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Biomedical subjects

J C Sinclair

Publications and source records attributed to J C Sinclair.

At least 19 recordsLinked to original sources
PubMed2004

Evidence-based therapy in neonatology: distilling the evidence and applying it in practice.

Three aspects of the role of clinical evidence in guiding therapy in the field of neonatology are presented: 1) what is embodied in the concept "evidence-based medicine"? 2) the contribution of the Cochrane Collaboration and its Neonatal Review Group in summarizing and disseminating evidence, in the form of systematic reviews of randomized controlled trials, concerning the benefits and risks of therapies in the field of neonatology; 3) approaches to bridging the gap between the evidence per se and the uptake and application of that evidence in practice.

Diffusion of Innovation↗
PubMed2001

Pulmonary oxygen consumption: a hypothesis to explain the increase in oxygen consumption of low birth weight infants with lung disease.

OBJECTIVE: We determined pulmonary oxygen consumption (VO2lung) in low-birthweight infants with acute lung disease to help explain the greater whole-body oxygen consumption (VO2wb) in these infants with than in those without lung disease. METHODS AND MATERIALS: Eleven infants (birth weight 1,076+/-364 g; gestational age 28+/-3 weeks) undergoing mechanical ventilation for respiratory distress syndrome were studied in their first week of life. We measured VO2wb by indirect calorimetry and simultaneously determined systemic oxygen uptake (VO2Fick) as the product of cardiac output (echocardiography) and the arterial-mixed venous oxygen content difference (cooximetry) assuming that VO2wb-VO2Fick accounts for VO2lung. Right atrial blood samples were used to determine mixed venous oxygenation, and infants were excluded if samples returned saturations greater than 89%. RESULTS: VO2lung was 1.92+/-1.74 ml x kg(-1) x min(-1), representing 25% of their VO2wb (7.58+/-1.48 ml x kg(-1) x min(-1)). VO2lung was not correlated with clinical measures of acute disease severity. However, infants with the most severe changes on follow-up radiography (Edwards score 5 as assessed by radiologist blinded for VO2 data) all had a VO2lung level greater than 2.0 ml x kg(-1) x min(-1). CONCLUSION: VO2lung can account for the elevated metabolic rate in low-birthweight infants with lung injury. We speculate that this reflects in part inflammatory pulmonary processes and may herald chronic lung disease.

Acute Disease↗
PubMed2001

When should an effective treatment be used? Derivation of the threshold number needed to treat and the minimum event rate for treatment.

Clinicians and patients must decide when treatment effects are large enough to more than offset the adverse effects and costs of therapy. Calculation of the number of patients one needs to treat (NNT) in order to prevent one patient from having the target event is one tool to help with this decision. Clinicians should treat patients when the NNT is lower than a threshold NNT at which point the therapeutic risk equals the therapeutic benefit. We aimed: (1) to identify the determinants of the threshold NNT, and (2) to derive equations for the explicit estimation of the threshold NNT and of the minimum expected rate of target event, without treatment, above which treatment is justified. We conceived the threshold number needed to treat to prevent one target event as the point at which the benefits of treating that number of patients equal the negative consequences of treating that same number of patients. After identifying the various elements comprising the treatment impact, we equated the benefits and negative consequences and solved the equation for threshold NNT. We then derived the minimum expected rate of target event which would justify treatment. We derived an equation that relates the threshold NNT to the treatment-attributable adverse event rates (AER) and the relative values (RV) of the adverse events compared to that of the target event prevented. Specifically, the threshold NNT, denoted NNT(T) is given by NNT(T) = 1/(AER(1).RV(1) +...+ AER(n).RV(n)). We also derived a more complex equation which addresses the costs incurred by treatment and costs avoided by preventing target events. Solving the equation that includes costs requires specifying both the value of preventing a target event and the values of adverse treatment effects in economic units. The threshold NNT and the relative risk reduction (RRR) for the target event determine the minimum target event rate above which treatment is justified. This minimum event rate for treatment is 1/(NNT(T).RRR). The values that clinicians and patients use determine the threshold NNT and therefore also the minimum target event rate, without treatment, above which treatment is justified. Quantification of the determinants of the threshold NNT and of the minimum event rate to justify treatment can assist clinicians and patients in the explicit use of underlying values when making treatment decisions.

Cost-Benefit Analysis↗
PubMed2000

Servo-control for maintaining abdominal skin temperature at 36C in low birth weight infants.

BACKGROUND: Randomized trials have shown that the neonatal mortality rate of low birth-weight babies can be reduced by keeping them warm. For low birth-weight babies nursed in incubators, warm conditions may be achieved either by heating the air to a desired temperature, or by servo-controlling the baby's body temperature at a desired set-point. OBJECTIVES: In low birth weight infants, to determine the effect on death and other important clinical outcomes of targeting body temperature rather than air temperature as the end-point of control of incubator heating. SEARCH STRATEGY: Standard search strategy of the Cochrane Neonatal Collaborative Review Group. SELECTION CRITERIA: Randomized or quasi-randomized trials which test the effects of having the heat output of the incubator servo-controlled from body temperature compared with setting a constant incubator air temperature. DATA COLLECTION AND ANALYSIS: Trial methodologic quality was systematically assessed. Outcome measures included death, timing of death, cause of death, and other clinical outcomes. Categorical outcomes were analyzed using relative risk and risk difference. Meta-analysis assumed a fixed effect model. MAIN RESULTS: Compared to setting a constant incubator air temperature of 31.8C, servo-control of abdominal skin temperature at 36C reduces the neonatal death rate among low birth weight infants: relative risk 0.72 (95% CI 0.54, 0.97); risk difference -12.7% (95% CI -1.6, -23.9). This effect is even greater among VLBW infants. REVIEWER'S CONCLUSIONS: During at least the first week after birth, low birth weight babies should be provided with a carefully regulated thermal environment that is near the thermoneutral point. For LBW babies in incubators, this can be achieved by adjusting incubator temperature to maintain an anterior abdominal skin temperature of at least 36C, using either servo-control or frequent manual adjustment of incubator air temperature.

Body Temperature Regulation↗
PubMed2000

Structure of arylamine N-acetyltransferase reveals a catalytic triad.

Enzymes of the arylamine N-acetyltransferase (NAT) family are found in species ranging from Escherichia coli to humans. In humans they are known to be responsible for the acetylation of a number of arylamine and hydrazine drugs, and they are strongly linked to the carcinogenic potentiation of certain foreign substances. In prokaryotes their substrate specificities may vary and members of the gene family have been linked to pathways including amide synthesis during rifamycin production. Here we report the crystal structure at 2.8 A resolution of a representative member of this family from Salmonella typhimurium in the presence and absence of a covalently bound product analog. The structure reveals surprising mechanistic information including the presence of a Cys-His-Asp catalytic triad. The fold can be described in terms of three domains of roughly equal length with the second and third domains linked by an interdomain helix. The first two domains, a helical bundle and a beta-barrel, make up the catalytic triad using a structural motif identical to that of the cysteine protease superfamily.

Acetanilides↗
PubMed1998

Purification, characterization, and crystallization of an N-hydroxyarylamine O-acetyltransferase from Salmonella typhimurium.

The N-hydroxyarylamine O-acetyltransferase from Salmonella typhimurium has been expressed as a histidine-tagged fusion protein in Escherichia coli and purified to apparent homogeneity using single-step immobilized metal ion chromatography. Sufficient quantities of the purified protein have been obtained to allow its characterization by physical methods including dynamic light scattering and electrospray mass spectrometry. The substrate specificity and temperature sensitivity of the enzymatic activity have also been assessed. The enzyme has been crystallized from sodium, potassium tartrate and X-ray diffraction data have been obtained to allow the identification of an orthorhombic unit cell, point group P21212, with dimensions a = 137 A, b = 223 A, and c = 105 A. These crystals will provide a route to a crystallographic determination of the structure of the protein.

Acetyltransferases↗
PubMed1997

Approaches to the definition of neonatal hypoglycemia.

There is no current agreement on the definition of neonatal hypoglycemia. Three different bases for the definition are presented, with a review of evidence of relevant to each approach. (1) Not commonly encountered; requires evidence of normal distribution of blood glucose concentrations. (2) Increased risk of adverse sequelae; requires evidence of short-term and long-term sequelae of different blood glucose concentrations. (3) Benefits of intervention outweigh risks; requires evidence from randomized trials of intervention. The usual distribution of neonatal blood glucose concentrations varies with birthweight, postnatal age, nutritional intake and other factors. Clinical signs occur in some but not all babies with low blood glucose concentrations, but such signs lack specificity. Abnormality in sensory evoked potentials is associated with variations in blood glucose concentrations; these changes suggest that values less than 2.6 mmol/L have acute effects in areas of the brain with high glucose demand. Among low birthweight babies, case series suggest a high risk of impairment (50%) following symptomatic hypoglycemia, and controlled studies generally confirm an association between very low neonatal blood glucose concentrations and adverse neurodevelopment. However, these studies do not establish a level of blood glucose concentration or duration of hypoglycemia that is critical. There are no reports of randomized trials that have assessed the effect on neurodevelopment of alternative policies of glucose provision in the neonatal period. There is a need for a randomized controlled trial to assess reliably the short- and long-term clinical effects of alternative policies of the clinical management of blood glucose concentration in babies at high risk both of low neonatal blood glucose concentrations and adverse neurodevelopment.

Central Nervous System↗
PubMed1995

Effect of the arterial oxygenation level on cardiac output, oxygen extraction, and oxygen consumption in low birth weight infants receiving mechanical ventilation.

OBJECTIVE: To investigate the effects on oxygenation of targeting the higher versus the lower end of the currently recommended range for pulse oximetry (Spo2). DESIGN: Nonrandomized crossover trial with the use of within-subject comparisons (two-tailed paired t test). SETTING: Level III neonatal intensive care unit of a university hospital. PATIENTS: Twenty infants whose lungs were mechanically ventilated (mean +/- SD: birth weight, 1192 +/- 396 gm; gestational age, 28.7 +/- 2.7 weeks; age at time of study, 42 +/- 26 hours). INTERVENTIONS: The inspired oxygen concentration was adjusted to achieve Spo2 readings of 93% to 96% versus 89% to 92% (Ohmeda pulse oximeter) or 95% to 98% versus 91% to 94% (Nellcor oximeter). MEASUREMENTS: Cardiac output was measured by echocardiography, oxygen content of arterial blood samples by cooximetry, and oxygen consumption by indirect calorimetry. RESULTS: The inspired oxygen concentrations required to achieve the Spo2 target ranges were 39.8% +/- 8.3% versus 28.7% +/- 6.1% (p < 0.001). The respective arterial oxygen contents were 18.0 +/- 2.6 ml/dl versus 16.9 +/- 2.5 ml/dl (p < 0.001). Oxygen consumption was unchanged. In the lower-oxygen condition no compensatory increase in cardiac output was detected; thus the estimated mixed venous oxygen tension decreased and the oxygen extraction ratio increased. Venous admixture increased from 15% +/- 6% to 31% +/- 9% in the lower-oxygen condition (p < 0.001). CONCLUSIONS: The "low normal" Spo2 target range allowed for less oxygen exposure. No signs of mismatch between systemic oxygen delivery and demand could be detected.

Blood Gas Analysis↗
PubMed1994

Clinically useful measures of effect in binary analyses of randomized trials.

The results of a randomized clinical trial can be reported using relative and/or absolute estimators of treatment effect. These various measures convey different information, and the choice can influence the physician's appreciation of the size of treatment effect and, subsequently, treatment decisions. We compare the estimators with respect to the clinically relevant information conveyed to physicians, and identify which clinical questions can and cannot be answered directly by each. We also identify opportunities for misinterpretation when one estimator is substituted for another, or when an estimator is mislabeled. Clinically important questions are addressed most directly by reporting both relative and absolute effects using relative risk and its complement, relative risk reduction, and risk difference and its reciprocal, number needed to treat. This is true of estimates of treatment effect derived from a single trial and also from meta-analysis of a group of trials. Because the control group's risk affects the numerical value of the odds ratio, the odds ratio cannot substitute for the risk ratio in conveying clinically important information to physicians. This is especially important when large treatment effects are shown in trials carried out in populations at high baseline risk.

Humans↗
PubMed1989

Searching MEDLINE for randomized clinical trials involving care of the newborn.

Randomized clinical trials make up only a small fraction of published articles concerning care of the newborn infant and an even smaller fraction of articles about all human subjects. The busy pediatrician who wants to keep abreast of the medical literature requires strategies to detect such relevant studies promptly and reliably. Computer searching of MEDLINE is an attractive, potentially powerful but not sufficiently validated means of achieving this goal. Therefore, the sensitivity, specificity, and positive predictive value of two MEDLINE search strategies designed to detect randomized clinical trials for prevention and treatment of newborn diseases among all original articles about human subjects appearing in ten pediatric and general medical journals during 1985 were determined. The yield of both MEDLINE searches was compared to that of a manual search. Fifty-three randomized clinical trials of newborn care were identified by hand search among 233 articles concerning care of the newborn and 2,988 original articles about human subjects. The sensitivities of the MEDLINE searches were 53% and 34%, respectively, and the positive predictive values were 82% and 69%, respectively. Specificity of both computer searches was virtually 100%. Twenty-one randomized clinical trials were not identified by either MEDLINE search strategy, 17 of them for failure of the indexer to assign any methodologic terms at all or failure to assign sufficiently stringent methodologic terms. Consequently, sensitivities were higher, 77% and 68% respectively, when no methodologic terms were used during repeat searches. However, positive predictive values decreased concomitantly to 20% or less.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗
PubMed1988

Patterns of cerebral glucose metabolism using 18FDG and positron tomography in the neurologic investigation of the full term newborn infant.

18F fluorodeoxyglucose (18FDG) and positron tomography (PT) were used in 20 full term babies with seizures or hypotonia to describe regional cerebral glucose metabolism. Among babies with seizures, birth asphyxia was the most common cause. PT was performed at age 6-17 days. One hour before PT, 18FDG (50-100 microCi/kg) was injected intravenously. Ten or more PT sections were obtained in each infant. The areas of the brain that were metabolically the most active were the cortex and the thalami. Six cortical areas and a white matter reference area were selected for analysis of relative rates of glucose metabolism as indicated by relative rates of fluorine-18 activity. Cortical fluorine-18 activity was highest in the pericentral (sensorimotor) regions and lowest in the frontal regions. The overall cortex/white matter ratio for fluorine-18 activity averaged 1.78 +/- 0.44 (SD). Four patterns of regional cerebral glucose metabolism were distinguished: 1) bilateral symmetry, 2) loss of metabolic definition, 3) hemispheral asymmetry, 4) focal hyper- or hypometabolism. Patterns 1) and 2) correlated with a history of birth asphyxia, a diagnosis of hypoxic-ischemic encephalopathy and the absence of focal echoes on cranial ultrasound. Hypodense areas on CT could be associated with either high or low fluorine-18 relative activity on PT. The prognostic significance of the presently reported patterns of cerebral glucose metabolism remains to be determined.

Brain↗