Early spectral EEG in preterm infants correlates with neurocognitive outcomes in late childhood.

BACKGROUND: Evidence regarding the predictive value of early amplitude-integrated electroencephalography (aEEG)/EEG on neurodevelopmental outcomes at school age and beyond is lacking. We  aimed to investigate whether there is an association between early postnatal EEG and neurocognitive outcomes in late childhood. METHODS: This study is an observational prospective cohort study of premature infants with a gestational age <28 weeks. The total absolute band powers (tABP) of the delta, theta, alpha, and beta bands were analyzed from EEG recordings during the first three days of life. At 10-12 years of age, neurocognitive outcomes were assessed using the Wechsler Intelligence Scale for Children 4th edition (WISC-IV), Vineland adaptive behavior scales 2nd edition, and Behavior Rating Inventory of Executive Function (BRIEF). The mean differences in tABP were assessed for individuals with normal versus unfavorable neurocognitive scores. RESULTS: Twenty-two infants were included. tABP values in all four frequency bands were significantly lower in infants with unfavorable results in the main composite scores (full intelligence quotient, adaptive behavior composite score, and global executive composite score) on all three tests (p < 0.05). CONCLUSIONS: Early postnatal EEG has the potential to assist in predicting cognitive outcomes at 10-12 years of age in extremely premature infants <28 weeks' gestation. IMPACT: Evidence regarding the value of early postnatal EEG in long-term prognostication in preterm infants is limited. Our study suggests that early EEG spectral analysis correlates with neurocognitive outcomes in late childhood in extremely preterm infants. Early identification of infants at-risk of later impairment is important to initiate early and targeted follow-up and intervention.

Amplitude-Integrated Electroencephalography Improves the Identification of Infants with Encephalopathy for Therapeutic Hypothermia and Predicts Neurodevelopmental Outcomes at 2 Years of Age.

OBJECTIVES: To examine whether using an amplitude-integrated electroencephalography (aEEG) severity pattern as an entry criterion for therapeutic hypothermia better selects infants with hypoxic-ischemic encephalopathy and to assess the time-to-normal trace for aEEG and magnetic resonance imaging (MRI) lesion load as 24-month outcome predictors. STUDY DESIGN: Forty-seven infants meeting Norwegian therapeutic hypothermia guidelines were enrolled prospectively. Eight-channel EEG/aEEG was recorded from 6 hours until after rewarming, and read after discharge. Neonatal MRI brain scans were scored for summated (range 0-11) regional lesion load. A poor outcome at 2 years was defined as death or a Bayley Scales of Infant-Toddler Development cognitive or motor composite score of <85 or severe hearing or visual loss. RESULTS: Three severity groups were defined from the initial aEEG; continuous normal voltage (CNV; n = 15), discontinuous normal voltage (DNV; n = 18), and a severe aEEG voltage pattern (SEVP; n = 14). Any seizure occurrence was 7% CNV, 50% DNV, and 100% SEVP. Infants with SEVP with poor vs good outcome had a significantly longer median (IQR) time-to-normal trace: 58 hours (9-79) vs 18 hours (12-19) and higher MRI lesion load: 10 (3-10) vs 2 (1-5). A poor outcome was noted in 3 of 15 infants with CNV, 4 of 18 infants with DNV, and 8 of 14 infants with SEVP. Using multiple stepwise linear regression analyses including only infants with abnormal aEEG (DNV and SEVP), MRI lesion load significantly predicted cognitive and motor scores. For the SEVP group alone, time-to-normal trace was a stronger outcome predictor than MRI score. No variable predicted outcome in infants with CNV. CONCLUSIONS: Selection of infants with encephalopathy for therapeutic hypothermia after perinatal asphyxia may be improved by including only infants with an early moderate or severely depressed background aEEG trace.

Combining MRI and Spectral EEG for Assessment of Neurocognitive Outcomes in Preterm Infants.

INTRODUCTION: Predicting impairment in preterm children is challenging. Our aim is to explore the association between MRI at term-equivalent age (TEA) and neurocognitive outcomes in late childhood and to assess whether the addition of EEG improves prognostication. METHODS: This prospective observational study included forty infants with gestational age 24 + 0-30 + 6. Children were monitored with multichannel EEG for 72 h after birth. Total absolute band power for the delta band on day 2 was calculated. Brain MRI was performed at TEA and scored according to the Kidokoro scoring system. At 10-12 years of age, we evaluated neurocognitive outcomes with Wechsler Intelligence Scale for Children 4th edition, Vineland adaptive behavior scales 2nd edition and Behavior Rating Inventory of Executive Function. We performed linear regression analysis to examine the association between outcomes and MRI and EEG, respectively, and multiple regression analysis to explore the combination of MRI and EEG. RESULTS: Forty infants were included. There was a significant association between global brain abnormality score and composite outcomes of WISC and Vineland test, but not the BRIEF test. The adjusted R2 was 0.16 and 0.08, respectively. For EEG, adjusted R2 was 0.34 and 0.15, respectively. When combining MRI and EEG data, adjusted R2 changed to 0.36 for WISC and 0.16 for the Vineland test. CONCLUSION: There was a small association between TEA MRI and neurocognitive outcomes in late childhood. Adding EEG to the model improved the explained variance. Combining EEG and MRI data did not have any additional benefit over EEG alone.

Feasibility of long-term continuous EEG monitoring during the first days of life in preterm infants: an automated quantification of the EEG activity.

Long-term EEG monitoring (LTM) with several electrodes could be a useful tool for surveillance of the brain during the first critical days of life. This study aimed to assess the feasibility of multichannel LTM for automated analysis of EEG activity from d 1 to 3 using eight electrodes. Premature infants (GA <31 wk; n = 48) were continuously monitored for 3 d. EEG monitoring for a total of 3257 h was successfully performed. Total absolute band power (tABP) was calculated per second. Artifacts were removed visually or by an algorithm removing the highest 5, 10, 15, and 20% tABPs. NS difference was found between the trends of visually edited and 5% mathematically trimmed data. Two groups were compared (24 ≤ GA < 28 wk and 28 ≤ GA < 31 wk) using the median of tABP for all frequency bands per day. The results showed that tABP differed between groups. The changes of tABP d 1-3 were equal in both groups. Automatically assessed LTM confirms that the EEG activity depends on GA. However, it reveals that the early changes (d 1-3) are independent of GA. The study demonstrates the feasibility of multichannel LTM and the possibility of developing automated EEG analyses.

Front dynamics in fractional-order epidemic models.

A number of recent studies suggest that human and animal mobility patterns exhibit scale-free, Lévy-flight dynamics. However, current reaction-diffusion epidemics models do not account for the superdiffusive spread of modern epidemics due to Lévy flights. We have developed a SIR model to simulate the spatial spread of a hypothetical epidemic driven by long-range displacements in the infective and susceptible populations. The model has been obtained by replacing the second-order diffusion operator by a fractional-order operator. Theoretical developments and numerical simulations show that fractional-order diffusion leads to an exponential acceleration of the epidemic's front and a power-law decay of the front's leading tail. Our results indicate the potential of fractional-order reaction-diffusion models to represent modern epidemics.

The Subjective Experience of Living with Parkinson's Disease: A Meta-Ethnography of Qualitative Literature.

BACKGROUND: A better understanding of the subjective experience of living with Parkinson's disease (PD) and the factors that influence this experience can be used to improve wellbeing of people with PD (PwP). OBJECTIVE: To gain more insight in the subjective experience of PD from the PwP's perspective, and the factors that contribute to this experience. METHODS: In this qualitative review, we performed a systematic search of qualitative studies discussing the subjective experience of PD and extracted reported themes (first order themes). Using a meta-ethnographic approach, we categorized the first order themes into second order themes, and created a third order construct: a holistic model of the subjective experience of living with PD. RESULTS: We included 20 studies with a total sample of 279 PwP. Data-extraction yielded 227 first order themes, which were categorized into the second order themes: 1) Awareness, 2) Disruption, 3) Adjustment, 4) The external environment, and 5) The changing self. With these themes, we developed the "model of dialectic change" which conceptualizes life with PD as a transformative journey, wherein PwP employ strategies to stabilize their changeable relationship with their external environment, while simultaneously redefining their self-concept. CONCLUSION: Our findings indicate that not only the symptoms of PD, but also the manner in which these cause disruptions in the PwP's interaction with their personal environment and self-concept, determine the subjective experience of PD andquality of life. Some PwP experience problems with adjusting, resulting in psychological distress. This calls for a holistic, multidisciplinary and participatory approach of PD.

Road Map to Safe and Well-Designed De-escalation Trials of Systemic Adjuvant Therapy for Solid Tumors.

An important challenge in the field of cancer is finding the balance between delivering effective treatments and avoiding adverse effects and financial toxicity caused by innovative, yet expensive, drugs. To address this, several treatment de-escalation trials have been conducted, but only a few of these have provided clear answers. A few trials had poor accrual or had design flaws that led to conflicting results. Members of the Breast International Group (BIG) and North American Breast Cancer Group (NABCG) believe the way forward is to understand the lessons from these trials and listen more carefully to what truly matters to our patients. We reviewed several adjuvant trials of different cancer types and developed a road map for improving the design and implementation of future de-escalation trials. The road map incorporates patients' insights obtained through focused group discussions across the BIG-NABCG networks. Considerations for the development of de-escalation trials for systemic adjuvant treatment, including noninferiority trial design, choice of end points, and prioritization of a patient's perspectives, are presented in this consensus article.

Human TGF-ß1 deficiency causes severe inflammatory bowel disease and encephalopathy.

Transforming growth factor (TGF)-ß1 (encoded by TGFB1) is the prototypic member of the TGF-ß family of 33 proteins that orchestrate embryogenesis, development and tissue homeostasis1,2. Following its discovery 3 , enormous interest and numerous controversies have emerged about the role of TGF-ß in coordinating the balance of pro- and anti-oncogenic properties4,5, pro- and anti-inflammatory effects 6 , or pro- and anti-fibrinogenic characteristics 7 . Here we describe three individuals from two pedigrees with biallelic loss-of-function mutations in the TGFB1 gene who presented with severe infantile inflammatory bowel disease (IBD) and central nervous system (CNS) disease associated with epilepsy, brain atrophy and posterior leukoencephalopathy. The proteins encoded by the mutated TGFB1 alleles were characterized by impaired secretion, function or stability of the TGF-ß1-LAP complex, which is suggestive of perturbed bioavailability of TGF-ß1. Our study shows that TGF-ß1 has a critical and nonredundant role in the development and homeostasis of intestinal immunity and the CNS in humans.

Combined Methylome and Transcriptome Analysis During Rat Hepatic Stellate Cell Activation.

Hepatic stellate cells (HSCs) are mesenchymal stem cells (MSCs) of the liver. They are unique among MSCs, since HSCs remain in a quiescent, retinoid-storing state in the normal liver but become activated after liver injury and contribute to tissue repair. The epigenetic mechanisms accompanying the transition of HSCs from a quiescent to an activated state are in the focus of the present study. We investigated the methylome and transcriptome during this process and observed profound changes. While the promoter methylation correlated negatively with gene expression, the gene-body methylation revealed no clear correlation. Most genes with altered expression were associated with cell differentiation. Among them, Wilms tumor 1 (Wt1) and Deltex4 (Dtx4) genes were identified as epigenetically regulated. Since HSCs were reported to derive from multipotent Wt1-positive cells and many differentially expressed genes were associated with cell differentiation during their activation, epigenetic alterations are presumably required to enable HSC development.

Epigenetic Changes during Hepatic Stellate Cell Activation.

BACKGROUND AND AIMS: Hepatic stellate cells (HSC), which can participate in liver regeneration and fibrogenesis, have recently been identified as liver-resident mesenchymal stem cells. During their activation HSC adopt a myofibroblast-like phenotype accompanied by profound changes in the gene expression profile. DNA methylation changes at single genes have been reported during HSC activation and may participate in the regulation of this process, but comprehensive DNA methylation analyses are still missing. The aim of the present study was to elucidate the role of DNA methylation during in vitro activation of HSC. METHODS AND RESULTS: The analysis of DNA methylation changes by antibody-based assays revealed a strong decrease in the global DNA methylation level during culture-induced activation of HSC. To identify genes which may be regulated by DNA methylation, we performed a genome-wide Methyl-MiniSeq EpiQuest sequencing comparing quiescent and early culture-activated HSC. Approximately 400 differentially methylated regions with a methylation change of at least 20% were identified, showing either hypo- or hypermethylation during activation. Further analysis of selected genes for DNA methylation and expression were performed revealing a good correlation between DNA methylation changes and gene expression. Furthermore, global DNA demethylation during HSC activation was investigated by 5-bromo-2-deoxyuridine assay and L-mimosine treatment showing that demethylation was independent of DNA synthesis and thereby excluding a passive DNA demethylation mechanism. CONCLUSIONS: In summary, in vitro activation of HSC initiated strong DNA methylation changes, which were associated with gene regulation. These results indicate that epigenetic mechanisms are important for the control of early HSC activation. Furthermore, the data show that global DNA demethylation during activation is based on an active DNA demethylation mechanism.

Effect of psychotherapy and relaxation on the psychosocial and somatic course of Crohn's disease: main results of the German Prospective Multicenter Psychotherapy Treatment study on Crohn's Disease.

OBJECTIVE: Few studies have been published on the influence of psychotherapy on the physical and psychosocial course of Crohn's disease (CD). METHODS: The present study, a prospective, randomized multicenter investigation conducted with 108 of 488 consecutive CD patients, was designed to investigate the influence of short-term psychodynamic therapy and relaxation in addition to a standardized glucocorticoid therapy on the somatic course of the disease as well as on patient psychosocial status. Based on the same standardized somatic treatment, the psychotherapy and control groups were compared after a 1-year treatment period and a follow-up of another year with regard to somatic course and psychosocial situation. RESULTS: A total of 81 (75%) of 108 randomized patients completed the psychosocial follow-up. The comparison between the therapy groups after 1 year showed no significant differences in the four main target criteria of psychosocial status (depression, anxiety, psychosocial-communicative status and health-related quality of life). The mean Beck's Depression Inventory (BDI) score at admission was 12.3 in the psychotherapy group and 8.7 in the control group. At the 1-year follow-up, the scores for depression have been 7.8 (psychotherapy group) and 7.8 (control group). In the 2-year follow-up, 84 patients were classified into four groups on the basis of somatic course; 23% of the control group and 30% of the psychotherapy group showed episode-free courses, 29% and 17% respectively underwent surgery due to failure of immunosuppressive or medical therapy, and a further subranking showed no significant differences between the two groups (P=.125). At the 1-year follow-up, the scores for depression of patients with an active episode respective remission were 14.6 vs. 5.8. From the patient's point of view, at the end of the 2-year follow-up, the overall subjective evaluation of the effectiveness of psychotherapy was positive. CONCLUSION: The patients included showed no psychosocial disturbances of clinical relevance. Although a tendency toward fewer surgical interventions, fewer relapses and reduction of depression was noted, the analysis was unable to demonstrate any benefit from psychosocial intervention on hypothesized parameters of psychosocial status and somatic course. Further studies should be performed to identify patient subgroups that may benefit from psychosocial intervention.