Late-onset Subgroup Research Articles

Serum lncRNAs TUG1, H19, and NEAT1 and their target miR-29b/SLC3A1 axis as possible biomarkers of preeclampsia: Potential clinical insights

To date, the epigenetic signature of preeclampsia (PE) is not completely deciphered. Oxidative stress-responsive long non-coding RNAs (lncRNAs) are deregulated in preeclamptic placenta; however, their circulating profiles and diagnostic abilities are still unexplored. We investigated serum redox-sensitive lncRNAs TUG1, H19, and NEAT1, and their target miR-29b/cystine/neutral/dibasic amino acids transporter solute carrier family 3, member 1 (SLC3A1) as potential non-invasive biomarkers of PE risk, onset, and severity. We recruited 82 patients with PE and 78 healthy pregnant women. We classified PE patients into early-onset (EOPE) and late-onset (LOPE) subgroups at a cut-off 34 gestational weeks and into severe and mild PE subgroups by blood pressure and proteinuria criteria. Bioinformatics analysis was employed to select lncRNAs/microRNA/target gene interactions. Serum H19, NEAT1, and SLC3A1 mRNA expression were reduced, meanwhile miR-29b levels were elevated, whereas there was no significant difference in TUG1 levels between PE patients and healthy pregnancies. Serum H19 levels were lower, whereas miR-29b levels were higher in EOPE versus LOPE. Serum miR-29b and H19 levels were higher in severe versus mild PE. ROC analysis identified serum H19, NEAT1, miR-29b, and SLC3A1 as potential diagnostic markers, with H19 (AUC = 0.818, 95%CI = 0.744–0.894) and miR-29b (AUC = 0.82, 95%CI = 0.755–0.885) were superior discriminators. Only H19 and miR-29b discriminated EOPE and severe PE cases. In multivariate logistic analysis, miR-29b and H19 were associated with EOPE, using maternal age and gestational age as covariates, while miR-29b was associated with severe PE, using maternal age as covariate. Studied markers were correlated with clinical and ultrasound data in the overall PE group. Serum H19 and TUG1 were negatively correlated with albuminuria in EOPE and LOPE, respectively. NEAT1 and SLC3A1 were correlated with ultrasound data in EOPE. Likewise, TUG1, miR-29b, and SLC3A1 showed significant correlations with ultrasound data in LOPE. Conclusively, this study configures SLC3A1 expression as a novel potential serum biomarker of PE and advocates serum H19 and miR-29b as biomarkers of EOPE and miR-29b as a biomarker of PE severity.

Blood pressure, arterial stiffness, and cardiovascular risk profiles in 8-12-year-old children following preeclampsia (FINNCARE-study).

The aim was to study if children following preeclampsia (PE) develop alterations in blood pressure (BP) and arterial stiffness already early in life, and how this is associated with gestational, perinatal and child cardiovascular risk profiles. One hundred eighty-two PE (46 early-onset with diagnosis before 34 gestational weeks, and 136 late-onset) and 85 non-PE children were assessed 8-12 years from delivery. Office and 24-h ambulatory BP, body composition, anthropometrics, lipids, glucose, inflammatory markers, and tonometry-derived pulse wave velocity (PWV) and central BPs were assessed. Office BP, central BPs, 24-h systolic BP (SBP) and pulse pressure (PP) were higher in PE compared with non-PE. Early-onset PE children had the highest SBP, SBP-loads, and PP. SBP nondipping during night-time was common among PE. The higher child 24-h mean SBP among PE was explained by maternal SBP at first antenatal visit and prematurity (birth weight or gestational weeks), but child 24-h mean PP remained related with PE and child adiposity after adjustments. Central and peripheral PWVs were elevated in late-onset PE subgroup only and attributed to child age and anthropometrics, child and maternal office SBP at follow-up, but relations with maternal antenatal SBPs and prematurity were not found. There were no differences in body anthropometrics, composition, or blood parameters. PE children develop an adverse BP profile and arterial stiffness early in life. PE-related BP is related with maternal gestational BP and prematurity, whereas arterial stiffness is determined by child characteristics at follow-up. The alterations in BP are pronounced in early-onset PE.Clinical Trial Registration information: https://clinicaltrials.gov/ct2/show/NCT04676295ClinicalTrials.gov Identifier: NCT04676295.

A biomarker-validated time scale in years of disease progression has identified early- and late-onset subgroups in sporadic Alzheimer’s disease

BackgroundIt is possible to calculate the number of years to the expected clinical onset (YECO) of autosomal-dominant Alzheimer’s disease (adAD). A similar time scale is lacking for sporadic Alzheimer’s disease (sAD). The purpose was to design and validate a time scale in YECO for patients with sAD in relation to CSF and PET biomarkers.MethodsPatients diagnosed with Alzheimer’s disease (AD, n = 48) or mild cognitive impairment (MCI, n = 46) participated in the study. They underwent a standardized clinical examination at the Memory clinic, Karolinska University Hospital, Stockholm, Sweden, which included present and previous medical history, laboratory screening, cognitive assessment, CSF biomarkers (Aβ42, total-tau, and p-tau), and an MRI of the brain. They were also assessed with two PET tracers, 11C-Pittsburgh compound B and 18F-fluorodeoxyglucose. Assuming concordance of cognitive decline in sAD and adAD, YECO for these patients was calculated using equations for the relationship between cognitive performance, YECO, and years of education in adAD (Almkvist et al. J Int Neuropsychol Soc 23:195-203, 2017).ResultsThe mean current point of disease progression was 3.2 years after the estimated clinical onset in patients with sAD and 3.4 years prior to the estimated clinical onset in patients with MCI, as indicated by the median YECO from five cognitive tests. The associations between YECO and biomarkers were significant, while those between chronological age and biomarkers were nonsignificant. The estimated disease onset (chronological age minus YECO) followed a bimodal distribution with frequency maxima before (early-onset) and after (late-onset) 65 years of age. The early- and late-onset subgroups differed significantly in biomarkers and cognition, but after control for YECO, this difference disappeared for all except the APOE e4 gene (more frequent in early- than in late-onset).ConclusionsA novel time scale in years of disease progression based on cognition was designed and validated in patients with AD using CSF and PET biomarkers. Two early- and late-disease onset subgroups were identified differing with respect to APOE e4.

Utility of sFtl-1 and Placental Growth Factor Ratio for Adequate Preeclampsia Management.

Introduction: The pathophysiology of preeclampsia is represented by placental ischemia and the release of angiogenic factors. Recent research suggests that using the value of the sFtl-1/PIGF ratio is more accurate for monitoring angiogenic activity. The aim of this study consists in assessing the clinical utility of the sFtl-1/PIGF ratio in determining the diagnosis and severity of preeclampsia. Material and Methods: In our study a descriptive and prospective plan was used for analyzing the specific value of the sFtl-1/PIGF ratio in women with preeclampsia and in women with gestational hypertension, depending on the gestational age and severity. Results: The study included 59 women with preeclampsia and 25 women with gestational hypertension. The mean value of the sFtl-1/PIGF ratio of pregnant women with preeclampsia was 209.2 pg/mL, while in the gestational hypertension group, the mean value of the sFtl-1/PIGF ratio was 46.08 pg/mL. The difference between the value of the sFtl-1/PIGF ratio of the group with preeclampsia and the gestational hypertension group was > 67 (pg/mL), with a sensitivity of 86.44% and a specificity of 92.00%. Significant differences were found between the median values of the sFtl-1/PIGF ratio in pregnant women with severe preeclampsia in the early-onset subgroup compared to those in the late-onset subgroup (307 pg/mL, and 98 pg/mL, respectively, p = 0.009 < α = 0.05). Conclusions: The sFtl-1/PIGF ratio may be an alternative method for diagnosing preeclampsia and it can provide data about this condition's severity.

The spectrum of epilepsy with eyelid myoclonia: delineation of disease subtypes from a large multicenter study.

Epilepsy with eyelid myoclonia (EEM) has been associated with marked clinical heterogeneity. Early epilepsy onset has been recently linked to lower chances of achieving sustained remission and to a less favorable neuropsychiatric outcome. However, much work is still needed to better delineate this epilepsy syndrome. In this multicenter retrospective cohort study, we included 267 EEM patients from 9 countries. Data about electroclinical and demographic features, intellectual functioning, migraine with or without aura, family history of epilepsy and epilepsy syndromes in relatives were collected in each patient. The impact of age at epilepsy onset (AEO) on EEM clinical features was investigated, along with the distinctive clinical characteristics of patients showing sporadic myoclonia over body regions other than eyelids (body-MYO). Kernel density estimation revealed a trimodal distribution of AEO and Fisher-Jenks optimization disclosed three EEM subgroups: early-onset (EO-EEM), intermediate-onset (IO-EEM) and late-onset subgroup (LO-EEM). EO-EEM was associated with the highest rate of intellectual disability, antiseizure medication refractoriness and psychiatric comorbidities and with the lowest rate of family history of epilepsy. LO-EEM was associated with the highest proportion of body-MYO and generalized tonic-clonic seizures (GTCS), whereas IO-EEM had the lowest observed rate of additional findings. A family history of EEM was significantly more frequent in IO-EEM and LO-EEM compared with EO-EEM. In the subset of patients with body-MYO (58/267), we observed a significantly higher rate of migraine and GTCS but no relevant differences in other electroclinical features and seizure outcome. Based on AEO, we identified consistent EEM subtypes characterized by distinct electroclinical and familial features. Our observations shed new light on the spectrum of clinical features of this generalized epilepsy syndrome and may help clinicians towards a more accurate classification and prognostic profiling of EEM patients.

Immunohistochemical evaluation of glucose transporter protein-1 density in the placenta in preeclampsia patients and its association with intrauterine growth retardation

Background/Aim: Preeclampsia (PE) complicates 2–8% of all pregnancies worldwide. Placental malperfusion and dysfunction are observed in PE. The supply of glucose, the main energy substrate for the fetus and placenta, is regulated by placental expression and activity of specific glucose transporter proteins (GLUTs), primarily GLUT1. GLUT1 expression is affected by uteroplacental malperfusion and oxidative stress, which are important components of PE. Very few studies have investigated GLUT1 expression in preeclamptic placentas. In this study, we aimed to compare GLUT1 staining intensity in the terminal villi of the placenta in healthy subjects and patients with E-PE or L-PE and determine whether there was a relationship between GLUT1 staining intensity and IUGR. Methods: This case-control study was carried out in our hospital’s gynecology and obstetrics clinic, a tertiary center for perinatology cases. A total of 94 placentas, 47 of which were preeclamptic and 47 were from uneventful pregnancies (controls), were included in the study. PE was diagnosed according to the American College of Obstetrics and Gynecologists 2019 diagnostic criteria for gestational hypertension and PE. Placentas in the control group were obtained from pregnancies without maternal, placental, or fetal pathology and resulted in spontaneous idiopathic preterm or term delivery. The PE group was divided into two subgroups as early onset PE (E-PE [≤33+6 gestational week]) and late-onset PE (L-PE [≥34+0 gestational week]), according to the gestational week of PE onset. Sections prepared from placental tissues were stained for GLUT-1 by immunohistochemical method. Slides were evaluated by light microscopy, and each slide was scored from 0 to 4 to determine the staining intensity. The results were compared between the control and PE group/PE sub-groups. Results: GLUT1 scores were significantly higher in both early- and late-onset PE subgroups compared to controls (P &lt; 0.001 for both). In the late-onset PE subgroup, GLUT1 scores were significantly higher in those with severe PE features than those without them (P = 0.039). While intrauterine growth restriction (IUGR) was not found in any cases in the control group, IUGR was present in 11 (23.4%) of 47 pregnant women with PE, including eight (53.3%) of the 15 pregnant women with early-onset PE and 3 (9.38%) of the 32 pregnant women with late-onset PE. GLUT1 scores were similar in placentas obtained from pregnant women who had PE with and without IUGR (P = 0.756). In the late-onset PE subgroup, GLUT1 scores were correlated negatively with maternal body mass index (r = -0.377, P = 0.033) and positively with placental weight-to-fetal weight ratio (r = 0.444, P = 0.011). Conclusions: Our findings show that GLUT1 expression might be increased due to placental adaptation to new conditions in PE and, thus, is unlikely to be the main factor in PE-related IUGR.

Mutation spectrum in a cohort with familial exudative vitreoretinopathy

PurposeTo expand the mutation spectrum of patients with familial exudative vitreoretinopathy (FEVR) disease.Participants74 probands (53 families and 21 sporadic probands) with familial exudative vitreoretinopathy (FEVR) disease and their available family members (n = 188) were recruited for sequencing.MethodsPanel‐based targeted screening was performed on all subjects. Before sanger sequencing, variants of LRP5, NDP, FZD4, TSPAN12, ZNF408, KIF11, RCBTB1, JAG1, and CTNNA1 genes were verified by a series of bioinformatics tools and genotype–phenotype co‐segregation analysis.Results40.54% (30/74) of the probands were sighted to possess at least one etiological mutation of the nine FEVR‐causative genes. The etiological mutation detection rate was 37.74% (20/53) in family‐attainable probands while 47.62% (10/21) in sporadic cases. The diagnosis rate of patients in the early‐onset subgroup (≤5 years old, 45.4%) is higher than that of the children or adolescence‐onset subgroup (6–16 years old, 42.1%) and the late‐onset subgroup (≥17 years old, 39.4%). A total of 36 etiological mutations were identified in this study, comprising 26 novel mutations and 10 reported mutations. LRP5 was the most prevalent mutant gene among the 36 mutation types with a percentage of 41.67% (15/36). Followed by FZD4 (10/36, 27.78%), TSPAN12 (5/36, 13.89%), NDP (4/36, 11.11%), KIF11 (1/36, 2.78%), and RCBTB1 (1/36, 2.78%). Among these mutations, 63.89% (23/36) were missense mutations, 25.00% (9/36) were frameshift mutations, 5.56% (2/36) were splicing mutations, 5.56% (2/36) were nonsense mutations. Moreover, the clinical pathogenicity of these variants was defined according to American College of Medical Genetics (ACMG) and genomics guidelines: 41.67% (15/36) were likely pathogenic variants, 27.78% (10/36) pathogenic variants, 30.55% (11/36) variants of uncertain significance. No etiological mutations discovered in the ZNF408, JAG1, and CTNNA1 genes in this FEVR cohort.ConclusionsWe systematically screened nine FEVR disease‐associated genes in a cohort of 74 Chinese probands with FEVR disease. With a detection rate of 40.54%, 36 etiological mutations of six genes were authenticated in 30 probands, including 26 novel mutations and 10 reported mutations. The most prevalent mutated gene is LRP5, followed by FZD4, TSPAN12, NDP, KIF11, and RCBTB1. In total, a de novo mutation was confirmed. Our study significantly clarified the mutation spectrum of variants bounded up to FEVR disease.

Clinical Manifestations of Early-Onset Dementia With Lewy Bodies Compared With Late-Onset Dementia With Lewy Bodies and Early-Onset Alzheimer Disease

Early-onset dementia, presenting in individuals younger than 65 years, is a diagnosis with significant social and financial implications. The early-onset form of dementia with Lewy bodies (DLB) is poorly understood. To investigate clinical features that distinguish early-onset DLB (onset and diagnosis at age <65 years) from late-onset DLB (onset at age ≥65 years) and from early-onset Alzheimer disease (AD) dementia. This is a retrospective case-control study on patients with pathologically confirmed DLB or AD enrolled in the National Alzheimer's Coordinating Center database from January 2005 to July 2017. The National Alzheimer's Coordinating Center Uniform Data Set comprised deidentified data collected by Alzheimer disease centers in the United States. Of patients fulfilling criteria for all-cause dementia at enrollment (n = 1152), those who at post mortem received a pathological diagnosis of either AD (n = 848) or Lewy body disease (n = 218) were selected. Excluding 52 patients owing to missing data and 12 diagnosed with Parkinson disease dementia, remaining patients were classified by age of symptom onset into early-onset AD, early-onset DLB, and late-onset DLB subgroups. Data were analyzed from June to December 2018 and from November to December 2021. Demographics, cognitive, behavioral, and motor features recorded at first clinic visit and neuropathological characteristics at autopsy were analyzed by disease subgroup. Concordance between initial etiologic diagnosis of dementia and final pathological diagnosis was assessed, as was time to death. A total of 542 individuals were categorized as having early-onset AD (n = 363; mean [SD] age, 53.0 [5.8] years; 208 [57.3%] male), early-onset DLB (n = 32; mean [SD] age, 57.9 [3.2] years; 23 [71.9%] male), and late-onset DLB (n = 147; mean [SD] age, 73.5 [5.5] years; 103 [70.1%] male). Early-onset DLB was clinically misdiagnosed in 16 individuals (50%). Features that predicted a diagnosis of early-onset DLB over early-onset AD included visual hallucinations (15 [46.9%] vs 42 [11.6%]), slowness (23 [71.9%] vs 95 [26.2%]), apathy (23 [71.9%] vs 189 [52.1%]), and motor deterioration that preceded cognitive and behavioral symptoms (7 [21.9%] vs 6 [1.7%]). Late-onset DLB had more amnestic features, but this was accounted for by a higher proportion of neocortical neuritic plaques and diffuse plaques (frequent in 79 [53.7%] vs 8 [25%]) than seen in early-onset DLB. This study found that early-onset DLB has clinical features that distinguish it from early-onset AD, whereas features of late-onset DLB are associated with a higher burden of AD copathology.

Clinical Features of Myasthenia Gravis With Antibodies to MuSK Based on Age at Onset: A Multicenter Retrospective Study in China.

IntroductionAntibodies to MuSK identify a rare subtype of myasthenia gravis (MuSK-MG). In western countries, the onset age of MuSK-MG peaks in the late 30's while it is unknown in Chinese population.MethodsIn this retrospective multicenter study, we screened 69 MuSK-MG patients from 2042 MG patients in five tertiary referral centers in China from October 2016 to October 2021 and summarized the clinical features and treatment outcomes. Then we subgrouped the patients into early-onset (<50 years old), late-onset (50–64 years old), and very-late-onset (≥65 years old) MG and compared the differences in weakness distribution, disease progression and treatment outcomes among three subgroups.ResultsThe patients with MuSK-MG were female-dominant (55/69) and their mean age at onset was 44.70 ± 15.84 years old, with a broad range of 17–81 years old. At disease onset, 29/69 patients were classified as MGFA Type IIb and the frequency of bulbar and extraocular involvement was 53.6 and 69.6%, respectively. There was no difference in weakness distribution. Compared with early-onset MuSK-MG, very-late-onset patients had a higher proportion of limb muscle involvement (12/15 vs.16/40, p = 0.022) 3 months after onset. Six months after onset, more patients with bulbar (14/15 vs. 26/39, p = 0.044) and respiratory involvement (6/15 vs. 0/13, p = 0.013) were seen in very-late-onset than in late-onset subgroup. The very-late-onset subgroup had the highest frequency of limb weakness (86.7%, p < 0.001). One year after onset, very-late-onset patients demonstrated a higher frequency of respiratory involvement than early-onset patients (4/12 vs. 2/35, p = 0.036). 39/64 patients reached MSE. Among 46 patients who received rituximab, very-late-onset patients started earlier than late-onset patients [6 (5.5–7.5) vs. 18 (12–65) months, p = 0.039], but no difference in the time and rate to achieving MSE was identified.ConclusionMuSK-MG patients usually manifested as acute onset and predominant bulbar and respiratory involvement with female dominance. Very-late-onset patients displayed an early involvement of limb, bulbar and respiratory muscles in the disease course, which might prompt their earlier use of rituximab. The majority MuSK-MG patients can benefit from rituximab treatment regardless of age at onset.

Rare and common variants in ROM1 and PRPH2 genes trans-modify Stargardt/ABCA4 disease.

Over 1,500 variants in the ABCA4 locus cause phenotypes ranging from severe, early-onset retinal degeneration to very late-onset maculopathies. The resulting ABCA4/Stargardt disease is the most prevalent Mendelian eye disorder, although its underlying clinical heterogeneity, including penetrance of many alleles, are not well-understood. We hypothesized that a share of this complexity is explained by trans-modifiers, i.e., variants in unlinked loci, which are currently unknown. We sought to identify these by performing exome sequencing in a large cohort for a rare disease of 622 cases and compared variation in seven genes known to clinically phenocopy ABCA4 disease to cohorts of ethnically matched controls. We identified a significant enrichment of variants in 2 out of the 7 genes. Moderately rare, likely functional, variants, at the minor allele frequency (MAF) <0.005 and CADD>25, were enriched in ROM1, where 1.3% of 622 patients harbored a ROM1 variant compared to 0.3% of 10,865 controls (p = 2.41E04; OR 3.81 95% CI [1.77; 8.22]). More importantly, analysis of common variants (MAF>0.1) identified a frequent haplotype in PRPH2, tagged by the p.Asp338 variant with MAF = 0.21 in the matched general population that was significantly increased in the patient cohort, MAF 0.25, p = 0.0014. Significant differences were also observed between ABCA4 disease subgroups. In the late-onset subgroup, defined by the hypomorphic p.Asn1868Ile variant and including c.4253+43G>A, the allele frequency for the PRPH2 p.Asp338 variant was 0.15 vs 0.27 in the remaining cohort, p = 0.00057. Known functional data allowed suggesting a mechanism by which the PRPH2 haplotype influences the ABCA4 disease penetrance. These associations were replicated in an independent cohort of 408 patients. The association was highly statistically significant in the combined cohorts of 1,030 cases, p = 4.00E-05 for all patients and p = 0.00014 for the hypomorph subgroup, suggesting a substantial trans-modifying role in ABCA4 disease for both rare and common variants in two unlinked loci.

Studying the relationship between clinical features and mental health among late-onset myasthenia gravis patients.

BACKGROUNDMental disorders are common comorbidities among individuals with neurological diseases, and the prevalence of depressive and anxiety-related symptoms in newly referred patients at neurology outpatient clinics is high. There have been few studies on the mental health of patients with late-onset myasthenia gravis (MG).AIMTo examine the relationship between clinical features and the mental health symptoms within late-onset MG patients.METHODSA total of 105 patients diagnosed with MG were recruited consecutively from a neuromuscular outpatient clinic between December 2020 and February 2021. Patients were classified into two groups: early-onset MG (age at onset < 50 years, n = 63) and late-onset MG (age at onset ≥ 50 years, n = 42). Social demographic data and information about marital status, education level, clinical symptoms, serum antibody levels, and therapies used were collected for all participants. Participants were also evaluated using the Myasthenia Gravis Composite scale, the Myasthenia Gravis Activities of Daily Living scale, the Myasthenia Gravis Quality of Life 15 (MG-QOL-15) questionnaire, the 17-item version of the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). The relationship between clinical features and mental health in late-onset MG patients was examined using multivariate logistic regression analyses. RESULTSLate-onset MG patients were more prone to dyspnea, had higher levels of serum anti-acetylcholine receptor antibodies, and higher total scores on the MG-QOL-15, HAM-D, and HAM-A questionnaires, than early-onset MG patients had (P < 0.05). Among those with late-onset MG, female patients had higher total HAM-D and HAM-A scores than male patients had (P < 0.05). High scores on the QOL-15 questionnaire were associated with higher incidences of anxiety and depression, and the association was found to be independent after adjusting for confounding risk factors. In the late-onset subgroup, the areas under the receiver operating characteristic curves for the MG-QOL-15 score-based diagnostic accuracy for anxiety and depression state were 0.816 (P = 0.001) and 0.983 (P < 0.001), respectively.CONCLUSIONHigher MG-QOL-15 scores were a risk factor for anxiety and depression in late-onset MG, and women with late-onset MG were more likely to have anxiety and depression than men were.

Augmentation index and pulse wave velocity in normotensive versus preeclamptic pregnancies: a prospective case–control study using a new oscillometric method

Objectives The objective of this study was to investigate whether oscillometric AS measurements are different in pregnant women with and without preeclampsia (PE). Study design This was a prospective case–control study in singleton pregnancies that had been diagnosed with PE (n = 46) versus normotensive controls (n = 46) between 2014 and 2019. In the case group, pregnancies complicated by PE were classified as either early-onset (<34 weeks of gestation) or late-onset (≥34 weeks of gestation) PE and subgroup analysis was performed. Main outcome measures Pulse wave velocity (PWV), augmentation index (Alx), and Alx at a heart rate of 75 beats per minute (Alx-75) were measured using a brachial cuff-based automatic oscillometric device (Mobil-O-Graph 24 h PWA). Results In pregnancies complicated by PE, in comparison with normotensive pregnancies, there were significant differences in PWV (p ˂ .001), and Alx-75 (p ˂ .001). In pregnancies complicated by early-onset PE, in comparison with pregnancies complicated by late-onset PE, there were significant differences in PWV (p = .006), and Alx-75 (p = .009). There was no significant difference in Alx in either of the analyses. Conclusions PWV and Alx-75 are higher in pregnancies complicated by PE, in comparison with normotensive pregnancies, as well as in early-onset PE, in comparison with late-onset PE. Key messages Pulse wave velocity is higher in pregnancies complicated by preeclampsia. Augmentation index at a heart rate of 75 beats per minute is higher in pregnancies complicated by preeclampsia. Arterial stiffness assessment is a promising risk-stratification tool for future cardiovascular complications but further studies are required.

Adults Receiving Defibrotide for the Treatment of Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Stem Cell Transplantation (HSCT): Final Results from the Expanded-Access Program

BackgroundVOD/SOS is an unpredictable, potentially life-threatening complication of conditioning regimens for HSCT or chemotherapy without HSCT. VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. One center with a primarily adult population (median age = 35.8 [range: 4-67] years), reported a Day +100 mortality rate of 79% in patients with unresolved severe VOD/SOS. For adult and pediatric patients, defibrotide is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States (US) and to treat severe hepatic VOD/SOS post-HSCT in the European Union. The European Society for Blood and Marrow Transplantation (EBMT) notes that clinical presentation of VOD/SOS differs between adult and pediatric patients, but most published results describe mixed age populations. Day +100 survival results specific to adults receiving defibrotide 25 mg/kg/day include those of a phase 2 dose-finding trial (33%, n=52) and a compassionate-use study (46.3%, n=141). Here, we report final adult subgroup outcomes data from the defibrotide expanded-access (T-IND) program, the largest prospective evaluation of defibrotide.MethodsThe T-IND was a multicenter, single-arm study designed to provide access to defibrotide prior to US approval. The original protocol required VOD/SOS diagnosis by Baltimore criteria or biopsy post-HSCT, with evidence of MOD (renal/pulmonary dysfunction). The study was amended to include patients without MOD (off-label), with VOD/SOS per modified Seattle criteria, or VOD/SOS following chemotherapy without HSCT (off-label). Defibrotide treatment (25 mg/kg/day) was recommended ≥21 days. Day +100 survival was analyzed for all adults, subgroups with and without MOD, and post hoc with VOD/SOS onset after Day +21 (ie, late-onset, per EBMT proposed criteria for adults). A post hoc exploratory analysis examined the relationship between Day +100 survival and time from VOD/SOS diagnosis to start of defibrotide treatment and included a trend test for treatment initiated on particular days post-diagnosis (Cochran-Armitage trend test).ResultsOf 1000 patients with VOD/SOS post-HSCT who enrolled in the T-IND study through April 2016 and received ≥1 dose of defibrotide, there were 430 adult patients: 231 had MOD and 199 did not. Median age at HSCT was 42.0 years (MOD subgroup, 41.0 years; no MOD subgroup, 43.0 years). Most common primary diseases were acute myelogenous leukemia (34.7%; MOD, 38.1%; no MOD, 30.7%) acute lymphocytic leukemia (22.1%; MOD, 20.8%; no MOD, 23.6%), non-Hodgkin lymphoma (8.4%; MOD, 6.5%; no MOD, 10.6%), and myelodysplastic syndrome (7.0%; MOD, 7.8%; no MOD, 6.0%). Most common graft-vs-host disease prophylaxes were tacrolimus (69.5%; MOD, 70.1%; no MOD, 68.8%), methotrexate (42.6%; MOD, 43.7%; no MOD, 41.2%), sirolimus (17.0%; MOD, 20.3%; no MOD, 13.1%), and cyclosporine (14.9%; MOD, 16.5%; no MOD, 13.1%). Characteristics were generally similar in the 169-patient late-onset subgroup (MOD, n=88; no MOD, n=81).Kaplan-Meier estimated Day +100 survival was similar between all adults post-HSCT (47.1% [39.0% for patients with MOD]) and the late-onset adult subgroup (48.7% [43.0% for patients with MOD]; Figure). Exploratory post hoc analysis in the adult patient subset found that earlier defibrotide initiation post-VOD/SOS diagnosis was associated with higher Day +100 survival; however, the P value was not significant (P=0.055)Of the 430 adult patients, adverse events (AEs) occurred in 77.9%, with treatment-related AEs in 20.5% (Table). Most common (>2%) treatment-related AEs (TRAEs) were gastrointestinal hemorrhage and epistaxis (3.5% each), pulmonary hemorrhage (2.3%), and hematuria and hypotension (2.1% each); most common (>1%) TRAEs leading to discontinuation were gastrointestinal hemorrhage (2.3%) and pulmonary hemorrhage (1.6%). No TRAEs led to death in ≥1%. In general, the safety profile was consistent for patients with late-onset VOD/SOS.ConclusionFinal results from the T-IND present data from the largest adult VOD/SOS population (with or without MOD and with or without late-onset VOD/SOS) treated with defibrotide. The survival rate in adults with VOD/SOS post-HSCT is consistent with prior results for adults receiving defibrotide, and no new safety signals were observed.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresRichardson:Oncopeptides AB: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Antin:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Ryan:Celator/Jazz: Employment, Equity Ownership. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Kernan:Gentium: Other: Received grants from Gentium during the conduct of the study and research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA 008748, Research Funding.

Efficacy and Safety of Defibrotide in Pediatric Patients with Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome (VOD/SOS) after Hematopoietic Stem Cell Transplantation (HSCT): Final Results from the Expanded-Access Program

BackgroundVOD/SOS is an unpredictable, potentially life-threatening complication of conditioning regimens for HSCT or post-chemotherapy without HSCT. VOD/SOS with multi-organ dysfunction (MOD) may be associated with >80% mortality. For pediatric and adult patients, defibrotide is approved to treat hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT in the United States and to treat severe hepatic VOD/SOS post-HSCT in the European Union. The European Society for Blood and Marrow Transplantation notes that clinical presentation, incidence, and survival rates of VOD/SOS may differ between pediatric and adult patients. Kaplan-Meier Day +100 estimated survival results specific to pediatric patients receiving defibrotide 25 mg/kg/day include those of pediatric patients with and without MOD in a compassionate-use study (CUP; 70.2%, n=131). Here, we report outcomes from the largest pediatric cohort of VOD/SOS patients treated with defibrotide.MethodsThe original T-IND protocol required VOD/SOS diagnosis by Baltimore criteria or biopsy post-HSCT, with MOD (renal or pulmonary). The study was amended to include patients without MOD (off-label), with VOD/SOS per modified Seattle criteria, or VOD/SOS post-chemotherapy without HSCT (off-label). Defibrotide (25 mg/kg/d) was recommended ≥21 days. Day +100 survival was analyzed for all pediatric patients, subgroups with and without MOD, and post hoc with VOD/SOS onset after Day +21 (ie, late-onset). A post hoc exploratory analysis examined the relationship between Day +100 survival and time from VOD/SOS diagnosis to start of defibrotide, using cutoffs before and after particular days (Fisher's exact test for each cutoff day) as well as for treatment initiated on particular days post-diagnosis (Cochran-Armitage trend test).ResultsOf 1000 patients with VOD/SOS post-HSCT enrolled in the T-IND and receiving ≥1 dose of defibrotide, 570 were aged ≤16 years: 281 (49.3%) had MOD and 289 (50.7%) did not (Table 1). Median age at HSCT was 4 years, with 52.5% aged 2 to 11 years. The most common primary diseases were acute myelogenous leukemia (AML; 19.6%), neuroblastoma (18.2%), and acute lymphocytic leukemia (ALL; 18.1%). Characteristics were similar in the 95-patient late-onset subgroup (MOD, n=51; no MOD, n=44); the median age was slightly higher (5 years), and neuroblastoma was the most common primary disease (n=24, 25.5%), followed by ALL (n=21, 22.3%), and AML (n=18, 19.1%).Kaplan-Meier estimated survival rate at Day +100 for the entire post-HSCT pediatric population was 67.9% (95% confidence interval [CI], 63.8%-71.6%): MOD patients, 58.1% (95% CI, 52.0%-63.7%); no MOD patients, 77.6% (95% CI, 72.2%-82.1%). In the late-onset group, Kaplan-Meier estimated Day +100 survival was: 60.4% (95% CI, 49.5%-69.7%) for the total group; with MOD, 45.4% (95% CI, 31.0%-58.6%); no MOD, 78.4% (95% CI, 62.5%-88.1%). In the timing of initiation analysis for the overall population, Day +100 survival was significantly higher with earlier treatment after diagnosis at most cutoff days (Figure 1A). The trend test was statistically significant over time for higher Day +100 survival with earlier initiation (P <.001; Figure 1B). Reasons for treatment delay were not assessed.Adverse events (AEs) were reported in 374/570 (65.6%) patients, with treatment-related AEs (TRAEs) in 122 (21.4%; Table 2). TRAEs in >1% of patients were pulmonary hemorrhage (n=36, 6.3%), gastrointestinal hemorrhage (n=15, 2.6%), hypotension (n=11, 1.9%), epistaxis (n=8, 1.4%), and lower gastrointestinal hemorrhage (n=6, 1.1%). TRAEs leading to discontinuation in >1% of patients were pulmonary hemorrhage (n=33, 5.8%) and gastrointestinal hemorrhage (n=8, 1.4%). The only TRAE leading to death in >1% of patients was pulmonary hemorrhage (n=10, 1.8%). The safety profile was similar for the subgroup with late-onset VOD/SOS.ConclusionsFinal analyses of the pediatric population in the T-IND study demonstrated Kaplan-Meier estimated Day +100 survival (67.9%). No new safety signals were observed. Post hoc analyses provided supportive evidence for the clinical utility of defibrotide in patients with VOD/SOS onset after Day +21. This post-hoc analysis showed that prompt treatment with defibrotide improved survival outcome for VOD/SOS in pediatric patients with and without MOD.Support: Jazz Pharmaceuticals. [Display omitted] DisclosuresKernan:Gentium: Other: Received grants from Gentium during the conduct of the study and research was supported by The National Cancer Institute of the National Institutes of Health under award number P30 CA 008748, Research Funding. Ryan:Celator/Jazz: Employment, Equity Ownership. Liang:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Hume:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Tappe:Jazz Pharmaceuticals, Inc.: Employment, Other: stock options. Grupp:Novartis Pharmaceuticals Corporation: Consultancy, Other: grant; Jazz Pharmaceuticals: Consultancy; University of Pennsylvania: Patents & Royalties; Adaptimmune: Consultancy.

Serum survivin is decreased in women with preeclampsia

ABSTRACT Objective: To evaluate the serum survivin level in preeclampsia. Methods: Eighty-eight pregnancies complicated with preeclampsia and 88 gestational-age (GA)-matched uncomplicated pregnancies were evaluated. Results: Mean serum survivin was detected to be significantly decreased in the early- (EOPE) and late-onset (LOPE) preeclampsia subgroups than the GA-matched control-groups; and were comparable in EOPE- and LOPE-groups after correction for GA. Serum survivin had weak negative correlations with systolic and diastolic arterial blood pressure. Conclusion: The serum survivin level was decreased in preeclamptic patients than the GA-matched controls. More comprehensive studies are needed to clarify the timing and extent of placental apoptosis in preeclampsia.

Epicardial adipose tissue thickness as a potential predictor of pre-eclampsia.

Pre-eclampsia (PE) is a leading cause of maternal and fetal morbidity and mortality. Our aim was to assess epicardial adipose tissue (EAT) thickness as a potential effective screening parameter to predict PE in the first trimester. 133 women with PE were enrolled in this study, and divided into the early-onset and late-onset subgroups. 150 healthy women were enrolled as control group. Anthropometric and echocardiographic parameters were obtained, including EAT thickness. Generalized linear models was used to assess the predict efficiency of EAT with fdds ratio (OR) and 95% confidence intervals (CIs). Compared to the controls, EAT thickness was higher in PE patients (P<0.05). Multivariate regression analysis indicated that EAT thickness was associated with PE risk (OR=1.50, 95%CI: 1.19-1.88, P<0.05). The area under curves of EAT thickness was 0.616. When the cutoff value for EAT thickness was set to 5.26mm, the sensitivity was 78.2% and the specificity was 44.7%. EAT thickness significantly both higher in the early-onset and late-onset groups compared to the controls; Meanwhile, EAT thickness was higher in the early-onset group than late-onset group (P<0.05). Logistic regressionrevealed the close relationship between onset time of PE and EAT thickness (OR=1.59, 95%CI: 1.28-1.98, P<0.001). Measured EAT thickness using echocardiography could identify high-risk people for PE as early as the first trimester. Echocardiographic EAT has the potential to be a predictor for PE prior to actual clinical diagnosis.

Outcome measures and treatment effectiveness in late onset myasthenia gravis

BackgroundRecently different subtypes of myasthenia gravis (MG) have been described. They differ for clinical features and pathogenesis but the prognosis and response to treatment is less clear. The aim of the study was to evaluate outcome and treatment effectiveness including side effects in late onset MG (LOMG) compared with early onset MG (EOMG).MethodsWe analysed retrospectively 208 MG patients. Clinical features were recorded as well as treatment and side effects. Outcome at the last follow-up was evaluated with MGSTI and MGPIS scales.ResultsThe 208 patients included were classified as follow: 36 ocular MG, 40 EOMG, 72 LOMG, 25 thymoma-associated, 14 anti-MuSK and 21 double seronegative. Similar positive outcome was achieved in either early and late onset subgroup. We found pharmacological remission and minimal manifestations at the MGFA-PIS in the 95% and 94,4% of EOMG and LOMG respectively but in LOMG a lower dose of immunosuppressors (MGSTI< 2) was required compared to EOMG (p = 0,048). Severe side effects were present in a small percentage of patients in both group but diabetes was more frequent in LOMG vs EOMG (2,2% vs 5%, p = 0.017).ConclusionsDespite LOMG has more comorbidities that might interfere with treatment and outcome, therapeutic management does not seem to differ between EOMG and LOMG. A similar positive outcome was seen in both subgroups but LOMG group seems to require lower doses of medication to control symptoms.

Insights into the genetic basis of HMGB1 in atrial fibrillation in a Chinese Han population.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. High mobility group box 1 (HMGB1) has been demonstrated to be involved in AF, but the genetic relationship between them is not clear yet. Here, we investigated the genetic association between functional variants in HMGB1 and AF in a Chinese Han population. Two common variants (the promoter one rs1045411T/C and the 3'UTR one rs1412125C/T) in HMGB1 were selected and genotyped in 576 AF patients and 869 control subjects. Traditional risk factors, such as age, gender, the history of smoking, hypertension and diabetes mellitus, were adjusted as covariates using a logistic regression analysis (SPSS, v.21.0). The haplotypic analysis was performed using SPSS (v.21.0, Inc., Chicago, IL, USA). Under the allelic association analysis, neither rs1045411T/C nor rs1412125C/T was associated with AF with all P values >0.05; under the genotypic association analysis, the 3'UTR variant rs1045411T showed a marginally significant association with AF under the recessive model (Padj=0.056, OR =0.42; 95% CI: 0.17-1.02). When divided the studied population by gender, we still found no significant association results between the selected variants and AF with P values more than 0.05; however, when divided the population into subgroups by the age onset of AF, we found that the 3'UTR variant rs1045411T was significantly associated with AF in the late-onset subgroup (Padj=0.009, OR =11.1; 95% CI: 1.82-50.0). The 3'UTR variant rs1045411T/C of HMGB1 might influence the risk of late-onset AF in the Chinese Han population, which provides an important target factor for the prevention and treatment study of AF.

"Mexican-origin youth substance use trajectories: Associations with cultural and family factors,": Correction to Cruz et al. (2018).

Reports an error in "Mexican-origin youth substance use trajectories: Associations with cultural and family factors" by Rick A. Cruz, Kevin M. King, Molly Mechammil, Mayra Bámaca-Colbert and Richard W. Robins (Developmental Psychology, 2018[Jan], Vol 54[1], 111-126). In the original article, Tables 3 through 6 contained formatting errors. In Tables 3 and 4, the headers for columns 6 and 7 (Overall X ² undefined and Occasional use M (SE)) were corrected to match the header formatting used in the other columns. The headers in Tables 5 and 6 for columns 2 and 3 (Late-onset and Adolescent limited) were repeated across the remaining columns. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-42050-001.) The current study identified alcohol and cannabis use trajectories among a sample of Mexican-origin youth and examined cultural and familial correlates from childhood to adolescence. Mexican-origin youth (N = 674) from Northern California were assessed annually from ages 10 to 17 (8 waves). Latent class growth modeling examined variability in developmental trajectories for last 3-month alcohol and cannabis use frequency. Analyses also examined between-trajectory differences in youth's cultural practices and values, family cultural conflict, general parent-child conflict, and parental monitoring at 4 time points from ages 10 to 16. Analyses resulted in a 4-class model for alcohol use, comprising nonusers (62%), early-increasing (10%), adolescent-limited (11%), and late-onset (17%) subgroups, and a 4-class model for cannabis use, including nonusers (74%), early-increasing (8%), occasional use (16%), and high-declining (2%) subgroups. Findings suggested that early language use (higher English at age 10 and lower Spanish at age 12) was a temporally distal marker for several alcohol and cannabis use trajectories, whereas lower traditional family values at ages 14 and 16 were associated with several classes characterized by early substance use. Elevations in familial (parent-child conflict, parental monitoring) risk factors co-occurred in time and generally suggested temporally proximal connections with substance use behavior. Further, there was evidence that a less prominent decline in certain protective factors (e.g., father monitoring) was associated with reductions in substance use. These findings inform the literature by describing youth subgroups with variable risk for substance use development, and suggest modifiable risk factors associated with more frequent substance use trajectories. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Mutation update for myelin protein zero-related neuropathies and the increasing role of variants causing a late-onset phenotype

Mutations of myelin protein zero gene (MPZ) are found in 5% of Charcot-Marie-Tooth patients. In 2004, Shy et al. identified two main phenotypes associated with them: an early-onset subtype with mainly demyelinating features and a late-onset subgroup with prominent axonal impairment. We evaluated whether novel MPZ mutations described in literature during the last 14years could still fit with this classification. We collected and revised reports of 69 novel MPZ mutations. Almost 90% of them could be alternatively classified as responsible for: (a) an early-onset phenotype, with first limitations starting before 3years (2.5 ± 0.50years), motor milestones delays, frequently severe course and upper limb MNCVs below 15m/s; (b) late-onset neuropathy, with mean age of onset of 42.8 ± 1.5years and mean upper limbs motor nerve conduction velocities (MNCVs) of 47.2 ± 1.4m/s; (c) a phenotype more similar to typical CMT1A neuropathy, with onset during the 2nd decade, MNCV in the range of 15-30m/s and slowly progressive course. The present work confirms that P0-related neuropathies may be separated into two main distinct phenotypes, while a third, relatively small, group comprehend patients carrying MPZ mutations and a childhood-onset disease, substantiating the subdivision into three groups proposed by Sanmaneechai et al. (Brain 138:3180-3192, 2015). Interestingly, during the last years, an increasing number of novel MPZ mutations causing a late-onset phenotype has been described, highlighting the clinical relevance of late-onset P0 neuropathies. Since the family history for neuropathy is often uncertain, due to the late disease onset, the number of patients carrying this genotype is probably underestimated.