Ethics for the pediatrician: obstetric conflict: when fetal and maternal interests are at odds.

The interests of the fetus generally are aligned with those of the pregnant woman. When they are not, the fetal best interests should be discussed, but respect for the autonomy of the pregnant woman and her bodily integrity should prevail. Gender bias and discrimination toward women should be avoided, and the circumstance of pregnancy should not be used as a reason to infringe upon or limit a competent woman's rights. Evidence indicates that providing prenatal care and treatment in a supportive, rather than coercive way is the most effective way to promote both maternal and child health. Concerns about potential harm to the fetus related to maternal decisions must be evaluated in the context of the best medical evidence, including what is known and what is uncertain. Threats or legal coercion should not be used to force treatment, in particular, to impose cesarean delivery. Hospital guidelines can be developed to support a framework of shared decision-making in the situation of maternal-fetal conflict and provide guidance for compassionate conflict resolution. Pediatricians have an important role in informing the discussion about care and outcomes. At times, an ethics consult maybe helpful to mediate conflict resolution. Intervention by the courts is rarely appropriate or indicated and should be avoided.

Shifting the care paradigm for opioid-exposed newborns in Southern Colorado.

OBJECTIVE: Compare Eat, Sleep, Console (ESC) and limited opioid treatment on birth length of stay (LOS), postnatal opioid exposure, and 30-day re-hospitalizations in opioid-exposed newborns (OENs) in two hospital systems. STUDY DESIGN: Quality improvement teams supported change from scheduled methadone using Finnegan scores to standardized non-pharmacologic support using ESC. Intermittent morphine was used only if needed. Statistical process control charts examined changes over time. RESULT: Between 2017 and 2019 we treated 280 OENs ≥35 weeks' gestation, 101 and 179 per hospital. Post-ESC, LOS decreased 51.2% (16.8-8.2 days), postnatal opioid treatment decreased from 64.1 to 29.9%; percent decline in both hospitals was similar. 30-day re-hospitalizations were 5/103 (4.8%) pre-ESC, and 7/177 (4.0%) post-ESC (p = 0.72, NS). Multiple substance co-exposures were common (226/280, 80.7%). CONCLUSION: ESC and as needed morphine decreased LOS and postnatal opioid exposure for OENs in two hospital systems without increasing 30-day readmissions. ESC appears effective in OENs with multiple co-exposures.

Respiratory subtype of relapsing polychondritis frequently presents as difficult asthma: a descriptive study of respiratory involvement in relapsing polychondritis with 13 patients from a single UK centre.

INTRODUCTION: Relapsing polychondritis is a rare multisystem vasculitis characterised by recurrent cartilage inflammation. Respiratory involvement, of which tracheobronchomalacia (TBM) is the commonest form, is difficult to treat and is linked to increased mortality. We describe 13 patients with respiratory involvement. METHODS: This is a retrospective study of all the patients with relapsing polychondritis at University Hospitals Coventry and Warwickshire NHS Trust (UHCW), a secondary care provider for ∼500 000. Only patients with respiratory involvement were included in this study. RESULTS: We identified 13 patients who fulfilled the inclusion criteria. Most patients were identified from the "difficult asthma" clinic. TBM was seen in 11 patients, whilst two patients had pleural effusions which resolved with immunosuppression and one patient had small airways disease. Computed tomography scans (inspiratory and expiratory) and bronchoscopy findings were useful in diagnosing TBM. Pulmonary function testing revealed significant expiratory flow abnormalities. All patients were treated with corticosteroids/disease-modifying anti-rheumatic drugs (DMARDs) and some were given cyclophosphamide or biological agents, although the response to cyclophosphamide (1 out of 4) or biologicals (2 out of 4) was modest in this cohort. Ambulatory continuous positive airway pressure ventilation was successful in four patients. CONCLUSIONS: Relapsing polychondritis may be overlooked in "difficult asthma" clinics with patients having TBM (not asthma) and other features of relapsing polychondritis. Awareness of this condition is crucial to enable early diagnosis and interventions to reduce the risk of life-threatening airway collapse. A number of patients respond well to DMARDs and are able to minimise corticosteroid use.

L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial.

CONTEXT: The amino acid L-arginine is a substrate for nitric oxide synthase and is increasingly used as a health supplement. Prior studies suggest that L-arginine has the potential to reduce vascular stiffness. OBJECTIVE: To determine whether the addition of L-arginine to standard postinfarction therapy reduces vascular stiffness and improves ejection fraction over 6-month follow-up in patients following acute ST-segment elevation myocardial infarction. DESIGN AND SETTING: Single-center, randomized, double-blind, placebo-controlled trial with enrollment from February 2002 to June 2004. PATIENTS: A total of 153 patients following a first ST-segment elevation myocardial infarction were enrolled; 77 patients were 60 years or older. INTERVENTION: Patients were randomly assigned to receive L-arginine (goal dose of 3 g 3 times a day) or matching placebo for 6 months. MAIN OUTCOME MEASURES: Change in gated blood pool-derived ejection fraction over 6 months in patients 60 years or older randomized to receive L-arginine compared with those assigned to receive placebo. Secondary outcomes included change in ejection fraction in all patients enrolled, change in noninvasive measures of vascular stiffness, and clinical events. RESULTS: Baseline characteristics, vascular stiffness measurements, and left ventricular function were similar between participants randomized to receive placebo or L-arginine. The mean (SD) age was 60 (13.6) years; of the participants, 104 (68%) were men. There was no significant change from baseline to 6 months in the vascular stiffness measurements or left ventricular ejection fraction in either of the 2 groups, including those 60 years or older and the entire study group. However, 6 participants (8.6%) in the L-arginine group died during the 6-month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment. CONCLUSIONS: L-arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L-arginine should not be recommended following acute myocardial infarction. Clinical Trial Registration ClinicalTrials.gov, NCT00051376.

Attenuated cardiovascular reserve during prolonged submaximal cycle exercise in healthy older subjects.

OBJECTIVE: The goal of this study was to determine the effect of age on the hemodynamic response to prolonged submaximal aerobic exercise in healthy volunteers. BACKGROUND: Reductions in peak work rate, heart rate (HR), and left ventricular (LV) emptying but higher blood pressure (BP) and systemic vascular resistance occur in healthy older versus younger humans during short bursts of graded maximal aerobic exercise. However, the effect of aging on the cardiovascular response to prolonged exercise at submaximal work rates typical of daily aerobic activities remains unknown. METHODS: We evaluated cardiovascular performance throughout prolonged submaximal upright cycle ergometry in 40 carefully screened healthy untrained volunteers, 8 men and 12 women <50 years old, mean = 37 +/- 8 years (younger), and 10 men and 10 women >/=50 years old, mean = 66 +/- 9 years (older), during upright cycle exercise at 70% of peak cycle oxygen consumption (VO(2)) to exhaustion or a maximum of 120 min. Cardiac volumes were acquired by gated blood pool scans with (99m)Tc at rest and every 10 min throughout exercise. RESULTS: Duration of exercise was similar in younger ([81 +/- 28 min] versus older [71+/- 29 min] subjects, p = NS). At 10 min of exercise in the steady state, older subjects demonstrated lower VO(2) (1.1 +/- 0.2 l/min vs. 1.3 +/- 0.3 l/min) and lower HR (118 +/- 17 vs. 135 +/- 11 beats/min, p < 0.001) but larger end-diastolic (80 +/- 11 ml/m(2) vs. 73 +/- 8 ml/m(2), p = 0.03) and end-systolic volume index (ESVI) 20 +/- 6 ml/m(2) vs. 17 +/- 4 ml/m(2), p < 0.05) than younger ones. Between 10 min and exercise termination, with VO(2) held constant in both groups, increases in HR (14.0 +/- 12.4 beats/min vs. 5.9 +/- 11.5 beats/min, p = 0.04), cardiac index (1.6 +/- 1.0 l/min/m(2) vs. 0.8 +/- 1.1 l/min/m(2), p = 0.03), and LV ejection fraction (7.1 +/- 4.0% vs. 2.9 +/- 4.4%, p = 0.003) were greater in younger than older subjects, respectively, as was the reduction in ESVI (-5.1 +/- 3.0 ml/m(2) vs. -1.8 +/- 3.3 ml/m(2), p = 0.002), despite similar declines in systolic BP (-12.3 +/- 6.3 mm Hg vs. -12.1 +/- 15.0 mm Hg, p = NS). CONCLUSIONS: Thus, age-associated deficits in chronotropic and LV systolic reserve performance occur during prolonged submaximal upright cycle ergometry, analogous to those observed during graded maximal exercise.

Effects of acute hormone therapy on recurrent ischemia in postmenopausal women with unstable angina.

OBJECTIVES: We tested whether acute hormone therapy reduces ambulatory electrocardiographic ischemia in postmenopausal (PMP) women with unstable angina (UA). BACKGROUND: Endothelial dysfunction contributes to the pathophysiology of UA. Acute estrogen administration improves endothelial function in PMP women with coronary artery disease and increases coronary artery blood flow. METHODS: Two hundred ninety-three PMP women with UA (mean age 69.7 years), treated with standard anti-ischemic therapy, were enrolled within 24 h of symptom onset. In a double-blind fashion, subjects were randomized to receive intravenous followed by oral conjugated estrogen for 21 days, intravenous estrogen followed by oral conjugated estrogen plus medroxyprogesterone for 21 days or placebo. The primary end point was the number of ambulatory electrocardiographic ischemic events over the first 48 h. Clinical events were also determined over six months of follow-up. RESULTS: Electrocardiographic ischemia did not differ among the three randomized groups. The mean number of ischemic events per patient over 48 h was 0.74 for estrogen, 0.86 for estrogen plus progesterone and 0.74 for the placebo groups (p = 0.87). The percentage of patients with ischemic events and the mean duration of ischemia did not differ between hormone- and placebo-treated patients. In-hospital and six-month rates of adverse clinical events were also similar among the three randomized groups. CONCLUSIONS: Acute hormone therapy does not reduce ischemia in PMP women with UA when added to standard anti-ischemic therapy.

Recidivism in medication-noncompliant serious juvenile offenders with bipolar disorder.

OBJECTIVE: To determine whether the recidivism rate varies for adolescent serious juvenile offenders with bipolar disorder in response to compliance with antimanic medication. METHOD: Probation records were reviewed for all adolescents (N = 31) released during a 1-year period (April 1, 1993-March 31, 1994) from a county juvenile corrections treatment facility who had DSM-III-R bipolar disorder, were stabilized on medication, and had agreed to continue treatment at an adolescent psychiatry clinic. New offenses and probation violations committed during the 12-month period after release were tallied. These recidivism records were then compared with medical records to ascertain whether these acts were committed while subjects were on (taking) or off (not taking) medication. RESULTS: The number of serious offenses (felonies and misdemeanors) was significantly reduced while subjects were on medication (4 offenses in 2992 days) versus off medication (39 offenses in 6108 days) (p < .0001). The off-medication rate of offending was 4.8 times higher than the on-medication rate. Probation violations were also significantly reduced while subjects were on medication (p < .001). CONCLUSION: Compliance with prescribed antimanic medication can markedly decrease recidivism in serious juvenile delinquents with bipolar disorder.

Response to catecholamine stimulation of polymorphisms of the beta-1 and beta-2 adrenergic receptors.

Previous studies have demonstrated that ß-adrenergic receptor polymorphisms affect outcomes in patients with heart failure or after an acute coronary syndrome. Whether ß-adrenergic polymorphisms influence catecholamine responses in patients with cardiovascular disease is not known. Cardiovascular responses to the ß1-receptor agonist dobutamine and the ß2-receptor agonist terbutaline were studied using gated blood pool scintigraphy in 21 patients on long-term ß-blocker therapy. Heart rate (HR), stroke volume (SV), and cardiac output (CO) increased, and end-systolic volume decreased with dobutamine and terbutaline. Changes in HR and CO with dobutamine were higher for those with ≥1 ß1 Arg389 allele than those homozygous for the Gly389 allele (change in HR 15 vs 1 beat/min, p = 0.02; change in CO 2.4 vs 1.0 L/min, p = 0.02). Increases in HR, CO, and SV with terbutaline were greater for those homozygous for the ß2 Glu27 allele than those with ≥1 Gln27 allele (change in HR 13.7 vs 4.8 beats/min, p = 0.048; change in CO 3.1 vs 1.6 L/min, p = 0.034; change in SV 28.3 vs 14.8 ml, p = 0.045). Changes in CO and volume with terbutaline were greater in those with an ejection fraction <40% than in those with an ejection fraction ≥40%. In conclusion, ß-receptor gene variants significantly influence inotropic and chronotropic responses to ß-agonist exposure in patients on ß-blocker therapy.

Discovery of human antibodies against the C5aR target using phage display technology.

Phage display technologies have been increasingly utilized for the generation of therapeutic, imaging and purification reagents for a number of biological targets. Using a variety of different approaches, we have developed antibodies with high specificity and affinity for various targets ranging from small peptides to large proteins, soluble or membrane-associated as well as to activated forms of enzymes. We have applied this approach to G-protein coupled receptors (GPCRs), often considered difficult targets for antibody therapeutics and targeting. Here we demonstrate the use of this technology for the identification of human antibodies targeting C5aR, the chemoattractant GPCR receptor for anaphylatoxin C5a. The N-terminal region (residues 1-31) of C5aR, one of the ligand binding sites, was synthesized, biotinylated and used as the target for selection. Three rounds of selection with our proprietary human Fab phage display library were performed. Screening of 768 isolates by phage ELISA identified 374 positive clones. Based on sequence alignment analysis, the positive clones were divided into 22 groups. Representative Fab clones from each group were reformatted into IgGs and tested for binding to C5aR-expressing cells, the differentiated U-937 cells. Flow cytometric analysis demonstrated that nine out of 16 reformatted IgGs bound to cells. Competition with a C5aR monoclonal antibody S5/1 which recognizes the same N-terminal region showed that S5/1 blocked the binding of positive cell binders to the peptide used for selections, indicating that the identified cell binding IgGs were specific to C5aR. These antibody binders represent viable candidates as therapeutic or imaging agents, illustrating that phage display technology provides a rapid means for developing antibodies to a difficult class of targets such as GPCRs.

Development of coagulation regulatory proteins in the fetal and neonatal lamb.

To investigate the development of coagulation regulatory proteins-protein C (PC), protein S (PS), and antithrombin (AT)-in relationship to the procoagulant protein factor X (FX), a chronically catheterized fetal ovine model was used. Infusion and sampling catheters were placed into pregnant ewes and their fetuses and maintained from mid-gestation. From a total of 110 fetuses, 17 lambs, and 63 ewes that were studied on one to 15 occasions, 212 fetal, 88 neonatal, and 157 maternal samples were obtained. Liver tissue was obtained from 31 fetuses and 15 ewes. Plasma levels of all proteins studied were higher in the ewe than in the fetus (p < 0.0001). Plasma levels of FX, PC, and PS achieved neonatal levels by mid-gestation with mild but significant decreases during mid- and late gestation. Fetal and early neonatal plasma concentrations of these vitamin K-dependent proteins fit a model with both quadratic (p < 0.01) and linear (p < 0.01) components. The discrepant levels in mRNA relative to plasma concentration were consistent with regulatory control beyond the level of transcription. In contrast, a simple linear increase in plasma protein levels was determined for the vitamin K-independent coagulation regulatory protein, AT (p for quadratic component > 0.05). This study suggests that fetal regulation of coagulation proteins follows characteristic patterns relative to the vitamin K dependence of the protein rather than its role as a procoagulant versus regulatory protein.