The intrinsic connectivity distribution: a novel contrast measure reflecting voxel level functional connectivity.

Resting-state fMRI (rs-fMRI) holds promise as a clinical tool to characterize and monitor the phenotype of different neurological and psychiatric disorders. The most common analysis approach requires the definition of one or more regions-of-interest (ROIs). However this need for a priori ROI information makes rs-fMRI inadequate to survey functional connectivity differences associated with a range of neurological disorders where the ROI information may not be available. A second problem encountered in fMRI measures of connectivity is the need for an arbitrary correlation threshold to determine whether or not two areas are connected. This is problematic because in many cases the differences in tissue connectivity between disease groups and/or control subjects are threshold dependent. In this work we propose a novel voxel-based contrast mechanism for rs-fMRI, the intrinsic connectivity distribution (ICD), that neither requires a priori information to define a ROI, nor an arbitrary threshold to define a connection. We show the sensitivity of previous methods to the choice of connection thresholds and evaluate ICD using a survey study comparing young adults born prematurely to healthy term control subjects. Functional connectivity differences were found in hypothesized language processing areas in the left temporal-parietal areas. In addition, significant clinically-relevant differences were found between preterm and term control subjects, highlighting the importance of whole brain surveys independent of a priori information.

Neonatal auditory activation detected by functional magnetic resonance imaging.

The objective of this study was to detect auditory cortical activation in non-sedated neonates employing functional magnetic resonance imaging (fMRI). Using echo-planar functional brain imaging, subjects were presented with a frequency-modulated pure tone; the BOLD signal response was mapped in 5 mm-thick slices running parallel to the superior temporal gyrus. Twenty healthy neonates (13 term, 7 preterm) at term and 4 adult control subjects. Blood oxygen level-dependent (BOLD) signal in response to auditory stimulus was detected in all 4 adults and in 14 of the 20 neonates. FMRI studies of adult subjects demonstrated increased signal in the superior temporal regions during auditory stimulation. In contrast, signal decreases were detected during auditory stimulation in 9 of 14 newborns with BOLD response. fMRI can be used to detect brain activation with auditory stimulation in human infants.

Regional brain volume abnormalities and long-term cognitive outcome in preterm infants.

CONTEXT: Preterm infants have a high prevalence of long-term cognitive and behavioral disturbances. However, it is not known whether the stresses associated with premature birth disrupt regionally specific brain maturation or whether abnormalities in brain structure contribute to cognitive deficits. OBJECTIVE: To determine whether regional brain volumes differ between term and preterm children and to examine the association of regional brain volumes in prematurely born children with long-term cognitive outcomes. DESIGN AND SETTING: Case-control study conducted in 1998 and 1999 at 2 US university medical schools. PARTICIPANTS: A consecutive sample of 25 eight-year-old preterm children recruited from a longitudinal follow-up study of preterm infants and 39 term control children who were recruited from the community and who were comparable with the preterm children in age, sex, maternal education, and minority status. MAIN OUTCOME MEASURES: Volumes of cortical subdivisions, ventricular system, cerebellum, basal ganglia, corpus callosum, amygdala, and hippocampus, derived from structural magnetic resonance imaging scans and compared between preterm and term children; correlations of regional brain volumes with cognitive measures (at age 8 years) and perinatal variables among preterm children. RESULTS: Regional cortical volumes were significantly smaller in the preterm children, most prominently in sensorimotor regions (difference: left, 14.6%; right, 14.3% [P<.001 for both]) but also in premotor (left, 11.2%; right, 12.6% [P<.001 for both]), midtemporal (left, 7.4% [P =.01]; right, 10.2% [P<.001]), parieto-occipital (left, 7.9% [P =.01]; right, 7.4% [P =.005]), and subgenual (left, 8.9% [P =.03]; right, 11.7% [P =.01]) cortices. Preterm children's brain volumes were significantly larger (by 105. 7%-271.6%) in the occipital and temporal horns of the ventricles (P<. 001 for all) and smaller in the cerebellum (6.7%; P =.02), basal ganglia (11.4%-13.8%; P

Adaptive mechanisms of developing brain. The neuroradiologic assessment of the preterm infant.

Since the 1980s, cranial sonography has been routinely performed in premature infants. This has produced a wealth of information about the more dramatic central nervous system lesions of IVH, PVL, and late VM. This information has included timing and evolution of these lesions and their eventual correlation with outcome. For two reasons the advent of MR imaging scanning has produced an interest in using this modality to evaluate these same infants. First, MR imaging gives an obviously superior image, and its ability to detect lesions is far superior to that of ultrasound. Second, the ability of cranial sonography to detect all of the children with CP or low IQ is limited. In our studies of outcome in very low-birth weight infants grade 3 to 4 IVH, PVL, or VM are able to detect only about 50% of the infants who developed CP by 3 years. This condition should be highly correlated with structural brain disease; an imaging modality that was more sensitive to central nervous system lesions should offer an advantage in predicting outcome. In the only prospective assessment of the ability of these two modalities to predict outcome at 3 years, van de Bor and colleagues found MR imaging did not do better than cranial sonography. This was largely because both modalities detected the most severe lesions, and most children with milder lesions on MR imaging had normal outcome. Studies of late (age 1 to teenage years) MR imaging scans in preterm infants show that a high percentage have white matter lesions but these lesions correlate poorly with outcome. If our concern when counseling parents is to alert them when a serious adverse outcome is likely in their child, then cranial sonography is to be favored precisely because it is less able to detect subtle lesions, which the developing brain has the capacity to overcome. On the other hand, if our aim is to detect all lesions, even though these lesions do not predict serious adverse outcomes, then MR imaging is to be favored. Research aimed at discovering etiologies and mechanisms of brain injury in these high-risk infants should use the more sensitive modality MR imaging. Finally, the interesting observation that preterm infants fare as well as they do despite MR imaging-identified lesions might stimulate research studying the adaptive mechanisms of developing brain.

Outcome of children in the indomethacin intraventricular hemorrhage prevention trial.

BACKGROUND: For preterm infants, intraventricular hemorrhage (IVH) may be associated with adverse neurodevelopmental outcome. We have demonstrated that early low-dose indomethacin treatment is associated with a decrease in both the incidence and severity of IVH in very low birth weight preterm infants. In addition, we hypothesized that the early administration of low-dose indomethacin would not be associated with an increase in the incidence of neurodevelopmental handicap at 4.5 years of age in our study children. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for the 384 very low birth weight survivors of the Multicenter Randomized Indomethacin IVH Prevention Trial. Three hundred thirty-seven children (88%) were evaluated at 54 months' corrected age, and underwent neurodevelopmental examinations, including the Wechsler Preschool and Primary Scale of Intelligence-Revised (WPPSI-R), the Peabody Picture Vocabulary Test-Revised (PPVT-R), and standard neurologic examinations. RESULTS: Of the 337 study children, 170 had been randomized to early low-dose indomethacin therapy and 167 children had received placebo. Twelve (7%) of the 165 indomethacin children and 11 (7%) of the 158 placebo children who underwent neurologic examinations were found to have cerebral palsy. For the 233 English-monolingual children for whom cognitive outcome data follow, the mean gestational age was significantly younger for the children who received indomethacin than for those who received placebo. In addition, although there were no differences in the WPPSI-R or the PPVT-R scores between the 2 groups, analysis of the WPPSI-R full-scale IQ by function range demonstrated significantly less mental retardation among those children randomized to early low-dose indomethacin (for the indomethacin study children, 9% had an IQ <70, 12% had an IQ of 70-80, and 79% had an IQ >80, compared with the placebo group, for whom 17% had an IQ <70, 18% had an IQ of 70-80, and 65% had an IQ >80). Indomethacin children also experienced significantly less difficulty with vocabulary skills as assessed by the PPVT-R when compared with placebo children. CONCLUSIONS: These data suggest that, for preterm neonates, the early administration of low-dose indomethacin therapy is not associated with adverse neurodevelopmental function at 54 months' corrected age.

The etiology and outcome of cerebral ventriculomegaly at term in very low birth weight preterm infants.

BACKGROUND: Despite improvements in survival data, the incidence of neurodevelopmental handicaps in preterm infants remains high. To prevent these handicaps, one must understand the pathophysiology behind them. For preterm infants, cerebral ventriculomegaly (VM) may be associated with adverse neurodevelopmental outcome. We hypothesized that although the causes of VM are multiple, the incidence of handicap at 4.5 years of age in preterm infants with this ultrasonographic finding at term would be high. METHODS: To test this hypothesis, we provided neurodevelopmental follow-up for all 440 very low birth weight survivors of the Multicenter Randomized Indomethacin Intraventricular Hemorrhage (IVH) Prevention Trial. A total of 384 children (87%) were evaluated at 54 months' corrected age (CA), and 257 subjects were living in English-speaking, monolingual households and are included in the following data analysis. RESULTS: Moderate to severe low pressure VM at term was documented in 11 (4%) of the English-speaking, monolingual survivors. High grade IVH and bronchopulmonary dysplasia (BPD) were both risk factors for the development of VM. Of 11 (45%) children with VM, 5 suffered grades 3 to 4 IVH, compared with 2/246 (1%) children without VM who experienced grades 3 to 4 IVH. Similarly, 9/11 (82%) children with VM had BPD, compared with 120/246 (49%) children without VM who had BPD. Logistic regression analysis was performed using birth weight, gestational age, gender, Apgar score at 5 minutes, BPD, sepsis, moderate to severe VM, periventricular leukomalacia, grade of IVH, and maternal education to predict IQ <70. Although maternal education was an important and independent predictor of adverse cognitive outcome, in this series of very low birth weight prematurely born children, VM was the most important predictor of IQ <70 (OR: 19.0; 95% CI: 4.5, 80.6). Of children with VM, 6/11 (55%) had an IQ <70, compared with 31/246 (13%) of children without VM. Children with VM had significantly lower verbal and performance scores compared with children without VM. CONCLUSIONS: These data suggest that, for preterm neonates, VM at term is a consequence of the vulnerability of the developing brain. Furthermore, its presence is an important and independent predictor of adverse cognitive and motor development at 4.5 years' CA.

Early-onset intraventricular hemorrhage in preterm neonates: incidence of neurodevelopmental handicap.

The neurodevelopmental outcome of very low birth weight infants experiencing early-onset intraventricular hemorrhage (IVH) occurring within the first 6 postnatal hours was compared with that of their peers without early-onset IVH at 3 years corrected age. The 440 surviving preterm infants (birth weight 600 to 1,250 g) who had been enrolled in a multicenter, prospectively randomized, controlled trial evaluating the efficacy of postnatal indomethacin to prevent IVH were evaluated with the Stanford-Binet Intelligence Scale and neurological examinations at 3 years corrected age. All study infants had echoencephalography between 5 and 11 hours of life, and testing is reported for all children residing in English monolingual households at 3 years corrected age (i.e., from the obstetric due date). Fifty five of the 73 (75%) infants with IVH within the first 5 to 11 hours survived to 3 years of age, compared with 385 of the 432 (89%) children without early-onset hemorrhage who were alive at 3 years corrected age (P<.001). Eleven of the 29 (38%) English monolingual children with early-onset IVH had Stanford-Binet intelligence quotient scores of less than 70, compared with 47 of the 249 (19%) children without early IVH (P = .03). Similarly, 7 of 28 (25%) early IVH children were found to have cerebral palsy, compared with 20 of 241 (8%) children without early IVH (P = .01). These data suggest that infants who experience the early onset of IVH are at high risk for both cognitive and motor handicaps at 3 years corrected age.

Redesigning nucleic acids.

A research program has applied the tools of synthetic organic chemistry to systematically modify the structure of DNA and RNA oligonucleotides to learn more about the chemical principles underlying their ability to store and transmit genetic information. Oligonucleotides (as opposed to nucleosides) have long been overlooked by synthetic organic chemists as targets for structural modification. Synthetic chemistry has now yielded oligonucleotides with 12 replicatable letters, modified backbones, and new insight into why Nature chose the oligonucleotide structures that she did.

Neurodevelopmental outcome at 36 months' corrected age of preterm infants in the Multicenter Indomethacin Intraventricular Hemorrhage Prevention Trial.

OBJECTIVES: Low-dose indomethacin has been shown to prevent intraventricular hemorrhage (IVH) in very low birth weight neonates, and long-term neurodevelopmental follow-up data are needed to validate this intervention. We hypothesized that the early administration of low-dose indomethacin would not be associated with adverse cognitive outcome at 36 months' corrected age (CA). METHODS: We enrolled 431 neonates of 600 to 1250 g birth weight with no IVH at 6 to 12 hours in a randomized, prospective trial to determine whether low-dose indomethacin would prevent IVH. A priori, neurodevelopmental follow-up examinations, including the Stanford-Binet Intelligence Scale and Peabody Picture Vocabulary Test-Revised, and standard neurologic examinations were planned at 36 months' CA. RESULTS: Three hundred eighty-four of the 431 infants survived (192 [92%] of 209 infants receiving indomethacin versus 192 [86%] of 222 infants receiving saline), and 343 (89%) children were examined at 36 months' CA. Thirteen (8%) of the 166 infants who received indomethacin and 14 (8%) of 167 infants receiving the placebo were found to have cerebral palsy. There were no differences in the incidence of deafness or blindness between the two groups. For the 248 English-monolingual children for whom IQ data follow, the mean gestational age was significantly younger for the infants who received indomethacin than for those who received the placebo. None of the 115 infants who received indomethacin was found to have ventriculomegaly on cranial ultrasound at term, compared with 5 of 110 infants who received the placebo. The mean +/- SD Stanford-Binet IQ score for the 126 English-monolingual children who had received indomethacin was 89.6 +/- 18.92, compared with 85.0 +/- 20.79 for the 122 English-monolingual children who had received the placebo. Although maternal education was strongly correlated with Stanford-Binet IQ at 36 months' CA, there was no difference in educational levels between mothers of the infants receiving indomethacin and the placebo. CONCLUSIONS: Indomethacin administered at 6 to 12 hours as prophylaxis against IVH in very low birth weight infants does not result in adverse cognitive or motor outcomes at 36 months' CA.

Diagnosis-related group refinement with diagnosis- and procedure-specific comorbidities and complications.

Diagnosis-related groups have been revised through more refined uses of secondary diagnoses. Under the refined diagnosis-related groups, patients are distinguished with respect to classes of secondary diagnoses that are disease- and procedure-specific. Each class represents a different level of utilization for a given principal diagnosis or surgical procedure. The refined system was evaluated with national data from the Medicare program. Estimates of hospital costs and utilization based on refined diagnosis-related groups were more precise than those based on unrefined diagnosis-related groups. This approach to diagnosis-related group refinement does not represent a radical departure from the current diagnosis-related group framework and does not require new data collection efforts. Moreover, a payment system based on the refined model is less affected by the ordering of the diagnoses than under the existing diagnosis-related group system. How the refined diagnosis-related group framework can accommodate future refinements at all levels of the classification scheme is also discussed.

Trinucleotide phosphoramidites: ideal reagents for the synthesis of mixed oligonucleotides for random mutagenesis.

Trinucleotide phosphoramidites representing codons for all 20 amino acids have been prepared and used in automated, solid-phase DNA synthesis. In contrast to an earlier report, we show that these substances can be used to introduce entire codons into oligonucleotides in excess of 98% yield, and are ideal reagents for the synthesis of mixed oligonucleotides for random mutagenesis.

Low-dose indomethacin therapy and extension of intraventricular hemorrhage: a multicenter randomized trial.

We enrolled 61 neonates of 600 to 1250 gm birth weight with evidence of low-grade intraventricular hemorrhage at 6 to 11 hours of age in a prospective, randomized, placebo-controlled trial to test the hypothesis that indomethacin (0.1 mg/kg given intravenously at 6 to 12 postnatal hours and every 24 hours for two more doses) would prevent extension of intraventricular hemorrhage. Twenty-seven infants were assigned to receive indomethacin; 34 infants received saline placebo. There were no significant differences between the two groups in birth weight, gestational age, sex, Apgar scores, percentage of infants treated with surfactant, or distribution of hemorrhages at the time of the first cranial sonogram (echo-encephalogram). Within the first 5 days, 9 of 27 indomethacin-treated and 12 of 34 saline solution-treated infants had extension of their initial intraventricular hemorrhage (p = 1.00). Four indomethacin-treated and three saline solution-treated infants had parenchymal extension of the hemorrhage. Indomethacin was associated with closure of a patent ductus arteriosus by the fifth day of life (p = 0.003). There were no differences in adverse events attributed to indomethacin. We conclude that in very low birth weight infants with low grade intraventricular hemorrhage within the first 6 postnatal hours, prophylactic indomethacin therapy promotes closure of the patent ductus arteriosus and is not associated with adverse events, but does not affect the cascade of events leading to parenchymal involvement of intracranial hemorrhage.

Oligonucleotide analogs with dimethylenesulfide, -sulfoxide, and -sulfone groups replacing phosphodiester linkages.

Two sets of experimental protocols are given for the synthesis of 3',5'-bis-homodeoxyribonucleosides, building blocks for the synthesis of oligodeoxynucleotide analogs where the -O-PO2-O- groups are replaced by -CH2-S-CH2-, -CH2-SO-CH2-, and -CH2-SO2-CH2- units. Conditions are presented for joining these building blocks to create short nucleic acid analogs. Since isosteric, achiral, and non-ionic analogs of natural oligonucleotides stable to both enzymatic and chemical hydrolysis, such molecules have potential application as probes in the laboratory, in studies of the biological function of individual genes, and as "antisense" oligonucleotide analogs.

Medical review and the newly revised emergency care obligations of Medicare hospitals.

The "anti-dumping" provisions under Section 1867 of the Social Security Act have been clarified and strengthened by recent amendments. Medicare-participating hospitals must post signs informing the public of their obligation to examine, treat, and appropriately transfer individuals who request emergency services in the emergency department. Inquiries about an individual's method of payment or insurance source may not delay examination or treatment. Qualified personnel must perform medical screening of all emergency patients, and those to be transferred with emergency medical conditions which have not been stabilized must receive treatment to minimize the risk of transfer. There are stepped-up requirements for informed patient consent and documentation that the medical benefits of a transfer outweigh the risks. In physician-initiated transfers, the receiving hospital must be sent certification by a physician that the benefits of transfer outweigh the risks. Since there is evidence that medically appropriate transfers of persons with emergency medical conditions may actually be underutilized, particularly in rural settings, medical reviewers should avoid an anti-transfer bias.

Federal antidumping law--hospital and physician responsibility.

National attention has been directed to the problem of "dumping" of uninsured patients upon public hospitals. Federal law addresses only transfers of emergency room patients without regard to possible financial motivation. All transfers, including those requested by patients, must meet criteria for appropriateness. A substantial proportion of confirmed violations have involved failure to adequately screen the patient for emergency conditions. Both the hospital and the physician responsible for the care of a patient who is transferred in violation of the law may be subject to Medicare sanctions, including termination or suspension from participation and fines up to $50,000 for each occurrence. Proposed regulations affirm that private practitioners who provide uncompensated emergency room services under an oral agreement may be subject to sanctions in the event of a violation.

Identifying patients who need social work services: an interdisciplinary analysis.

Factors that affect decisions made by professionals in the referral of hospital patients for social work services are analyzed. A multidisciplinary approach was used, in which social workers, nurses, and physicians individually evaluated the social service needs of a sample of patients hospitalized in an intermediate care section at a Veterans Administration medical center. The study helped to identify sources of divergent views held by health care professionals in different disciplines.

Evaluating and predicting outcome of acute cerebral vascular accident.

An innovative evaluation method is used to study the outcomes and clinical predictions for 97 patients with acute cerebral vascular accidents. The technique involved the participation of several professional disciplines in selecting baseline and treatment variables and making independent predictions about the functional status of patients upon discharge from the stroke treatment center. The data suggest that (1) baseline variables were more important than treatment variables in the participants' predictions about the patients' short-term outcomes; (2) stroke unit staff members were generally successful in predicting patients' functional status; and (3) stroke extensions and other complications are important factors which affect stroke patients' short-term outcomes.

High users of VA emergency room facilities: are outpatients abusing the system or is the system abusing them?

A phenomenon well known to emergency room personnel is the high use of ER facilities by a small number of patients. In this study of 335 patients followed in outpatient specialty clinics at a university-affiliated VA medical center, 23% of the patients accounted for 73% of the ER visits. Although some patients may be abusing the system, the problem is difficult to correct because of congressional legislation that deters the VA from providing primary care. Thus, a small subset of patients with chronic medical problems who live close to the hospital are likely to continue to consume a disproportionate amount of ER resources.