Maternal factors and the risk of birth defects after IVF and ICSI: a whole of population cohort study.

OBJECTIVE: To assess the contribution of maternal factors to major birth defects after in vitro fertilisation (IVF), intracytoplasmic sperm injection (ICSI), and natural conception. DESIGN: Retrospective cohort study in South Australia for the period January 1986 to December 2002. SETTING: A whole of population study. POPULATION: A census of all IVF and ICSI linked to registries for births, pregnancy terminations, and birth defects (diagnosed before a child's fifth birthday). METHODS: Odds ratios (ORs) for birth defects were calculated among IVF, ICSI, and natural conceptions for maternal age, parity, pre-pregnancy BMI, smoking, pre-existing diseases, and conditions in pregnancy, with adjustment for confounding factors. MAIN OUTCOME MEASURES: Birth defects classified by International Classification of Diseases (ninth revision) and British Paediatric Association (ICD9-BPA) codes. RESULTS: There were 2211 IVF, 1399 ICSI, and 301 060 naturally conceived births. The unadjusted prevalence of any birth defect was 7.1, 9.9, and 5.7% in the IVF, ICSI, and natural conception groups, respectively. As expected, the risk of birth defects increased with maternal age among the natural conceptions. In contrast, for IVF and ICSI combined, relative to natural conceptions, births to women aged ≤29 years had a higher risk (adjusted odds ratio, aOR 1.42; 95% confidence interval, 95% CI 1.04-1.94), births to women aged 35-39 years had no difference in risk (aOR 1.01; 95% CI 0.74-1.37), and births to women aged ≥40 years had a lower risk of defects (aOR 0.45; 95% CI 0.22-0.92). Defects were also elevated for nulliparity, anaemia, and urinary tract infection in births after ICSI, but not after IVF. CONCLUSIONS: The usual age-birth defect relationship is reversed in births after IVF and ICSI, and the associations for other maternal factors and defects vary between IVF and ICSI. TWEETABLE ABSTRACT: Risk of birth defects in women over 40 years is lower after infertility treatment than for natural conceptions.

Spontaneous loss of a co-twin and the risk of birth defects after assisted conception.

The study of very early pregnancy loss is impractical in the general population, but possible amongst infertility patients receiving carefully monitored treatments. We examined the association between fetal loss and the risk of birth defects in the surviving co-twin in a retrospective cohort study of infertility patients within an infertility clinic in South Australia from January 1986 to December 2002, linked to population registries for births, terminations and birth defects. The study population consisted of a total of 5683 births. Births from singleton pregnancies without loss were compared with survivors from (1) pregnancies with an empty fetal sac at 6-8 weeks after embryo transfer, (2) fetal loss subsequent to 8-week ultrasound and (3) multiple pregnancy continuing to birth. Odds ratios (OR) for birth defects were calculated with adjustment for confounders. Amongst infertility patients, the prevalence of birth defects was 7.9% for all twin pregnancies without fetal loss compared with 14.6% in pregnancies in which there had been an empty sac at ultrasound, and 11.6% for pregnancies with fetal loss after 6-8 weeks. Compared with singleton pregnancies without loss, the presence of an empty sac was associated with an increased risk of any defect (OR=1.90, 95% confidence intervals (CI)=1.09-3.30) and with multiple defects (OR=2.87, 95% CI=1.31-6.28). Twin pregnancies continuing to birth without loss were not associated with an overall increased prevalence of defects. We conclude that the observed loss of a co-twin by 6-8 weeks of pregnancy is related to the risk of major birth defects in the survivor.

UGT2B17 genetic polymorphisms dramatically affect the pharmacokinetics of MK-7246 in healthy subjects in a first-in-human study.

MK-7246, an antagonist of the chemoattractant receptor on T helper type 2 (Th2) cells, is being developed for the treatment of respiratory diseases. In a first-in-human study, we investigated whether genetic polymorphisms contributed to the marked intersubject variability in the pharmacokinetics of MK-7246 and its glucuronide metabolite M3. Results from in vitro enzyme kinetic studies suggested that UGT2B17 is probably the major enzyme responsible for MK-7246 metabolism in both the liver and the intestine. As compared with those with the UGT2B17*1/*1 wild-type genotype, UGT2B17*2/*2 carriers, who possess no UGT2B17 protein, had 25- and 82-fold greater mean dose-normalized values of area under the plasma concentration-time curve (AUC) and peak concentration of MK-7246, respectively, and a 24-fold lower M3-to-MK-7246 AUC ratio. The apparent half-life of MK-7246 was not as variable between these two genotypes. Therefore, the highly variable pharmacokinetics of MK-7246 is attributable primarily to the impact of UGT2B17 genetic polymorphisms and extensive first-pass metabolism of MK-7246.

Birthweight and thinness at birth independently predict symptoms of polycystic ovary syndrome in adulthood.

BACKGROUND: The aetiology of polycystic ovary syndrome (PCOS) is unknown and contested. While it has been suggested that PCOS could have origins in perturbed development, epidemiological findings have been inconclusive. We aimed to examine potential fetal origins of PCOS. METHODS: A retrospective birth cohort of 948 singleton female babies born at one hospital in South Australia in 1973-1975 was assembled. Birth characteristics were obtained from hospital records and PCOS symptoms were identified through interview and clinical examination when women were ~30 years old. Based on the combination of PCOS symptoms, women formed seven outcome groups. A multinomial logistic regression analysis was used to investigate associations between birth characteristics and these outcome groups. RESULTS: After adjusting for gestational age, two distinct birth characteristics were associated with two PCOS symptom groups. Each 100 g increase in birthweight increased the risk of hyperandrogenism (as a single symptom) in adulthood by 5% [relative risk ratio: 1.05, 95% confidence interval (CI): 1.01-1.09]. In contrast, each one unit increase in the ponderal index at birth decreased the risk of all three key PCOS symptoms (hyperandrogenism, menstrual dysfunction and polycystic ovaries) by 21% (0.79, 95% CI: 0.66-0.93). CONCLUSIONS: These results suggest two discrete fetal programming pathways (related to high birthweight and to thinness at birth) are operating. Our findings point to differing aetiologies for symptom clusters, and inform the debate over symptoms that best represent the disorder.

Effects of central administration of insulin or l-NMMA on rat skeletal muscle microvascular perfusion.

AIM: Intracerebroventricular (ICV) administration of a nitric oxide synthase (NOS) inhibitor to rats has been reported to raise blood pressure (BP) and cause insulin resistance, suggestive of a central effect of insulin that is NO dependent. Herein we test whether ICV insulin has peripheral haemodynamic and metabolic effects and whether peripheral effects of systemic insulin are affected by the ICV administration of the NOS inhibitor N(G) -methyl-l-arginine (l-NMMA). METHODS: Anaesthetized rats were fitted with an ICV cannula for insulin, artificial cerebrospinal fluid (aCSF) or l-NMMA infusion. Rats receiving ICV l-NMMA (500 µg) underwent systemic insulin clamp (10 mU/min/kg) or saline treatment for 70 min and were compared with animals receiving an equal amount of l-NMMA infused systemically. RESULTS: ICV aCSF or insulin (135 mU/min/kg brain) for 70 min or systemic l-NMMA (500 µg) had no effect on BP, heart rate (HR), femoral blood flow (FBF), glucose infusion rate, muscle 2-deoxyglucose uptake, microvascular perfusion or plasma insulin. However, ICV l-NMMA reduced systemic insulin-mediated increases in FBF (2.05 ± 0.08 to 1.55 ± 0.15 ml/min), 2-deoxyglucose uptake (17.7 ± 0.15 to 10.0 ± 0.03 µg/g/min) and microvascular perfusion (10.5 ± 0.5 to 6.6 ± 1.1 mol/min) (each mean ± SE, p < 0.05); plasma insulin, HR and BP were unaffected. CONCLUSIONS: Central insulin administration had no effect on skeletal muscle haemodynamics or glucose metabolism. However, systemic insulin-mediated increases in limb blood flow, muscle microvascular perfusion and glucose uptake may be regulated by a central pathway that is NO dependent.

Bilateral medialization thyroplasty: an effective approach to severe, chronic aspiration.

AIMS: To demonstrate the efficacy of bilateral medialization thyroplasty as a treatment for severe, chronic aspiration. To review the literature on surgical options available in the treatment of severe aspiration. MATERIALS AND METHODS: Three cases that underwent bilateral medialization thyroplasty are described. The technique used was the standard medialization thyroplasty described by Isshiki as a unilateral procedure. The assessment and rehabilitation of these patients is discussed. RESULTS: All patients stopped aspirating following surgery. One patient returned to a normal diet and one patient returned to a solid diet. All patients required a permanent tracheostomy. CONCLUSION: Bilateral medialization thyroplasty offers an effective surgical option in the treatment of severe, chronic aspiration. It maintains good voice, with a possible return to oral diet. The operation is easily reversible if the patient's condition alters.

Haemodynamic effects of changes in atrioventricular and interventricular delay in cardiac resynchronisation therapy show a consistent pattern: analysis of shape, magnitude and relative importance of atrioventricular and interventricular delay.

OBJECTIVE: To assess the haemodynamic effect of simultaneously adjusting atrioventricular (AV) and interventricular (VV) delays. METHOD: 35 different combinations of AV and VV delay were tested by using digital photoplethysmography (Finometer) with repeated alternations to measure relative change in systolic blood pressure (SBP(rel)) in 15 patients with cardiac resynchronisation devices for heart failure. RESULTS: Changing AV delay had a larger effect than changing VV delay (range of SBP(rel) 21 v 4.2 mm Hg, p < 0.001). Each had a curvilinear effect. The curve of response to AV delay fitted extremely closely to a parabola (average R2 = 0.99, average residual variance 0.8 mm Hg2). The response to VV delay was significantly less curved (quadratic coefficient 67 v 1194 mm Hg/s2, p = 0.003) and therefore, although the residual variance was equally small (0.8 mm Hg2), the R2 value was 0.7. Reproducibility at two months was good, with the SD of the difference between two measurements of SBP(rel) being 2.5 mm Hg for AV delay (2% of mean systolic blood pressure) and 1.5 mm Hg for VV delay (1% of mean systolic blood pressure). CONCLUSIONS: Changing AV and VV delays results in a curvilinear acute blood pressure response. This shape fits very closely to a parabola, which may be valuable information in developing a streamlined clinical protocol. VV delay adjustment provides an additional, albeit smaller, haemodynamic benefit to AV optimisation.

Characterizing the microscopic physics near moving contact lines using dynamic contact angle data.

Directly probing the fluid flow and liquid-vapor interface shape in the microscopic immediate vicinity of the moving contact line can only be accomplished in very specific and isolated cases. Yet this physics is critical to macroscopic dynamic wetting. Here we examine the microscopic (or inner) physics of spreading silicone fluids using data of macroscopic dynamic contact angle versus Capillary number Ca=U mu/sigma. This dynamic contact angle is precisely defined so that it can be related back to the microscopic behavior through detailed theory. Our results indicate that the parameters describing the inner region have a detectable dependence on spreading velocity when this velocity exceeds a critical value. This dependence is not scaled (i.e., the data are not collapsed) by Ca, which suggests that an additional time scale must be present in the model of the inner region.

Who remains undelivered more than seven days after a single course of prenatal corticosteroids and gives birth at less than 34 weeks?

UNLABELLED: Minimal information exists as to how women who give birth more than seven days after initial corticosteroid treatment, who may benefit from repeat prenatal corticosteroids, differ from women who give birth within seven days, at < 34 weeks gestation. OBJECTIVES: To examine the differences, if any, between women who received a single course of prenatal corticosteroids and remained undelivered more than seven days later and women who gave birth within seven days of treatment, at < 34 weeks gestation. DESIGN: Retrospective cohort. SETTING: Women's and Children's Hospital, Adelaide. POPULATION: Women who gave birth at < 34 weeks gestation from 1 January 1994 to 31 December 1996. METHODS: Data were extracted from medical records and retrieved from the hospital's database. MAIN POTENTIAL PREDICTORS COLLECTED: Prenatal corticosteroid exposure, reason for risk of preterm birth, maternal demographics and previous and current obstetric history. RESULTS: Of the 506 women, 122 (24%) remained undelivered more than seven days following prenatal corticosteroid therapy Initial corticosteroid treatment was given on average 1.6 weeks earlier to women who remained undelivered more than seven days after treatment. Women who were given prenatal corticosteroids for placenta praevia (RR 6.03, 95% CI 2.67-13.61, p < 0.01) or cervical incompetence (RR 3.40, 95% CI 1.06-10.95, p = 0.04) were more likely to give birth more than seven days after corticosteroid treatment. CONCLUSIONS: Women who give birth very preterm, who remain undelivered more than seven days after prenatal corticosteroids, differ in the reasons for and timing of their first course from women who give birth within seven days.

Evaluation of amylase and lipase in the diagnosis of acute pancreatitis.

BACKGROUND: The diagnosis of acute pancreatitis relies heavily on a raised amylase. METHODS: In the present study patients were prospectively categorized, without knowledge of pancreatic enzyme levels, into acute pancreatitis (AP; n = 51), disease controls (n = 35), indeterminate as to pancreatitis (n = 189) or exclusions (non-pancreatitis diseases where amylase may be elevated; n = 53). RESULTS: Enzyme levels were analysed by receiver operator characteristics (ROC) curves, with specificity > 80%. Day 1 serum lipase gave the greatest diagnostic accuracy (area under ROC curve = 0.128; P = 0.041 vs serum amylase). At the calculated diagnostic threshold of 208 U/L, lipase gave a sensitivity of 67% and a specificity of 97%. Other diagnostic thresholds (day 1) were: serum total amylase, 176 U/L (ROC 0.104, sensitivity 45%, specificity 97%), urinary total amylase, 550 U/L (ROC 0.108, sensitivity 62%, specificity 97%) and serum pancreatic isoamylase, 41 U/L (ROC 0.107, sensitivity 63%, specificity 85%). At delayed diagnosis (3 days) no enzyme was superior to lipase. The combination of lipase and amylase did not increase diagnostic accuracy. CONCLUSION: Serum lipase is recommended for diagnosis of AP, both early and late in the disease. Although highly specific when elevated, all pancreatic enzymes have low sensitivity for diagnosis.

Changes in nutrient intake during the menstrual cycle of overweight women with premenstrual syndrome.

This study presents the nutrient data collected from women who were being screened for premenstrual syndrome (PMS) for entry into an intervention study. Screening was by the Steiner self-rated questionnaire. One hundred and forty-four overweight women completed the screening process and eighty-eight met the criteria for PMS. All women kept 4 d diet diaries pre- and postmenstrually over two menstrual cycles. The mean energy and macronutrient intakes were compared between the pre- and postmenstrual phases. Energy and macronutrient intake was also calculated according to food categories. Goldberg's cut-off limit for the ratio of energy intake to estimated basal metabolic rate was used to exclude data that was incompatible with predicted energy requirements. The diet diaries were also used to determine the mean number of meals or snacks eaten pre- and postmenstrually. Nutrient analysis of the diet diaries of the women with PMS showed a significant increase (P < 0.001) in total energy and all macronutrients premenstrually when compared to nutrient intake postmenstrually. Women who did not meet the criteria for PMS showed a significant increase in energy and fat intake (P < 0.05) but not in the other macronutrients. When adjusted for energy, data collected from women with PMS showed a premenstrual significant increase in fat, carbohydrate (P < 0.05) and simple sugars (P < 0.001). There was a significant decrease (P < 0.001) in protein premenstrually. Women not meeting the PMS criteria showed no significant difference between pre- and postmenstrual intakes when adjusted for energy. Analysis according to food categories in women with PMS showed a significantly greater intake premenstrually of energy and all macronutrients for cereals, cakes and desserts and high-sugar foods (P < 0.001). In women with PMS there was a significantly greater number of 'episodes of eating' premenstrually (P < 0.001). This study provides further evidence, to support the very limited number of earlier studies, that there is a group of women with PMS who increase their nutrient intake during the premenstrual phase. This could potentially be a contributing factor for some women experiencing difficulties adhering to suggested dietary modification and should be considered when counselling premenopausal women.

Quantitative general theory for periodic breathing in chronic heart failure and its clinical implications.

BACKGROUND: In patients with chronic heart failure (CHF), periodic breathing (PB) predicts poor prognosis. Clinical studies have identified numerous risk factors for PB (which also includes Cheyne-Stokes respiration). Computer simulations have shown that oscillations can arise from delayed negative feedback. However, no simple general theory quantitatively explains PB and its mechanisms of treatment using widely-understood clinical concepts. Therefore, we introduce a new approach to the quantitative analysis of the dynamic physiology governing cardiorespiratory stability in CHF. METHODS AND RESULTS: An algebraic formula was derived (presented as a simple 2D plot), enabling prediction from easily acquired clinical data to determine whether respiration will be unstable. Clinical validation was performed in 20 patients with CHF (10 with PB and 10 without) and 10 healthy normal subjects. Measurements, including chemoreflex sensitivity (S) and delay (delta), alveolar volume (V(L)), and end-tidal CO(2) fraction (C), were applied to the stability formula. The breathing pattern was correctly predicted in 28 of the 30 subjects. The principal combined parameter (CS)x(delta/V(L)) was higher in patients with PB (14.2+/-3.0) than in those without PB (3.1+/-0.5; P:=0.0005) or in normal controls (2.4+/-0.5; P:=0.0003). This was because of differences in both chemoreflex sensitivity (1749+/-235 versus 620+/-103 and 526+/-104 L/min per atm CO(2); P:=0.0001 and P:<0.0001, respectively) and chemoreflex delay (0.53+/-0.06 vs 0.40+/-0.06 and 0.30+/-0.04 min; P:=NS and P:=0.02). CONCLUSION: This analytical approach identifies the physiological abnormalities that are important in the genesis of PB and explicitly defines the region of predicted instability. The clinical data identify chemoreflex gain and delay time (rather than hyperventilation or hypocapnia) as causes of PB.

Very-low-frequency oscillations in heart rate and blood pressure in periodic breathing: role of the cardiovascular limb of the hypoxic chemoreflex.

In chronic heart failure, very-low-frequency (VLF) oscillations (0.01-0.04 Hz) in heart rate and blood pressure may be related to periodic breathing, although the mechanism has not been fully characterized. Groups of ten patients with chronic heart failure and ten healthy controls performed voluntary periodic breathing with computer guidance, while ventilation, oxygen saturation, non-invasive blood pressure and RR interval were measured. In air, voluntary periodic breathing induced periodic desaturation and prominent VLF oscillations when compared with free breathing in both patients [RR interval spectral power from 179 to 358 ms2 (P<0.05); systolic blood pressure (SBP) spectral power from 3.44 to 6.25 mmHg2 (P<0.05)] and controls [RR spectral power from 1040 to 2307 ms2 (P<0.05); SBP spectral power from 3.40 to 9.38 mmHg2 (P<0.05)]. The peak in RR interval occurred 16-26 s before that in SBP, an anti-baroreflex pattern. When the patients followed an identical breathing pattern in hyperoxic conditions to prevent desaturation, the VLF RR interval spectral power was 50% lower (179.0+/-51.7 ms2; P<0.01) and the VLF SBP spectral power was 44% lower (3.51+/-0.77 mmHg(2); P<0.01); similar effects were seen in controls (VLF RR power 20% lower, at 1847+/-899 ms2, P<0.05; VLF SBP power 61% lower, at 3.68+/-0.92 mmHg2, P=0.01). Low- and high-frequency spectral powers were not significantly affected. Thus periodic breathing causes oxygen-sensitive (and by implication chemoreflex-related) anti-baroreflex VLF oscillations in RR interval and blood pressure in both patients with chronic heart failure and normal controls.

True shape and area of proximal isovelocity surface area (PISA) when flow convergence is hemispherical in valvular regurgitation.

The proximal isovelocity surface area (PISA) method for quantifying valvular regurgitation uses an echocardiographic image with superimposed colour Doppler mapping to visualise the contours of velocity in the blood travelling towards the regurgitant orifice. The flux of blood through the regurgitant orifice is obtained as the product of the area of one of these (presumed hemispherical) contours and the speed of the blood passing through it. However, colour Doppler mapping measures the velocity component towards the echo probe (v cos theta;) rather than speed (v), so that the contours of equal Doppler velocity (isodoppler velocity contours) differ from isospeed contours. We derive the shape of the isodoppler contour surface obtainable by colour Doppler mapping, and show that its area is much less than that of the hemispherical isospeed contour. When regurgitant flux is derived from an appropriate single measure of contour dimension, an appropriate result may be obtained. However, if the true echocardiographic surface area is measured directly, the regurgitant flux will be substantially underestimated. Indeed, the conditions necessary for isodoppler velocity contours to be hemispherical are extraordinary. We should not therefore make deductions from the apparent shape for the convergence zone without considering the principles by which the image is generated. The discrepancy will assume practical significance when increased resolution of colour Doppler technology makes measurement of apparent surface area feasible. Assuming the flow contours are indeed hemispherical, a 'correction' factor of 1.45 would be required.

Health effects of daily indoor nitrogen dioxide exposure in people with asthma.

Household gas appliances produce nitrogen dioxide (NO2), which may be associated with an increase in symptoms in asthmatics. The relationship between indoor NO2 exposure, and respiratory symptoms in people with asthma was evaluated. Self-reported asthmatics (n=125) wore lapel badges that measured NO2 daily over 6 weeks at home. Outdoor pollutants, spores and meteorological parameters were measured daily, in addition to smoking status and demographic factors. Seven asthma symptoms were recorded in diaries, for analysis by same day and also with 1 day lag exposures, using a generalized estimating equation. Significant interactions were demonstrated between NO2 at age < or =14 yrs, with respect to the symptoms of chest tightness on the same day (odds ratio (OR): 1.29, 95% confidence interval (CI): 1.16-1.43) and with a 1 day lag (OR: 1.29, 95% CI: 1.14-1.46), breathlessness on exertion with a 1 day lag (OR: 1.13, 95% CI: 1.00-1.28), daytime asthma attacks on the same day (OR: 1.13, 95% CI: 1.02-1.26) night asthma attacks on the same day (OR: 1.16, 95% CI:1.03-1.30) and with a 1 day lag (OR: 1.15, 95% CI; 1.03-1.29) after adjustment for potential confounders. A significant interaction between NO2 and age 35-49 yrs was demonstrated for coughs with a 1 day lag (OR: 1.15, 95% CI: 1.01-1.31). Daily personal exposures to NO2 are associated with asthmatic symptoms in children.

Is an ultrasound assessment of gestational age at the first antenatal visit of value? A randomised clinical trial.

OBJECTIVES: To assess the efficacy of an ultrasound scan at the first antenatal visit. DESIGN: Randomised clinical trial. SETTING: Women's and Children's tertiary level hospital, Adelaide, Australia. POPULATION: Six hundred and forty-eight women attending for their first antenatal visit at less than 17 weeks of gestation who had no previous ultrasound scan in the pregnancy, who were expected to give birth at the hospital, and for whom there was no indication for an ultrasound at their first visit. METHODS: Eligible consenting women were enrolled by telephone randomisation into either the ultrasound at first visit group, who had an ultrasound at the time of their first antenatal visit, or the control group in whom no ultrasound assessment was done at their first antenatal visit. Both groups of women completed a questionnaire at the end of the first visit on their feelings towards the pregnancy and anxiety levels. Data were collected on details of any ultrasound assessments, including the 18 to 20 weeks morphology scan, and pregnancy outcome. All primary analyses were on an intention-to-treat basis. MAIN OUTCOME MEASURES: The number of women who needed adjustment in dates of 10 days or more on the basis of their 18 to 20 weeks ultrasound morphology scan, who were booked for their morphology scan at sub-optimal gestations, who had a repeat of their maternal serum screening test, or who felt worried about their pregnancy at the end of the first antenatal visit. RESULTS: Fewer women (9%) in the ultrasound at first visit group needed adjustment of their expected date of delivery as a result of the 18 to 20 week ultrasound, compared with 18% of women in the control group (RR 0.52, 95% CI 0.34-0.79; P = 0.002). The number of women who had the 18 to 20 week ultrasound assessment timed suboptimally was similar to that in the control group (16% vs. 21%), as was the number of women who had a repeat blood sample taken for maternal serum screening (6% vs. 6%). Fewer women in the ultrasound at first visit group reported feeling worried about their pregnancy (RR 0.80, 95% CI 0.65-0.99; P = 0.04) or not feeling relaxed about their pregnancy (RR 0.73, 95% CI 0.56-0.96; P = 0.02), compared with women in the control group. CONCLUSIONS: A routine ultrasound assessment for dating offered to women at the first antenatal visit provides more precise estimates of gestational age and reduces the need to adjust the estimate of the date of delivery in mid-gestation. Women who had an ultrasound at the first visit reported more positive feelings about their pregnancy, compared with women in the control group at that time.

Oxygenation in patients with a functionally univentricular circulation and complete mixing of blood: are saturation and flow interchangeable?

BACKGROUND: Perioperative management of patients with complete mixing of pulmonary and systemic blood centers on approximately equating pulmonary (Qp) and systemic (Qs) blood flow (Qp/Qs approximately 1). This empirically derived target is opposed by theoretical studies advocating a target Qp/Qs well below 1. We studied the cause of this persistent discrepancy. METHODS AND RESULTS: Classic theoretical studies have concentrated on maximizing 1 of many potential combination parameters of arterial oxygen content (CaO(2)) and systemic blood flow: total oxygen delivery (DO(2))=CaO(2)xQs. We defined "useful" oxygen delivery as the amount of oxygen above a notional saturation threshold (Sat(Thresh)): D(u)O(2)=carrying capacityx(SaO(2)-Sat(Thresh))xQs. Whereas DO(2) peaks at Qp/Qs ratios <1, D(u)O(2) peaks at higher Qp/Qs ratios, nearer to (or exceeding) 1. Systemic venous saturation (which mirrors tissue oxygen tension) peaks at Qp/Qs=1. CONCLUSIONS: First, the standard model of single-ventricle physiology can be reexpressed in a form allowing analysis by differential calculus, which allows broader conclusions to be drawn than does computer modeling alone. Second, the classic measure DO(2) fails to reflect the fact that proportional changes in saturation and flow are not clinically equivalent. Recognizing this asymmetry by using D(u)O(2) can give a target Qp:Qs balance that better represents clinical experience. Finally, to avoid an arbitrary choice of Sat(Thresh), systemic venous oxygen saturation (SsvO(2)) may be a useful parameter to maximize: this occurs at a Qp/Qs ratio of 1. Attempts to increase DO(2) by altering Qp/Qs away from this value will inevitably reduce SsvO(2) and therefore tissue oxygenation. Oxygen delivery is far from synonymous with tissue oxygen status.

Impact of periodic breathing on V(O2) and V(CO2): a quantitative approach by Fourier analysis.

Oscillations in oxygen uptake (V(O2)) and carbon dioxide production (V(CO2)) in patients with chronic heart failure differ in amplitude and phase from the oscillations in ventilation (periodic breathing, PB), leading some to doubt whether they result from PB. We applied Fourier transforms to a pulmonary gas exchange model to quantify the effects of fluctuations in alveolar ventilation (V(A)). We found that PB causes oscillations in V(O2) and V(CO2), but their amplitude and phase are complex, and vary with workload. At low workloads, the relative oscillations in V(O2) and V(CO2) closely mirror the relative oscillations in V(A). But at high workloads, the metabolic oscillations are attenuated (V(O2) most severely), and the V(O2) peaks precede the ventilatory peaks significantly. This study also explains why normal controls simulating PB at higher workloads fail to reproduce the V(O2) and V(CO2) oscillations seen in spontaneous PB of heart failure.

Otologic management in children with the CHARGE association.

OBJECTIVES: To characterize otologic management of two patient groups, those with the CHARGE association and those not strictly labeled as CHARGE but with several features of the disorder (CHARGE-like), in order to determine: (1) the clinical validity and utility of managing CHARGE-like children in a similar manner to patients with the strictly defined CHARGE association, (2) the progression and prognosis of hearing loss and (3) the identification of factors that may predict the degree of hearing loss. DESIGN: Case series. SETTING: Tertiary care urban children's hospital. PATIENTS: 37 children, 22 in the CHARGE group and 15 in the CHARGE-like group. INTERVENTIONS: Otorhinolaryngologic and audiologic management. MAIN OUTCOME MEASURES: Otorhinolaryngologic and audiologic evaluation. RESULTS: All patients required otologic and/or audiologic care. Bilateral hearing loss was found in 32 patients (86%) and unilateral hearing loss in five patients (14%) when hearing was assessed in the absence of otitis media. Among the 32 patients with bilateral hearing loss, 31 (97%) were able to be fit with useful hearing aids. External ear anomalies were present in 25/37 (68%) patients, and middle ear and ossicular anomalies were identified in four cases (4/37, 11%), 36/37 (97%) patients required surgical management of otitis media. Three patients (3/37, 8%) exhibited radiographic evidence of inner ear deformity. Facial nerve dysfunction was noted in the records of 14/37 (38%) patients. No statistically significant difference was found when CHARGE and CHARGE-like patients were compared for degree of hearing loss (P = 0.5964), type of hearing loss (P = 0.2657), worsening of hearing level (P = 0.7908), or anomalies of the external ear (P = 0.6921), ossicles (P = 0.7908), inner ear (P = 0.7908) or facial nerve (P = 0.6409). Patients with external ear anomalies did not exhibit statistically different degrees (P = 0.3125) or types (P = 0.1515) of hearing loss from patients without auricular anomalies. The presence of facial nerve anomaly correlated significantly (P = 0.0021) with profound hearing loss. CONCLUSIONS: Children who are CHARGE-like may be may be considered equivalent in terms of otologic and audiologic management to children strictly defined as CHARGE patients. These children all require otologic care due to the high prevalence of middle ear disease and the underlying permanent hearing loss that is both stable and aidable. The degree of hearing loss cannot be predicted by external ear morphology, but may be predicted by facial nerve palsy.

Relating physical activity to health status, social connections and community facilities.

An important public health goal is to increase the population's participation in regular, moderate physical activity. Descriptive epidemiological studies that focus only on associations between physical activity and demographic and psychological factors are not sufficient to inform exercise promotion strategies, and a broader view of health is required. This study investigates the additional factors of health status, social connections and satisfaction with local area facilities by analysing data from a 1987 community health survey of 1765 residents of Adelaide. Factors associated with low activity were age group, education, general health (women), reduced mobility, number of social connections (men) and degree of satisfaction with recreation facilities. Including social and structural factors is valuable for research into interventions, policy and theory relating to physical activity as it brings theoretical perspectives and links to other areas of public health and social research.