Marcello Pagano

Maternal infection, fetal inflammatory response, and brain damage in very low birth weight infants

Echolucent images (EL) of cerebral white matter, seen on cranial ultrasonographic scans of very low birth weight newborns, predict motor and cognitive limitations. We tested the hypothesis that markers of maternal and feto-placental infection were associated with risks of both early (diagnosed at a median age of 7 d) and late (median age = 21 d) EL in a multi-center cohort of 1078 infants <1500 ×g. Maternal infection was indicated by fever, leukocytosis, and receipt of antibiotic; feto-placental inflammation was indicated by the presence of fetal vasculitis (i.e. of the placental chorionic plate or the umbilical cord). The effect of membrane inflammation was also assessed. All analyses were performed separately in infants born within 1 h of membrane rupture (n= 537), or after a longer interval (n= 541), to determine whether infection markers have different effects in infants who are unlikely to have experienced ascending amniotic sac infection as a consequence of membrane rupture. Placental membrane inflammation by itself was not associated with risk of EL at any time. The risks of both early and late EL were substantially increased in infants with fetal vasculitis, but the association with early EL was found only in infants born ≥1 after membrane rupture and who had membrane inflammation (adjusted OR not calculable), whereas the association of fetal vasculitis with late EL was seen only in infants born <1 h after membrane rupture (OR = 10.8;p= 0.05). Maternal receipt of antibiotic in the 24 h just before delivery was associated with late EL only if delivery occurred <1 h after membrane rupture (OR = 6.9;p= 0.01). Indicators of maternal infection and of a fetal inflammatory response are strongly and independently associated with EL, particularly late EL.

Short-Term Effects of Carbon Monoxide Exposure on the Exercise Performance of Subjects with Coronary Artery Disease

Patients with atherosclerotic cardiovascular disease may be adversely affected by the presence of carboxyhemoglobin, even at low concentrations. We investigated the effects of carbon monoxide exposure on myocardial ischemia during exercise in 63 men with documented coronary artery disease. On each test day, subjects performed two symptom-limited incremental exercise tests on a treadmill; the tests were separated by a recovery period and 50 to 70 minutes of exposure to either room air or air containing one of two concentrations of carbon monoxide (117 +/- 4.4 ppm or 253 +/- 6.1 ppm). The order of exposure was assigned randomly. On each occasion, neither the subjects nor the study personnel knew whether the subjects had been exposed to room air or to one of the concentrations of carbon monoxide. Exposure to room air resulted in a mean carboxyhemoglobin level of 0.6 percent, exposure to the lower level of carbon monoxide resulted in a carboxyhemoglobin level of 2.0 percent, and exposure to the higher level of carbon monoxide resulted in a level of 3.9 percent. An effect of carbon monoxide on myocardial ischemia was demonstrated objectively by electrocardiographic changes during exercise. We observed a decrease of 5.1 percent (90 percent confidence interval, 1.5 to 8.7 percent; P = 0.02) and a decrease of 12.1 percent (90 percent confidence interval, 9.0 to 15.3 percent; P less than or equal to 0.0001) in the length of time to a threshold ischemic ST-segment change (ST end point) after carbon monoxide exposures that produced carboxyhemoglobin levels of 2.0 percent and 3.9 percent, respectively. The length of time to the onset of angina decreased by 4.2 percent (90 percent confidence interval, 0.7 to 7.9 percent; P = 0.054) at the 2.0 percent carboxyhemoglobin level and by 7.1 percent (90 percent confidence interval, 3.1 to 10.9 percent; P = 0.004) at the 3.9 percent carboxyhemoglobin level. Significant dose-response relations were found in both the change in the length of time to the ST end point (P less than or equal to 0.0001) and the change in the length of time to the onset of angina (P = 0.02). We conclude that low levels of carboxyhemoglobin exacerbate myocardial ischemia during graded exercise in subjects with coronary artery disease.

Estimation of the reproductive number and the serial interval in early phase of the 2009 influenza A/H1N1 pandemic in the USA

Background  The United States was the second country to have a major outbreak of novel influenza A/H1N1 in what has become a new pandemic. Appropriate public health responses to this pandemic depend in part on early estimates of key epidemiological parameters of the virus in defined populations.

Variability in Surgical Caseload and Access to Intensive Care Services

Background Variability in the demand for any service is a significant barrier to efficient distribution of limited resources. In health care, demand is often highly variable and access may be limited when peaks cannot be accommodated in a downsized care delivery system. Intensive care units may frequently present bottlenecks to patient flow, and saturation of these services limits a hospitals responsiveness to new emergencies. Methods Over a 1-yr period, information was collected prospectively on all requests for admission to the intensive care unit of a large, urban childrens hospital. Data included the nature of each request, as well as each patients final disposition. The daily variability of requests was then analyzed and related to the units ability to accommodate new admissions. Results Day-to-day demand for intensive care services was extremely variable. This variability was particularly high among patients undergoing scheduled surgical procedures, with variability of scheduled admissions exceeding that of emergencies. Peaks of demand were associated with diversion of patients both within the hospital (to off-service care sites) and to other institutions (ambulance diversions). Although emergency requests for admission outnumbered scheduled requests, diversion from the intensive care unit was better correlated with scheduled caseload (r = 0.542, P < 0.001) than with unscheduled volume (r = 0.255, P < 0.001). During the busiest periods, nearly 70% of all diversions were associated with variability in the scheduled caseload. Conclusions Variability in scheduled surgical caseload represents a potentially reducible source of stress on intensive care units in hospitals and throughout the healthcare delivery system generally. When uncontrolled, variability limits access to care and impairs overall responsiveness to emergencies.

Maternal Toxemia Is Associated With Reduced Incidence of Germinal Matrix Hemorrhage in Premature Babies

To evaluate prenatal and perinatal risk factors for development of germinal matrix hemorrhage-intraventricular hemorrhage (GMH-IVH), we conducted a prospective epidemiologic study of 449 babies whose birth weight was less than 1501 grams. This study permitted us to test our previously generated hypothesis that babies born to mothers with preeclampsia were at substantially reduced risk of developing GMH-IVH. Seventy-two (16%) of the babies in this population developed GMH-IVH. One (2.5%) of the 40 mothers with a diagnosis of preeclampsia and 71 (17.4%) of 409 mothers without preeclampsia gave birth to babies who developed GMH-IVH. GMH-IVH was seen in 6/107 (5.6%) of babies born to women with hypertension including 4/69 (5.8%) of babies born to women with pregnancy-induced hypertension, compared to 66/352 (18.8%) of babies born to mothers who did not have hypertension. Only 7.3% (8/108) of babies born to women who had proteinuria had GMH-IVH, compared to 18.3% (64/350) of babies whose mothers did not have proteinuria. GMH-IVH was seen in 5/89 (5.6%) of babies whose mothers had both hypertension and proteinuria, whereas 63/332 (19%) of babies born to mothers who lacked both factors, developed GMH-IVH. In stepwise logistic regression analysis, these significant findings were not explained by the presence of labor, postnatal acidemia, need for intubation, antenatal administration of steroids, birth weight, or gestational age. In addition, we found that maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia. We postulate that the association of preeclampsia and GVH-IVH may be related to prostaglandin effects. Reduced maternal, placental, and umbilical prostaglandin I2 (PGI2) values are characteristic of women with preeclampsia. Thus, babies born to mothers with preeclampsia may have a physiologic state similar to those having received indomethacin, a cyclooxygenase blocker that causes diminished PGI2 levels and an effective GMH-IVH prophylactic agent. We conclude that early third-trimester maternal preeclampsia/toxemia is associated with reduced risk of GMH-IVH in the preterm newborn. (J Child Neurol 1992;7:70-76).

White matter disorders of prematurity: Association with intraventricular hemorrhage and ventriculomegaly

OBJECTIVES Because intraventricular hemorrhage (IVH) often precedes the development of sonographically defined white matter damage (WMD) in very preterm infants, we sought to identify the IVH characteristics that predict WMD. HYPOTHESES We evaluated variations on the null hypothesis that infants with IVH are no more likely than infants without IVH to have WMD. These variations dealt with characteristics of the IVH (presence or absence of ventriculomegaly) or characteristics of the WMD (size, localization, and laterality). METHODS A total of 1605 infants weighing 500 to 1500 g at birth between January 1991 and December 1993 underwent standardized cranial ultrasound studies with 6 standard coronal and 5 sagittal views at postnatal days 1 to 3, 7 to 10, and at 3 to 8 weeks. RESULTS A total of 129 (8%) infants had WMD, either an echodensity alone (n = 59), an echolucency alone (n = 18), or both (n = 52). In analyses that controlled for gestational age, IVH was associated with a fivefold to ninefold increased risk of WMD regardless of size, laterality, or extent of lesions (P </=.0005). Compared with infants with neither IVH nor ventriculomegaly, infants with both were at 18- to 29-fold greater risk of WMD (P </=.0005). CONCLUSIONS In this study IVH and ventriculomegaly were powerful predictors of WMD occurrence, whether small or large, unilateral or bilateral, localized or diffuse.

Using temporal context to improve biosurveillance

Current efforts to detect covert bioterrorist attacks from increases in hospital visit rates are plagued by the unpredictable nature of these rates. Although many current systems evaluate hospital visit data 1 day at a time, we investigate evaluating multiple days at once to lessen the effects of this unpredictability and to improve both the timeliness and sensitivity of detection. To test this approach, we introduce simulated disease outbreaks of varying shapes, magnitudes, and durations into 10 years of historical daily visit data from a major tertiary-care metropolitan teaching hospital. We then investigate the effectiveness of using multiday temporal filters for detecting these simulated outbreaks within the noisy environment of the historical visit data. Our results show that compared with the standard 1-day approach, the multiday detection approach significantly increases detection sensitivity and decreases latency while maintaining a high specificity. We conclude that current biosurveillance systems should incorporate a wider temporal context to improve their effectiveness. Furthermore, for increased robustness and performance, hybrid systems should be developed to capitalize on the complementary strengths of different types of temporal filters.

Incidence of multidrug-resistant tuberculosis disease in children: systematic review and global estimates.

BACKGROUND Multidrug-resistant tuberculosis threatens to reverse recent reductions in global tuberculosis incidence. Although children younger than 15 years constitute more than 25% of the worldwide population, the global incidence of multidrug-resistant tuberculosis disease in children has never been quantified. We aimed to estimate the regional and global annual incidence of multidrug-resistant tuberculosis in children. METHODS We developed two models: one to estimate the setting-specific risk of multidrug-resistant tuberculosis among child cases of tuberculosis, and a second to estimate the setting-specific incidence of tuberculosis disease in children. The model for risk of multidrug-resistant tuberculosis among children with tuberculosis needed a systematic literature review. We multiplied the setting-specific estimates of multidrug-resistant tuberculosis risk and tuberculosis incidence to estimate regional and global incidence of multidrug-resistant tuberculosis disease in children in 2010. FINDINGS We identified 3403 papers, of which 97 studies met inclusion criteria for the systematic review of risk of multidrug-resistant tuberculosis. 31 studies reported the risk of multidrug-resistant tuberculosis in both children and treatment-naive adults with tuberculosis and were used for evaluation of the linear association between multidrug-resistant disease risk in these two patient groups. We identified that the setting-specific risk of multidrug-resistant tuberculosis was nearly identical in children and treatment-naive adults with tuberculosis, consistent with the assertion that multidrug-resistant disease in both groups reflects the local risk of transmitted multidrug-resistant tuberculosis. After application of these calculated risks, we estimated that around 999,792 (95% CI 937,877-1,055,414) children developed tuberculosis disease in 2010, of whom 31,948 (25,594-38,663) had multidrug-resistant disease. INTERPRETATION Our estimates underscore that many cases of tuberculosis and multidrug-resistant tuberculosis disease are not being detected in children. Future estimates can be refined as more and better tuberculosis data and new diagnostic instruments become available. FUNDING US National Institutes of Health, the Helmut Wolfgang Schumann Fellowship in Preventive Medicine at Harvard Medical School, the Norman E Zinberg Fellowship at Harvard Medical School, and the Doris and Howard Hiatt Residency in Global Health Equity and Internal Medicine at the Brigham and Womens Hospital.

A nonparametric scoring algorithm for identifying informative genes from microarray data.

Microarray data routinely contain gene expression levels of thousands of genes. In the context of medical diagnostics, an important problem is to find the genes that are correlated with given phenotypes. These genes may reveal insights to biological processes and may be used to predict the phenotypes of new samples. In most cases, while the gene expression levels are available for a large number of genes, only a small fraction of these genes may be informative in classification with statistical significance. We introduce a nonparametric scoring algorithm that assigns a score to each gene based on samples with known classes. Based on these scores, we can find a small set of genes which are informative of their class, and subsequent analysis can be carried out with this set. This procedure is robust to outliers and different normalization schemes, and immediately reduces the size of the data with little loss of information. We study the properties of this algorithm and apply it to the data set from cancer patients. We quantify the information in a given set of genes by comparing its distribution of the score statistics to a set of distributions generated by permutations that preserve the correlation structure among the genes.

Hydration during the first days of life and the risk of bronchopulmonary dysplasia in low birth weight infants

We conducted a case-control study of antecedents of bronchopulmonary dysplasia (BPD) in 223 infants enrolled in a prospective, randomized clinical trial of phenobarbital prophylaxis for intracranial hemorrhage. The trial took place at three Boston neonatal intensive care units between June 1981 and April 1984. The 76 babies with BPD had radiographic evidence of the condition and required oxygen therapy for 28 days or more. All 147 control babies survived until day 28 of life without meeting either of these criteria for BPD. Compared with control infants, those with BPD received greater quantities of total, crystalloid, and colloid fluids per kilogram per day in the first 4 days of life. In addition, infants with BPD generally had a net weight gain in the first 4 days of life in contrast to the normal pattern of weight loss seen in control infants. Finally, the infants with BPD were more likely to be given a clinical diagnosis of patent ductus arteriosus and to have received furosemide on days 3 and 4 of life. From these observations we infer that early postnatal phenomena such as excessive fluid therapy may be important in the pathogenesis of BPD.