overlapping, cooperative functions in mitochondrial copper delivery, and size exclusion chromatography suggests that both the proteins function as homodimers.
Abstract: Human SCO1 and SCO2 are paralogous genes that code for metallochaperone proteins with essential, but poorly understood, roles in copper delivery to cytochrome c oxidase (COX). Mutations in these genes produce tissue-specific COX deficiencies associated with distinct clinical phenotypes, although both are ubiquitously expressed. To investigate the molecular function of the SCO proteins, we characterized the mitochondrial copper delivery pathway in SCO and SCO2 patient backgrounds. Immunoblot analysis of patient cell lines showed reduced levels of the mutant proteins, resulting in a defect in COX assembly, and the appearance of a common assembly intermediate. Overexpression of the metallochaperone COX17 rescued the COX deficiency in SCO2 patient cells but not in SCO1 patient cells. Overexpression of either wild-type SCO protein in the reciprocal patient background resulted in a dominant-negative phenotype, suggesting a physical interaction between SCO1 and SC02. Chimeric proteins, constructed from the C-terminal copper-binding and N-terminal matrix domains of the two SCO proteins failed to complement the COX deficiency in either patient background, but mapped the dominant-negative phenotype in the SCO2 background to the N-terminal domain of SCO1, the most divergent part of the two SCO proteins. Our results demonstrate that the human SCO proteins have non-overlapping, cooperative functions in mitochondrial copper delivery. Size exclusion chromatography suggests that both the proteins function as homodimers. We propose a model in which COX17 delivers copper to SC02, which in turn transfers it directly to the Cu A site at an early stage of COX assembly in a reaction that is facilitated by SCO1.
219 citations
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TL;DR: A mitochondrial pathway for the regulation of cellular copper content that involves signaling through SCO1 and SCO2, perhaps by their thiol redox or metal-binding state is suggested.
206 citations
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TL;DR: Twenty-four hour urine collection is frequently inaccurate and not a precise measure of proteinuria or creatinine clearance, according to maternal weight for single collections and between-measurement difference for serial collections.
165 citations
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TL;DR: Decision aids reduced the proportion of undecided participants and appeared to have a positive effect on patient-clinician communication, and those exposed to a decision aid were either equally or more satisfied with their decision, the decision-making process, and the preparation for decision making compared to usual care.
Abstract: Background
Decision aids are intended to help people participate in decisions that involve weighing the benefits and harms of treatment options often with scientific uncertainty.
Objectives
To assess the effects of decision aids for people facing treatment or screening decisions.
Search methods
For this update, we searched from 2009 to June 2012 in MEDLINE; CENTRAL; EMBASE; PsycINFO; and grey literature. Cumulatively, we have searched each database since its start date including CINAHL (to September 2008).
Selection criteria
We included published randomized controlled trials of decision aids, which are interventions designed to support patients' decision making by making explicit the decision, providing information about treatment or screening options and their associated outcomes, compared to usual care and/or alternative interventions. We excluded studies of participants making hypothetical decisions.
Data collection and analysis
Two review authors independently screened citations for inclusion, extracted data, and assessed risk of bias. The primary outcomes, based on the International Patient Decision Aid Standards (IPDAS), were:
A) 'choice made' attributes;
B) 'decision-making process' attributes.
Secondary outcomes were behavioral, health, and health-system effects. We pooled results using mean differences (MD) and relative risks (RR), applying a random-effects model.
Main results
This update includes 33 new studies for a total of 115 studies involving 34,444 participants. For risk of bias, selective outcome reporting and blinding of participants and personnel were mostly rated as unclear due to inadequate reporting. Based on 7 items, 8 of 115 studies had high risk of bias for 1 or 2 items each.
Of 115 included studies, 88 (76.5%) used at least one of the IPDAS effectiveness criteria: A) 'choice made' attributes criteria: knowledge scores (76 studies); accurate risk perceptions (25 studies); and informed value-based choice (20 studies); and B) 'decision-making process' attributes criteria: feeling informed (34 studies) and feeling clear about values (29 studies).
A) Criteria involving 'choice made' attributes:
Compared to usual care, decision aids increased knowledge (MD 13.34 out of 100; 95% confidence interval (CI) 11.17 to 15.51; n = 42). When more detailed decision aids were compared to simple decision aids, the relative improvement in knowledge was significant (MD 5.52 out of 100; 95% CI 3.90 to 7.15; n = 19). Exposure to a decision aid with expressed probabilities resulted in a higher proportion of people with accurate risk perceptions (RR 1.82; 95% CI 1.52 to 2.16; n = 19). Exposure to a decision aid with explicit values clarification resulted in a higher proportion of patients choosing an option congruent with their values (RR 1.51; 95% CI 1.17 to 1.96; n = 13).
B) Criteria involving 'decision-making process' attributes:
Decision aids compared to usual care interventions resulted in:
a) lower decisional conflict related to feeling uninformed (MD -7.26 of 100; 95% CI -9.73 to -4.78; n = 22) and feeling unclear about personal values (MD -6.09; 95% CI -8.50 to -3.67; n = 18);
b) reduced proportions of people who were passive in decision making (RR 0.66; 95% CI 0.53 to 0.81; n = 14); and
c) reduced proportions of people who remained undecided post-intervention (RR 0.59; 95% CI 0.47 to 0.72; n = 18).
Decision aids appeared to have a positive effect on patient-practitioner communication in all nine studies that measured this outcome. For satisfaction with the decision (n = 20), decision-making process (n = 17), and/or preparation for decision making (n = 3), those exposed to a decision aid were either more satisfied, or there was no difference between the decision aid versus comparison interventions. No studies evaluated decision-making process attributes for helping patients to recognize that a decision needs to be made, or understanding that values affect the choice.
C) Secondary outcomes
Exposure to decision aids compared to usual care reduced the number of people of choosing major elective invasive surgery in favour of more conservative options (RR 0.79; 95% CI 0.68 to 0.93; n = 15). Exposure to decision aids compared to usual care reduced the number of people choosing to have prostate-specific antigen screening (RR 0.87; 95% CI 0.77 to 0.98; n = 9). When detailed compared to simple decision aids were used, fewer people chose menopausal hormone therapy (RR 0.73; 95% CI 0.55 to 0.98; n = 3). For other decisions, the effect on choices was variable.
The effect of decision aids on length of consultation varied from 8 minutes shorter to 23 minutes longer (median 2.55 minutes longer) with 2 studies indicating statistically-significantly longer, 1 study shorter, and 6 studies reporting no difference in consultation length. Groups of patients receiving decision aids do not appear to differ from comparison groups in terms of anxiety (n = 30), general health outcomes (n = 11), and condition-specific health outcomes (n = 11). The effects of decision aids on other outcomes (adherence to the decision, costs/resource use) were inconclusive.
Authors' conclusions
There is high-quality evidence that decision aids compared to usual care improve people's knowledge regarding options, and reduce their decisional conflict related to feeling uninformed and unclear about their personal values. There is moderate-quality evidence that decision aids compared to usual care stimulate people to take a more active role in decision making, and improve accurate risk perceptions when probabilities are included in decision aids, compared to not being included. There is low-quality evidence that decision aids improve congruence between the chosen option and the patient's values.
New for this updated review is further evidence indicating more informed, values-based choices, and improved patient-practitioner communication. There is a variable effect of decision aids on length of consultation. Consistent with findings from the previous review, decision aids have a variable effect on choices. They reduce the number of people choosing discretionary surgery and have no apparent adverse effects on health outcomes or satisfaction. The effects on adherence with the chosen option, cost-effectiveness, use with lower literacy populations, and level of detail needed in decision aids need further evaluation. Little is known about the degree of detail that decision aids need in order to have a positive effect on attributes of the choice made, or the decision-making process.
5,042 citations
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TL;DR: In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children, and with height measured in cm, a bedside calculation provides a good approximation to the estimated GFR formula.
Abstract: The Schwartz formula was devised in the mid-1970s to estimate GFR in children. Recent data suggest that this formula currently overestimates GFR as measured by plasma disappearance of iohexol, likely a result of a change in methods used to measure creatinine. Here, we developed equations to estimate GFR using data from the baseline visits of 349 children (aged 1 to 16 yr) in the Chronic Kidney Disease in Children (CKiD) cohort. Median iohexol-GFR (iGFR) was 41.3 ml/min per 1.73 m(2) (interquartile range 32.0 to 51.7), and median serum creatinine was 1.3 mg/dl. We performed linear regression analyses assessing precision, goodness of fit, and accuracy to develop improvements in the GFR estimating formula, which was based on height, serum creatinine, cystatin C, blood urea nitrogen, and gender. The best equation was: GFR(ml/min per 1.73 m(2))=39.1[height (m)/Scr (mg/dl)](0.516) x [1.8/cystatin C (mg/L)](0.294)[30/BUN (mg/dl)](0.169)[1.099](male)[height (m)/1.4](0.188). This formula yielded 87.7% of estimated GFR within 30% of the iGFR, and 45.6% within 10%. In a test set of 168 CKiD patients at 1 yr of follow-up, this formula compared favorably with previously published estimating equations for children. Furthermore, with height measured in cm, a bedside calculation of 0.413*(height/serum creatinine), provides a good approximation to the estimated GFR formula. Additional studies of children with higher GFR are needed to validate these formulas for use in screening all children for CKD.
2,816 citations
01 Jan 2011
TL;DR: The sheer volume and scope of data posed by this flood of data pose a significant challenge to the development of efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data.
Abstract: Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.
2,187 citations
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TL;DR: It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences, as they are no different from other major macromolecular building blocks of life, simply more rapidly evolving and complex.
Abstract: Simple and complex carbohydrates (glycans) have long been known to play major metabolic, structural and physical roles in biological systems. Targeted microbial binding to host glycans has also been studied for decades. But such biological roles can only explain some of the remarkable complexity and organismal diversity of glycans in nature. Reviewing the subject about two decades ago, one could find very few clear-cut instances of glycan-recognition-specific biological roles of glycans that were of intrinsic value to the organism expressing them. In striking contrast there is now a profusion of examples, such that this updated review cannot be comprehensive. Instead, a historical overview is presented, broad principles outlined and a few examples cited, representing diverse types of roles, mediated by various glycan classes, in different evolutionary lineages. What remains unchanged is the fact that while all theories regarding biological roles of glycans are supported by compelling evidence, exceptions to each can be found. In retrospect, this is not surprising. Complex and diverse glycans appear to be ubiquitous to all cells in nature, and essential to all life forms. Thus, >3 billion years of evolution consistently generated organisms that use these molecules for many key biological roles, even while sometimes coopting them for minor functions. In this respect, glycans are no different from other major macromolecular building blocks of life (nucleic acids, proteins and lipids), simply more rapidly evolving and complex. It is time for the diverse functional roles of glycans to be fully incorporated into the mainstream of biological sciences.
1,588 citations
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TL;DR: Recommendations for the prevention and management of venous thrombo-embolism in pregnancy and puerperium and the associated risk groups according to risk factors: definition and preventive measures are presented.
Abstract: Table 1. Classes of recommendation
Table 2. Levels of evidence
Table 3. Estimated fetal and maternal effective doses for various diagnostic and interventional radiology procedures
Table 4. Predictors of maternal cardiovascular events and risk score from the CARPREG study
Table 5. Predictors of maternal cardiovascular events identified in congential heart diseases in the ZAHARA and Khairy study
Table 6. Modified WHO classification of maternal cardiovascular risk: principles
Table 7. Modified WHO classification of maternal cardiovascular risk: application
Table 8. Maternal predictors of neonatal events in women with heart disease
Table 9. General recommendations
Table 10. Recommendations for the management of congenital heart disease
Table 11. Recommendations for the management of aortic disease
Table 12. Recommendations for the management of valvular heart disease
Table 13. Recommendations for the management of coronary artery disease
Table 14. Recommendations for the management of cardiomyopathies and heart failure
Table 15. Recommendations for the management of arrhythmias
Table 16. Recommendations for the management of hypertension
Table 17. Check list for risk factors for venous thrombo-embolism
Table 18. Prevalence of congenital thrombophilia and the associated risk of venous thrombo-embolism during pregnancy
Table 19. Risk groups according to risk factors: definition and preventive measures
Table 20. Recommendations for the prevention and management of venous thrombo-embolism in pregnancy and puerperium
Table 21. Recommendations for drug use
ABPM
: ambulatory blood pressure monitoring
ACC
: American College of Cardiology
ACE
: angiotensin-converting enzyme
ACS
: acute coronary syndrome
AF
: atrial fibrillation
AHA
: American Heart Association
aPTT
: activated partial thromboplastin time
ARB
: angiotensin receptor blocker
AS
: aortic stenosis
ASD
: atrial septal defect
AV
: atrioventricular
AVSD
: atrioventricular septal defect
BMI
: body mass index
BNP
: B-type natriuretic peptide
BP
: blood pressure
CDC
: Centers for Disease Control
CHADS
: congestive heart failure, hypertension, age (>75 years), diabetes, stroke
CI
: confidence interval
CO
: cardiac output
CoA
: coarction of the aorta
CT
: computed tomography
CVD
: cardiovascular disease
DBP
: diastolic blood pressure
DCM
: dilated cardiomyopathy
DVT
: deep venous thrombosis
ECG
: electrocardiogram
EF
: ejection fraction
ESC
: European Society of Cardiology
ESH
: European Society of Hypertension
ESICM
: European Society of Intensive Care Medicine
FDA
: Food and Drug Administration
HCM
: hypertrophic cardiomyopathy
ICD
: implantable cardioverter-defibrillator
INR
: international normalized ratio
i.v.
: intravenous
LMWH
: low molecular weight heparin
LV
: left ventricular
LVEF
: left ventricular ejection fraction
LVOTO
: left ventricular outflow tract obstruction
MRI
: magnetic resonance imaging
MS
: mitral stenosis
NT-proBNP
: N-terminal pro B-type natriuretic peptide
NYHA
: New York Heart Association
OAC
: oral anticoagulant
PAH
: pulmonary arterial hypertension
PAP
: pulmonary artery pressure
PCI
: percutaneous coronary intervention
PPCM
: peripartum cardiomyopathy
PS
: pulmonary valve stenosis
RV
: right ventricular
SBP
: systolic blood pressure
SVT
: supraventricular tachycardia
TGA
: complete transposition of the great arteries
TR
: tricuspid regurgitation
UFH
: unfractionated heparin
VSD
: ventricular septal defect
VT
: ventricular tachycardia
VTE
: venous thrombo-embolism
WHO
: World Health Organization
Guidelines summarize and evaluate all available evidence, at the time of the writing process, on a particular issue with the aim of assisting physicians in selecting the best management strategies for an individual patient, with a given condition, taking into account the impact on outcome, as well as the risk–benefit ratio of particular diagnostic or therapeutic means. Guidelines are no substitutes but are complements for textbooks and cover the European Society of Cardiology (ESC) Core Curriculum topics. Guidelines and recommendations should help the …
1,502 citations