Combination of the clock drawing test with the physical phenotype of frailty for the prediction of mortality and other adverse outcomes in older community dwellers without dementia.

BACKGROUND: Cognitive assessment is thought to increase the ability of the physical phenotype of frailty to identify older persons at a higher risk for adverse outcomes. OBJECTIVE: Data from a cohort of dementia-free community dwellers were used to investigate whether the clock drawing test (CDT), a quick and easy cognitive screening test, is associated with adverse health outcomes independently of the physical phenotype of frailty. METHODS: This was a prospective population-based cohort study of 766 dementia-free Italian community dwellers aged 65 years or older. Baseline assessment included the physical phenotype of frailty, 3 different CDT protocols [Sunderland, Shulman, and the clock drawing interpretation scale (CDIS)], and several health confounders. Hazard ratios (HR) and odds ratio (OR) along with their corresponding 95% confidence intervals (CI) from models adjusted for frailty and sociodemographic and health confounders were used to estimate the independent association of the CDT with the 7-year risk of all-cause mortality and the 3-year risk of new and worsening disability, hospitalization, and fractures. RESULTS: After adjustment for confounders, the Sunderland CDT was significantly associated with all-cause mortality independently of the physical phenotype of frailty (HR = 1.44, 95% CI 1.03-2.01, p = 0.031). However, compared to all nonfrail participants with a normal Sunderland CDT, the HR was 1.57 (95% CI 1.09-2.26, p = 0.016) for those with impairment on the Sunderland CDT only, 2.48 (95% CI 1.46-4.20, p = 0.001) for those with frailty only, and 2.52 (95% CI 1.34-4.77, p = 0.004) for those with both frailty and impairment on the Sunderland CDT. Mortality was unrelated to the CDIS CDT (p = 0.359) and the Shulman CDT (p = 0.281). No statistically significant relationship was found between nonlethal outcomes and any CDT protocol, although trends were found for an association of both the Sunderland CDT (p = 0.118) and the CDIS CDT with worsening disability (p = 0.154). CONCLUSIONS: In older persons, depending on the scoring system, the CDT may predict the mortality risk independently of the physical phenotype of frailty. However, combining the two measurements does not improve their individual prognostic abilities.

Infant sex, obstetric risk factors, and 2-year neurodevelopmental outcome among preterm infants.

AIM: To evaluate the effect of the interaction between fetal sex and obstetric variables on the risk of neurodevelopmental impairment among preterm infants. METHOD: A cohort study of 394 male and 360 female surviving infants born at 24 to 33 completed weeks of gestational age. Neurological examination and cognitive assessment of the infants (Bayley Scales of Infant Development) were performed at 2 years corrected age. RESULTS: Mean gestational age was 30.4 weeks (SD 2.4). Rates of mild and moderate-to-severe neurodevelopmental impairment were 14.6% (110/754) and 7% (53/754) respectively. In logistic analysis, male sex was associated with an increased risk of neurodevelopmental impairment (odds ratio 1.8, 95% confidence interval 1.21-2.68) compared with females. The excess risk of neurodevelopmental impairment associated with male sex was higher among preeclamptic than normotensive pregnancies (p for interaction=0.004), among infants who were either small for gestational age or delivered to a mother with preeclampsia (p for interaction=0.001) and in iatrogenic as opposed to spontaneous preterm birth or preterm premature rupture of membranes (p for interaction=0.035). INTERPRETATION: The excess risk of neurodevelopmental impairment associated with male sex among preterm infants is modulated by obstetric risk factors.

Prognostic significance of the interaction between abnormal umbilical and middle cerebral artery Doppler velocimetry in pregnancies complicated by fetal growth restriction.

OBJECTIVE: To evaluate the prognostic significance of the interaction between umbilical artery (UA) and middle cerebral artery (MCA) Doppler measurements in pregnancies complicated by fetal growth restriction (FGR). DESIGN: Cohort study. SETTING: Third-level Perinatology Center in Northern Italy. POPULATION: A study of 184 singleton pregnancies at 24-35 weeks' gestational age complicated by FGR and abnormal UA Doppler measurements. METHODS: FGR was diagnosed by serial ultrasonograms. Neonatal brain damage was defined as the presence of cystic leukomalacia or grade III-IV intraventricular hemorrhage. MAIN OUTCOME MEASURES: Perinatal death and neonatal brain damage. RESULTS: The prevalence of fetal/neonatal death or brain damage was 18.2% (16/88) in pregnancies with UA absent/reversed diastolic flow and 4.2% (4/96) in those with increased UA Doppler pulsatility. Stepwise logistic regression identified decreasing gestational age (OR=1.75, 95% confidence interval, CI=1.35-2.22) and absent/reversed UA blood flow (OR=3.34, 95% CI=1.1-10.9) as predictors of fetal/neonatal death or brain damage. A MCA pulsatility index below the 10th percentile was a risk factor for fetal/neonatal death or brain damage among women with absent/reversed UA diastolic flow (14/53 as compared to 2/35; OR=5.9, CI =1.4-40.3) but not in pregnancies with forward velocity (1/33 as compared to 3/63; OR=0.63, 95% CI=0.02-6.13, Synergy index=27.7, p=0.007). CONCLUSIONS: In pregnancies complicated by FGR and absent/reversed UA end diastolic flow, vasodilatation of the MCA is a risk factor for neonatal death or brain damage.

The impact of first-trimester serum free beta-human chorionic gonadotropin and pregnancy-associated plasma protein A on the diagnosis of fetal growth restriction and small for gestational age infant.

OBJECTIVE: To evaluate the risk of fetal growth restriction (FGR) associated with first-trimester maternal serum concentrations of pregnancy-associated plasma protein A (PAPP-A) and free beta-human chorionic gonadotropin (beta-hCG). METHODS: A longitudinal study of 2,178 women who underwent first-trimester evaluation of serum PAPP-A and free beta-hCG. FGR was defined as a decrement of the fetal abdominal circumference to below the 10th percentile of our standard growth curve in the presence of Doppler signs of impaired placental perfusion. Logistic regression was used to compute multivariable odds ratios and the estimated prevalences of outcomes associated with first-trimester serum marker concentrations. RESULTS: The prevalences of small for gestational age (SGA, <10th percentile birth-weight) neonates and FGR were significantly higher among women with serum PAPP-A concentrations below the 10th percentile than in controls: 40/206 compared to 183/1,928, for SGA, adjusted odds ratio = 2.1, 95% confidence intervals (CI) 1.4-3.03; 24/75 compared to 182/1,900, for FGR, adjusted odds ratio = 3.9, 95% CI 2.3-6.5. The adjusted prevalences of FGR and SGA among women with simultaneous low first-trimester values of PAPP-A and free beta-hCG were 0.21 (95% CI 0.13-0.33) and 0.26 (95% CI 0.17-0.36), respectively. CONCLUSION: Low first-trimester maternal serum PAPP-A concentrations are significantly associated with reduced fetal size and increased risk of FGR with Doppler signs of impaired placental perfusion.

The effect of newly diagnosed undifferentiated connective tissue disease on pregnancy outcome.

OBJECTIVE: The purpose of this study was to evaluate pregnancy outcome in a cohort of patients with newly diagnosed undifferentiated connective tissue disease (UCTD). STUDY DESIGN: We conducted a nested case-control study that compared 41 patients who had early UCTD that was diagnosed at 11-14 weeks of pregnancy with 82 healthy control subjects. RESULTS: During pregnancy, UCTD progressed to a definite connective tissue disease in 2 of 41 patients (4.9%). Sixteen of the 41 patients (39%) with UCTD tested positive for anti-Ro (SSA) antibodies. Compared with the control subjects, the women with UCTD had higher rates of small for gestational age (SGA; 12/40 vs 11/80; P = .05). The rate of complications of pregnancy (preterm delivery at

Multimod Data Manager: a tool for data fusion.

Nowadays biomedical engineers regularly have to combine data from multiple medical imaging modalities, biomedical measurements and computer simulations and this can demand the knowledge of many specialised software tools. Acquiring this knowledge to the depth necessary to perform the various tasks can require considerable time and thus divert the researcher from addressing the actual biomedical problems. The aim of the present study is to describe a new application called the Multimod Data Manager, distributed as a freeware, which provides the end user with a fully integrated environment for the fusion and manipulation of all biomedical data. The Multimod Data Manager is generated using a software application framework, called the Multimod Application Framework, which is specifically designed to support the rapid development of computer aided medicine applications. To understand the general logic of the Data Manager, we first introduce the framework from which it is derived. We then illustrate its use by an example--the development of a complete subject-specific musculo-skeletal model of the lower limb from the Visible Human medical imaging data to be used for predicting the stresses in the skeleton during gait. While the Data Manager is clearly still only at the prototype stage, we believe that it is already capable of being used to solve a large number of problems common to many biomedical engineering activities.

Prognostic value of umbilical artery Doppler studies in unselected preterm deliveries.

OBJECTIVE: To evaluate the prognostic value of umbilical artery Doppler studies in premature deliveries. METHODS: In this cohort study of 582 singleton pregnancies delivered between 24 and 35 weeks of gestation, we evaluated the ratio of peak-systolic to end-diastolic (S/D) blood flow velocities in the umbilical artery of all the patients. The correlations among the results of the Doppler studies, short-term neonatal complications, and the infants' neurodevelopmental outcome at 2 years were studied by univariable and multivariable methods. RESULTS: The prevalences of either neonatal death or cerebral palsy among the 266 (45.7%) growth restricted fetuses were 3.4% (3/88) in pregnancies with a S/D ratio below the 95th percentile, 4.9% (5/103) in pregnancies with a S/D at or above the 95th percentile, and 17.3% (13/75) in those with absent or reversed end-diastolic blood flow in the umbilical artery (P for trend = .001). The corresponding figures in the 316 pregnancies with adequate fetal growth were 6.4% (15/234) and 4.3% (3/69) among pregnancies with a S/D ratio below and at or above 95th percentile, respectively, whereas no cases of either neonatal death or cerebral palsy were recorded in the 13 pregnancies with adequate fetal growth and absent or reversed end-diastolic blood flow velocity (P for trend = .28; chi(2) for heterogeneity of linear trends compared with growth-restricted infants = 7.02, P = .008). In logistic regression, in pregnancies complicated by fetal growth restriction, absent or reversed end-diastolic blood flow in the umbilical artery was still associated with an increased risk of either neonatal death or cerebral palsy even after adjustment for gestational age and proportion of expected birth weight, (odds ratio 3.2, 95% confidence interval 1.18-8.66, P = .02). CONCLUSION: Absent or reversed end-diastolic flow in the umbilical artery is an independent predictor of either neonatal death or cerebral palsy in preterm growth-restricted fetuses. In the absence of fetal growth restriction, umbilical artery Doppler study was associated with none of the infant outcome parameters studied.

Mechanisms underlying the impaired regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in aged rat liver.

As the main risk factor for cardiovascular disease, hypercholesterolemia is one of the most studied age-related metabolic alterations. In the liver, cholesterol homeostasis is strictly regulated through the modulation of the 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the key enzyme of cholesterol biosynthesis. With ageing, hepatic HMG-CoA reductase becomes completely activated and cholesterol content increases in the blood. The research reported in this paper uses the regulatory enzymes of reductase (i.e., the AMP-dependent kinase (AMPK) and the protein phosphatase 2A (PP2A)), the HMG-CoA reductase thermodependent activity and the "in vitro" enzyme degradation to elucidate the role played by the HMG-CoA reductase regulation and its membrane interaction. Related experiments were performed on 3 and 24 months "ad libitum" (AL) fed rats and 24 months caloric-restricted rats. The results show no changes in the PP2A level and the activation state of AMP dependent kinase in aged "ad libitum" fed rats. By contrast, the activation state of the kinase is enhanced in the aged caloric-restricted animals. With respect to the adult, the thermodependent activity of reductase remains unchanged, while the degradation rate of the HMG-CoA reductase is slower and independent on proteasome. These findings support the hypothesis that a different arrangement of the HMG-CoA reductase membrane domain in aged rats is a cause of reductase deregulation.

Fetal growth and infant neurodevelopmental outcome after preterm premature rupture of membranes.

OBJECTIVE: To evaluate the prognostic values of fetal size before birth and fetal growth during the latency period in patients with preterm premature rupture of the membranes (PROM). METHODS: A prospective cohort study of 69 singleton pregnancies complicated by prolonged (14 days or more) PROM (24 to 31 weeks of gestation). Measures of fetal size and growth were compared with corresponding expected values from our reference curves. The correlations between deviations from expected measures of fetal size and growth, short-term neonatal complications, and infant neurodevelopmental outcome at 2 years were studied by univariate methods and logistic regression. RESULTS: The mean gestational ages and standard deviations at membrane rupture and at birth were 27.9 +/- 2.4 and 31.5 +/- 2.1 weeks. At a corrected age of 2 years, of the 65 (94.2%) survivors, 3 infants (4.6%) had cerebral palsy, 13 (20%) had minor neurodevelopmental impairment, and 49 (75.4%) were judged to have had normal development. Compared with surviving infants without a major handicap, the group of infants who died and those with cerebral palsy had lower proportions of expected birth weight (0.766 +/- 0.1 as compared with 0.859 +/- 0.13, P =.029), head (0.869 +/- 0.07 as compared with 0.950 +/- 0.07, P =.05), and abdominal (0.793 +/- 0.04 as compared with 0.888 +/- 0.1, P =.001) circumference growth during latency period. In logistic regression analysis, lower-than-expected ultrasound measures of fetal abdominal circumference before birth (odds ratio 1.09; 95% confidence interval 1.01, 1.18) or of abdominal circumference growth during the latency period (odds ratio 1.1; 95% confidence interval 1.01, 1.2) were significantly associated with an increased likelihood of an infant neurodevelopmental abnormality at 2-year follow-up. CONCLUSION: In pregnancies complicated by preterm PROM, lower-than-expected measures of fetal size and fetal growth were associated with an increased rate of infant neurodevelopmental outcome at 2-year follow-up. LEVEL OF EVIDENCE: II-2

Psychological correlates of decision-making during prenatal diagnosis: a prospective study.

OBJECTIVE: Decision-making during prenatal diagnosis has not been extensively studied. We aimed to determine psychological correlates and level of decisional conflict following prenatal diagnosis. METHOD: A total of 159 pregnant women were consecutively enrolled. All participants completed three questionnaires (the Hospital Anxiety and Depression scale, the Berlin Social Support scales and the Decisional Conflict scale) at three time points (T1 - waiting period between prenatal testing and disclosure of the results; T2 - decision phase within 3 days from test result disclosure; T3 - digestion period within 3 weeks from disclosure). RESULTS: Women with fetal anomaly who terminate pregnancy were significantly more anxious and depressed than controls at each time point. Additionally, women with a normal fetus who terminate pregnancy presented higher level of anxiety and depression compared with controls at T2. Women who terminated pregnancy showed increased uncertainty scores at T2 and T3. Anxious and depressed individuals at T2 (decision period) were more uncertain about their choice at T3 compared to women with normal levels of anxiety and depression. CONCLUSION: The decision to terminate pregnancy, irrespective of test results, may determine emotional distress and psychiatric morbidity. Women who were anxious and depressed at decision appeared to be more uncertain about their choices as time passed by. A careful assessment of women during prenatal diagnosis should be useful to identify women who may benefit from psychological support.

Implementing non-invasive RHD genotyping on cell-free foetal DNA from maternal plasma: the Pavia experience.

BACKGROUND: The occurrence of cell-free foetal DNA in maternal circulation opens new possibilities in non-invasive antenatal diagnosis. Real-time polymerase chain reaction (PCR) analysis is an useful approach to foetal RhD blood group determination, thus being important in the prevention of haemolytic disease of foetus and new-born (HDFN). STUDY DESIGN AND METHODS: Using real-time PCR assays we typed 20 samples of plasma, provided in a blinded fashion, from the International Reference Laboratory, two plasma samples sent by the "2010 Workshop on Molecular Blood Group Genotyping"; seven samples from D-negative mothers at the 16th week of gestation provided by our Hospital as prospective validation cases, and two plasma samples received from the "1(st) Collaborative study establishing the sensitivity standard for non-invasive prenatal determination of foetal RHD genotype". To confirm the RHD typing of the seven prospective samples, PCR with sequence specific primers (PCR-SSP) was applied on genomic DNA from amniocytes (5 cases) and paternal peripheral blood (2 cases). RESULTS: The results for the 31 investigated samples showed 100% concordance. Our measurable benefits were: confidence with a new technology, awareness of having gained the European standard level and increased self-assurance regarding the introduction of this typing technique in prenatal diagnostics. DISCUSSION: These results demonstrate the feasibility and accuracy of our validation protocol. RHD typing on cell-free foetal DNA is a procedure which requires particular care and a great degree of expertise for diagnostic use. International collaborations are essential for monitoring the performance of laboratories in the absence of specific quality control programmes.

Role of prenatal diagnosis and counseling in the management of 735 pregnancies complicated by primary human cytomegalovirus infection: a 20-year experience.

BACKGROUND: The burden of congenital human cytomegalovirus (HCMV) infection is well recognized. However, screening for maternal infection remains controversial in view of diagnostic challenges, counseling difficulties, and absence of medical treatment. OBJECTIVE: To assess the role of prenatal diagnosis and counseling in the management of pregnancy complicated by primary HCMV infection. STUDY DESIGN: Retrospective study aimed at investigating diagnostic features, options, and pregnancy outcome in 735 women with primary HCMV infection over a period of 20 years (1990-2009). RESULTS: Overall, 25.6% women were found to be seronegative before the actual pregnancy. However, none were informed about HCMV infection and potential prevention strategies. Diagnosis of primary HCMV infection was achieved by seroconversion in 44.4% cases and by different combinations of virus-specific IgM, low IgG avidity, and DNAemia in 43.9% cases. Non-specific symptoms and/or haematological/biochemical alterations were recalled by 73.5% women. The onset of infection could be established, and counseling adjusted accordingly in >90% cases. The overall rate of vertical transmission was 37.1%, ranging from 5.6% for preconceptional infections to 64.1% for third trimester infections. Amniocentesis was chosen by 43.1% women, whereas pregnancy termination was requested by 15.6%. CONCLUSIONS: Reference virology centers and ad hoc trained and experienced physicians are required for accurate diagnosis of primary infection in pregnancy and ensuing counseling. Prenatal diagnosis has a central role in the management of pregnancies complicated by primary HCMV infection. HCMV-seronegative women should receive adequate information.

The use of non-physiological conditions to isolate fetal cells from maternal blood.

Fetal cells are always present in maternal blood starting in the first trimester of pregnancy, however a rapid, simple, and consistent procedure for their isolation for prenatal non-invasive genetic investigation is still lacking. Sensitivity and recovery of fetal cells is jeopardized by the minute amount of circulating fetal cells and their loss during the enrichment procedure. We report here a single-step approach to isolate fetal cells from maternal blood which relies on the use of non-physiological conditions to modify cell densities before their separation in a density gradient and in a newly developed cell separation device. Isolated fetal cells have been investigated using cytochemistry, Soret band absorption microscopy, monoclonal antibodies for epsilon- and gamma-chain-Hb, monoclonal antibody for i-antigen, and by fluorescence in situ hybridization (FISH). Fetal cells were always detected in all 105 maternal blood samples investigated and fetal aneuploidies were correctly diagnosed by FISH, in a pilot study of pathological pregnancies, in fetal cells isolated from maternal blood obtained either before or after invasive procedure.

Interaction between risk factors for fetal growth retardation associated with abnormal umbilical artery Doppler studies.

BACKGROUND: The role of antenatal risk factors associated with the occurrence of fetal growth restriction complicated by abnormal umbilical artery Doppler studies has not yet been studied extensively. We evaluated the role and the interactions of antenatal antecedents of fetal growth restriction complicated by abnormal umbilical artery end-diastolic velocities. METHODS: We compared antenatal variables in 183 pregnancies complicated by fetal growth retardation and abnormal umbilical artery Doppler studies and 549 appropriately grown fetuses with normal end-diastolic velocity waveform in the umbilical artery. Logistic regression was used to evaluate the association between antenatal variables and fetal growth retardation and to test for interaction. RESULTS: In logistic models, increasing maternal age [odds ratio (OR) 1.06, 95% confidence interval (CI) 1.01-1.11], nulliparity (OR 2.2, 95% CI 1.37-3.5), smoking during pregnancy (OR 2.56, 95% CI 1.56-4.22), preeclampsia (OR 27.5, 95% CI 15.1-49.9), first-trimester hemorrhage (OR 2.25, 95% CI 1.32-3.82) and low (< 0.2 kg/week) weight gain in pregnancy (OR 3.48, 95% CI 1.71-3.05) were significantly associated with an increased risk of fetal growth restriction complicated by abnormal Doppler studies. These risk factors were also significantly correlated with the occurrence of absent/reversed end-diastolic blood flow in the umbilical artery. Maternal smoking during pregnancy interacted negatively with preeclampsia but positively with a low weight gain in pregnancy. CONCLUSIONS: The results of this study have shown that antenatal risk factors for intrauterine growth retardation (IUGR) complicated by abnormal Doppler studies are similar to those associated with the birth of a small-for-gestational-age infant. Preeclampsia, maternal smoking and low weight gain in pregnancy play a significant causal role in the origin of fetal growth restriction associated with abnormal uteroplacental blood flow.