Generalized Rapid Synthesis of Supported Nanocluster Catalyst for Mild Hydrogenation of Phenol toward KA Oil.

Homogeneous and nanometric metal clusters with unique electronic structures are promising for catalysis, however, common synthesis techniques for metal clusters suffer from large size and even metal nanocrystals attributing to their high surface energy and unsaturated configurations. Herein, a generalized rapid annealing strategy for synthesizing a series of supported metal clusters as superior catalysts is developed. Remarkably, TiO2 supported platinum nanoclusters (Pt NC/TiO2 ) exhibits the excellent catalytic activity to realize phenol hydrogenation under mild conditions. The complete phenol conversion rate and 100% selectivity toward KA oil are achieved in aqueous solution at room temperature and normal pressure. Semi-continuous scale up production of KA oil is successfully performed under mild conditions. Such excellent performance mainly originates from the partial reconstruction of Pt NC/TiO2 in aqueous phenol solution. Considering that the phenol can be produced from lignin, this study underpins a facile, sustainable, and economical route to synthesize nylon from biomass.

Saving 80% Polypropylene in Facemasks by Laser-Assisted Melt-Blown Nanofibers.

The ongoing coronavirus (COVID-19) pandemic requires enormous production of facemasks and related personal protection materials, thereby increasing the amount of nondegradable plastic waste. The core material for facemasks is melt-blown polypropylene (PP) fiber. Each disposable facemask consumes ∼0.7 g of PP fibers, resulting in annual global consumption and disposal of more than 1 150 000 tons of PP fibers annually. Herein, we developed a laser-assisted melt-blown (LAMB) technique to manufacture PP nanofibers with a quality factor of 0.17 Pa-1 and significantly reduced the filter's weight. We demonstrated that a standard surgical facemask could be made with only 0.13 g of PP nanofibers, saving approximately 80% of the PP materials used in commercial facemasks. Theoretical analysis and modeling were also conducted to understand the LAMB process. Importantly, nanofibers can be easily scaled up for mass production by upgrading traditional melt blown line with scanning laser-assisted melt-blown (SLAMB).

Generation and characterization of dipeptidyl peptidase-IV inhibitory peptides from trypsin-hydrolyzed α-lactalbumin-rich whey proteins.

Dipeptidyl peptidase-IV (DPP-IV) is an enzyme that break down the antidiabetic hormone glucagon-like peptide-1. Therefore, inhibition of DPP-IV could be an effective strategy to treat Type 2 diabetes (T2D). The α-lactalbumin-rich whey protein concentrate was hydrolyzed by trypsin, and the hydrolysates were then fractionated at a semi-preparative scale using a Superdex Gel filtration Chromatography. The peptides were analyzed by using HPLC coupled with tandem mass spectrometry (RP-HPLC-MS/MS), and their Dipeptidyl peptidase-IV inhibitory activity was determined by the enzymatic assay. Among tested fragments, a potent fragment (LDQWLCEKL), with the half-maximal inhibitory concentration (IC50) of 131 µM was obtained. Further analysis shows that the LDQWLCEKL peptide corresponds to the amino acid sequence of f(115-123) in α-lactalbumin. Furthermore, LDQWLCEKL exhibited a typical non-competitive mode of inhibition. The results indicate that α-lactalbumin contains active peptides with DPP-IV inhibitory activity that may be used to prevent and treat T2D.

Full-term newborn infant with blistering skin lesions-Caution regarding use of pain medications.

Multiple opioids are known to trigger mast cell degranulation. We report the case of a neonate with blistering skin lesions at birth who died of multi-organ failure after administration of morphine. Given the excessive histamine release and potential complications associated with morphine administration, alternative opioids and adjuvants should be considered in infants presenting with evidence of bullous or infiltrative skin lesions until mastocytosis is ruled out.

Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of HIF-prolyl 4-hydroxylases for treatment of ischemic diseases.

SIGNIFICANCE: In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans. RECENT ADVANCES: Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent "oxygen paradox" must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases. CRITICAL ISSUES: Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases. FUTURE DIRECTIONS: This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.

Short-term neonatal outcomes in diamniotic twin pregnancies delivered after 32 weeks and indications of late preterm deliveries.

OBJECTIVE: We sought to compare neonatal outcomes in twin pregnancies following moderately preterm birth (MPTB), late preterm birth (LPTB), and term birth and determine the indications of LPTB. STUDY DESIGN: We performed a retrospective cohort study. MPTB was defined as delivery between 32(0/7) and 33(6/7) weeks and LPTB between 34(0/7) and 36(6/7) weeks. The composite neonatal adverse respiratory outcome was defined as respiratory distress syndrome and/or bronchopulmonary dysplasia. The composite neonatal adverse nonrespiratory outcome included early onset culture-proven sepsis, necrotizing enterocolitis, retinopathy of prematurity, intraventricular hemorrhage, or periventricular leukomalacia. LPTB cases were categorized as spontaneous (noniatrogenic), evidence-based iatrogenic, and non-evidence-based (NEB) iatrogenic. RESULTS: Of the 747 twin deliveries during the study period, 453 sets met the inclusion criteria with 22.7% (n = 145) MPTB, 32.1% (n = 206) LPTB, and 15.9% (n = 102) term births. Compared with term neonates, the composite neonatal adverse respiratory outcome was increased following MPTB (relative risk [RR] 24; 95% confidence interval [CI] 3.0 to 193.6) and LPTB (RR 13.7; 95% CI 1.8 to 101.8). Compared with term neonates, the composite neonatal adverse nonrespiratory outcome was increased following MPTB (RR 22.3; 95% CI 3.9 to 127.8) and LPTB (RR 5.5; 95% CI 1.1 to 27.6). Spontaneous delivery of LPTB was 63.6% (n = 131/206) and the rate of iatrogenic delivery was 36.4% (n = 75/206). The majority, 66.6% (n = 50/75), of these iatrogenic deliveries were deemed NEB, giving a total of 24.2% (50/206) NEB deliveries in LPTB group. CONCLUSION: Our data demonstrate a high rate of late preterm birth among twin pregnancies, with over half of nonspontaneous early deliveries due to NEB indications. Although our morbidity data will be helpful to providers in counseling patients, our finding of high NEB indications underscores the need for systematic evaluation of indications for delivery in LPTB twin deliveries. Furthermore, this may lead to more effective LPTB rate reduction efforts.

Developmental effects of tobacco smoke exposure during human embryonic stem cell differentiation are mediated through the transforming growth factor-ß superfamily member, Nodal.

While the pathologies associated with in utero smoke exposure are well established, their underlying molecular mechanisms are incompletely understood. We differentiated human embryonic stem cells in the presence of physiological concentrations of tobacco smoke and nicotine. Using post hoc microarray analysis, quantitative PCR, and immunoblot analysis, we demonstrated that tobacco smoke has lineage- and stage-specific effects on human embryonic stem cell differentiation, through both nicotine-dependent and -independent pathways. We show that three major stem cell pluripotency/differentiation pathways, Notch, canonical Wnt, and transforming growth factor-ß, are affected by smoke exposure, and that Nodal signaling through SMAD2 is specifically impacted by effects on Lefty1, Nodal, and FoxH1. These events are associated with upregulation of microRNA-302a, a post-transcriptional silencer of Lefty1. The described studies provide insight into the mechanisms by which tobacco smoke influences fetal development at the cellular level, and identify specific transcriptional, post-transcriptional, and signaling pathways by which this likely occurs.

Predictors of successful discontinuation of supplemental oxygen in very low-birth-weight infants with bronchopulmonary dysplasia approaching neonatal intensive care unit discharge.

We sought to identify factors associated with readiness to discontinue supplemental oxygen and to gain weight in very low-birth-weight (VLBW) infants with bronchopulmonary dysplasia (BPD) approaching neonatal intensive care unit (NICU) discharge. From 2004 to 2009, VLBW infants ≥34 weeks' postmenstrual age (PMA) on nasal cannula supplemental oxygen were challenged with room air at rest, during activity, and feeding as routine care. Outcome and clinical data were collected retrospectively. Challenges were divided into derivation and validation cohorts. We performed comparative and hierarchical logistic regression analyses, constructing a predictive model with passed challenge as outcome. Of 233 infants (birth weight 901 ± 245 g, gestational age 26(6)/(7) ± 2 weeks), 988 had challenges at 38(2)/(7) ± 3 weeks' PMA. Weight gain was 12.4 ± 5 g/kg/d in the week following passed challenges and 11.2 ± 5.3 g/kg/d following failed challenges (p = 0.08). Increasing weight at time of challenge was associated with increased adjusted odds of passing. Increasing capillary pco(2), cannula flow rate, pulmonary acuity score, and history of patent ductus arteriosus (PDA) ligation decreased odds of passing. Receiver operating characteristic curve area was 0.82 in the validation cohort. The model performed well within pco(2) and pulmonary acuity score subgroups. Weight, pco(2), cannula flow rate, pulmonary acuity score, and history of PDA ligation identify infants with BPD ready to maintain saturation and gain weight without supplemental oxygen.

Optimal time for delivery with preterm premature rupture of membranes from 32 to 36 6/7 weeks.

OBJECTIVE: To evaluate the optimal time for delivery in singleton pregnancies with preterm premature rupture of membranes (PPROM) when delivered between 32 and 36 6/7 weeks gestational age (GA). STUDY DESIGN: We performed a retrospective cohort study of all singleton pregnancies with PPROM who delivered between 32 and 36 6/7 weeks gestation at our institution. We matched the delivery and NICU datasets to determine composite morbidity (COMP MORB) and NICU length of stay (LOS) stratified by weeks of gestation. COMP MORB was defined as one or more of: bronchopulmonary dysplasia, respiratory distress syndrome, necrotizing entercolitis, intraventricular hemorrhage, dissiminated intravascular coagulation, and culture proven sepsis. We used χ² and student 't' test as appropriate and a receiver operating characteristc curve (ROC). RESULTS: There were 195 newborns with PPROM with a range of 30 babies at 36 weeks to a high of 53 at 34 weeks. The mean (± SD) NICU LOS was 22.5 (± 9.9) days at 32 weeks, 17.8 (± 10.0) days at 33 weeks, 14.8 (± 11.0) days at 34 weeks, 4.5 (± 4.7) days at 35 weeks, and 1.5 (± 4.4) days at 36 weeks (p < 0.0001). There was no difference in duration of ROM by GA with a range of 6.8 to 1.9 by week (p = NS). The ROC curve had a cut point for COMP MORB at 34.1 weeks GA (sens = 95%, FPR 48.6%, area under curve 0.782, p = 0.0002). CONCLUSION: Our study suggests that delivery of PPROM pregnancies at 34.1 weeks GA avoids 95% of composite morbidity, and delivery after 35 weeks GA will decrease the NICU LOS.

Surfactant protein A stimulates release of neutrophil chemotactic factors by alveolar type II pneumocytes.

Mucosal immunity is an important mechanism in the response to injury. Our hypothesis is that surfactant protein A (SP-A) is an autocrine factor that stimulates alveolar type II epithelial cell release of neutrophil chemotactic factors by binding to the SP-A receptor expressed by these cells. We examined (1) the effect of SP-A (20 µg/ml) or IL-1ß (10 ng/ml) on release of neutrophil chemotactic factors by primary cultures of type II cells or alveolar macrophages, and (2) the effect of intratracheal instillation of the blocking antibody to the SP-A receptor on the response to oleic acid-induced lung injury in vivo. All media and cell culture supernates were assayed for neutrophil chemotactic activity, and bronchoalveolar lavage fluid from the in vivo experiments was analyzed for inflammatory cell counts. While SP-A and media used for the cell cultures has no intrinsic neutrophil chemotactic activity, supernates from primary cultures of type II cells incubated in either SP-A or IL-1ß had twofold higher neutrophil chemotactic factor activity compared to supernates from controls. SP-A had no effect on release of neutrophil chemotactic factor by alveolar macrophages. Oleic acid-induced lung injury resulted in a marked influx of neutrophils into BAL, and this influx was reduced by 70% by pretreatment with the antibody to SP-A receptor. We conclude that SP-A stimulates the release of neutrophil chemotactic factor by alveolar type II cells, and this effect is mediated by the receptor for SP-A specifically expressed by these cells.

Infantile hemangiomas and retinopathy of prematurity: possible association.

OBJECTIVE: The goal was to study the clinical association between infantile hemangiomas and retinopathy of prematurity in preterm infants. METHODS: A retrospective study of preterm neonates weighing /=1 cm in size. Univariate analyses showed lower gestational age, lower birth weight, and postnatal steroid use to be predictors of retinopathy of prematurity, whereas prenatal steroid use, race, and gender were not significantly related. In multivariate logistic regression analyses controlling for gestational age and postnatal steroid use, infantile hemangiomas were found to be independently associated with any stage of retinopathy of prematurity. Neither the number nor the size of infantile hemangiomas showed any association with the severity of retinopathy of prematurity. CONCLUSIONS: Infantile hemangiomas are associated with the development of retinopathy of prematurity in infants weighing

Genetic contribution to patent ductus arteriosus in the premature newborn.

BACKGROUND: The most common congenital heart disease in the newborn population, patent ductus arteriosus, accounts for significant morbidity in preterm newborns. In addition to prematurity and environmental factors, we hypothesized that genetic factors play a significant role in this condition. OBJECTIVE: The objective of this study was to quantify the contribution of genetic factors to the variance in liability for patent ductus arteriosus in premature newborns. PATIENTS AND METHODS: A retrospective study (1991-2006) from 2 centers was performed by using zygosity data from premature twins born at < or =36 weeks' gestational age and surviving beyond 36 weeks' postmenstrual age. Patent ductus arteriosus was diagnosed by echocardiography at each center. Mixed-effects logistic regression was used to assess the effect of specific covariates. Latent variable probit modeling was then performed to estimate the heritability of patent ductus arteriosus, and mixed-effects probit modeling was used to quantify the genetic component. RESULTS: We obtained data from 333 dizygotic twin pairs and 99 monozygotic twin pairs from 2 centers (Yale University and University of Connecticut). Data on chorioamnionitis, antenatal steroids, gestational age, body weight, gender, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, oxygen supplementation, and bronchopulmonary dysplasia were comparable between monozygotic and dizygotic twins. We found that gestational age, respiratory distress syndrome, and institution were significant covariates for patent ductus arteriosus. After controlling for specific covariates, genetic factors or the shared environment accounted for 76.1% of the variance in liability for patent ductus arteriosus. CONCLUSIONS: Preterm patent ductus arteriosus is highly familial (contributed to by genetic and environmental factors), with the effect being mainly environmental, after controlling for known confounders.

Effects of prenatal tobacco exposure on gene expression profiling in umbilical cord tissue.

Maternal smoking doubles the risk of delivering a low birth weight infant. The purpose of this study was to analyze differential gene expression in umbilical cord tissue as a function of maternal smoking, with an emphasis on growth-related genes. We recruited 15 pregnant smokers and 15 women who never smoked during pregnancy to participate. RNA was isolated from umbilical cord tissue collected and snap frozen at the time of delivery. Microarray analysis was performed using the Affymetrix GeneChip Scanner 3000. Six hundred seventy-eight probes corresponding to 545 genes were differentially expressed (i.e. had an intensity ratio > +/- 1.3 and a corrected significance value p < 0.005) in tissue obtained from smokers versus nonsmokers. Genes important for fetal growth, angiogenesis, or development of connective tissue matrix were upregulated among smokers. The most highly upregulated gene was CSH1, a somatomammotropin gene. Two other somatomammotropin genes (CSH2 and CSH-L1) were also upregulated. The most highly downregulated gene was APOBEC3A; other downregulated genes included those that may be important in immune and barrier protection. Validation of the three somatomammotropin genes showed a high correlation between qPCR and microarray expression. We conclude that maternal smoking may be associated with altered gene expression in the offspring.

Effect of a short course of prednisolone in infants with oxygen-dependent bronchopulmonary dysplasia.

OBJECTIVE: The purpose of this work was to determine whether oral prednisolone is effective in weaning infants with bronchopulmonary dysplasia, after 36 weeks' postmenstrual age, off supplemental oxygen and to identify factors associated with successful weaning. METHODS: Data were abstracted from a standardized prospectively collected database at the John Dempsey Hospital NICU. Logistic regression and receiver operating curve analyses were used. RESULTS: Of 385 infants, 131 (34%) received oral prednisolone and 254 (66%) did not. There was no significant difference in race, gender, birth weight, or gestational age between the groups receiving and not receiving oral prednisolone. Infants in the oral prednisolone group were more likely to have received previous dexamethasone therapy, had longer duration of mechanical ventilation, had longer length of hospital stay, and were more likely to be discharged from the hospital on oxygen. Of those in the oral prednisolone group, 63% responded to treatment. Pulmonary acuity score and PCO2 were the only parameters that remained significant on multiple logistic regression analyses. The oral prednisolone-responsive group had a lower pulmonary acuity score compared with the oral prednisolone-nonresponsive group. A pulmonary acuity score value of < or = 0.5 had a sensitivity of 20% and specificity of 97.4%, with positive and negative predictive values of 94.1% and 42.1%, respectively. Capillary PCO2 values were significantly lower in the oral prednisolone-responsive group compared with the oral prednisolone-nonresponsive group. In predicting a successful response to oral prednisolone, a capillary PCO2 value of < 48.5 mmHg had a sensitivity of 50% and specificity of 89.7%, with positive and negative predictive values of 89.1% and 51.8%, respectively. CONCLUSIONS: Oral prednisolone therapy is effective in weaning off supplemental oxygen in a postterm infant with oxygen-dependent bronchopulmonary dysplasia who has a pulmonary acuity score of < 0.5 and PCO2 of < 48.5 mmHg. In addition, if a single course of prednisolone fails, there is no clear benefit of using multiple courses.

Genetic susceptibility to retinopathy of prematurity.

OBJECTIVES: The goals were to isolate and to estimate the genetic susceptibility to retinopathy of prematurity. METHODS: A retrospective study (1994-2004) from 3 centers was performed with zygosity data for premature twins who were born at a gestational age of < or = 32 weeks and survived beyond a postmenstrual age of 36 weeks. Retinopathy of prematurity was diagnosed and staged by pediatric ophthalmologists at each center. Data analyses were performed with mixed-effects logistic regression analysis and latent variable probit modeling. RESULTS: A total of 63 monozygotic and 137 dizygotic twin pairs were identified and analyzed. Data on gestational age, birth weight, gender, respiratory distress syndrome, retinopathy of prematurity, bronchopulmonary dysplasia, duration of ventilation and supplemental oxygen use, and length of stay were comparable between monozygotic and dizygotic twins. In the mixed-effects logistic regression analysis for retinopathy of prematurity, gestational age and duration of supplemental oxygen use were significant covariates. After controlling for known and unknown nongenetic factors, genetic factors accounted for 70.1% of the variance in liability for retinopathy of prematurity. CONCLUSION: In addition to prematurity and environmental factors, there is a strong genetic predisposition to retinopathy of prematurity.

Gastroesophageal reflux in infants < 32 weeks gestational age at birth: lack of relationship to chronic lung disease.

The objective of this study was to determine the incidence of gastroesophageal reflux (GER) as documented by extended esophageal pH monitoring in symptomatic premature infants and to identify its relationship with chronic lung disease (CLD). This was a retrospective study of 629 infants born < 32 weeks gestational age and admitted to the neonatal intensive care unit during the study period. Univariate analyses were done on the 137 infants undergoing the test for the association of the following risk factors with acid reflux: birth weight, gestational age, race, sex, length of stay, bronchopulmonary dysplasia (BPD; O2 requirement at 28 days), and severe CLD (O2 requirement at 36 weeks postmenstrual age). Eighty-seven of 137 infants were positive for GER. There was no association of GER with the risk factors studied, nor were there correlations with BPD or severe CLD. GER is common (63%) in premature infants < 32 weeks gestational age but clinical symptoms and CLD are poorly correlated with this diagnosis.

Inguinal hernia in preterm infants (< or = 32-week gestation).

The current incidence of inguinal hernia (IH) in premature infants is not well-established. It is also unclear whether common co-morbidities in this population, i.e., chronic lung disease (CLD) or nutritional status or both contribute to the development of IH. The purpose of this study was to establish the epidemiologic profile of preterm infants of 32 weeks gestational age (GA) or less at birth with IH and determine whether the severity of CLD or poor nutritional status predisposes to the development of IH. Perioperative profiles of infants undergoing surgery were also reviewed. A retrospective study of 1,057 infants born at 23-32 weeks GA from January 1990 to December 1995 was done. Specific risk and demographic factors were identified. Factors used to determine severity of CLD were: days on intermittent mandatory ventilation (IMV); days on positive pressure (IMV + continuous positive airway pressure); and total number of days on supplemental oxygen. Overall nutritional status was determined by weight gain in g/kg per day. The incidence of IH in preterm infants of 32 weeks GA or less who were admitted for 28 days or more was 9.34% (65/696) prior to discharge. The incidence in infants weighing 1,500 g or less was 11.11% (63/567) and in infants 1,000 g or less 17.39% (48/276). All parameters that determined the severity of CLD were statistically significant in infants with IH by univariate analysis. In a multivariate regression model, male gender was the most important variable that was significantly associated with IH (odds ratio OR=9.6; 95% confidence interval CI=3.90-23.59), followed by total days on supplemental oxygen (adjusted OR=1.00; 95% CI= 1.01-1.02). Weight gain (g/kg per day) was not significantly different between the two groups. Surgical correction before discharge was well tolerated. We conclude that the incidence of IH is GA-dependent. Factors related to severity of CLD play a more important role than weight gain in predisposing to IH.

Hypospadias and early gestation growth restriction in infants.

OBJECTIVE: There has been a major increase in the incidence of hypospadias in infants in the 1990s, but the risk factors are not known. Although there are scattered reports in the literature regarding the association of low birth weight and hypospadias, this has not been systematically studied. The objective of this study was to determine the association between early gestation intrauterine growth and hypospadias. METHODS: A retrospective review of 13 years of admissions to 2 tertiary care neonatal intensive care units (NICUs) in Connecticut (1987--2000) showed that 112 (1.66%) of 6746 male infants had any degree of hypospadias. Of these, 8 were part of a genetic syndrome and were excluded. A retrospective cohort analysis of these 6738 infants was performed. Infant growth parameters at birth (weight, head circumference, and length) were analyzed along with maternal risk factors known to be associated with changes in fetal growth, including maternal age, race, diagnosis of preeclampsia, gestational diabetes, and maternal use of alcohol or tobacco or substance abuse during pregnancy. RESULTS: The incidence of hypospadias in the NICU population increased 10-fold from 0.4% in 1987 to 4% in the first quarter of 2000. Hypospadias was significantly more common in infants who had uniformly poor intrauterine growth (<10th percentiles) in the various parameters measured: birth weight, length, or head circumference. There were no significant differences in maternal age or race, nor were there differences in the use of alcohol, tobacco, or street drugs by the mother. There were no differences between singletons and multiple-gestation births. However, the frequency of occurrence was significantly higher among first-born infants (1.9%) compared with all other infants (0.9%). CONCLUSIONS: The incidence of hypospadias in our NICU population has increased 10-fold during the 13-year period of study. There was a significant association of hypospadias with poor intrauterine growth. The growth restriction was probably of early gestational cause as there was proportionate involvement of somatic (weight and length) and brain growth (head circumference). The increasing frequency of hypospadias and its association with poor intrauterine growth originating in early gestation suggests that common environmental factor(s) that have an impact on both conditions may be involved.