Final validation of the ProMisE molecular classifier for endometrial carcinoma in a large population-based case series.

Background: We have previously developed and confirmed a pragmatic molecular classifier for endometrial cancers; ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer). Inspired by the Cancer Genome Atlas, ProMisE identifies four prognostically distinct molecular subtypes and can be applied to diagnostic specimens (biopsy/curettings) enabling earlier informed decision-making. We have strictly adhered to the Institute of Medicine (IOM) guidelines for the development of genomic biomarkers, and herein present the final validation step of a locked-down classifier before clinical application. Patients and methods: We assessed a retrospective cohort of women from the Tübingen University Women's Hospital treated for endometrial carcinoma between 2003 and 2013. Primary outcomes of overall, disease-specific, and progression-free survival were evaluated for clinical, pathological, and molecular features. Results: Complete clinical and molecular data were evaluable from 452 women. Patient age ranged from 29 to 93 (median 65) years, and 87.8% cases were endometrioid histotype. Grade distribution included 282 (62.4%) G1, 75 (16.6%) G2, and 95 (21.0%) G3 tumors. 276 (61.1%) patients had stage IA disease, with the remaining stage IB [89 (19.7%)], stage II [26 (5.8%)], and stage III/IV [61 (13.5%)]. ProMisE molecular classification yielded 127 (28.1%) MMR-D, 42 (9.3%) POLE, 55 (12.2%) p53abn, and 228 (50.4%) p53wt. ProMisE was a prognostic marker for progression-free (P = 0.001) and disease-specific (P = 0.03) survival even after adjusting for known risk factors. Concordance between diagnostic and surgical specimens was highly favorable; accuracy 0.91, κ 0.88. Discussion: We have developed, confirmed, and now validated a pragmatic molecular classification tool (ProMisE) that provides consistent categorization of tumors and identifies four distinct prognostic molecular subtypes. ProMisE can be applied to diagnostic samples and thus could be used to inform surgical procedure(s) and/or need for adjuvant therapy. Based on the IOM guidelines this classifier is now ready for clinical evaluation through prospective clinical trials.

Lenalidomide and cyclophosphamide immunoregulation in patients with metastatic, castration-resistant prostate cancer.

Lenalidomide (LEN) and metronomic cyclophosphamide (CTX) regulate angiogenesis and immunosuppressive cells linked to the progression of metastatic castration-resistant prostate cancer (mCRPC). A phase-I/II, dose-escalation trial of LEN plus oral CTX was conducted in patients with previously treated mCRPC. In the phase-I study, CTX was given at 50 mg (day 1-28) and LEN at 10-25 mg (day 1-21) on a 28-day cycle using a "3+3" study design. In phase II, patients received LEN at 25 mg (day 1-21) with CTX at 50 mg PO QD (day 1-28) on a 28-day cycle. Nineteen patients in phase I were evaluable for toxicity. The maximum tolerated dose (MTD) was not observed at any of the dose levels (DLs) tested. Six patients received treatment in phase II before the trial was closed. A ≥ 50% reduction in PSA was observed in 31.7% evaluable patients. Radiographically, one patient had a partial response. Stable disease was documented in 68% of evaluable patients after two therapy cycles. Circulating tumor cells (CTCs) decreased in 22.7% and remained stable in 31.8% of patients. Baseline numbers of peripheral MDSCs (MDSC; Lin-DR(-)CD11b(+)) were significantly increased in patients versus normal donors, and were decreased by chemotherapy. At baseline, MDSCs correlated directly with CTCs, and inversely with T- and B cell frequency supporting their immunosuppressive activity. The combination of LEN and metronomic CTX can be safely administered, reversing cellular immunosuppression in this group of elderly patients with mCRPC. Further research is required to identify responsive subgroup(s) and validate the biomarkers.

Cryopreservation of adenovirus-transfected dendritic cells (DCs) for clinical use.

In this study, we examined the effects of cryoprotectant, freezing and thawing, and adenovirus (Adv) transduction on the viability, transgene expression, phenotype, and function of human dendritic cells (DCs). DCs were differentiated from cultured peripheral blood (PB) monocytes following Elutra isolation using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4) for 6 days and then transduced using an Adv vector with an IL-12 transgene. Fresh, cryopreserved, and thawed transduced immature DCs were examined for their: 1) cellular concentration and viability; 2) antigenicity using an allogeneic mixed lymphocyte reaction (MLR); 3) phenotype (HLA-DR and CD11c) and activation (CD83); and 4) transgene expression based on IL-12 secretion. Stability studies revealed that transduced DCs could be held in cryoprotectant for as long as 75 min at 2-8°C prior to freezing with little effect on their viability and cellularity. Further, cryopreservation, storage, and thawing reduced the viability of the transduced DCs by an average of 7.7%; and had no significant impact on DC phenotype and activation. In summary, cryopreservation, storage, and thawing had no significant effect on DC viability, function, and transgene expression by Adv-transduced DCs.

An efficient synthesis of epoxydiynes and a key fragment of neocarzinostatin chromophore.

[reaction: see text] A key structural feature of the Neocarzinostatin chromophore is a reactive epoxydiyne. We present here a new method for the preparation of epoxydiynes by the addition of an allenyl zinc bromide to a propargylic ketone.

Application of current knowledge to the management of bleeding events during immune tolerance induction.

The development of inhibitors to factor VIII is the most serious adverse event associated with the treatment of haemophilia A, predisposing patients to uncontrollable haemorrhage, disability and premature death. Eradication of inhibitors via immune tolerance induction (ITI) is effective in the majority of patients, but may require months to years to achieve success. In the interim, the treatment and prevention of acute bleeding episodes are primary foci of care. Regrettably, there is a paucity of information regarding management of bleeding episodes in inhibitor patients undergoing tolerization. Until specific data from ongoing clinical trials are available to provide more guidance in this patient group, it is reasonable and useful to rely on the broader base of medical literature pertaining to patients not being tolerized to deduce strategies for controlling acute and perioperative bleeding episodes in inhibitor patients during ITI.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

Maternal postpartum behaviors and mother-infant relationship during the first year of life.

OBJECTIVE: To assess the hypothesis that maternal postpartum behaviors toward the newborn may predict the quality of the maternal-infant relationship during the first year. DESIGN: Prospective, non-randomized, longitudinal cohort study of 174 maternal-infant dyads. METHODS: A Postpartum Parenting Behavior Scale (PPBS) was formulated to measure clearly defined observed maternal behaviors toward the infant shortly after birth. The quality of the maternal-infant relationship was assessed at 6 months after birth with the Nursing Child Assessment Satellite Training (NCAST) Feeding Scale and at 12 months after birth with the NCAST Teaching Scale and Ainsworth Strange Situation. RESULTS: The PPBS score correlated significantly with the Feeding Scale score (r =.27, P <.005) and with the Teaching Scale score (r =.23, P <.01). Mothers whose infants were later classified as securely attached in the Ainsworth Strange Situation had higher PPBS scores than mothers of infants classified as insecurely attached (mean +/- SD: 5.18 +/- 1.51 vs 4.63 +/- 1.69, respectively, P <.05). In regression models adjusting for social and demographic factors, the PPBS remained a significant predictor of the Feeding Scale score, the Teaching Scale score, and security of attachment. CONCLUSIONS: Maternal behaviors in the immediate postpartum period may aid in predicting quality of the maternal-infant relationship during the subsequent 12 months, suggesting the potential for early identification of suboptimal parenting.

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.

Early perinatal hospital discharge and parenting during infancy.

OBJECTIVE: To evaluate the relationship between early perinatal hospital discharge and several parenting outcomes during infancy, including breastfeeding, mother-infant interaction, and mother-infant attachment. STUDY DESIGN: A prospective, longitudinal, nonrandomized study of mother-infant dyads discharged 36 hours after birth (late discharge). METHODS: Demographic, perinatal, and psychosocial factors were determined from medical record review and maternal questionnaires. Questionnaires also assessed maternal perceptions of the hospital stay and breastfeeding rates. Mother-infant interaction was assessed at 3 months after birth using the NCAST Feeding Scale and at 9 months after birth using the NCAST Teaching Scale. Security of attachment was measured in the Ainsworth Strange Situation at 12 months after birth. RESULTS: Early and late discharge groups were similar with respect to major demographic, perinatal, and psychosocial characteristics and perceptions of the hospital stay. Even after adjusting for these factors in regression analyses, no significant association was found between early discharge and breastfeeding at 3 months, NCAST scores at 3 and 9 months, and security of attachment at 12 months. CONCLUSION: Parenting outcomes, such as breastfeeding, mother-infant interaction, and attachment, are not influenced by early perinatal hospital discharge.

A new measure for distress during child sexual abuse examinations: the genital examination distress scale.

OBJECTIVE: The primary aim was to develop a simple scale to quantify indices of emotional distress during the rectal-genital (anogenital) phase of a child sexual abuse examination. METHOD: A scale successfully developed to measure reactions of children to painful procedures, in particular bone marrow aspirations, was used as a model (Elliot, Jay, & Woody, 1987). This new scale was developed to have a simplified rating format, more relevant operational definitions and possibly a different set of behavioral categories. This new scale was developed using 300 children being examined for possible child sexual abuse. Intraclass correlation coefficients identified reliable items to use. Factor analysis and Cronbach alpha were employed to understand the internal structure of the scale. Paired t-tests, Pearson correlations and hierarchical regression were used to explore validity. RESULTS: A simple 7-item scale was developed along with two subscales representing agitated and verbally mediated distress. Ratings of distress were significantly greater during the anogenital phase than the general physical part of the examination. Increased distress was associated with positive physical findings. Ratings by the children that they disliked the physician looking at their bodies provided discriminant validity by correlating with increased scores for emotional distress during the anogenital segment of the examination. CONCLUSION: The Genital Examination Distress Scale (GEDS) has been developed for measuring the emotional distress of children during the anogenital component of child sexual abuse examinations. The GEDS has been provided for prudent use. Descriptive data offer a comparative standard for other programs and research.

The clinical spectrum in a large kindred with autoimmune lymphoproliferative syndrome caused by a Fas mutation that impairs lymphocyte apoptosis.

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic, histologically benign splenomegaly and generalized lymphadenopathy, hypergammaglobulinemia, and autoantibody formation. ALPS has been attributed to defective programmed cell death of lymphocytes, most often arising as a result of mutations in the gene encoding the lymphocyte apoptosis receptor Fas/APO-l/CD95. We identified a novel mutation in the intracellular apoptosis signaling domain of Fas in 11 members of a family, individual members of which have been monitored for up to 25 years, with 1 or more features of ALPS. This study of a large number of family members carrying the same Fas defect demonstrates that ALPS is inherited in an autosomal dominant fashion but with a high degree of variability in clinical expression. Although 1 affected individual died of postsplenectomy sepsis and 1 has been treated for lymphoma, the Fas mutation in this family has been compatible with a healthy adulthood, as clinical features of ALPS have receded with increasing age.

Mechanism of carbamoyl phosphate synthetase from Escherichia coli--binding of the ATP molecules used in the reaction and sequestration by the enzyme of the ATP molecule that yields carbamoyl phosphate.

The conflicting data on the binding of the two molecules of ATP that are involved in the overall reaction catalyzed by carbamoyl-phosphate synthetase (CPS) of Escherichia coli, and a mechanism recently proposed for this reaction, has led us to reexamine ATP binding using pulse/chase techniques. With [gamma-32P]ATP and bicarbonate in the pulse solution, there is a positive intercept at zero time of approximately 1 mol Pi/mol CPS in the plot of 32Pi formation against time, irrespective of whether the incubation is terminated by the addition of acid or by addition of a chase solution containing glutamine, excess unlabeled ATP and bicarbonate. The intercept is decreased to about 50% if the excess unlabeled ATP is added prior to the addition of the glutamine. These are the expected results if the intercept reflects the reversible formation of enzyme-bound ADP and carboxyphosphate. Approximately 0.6 mol carbamoyl [32P]phosphate/mol enzyme is formed in these experiments when the pulse step is terminated by addition to the chase solution. The ATP molecule that provides the phosphoryl group of carbamoyl phosphate, therefore, also binds to the enzyme in the absence of ammonia or glutamine and reacts in the chase to give carbamoyl phosphate before it can dissociate from the enzyme. At 1 mM ATP, the binding of both ATP molecules is essentially complete at 2.5 s, but the dissociation of the ATP that yields carbamoyl phosphate is extremely slow (t(1/2) of about 6 min at 22 degrees C; HCO3-, 40 mM), although it is faster in the absence of bicarbonate. The extreme sequestration from the aqueous environment of this ATP allows the enzyme-ATP complex to be separated from the surrounding ATP by centrifugal gel filtration. After two successive steps of gel filtration through Sephadex G-50 equilibrated with unlabeled ATP and bicarbonate, the majority of the radioactivity remaining in the solution is bound to the enzyme and is released as [gamma-32P]ATP if acid is added, or is converted to carbamoyl [32P]phosphate by addition to chase solution, without concomitant release of 32Pi. K+ is necessary in the pulse solution, but not in the chase solution, to demonstrate this binding. These findings and other confirmatory experiments demonstrate conclusively that, in the presence of K+, both ATP molecules bind to the enzyme in the absence of ammonia or glutamine. The bound ATP that yields Pi in the overall reaction is replaced relatively rapidly by exchange and by hydrolysis in the bicarbonate-dependent ATPase activity of the enzyme, whereas the bound ATP that provides the phosphoryl group of carbamoyl phosphate is replaced very slowly. The temporal pattern of carbamoyl [32P]phosphate formation from [gamma-32P]ATP, in pulse/chase experiments in which a small concentration of ammonia is added to the pulse solution, shows that, in the normal enzyme reaction, this last ATP molecule binds to the enzyme before ammonia. These findings exclude a recently proposed mechanism [Kothe, M., Eroglu, B., Mazza, H., Samudera, H. & Powers-Lee, S. (1997) Proc. Natl Acad. Sci. USA 94, 12348-12353] in which a single molecule of ATP bound at the catalytic center phosphorylates bicarbonate and provides the phosphoryl group of carbamoyl phosphate. A mechanism in which a single ATP molecule binds, followed by the binding of bicarbonate and ammonia (from glutamine) and the release of Pi before the second molecule of ATP is bound is also excluded. We have previously reported very similar findings for carbamoyl-phosphate synthetase (ammonia), strongly suggesting that the different types of CPS share a common mechanism. The virtual sequestration of the ATP that provides the phosphoryl group of carbamoyl phosphate is consistent with a palmate-binding site, with the nucleotide bound within a beta-sheet sandwich, and a loop closure mechanism triggered by the binding of bicarbonate or the formation of carboxyphosphate.

Perinatal screening for child abuse and neglect.

An increased awareness of the frequency and severity of child abuse and neglect in our society has prompted consideration of the feasibility of perinatal screening and early intervention for this problem. This article reviews the available information on screening and early intervention for high-risk parenting in the perinatal period. The advantages, disadvantages, and cost-effectiveness of screening and intervention for children and families at risk for abuse and neglect are also discussed.

Pediatric male rectal and genital trauma: accidental and nonaccidental injuries.

OBJECTIVE: To characterize accidental pediatric rectal/genital trauma in males and compare these physical findings to a cohort of boys evaluated for sexual abuse. DESIGN: Retrospective chart review. SETTING: Tertiary pediatric trauma center/sexual abuse clinic. PARTICIPANTS: Male patients evaluated in the emergency department for rectal/genital trauma from 9/1/89 through 10/31/93 ("accidental group"). Male patients referred to Child Protection Services for suspected sexual abuse from 1/1/93 through 12/31/95 who had abnormal genital physical findings ("sexual abuse group"). MAIN OUTCOME MEASURES: Outcomes measured included age, mechanism of injury, category of diagnosis, location of injury, and type of injury. RESULTS: Forty-four male patients comprised the accidental group, aged six months to 17 years. The most common mechanism was a fall onto an object (34%). The most common injuries were lacerations/perforations of the scrotum (36%) followed by penile lacerations/perforations (25%). No patient had an isolated rectal laceration. Forty-four male patients with positive physical findings comprised the sexual abuse group. Ages ranged from seven months to 18 years. All patients had rectal lesions. Penile lacerations/perforations were the only other injuries documented, occurring in two patients. CONCLUSIONS: Accidental rectal/genital trauma in the pediatric population is uncommon; scrotal trauma occurs much more frequently than rectal trauma. Rectal/genital injury in the sexual abuse group typically involves only the rectal area. Sexual assault should be considered in patients with isolated rectal injury or whenever the alleged history does not correlate with physical findings.

Symptomatic splenic hamartoma: case report and literature review.

An 11-year-old girl with low-grade fever, night sweats, thrombocytopenia, and an 8-year history of progressive splenomegaly underwent an elective splenectomy. Pathologic diagnosis was multiple splenic hamartoma. The patient's symptoms resolved after the splenectomy. Since first described by Rokitansky in 1861, approximately 140 cases of splenic hamartoma have been described in the literature. Most of the splenic hamartomas were discovered incidentally. A minority of these lesions were associated with hematologic symptoms such as pancytopenia, anemia, and thrombocytopenia. Only 20 of the reported cases of splenic hamartoma occurred in pediatric patients. However, compared with the adult patients, nearly half of these cases in pediatric patients was associated with symptoms. Splenectomy and partial splenectomy have relieved these symptoms. With advances in imaging, splenic hamartomas are being discovered with increasing frequency. A multimodal radiologic work-up has enabled some cases of splenic hamartoma to be diagnosed preoperatively. Inclusion of this benign entity in the differential diagnoses of symptomatic splenomegaly in a pediatric patient is important in the preoperative management and counseling of the patient and family. In patients who have discrete lesions, consideration of this entity preoperatively may avoid total splenectomy.

Isomerization of the free enzyme versus induced fit: effects of steps involving induced fit that bypass enzyme isomerization on flux ratios and countertransport.

In a single-substrate-single-product enzyme reaction, "counter transport', which indicates that the ratio of the forward to the reverse fluxes is less than that expected from the Independence Relationship, is regarded as strong evidence for the free enzyme existing in two states, one of which combines with the substrate and the other with the product, with a slow isomerization between the two conditions. To account for positive and negative co-operativity, found with some enzymes, additional induced-fit reactions bypassing at least part of the isomerization have been proposed. The effects of such additional steps have been examined, using two models: in one, (a), the enzyme passes through an intermediate state during its isomerization, and both substrate and product may react with this state to give rise to the binary complexes; in the other, (b), the substrate may react with the enzyme as soon as the product is released and similarly with the reverse reaction, the isomerization thereby being bypassed completely. In the presence of such additional steps, the following can be concluded. (i) The data should be analysed in terms of the flux ratios, rather than observation of the amount of countertransport. (ii) The additional bypassing steps markedly change the pattern of dependence of the flux ratio on substrate and product concentrations. At high substrate and product concentrations, the ratio remains very dependent on how far the reaction is from equilibrium, and the kinetics are asymmetric. (iii) The mechanism causing the flux ratio to be less than that given by the Independence Relationship differs from that previously described, in that, at least in part, it arises from a 1:1 exchange between substrate and product. (iv) Despite this novel mechanism, there must be two states of the enzyme, combining respectively with substrate and product, and these must not be in rapid exchange. Thus countertransport remains very strong evidence for the existence of two such states. It is no longer a requirement that the enzyme states should be linked by an isomerization step. (v) Under no conditions can the flux ratio exceed that given by the Independence Relationship. (vi) Under unusual conditions the isomerization of the enzyme in model (b) may be undetectable by steady-state kinetics. (vii) Measurements of the coefficients in the flux ratio equations enable limits to be set to certain ratios of the rate constants. In addition to these conclusions, methods are described for (viii) analysing flux ratio data for the presence of induced fit steps and (ix) determining flux ratios from induced transport curves. The derivation of steady state-velocity equations show that: (x) both models may give rise to positive and negative 'co-operativity' and sigmoid substrate-velocity curves, but that, under conditions giving rise to sigmoid curves, the deviation of the flux ratio from that required by the Independence Relationship may be difficult to demonstrate because of the asymmetry of the system. Under all conditions the fluxes at equilibrium should obey hyperbolic kinetics.

Glucosephosphate isomerase (GPI) deficiency mutations associated with hereditary nonspherocytic hemolytic anemia (HNSHA).

Five unrelated patients with hereditary glucosephosphate isomerase (GPI) deficiency resulting in nonspherocytic hemolytic anemia were studied. Three new mutations were found in the coding region of the GPI gene: two patients were heterozygous for 223 A-->G (R75G) and 898 G-->C(R300P), respectively and one was homozygous for 1415G-->A(R472H). Surprisingly, 2 previously reported mutations, 286 C-->T and 1039 C-->T, were found in 2 and 3 patients respectively. Until now only 4 of 18 GPI mutations had been found more than once in unrelated patients and these 4 in only 2 patients each. Eleven of the 20 known point mutations have occurred at CpG "hot spots" and the 286 C-->T and 1039 C-->T are among these. The 489 G/A polymorphism in the GPI coding region was used to demonstrate unequivocally that the 1039 C-->T mutation occurred in both haplotypes and therefore probably originated more than once. Because no common GPI mutation has been found we suggest that heterozygosity for GPI confers little if any selective advantage.

Neonatal mortality and length of newborn hospital stay.

OBJECTIVE: To investigate the effect of hospital discharge time on neonatal mortality of term newborns. DESIGN: Infants who were discharged home at 5 days of age of younger and who subsequently died were compared with control infants using a retrospective case-control design. Descriptive information was collected from records of infants who were not discharged home from the hospital of birth (because of death or transfer to a tertiary care hospital) to determine the age at which their illnesses presented. METHODS: We reviewed death certificates for all infants with birth weights of 2500 g or greater born at 37 weeks' gestational age or greater who died in the first 28 days of life and who were born in one of four Utah counties (1985 through 1989). Of the 109,256 eligible births, 115 infants were found who had died in the neonatal period. Eighty-four infants had not been discharged home from the hospital of birth, 5 infants had had hospital stays of more than 5 days, 9 records could not be located, 17 presumed healthy infants were discharged from the hospital at 5 days of age or younger. These 17 infants were each matched with 3 control infants. Newborn nursery charts were reviewed to determine hospital discharge times for case and control infants. Descriptive information regarding the time of presentation of illness was collected for the other 89 infants. RESULTS: The mean age of hospital discharge was 43 +/- 21 hours for the 17 case infants and 47 +/- 25 hours for the 51 control infants. The odds ratio for neonatal mortality for discharge at less than 24 hours was 1.65 (95% confidence interval, 0.42 to 3.34) and for discharge at less than 48 hours was 1.16 (95% confidence interval, 0.4 to 3.34). Of the 84 infants who were not discharged home from the hospital of birth, 93% had been symptomatic by 12 hours of age, and 99% were symptomatic by 18 hours. CONCLUSIONS: Most full-term infants who die in the neonatal period are symptomatic within the first 18 hours after birth. We could not demonstrate an association between early hospital discharge and neonatal mortality in those infants who died after discharge home.