Functioning and neurocognition in very early and early-life onset bipolar disorders: the moderating role of bipolar disorder type.

Defining homogeneous subgroups of bipolar disorder (BD) is a major goal in personalized psychiatry and research. According to the neurodevelopmental theory, age at onset may be a key variable. As potential trait markers of neurodevelopment, cognitive and functional impairment should be greater in the early form of the disease, particularly type 1 BD (BD I). The age at onset was assessed in a multicenter, observational sample of 4190 outpatients with BD. We used a battery of neuropsychological tests to assess six domains of cognition. Functioning was measured using the Functioning Assessment Short Test (FAST). We studied the potential moderation of the type of BD on the associations between the age at onset and cognitive and functioning in a subsample of 2072 euthymic participants, controlling for potential clinical and socio-demographic covariates. Multivariable analyses showed cognition to not be impaired in individuals with early (21-30 years) and very early-life (before 14 years) onset of BD. Functioning was equivalent between individuals with early and midlife-onset of BD II and NOS but better for individuals with early onset of BD I. In contrast, functioning was not worse in individuals with very early-onset BD I but worse in those with very early-onset BD II and NOS. Early-life onset BDs were not characterized by poorer cognition and functioning. Our results do not support the neurodevelopmental view that a worse cognitive prognosis characterizes early-life onset BD. This study suggests that functional remediation may be prioritized for individuals with midlife-onset BD I and very early life onset BD 2 and NOS.

Impedance-based Real-time Monitoring of Neural Stem Cell Differentiation.

We present here the first impedance-based characterization of the differentiation process of two human mesencephalic fetal neural stem lines. The two dopaminergic neural stem cell lines used in this study, Lund human mesencephalic (LUHMES) and human ventral mesencephalic (hVM1 Bcl-XL), have been developed for the study of Parkinsonian pathogenesis and its treatment using cell replacement therapy. We show that if only relying on impedance magnitude analysis, which is by far the most usual approach in, e.g., cytotoxicity evaluation and drug screening applications, one may not be able to distinguish whether the neural stem cells in a population are proliferating or differentiating. However, the presented results highlight that equivalent circuit analysis can provide detailed information on cellular behavior, e.g. simultaneous changes in cell morphology, cell-cell contacts, and cell adhesion during formation of neural projections, which are the fundamental behavioral differences between proliferating and differentiating neural stem cells. Moreover, our work also demonstrates the sensitivity of impedance-based monitoring with capability to provide information on changes in cellular behavior in relation to proliferation and differentiation. For both of the studied cell lines, in already two days (one day after induction of differentiation) equivalent circuit analysis was able to show distinction between proliferation and differentiation conditions, which is significantly earlier than by microscopic imaging. This study demonstrates the potential of impedance-based monitoring as a technique of choice in the study of stem cell behavior, laying the foundation for screening assays to characterize stem cell lines and testing the efficacy epigenetic control.

Impact and trends in embedding field programmable gate arrays and microcontrollers in scientific instrumentation.

Microcontrollers and field-programmable gate arrays have been largely leveraged in scientific instrumentation since decades. Recent advancements in the performance of these programmable digital devices, with hundreds of I/O pins, up to millions of logic cells, >10 Gb/s connectivity, and hundreds of MHz multiple clocks, have been accelerating this trend, extending the range of functions. The diversification of devices from very low-cost 8-bit microcontrollers up to 32-bit ARM-based ones and a system of chip combining programmable logic with processors make them ubiquitous in modern electronic systems, addressing diverse challenges from ultra-low power operation, with sub-µA quiescent current in sleep mode for portable and Internet of Things applications, to high-performance computing, such as in machine vision. In this Review, the main motivations (compactness, re-configurability, parallelization, low latency for sub-ns timing, and real-time control), the possible approaches of the adoption of embedded devices, and the achievable performances are discussed. Relevant examples of applications in opto-electronics, physics experiments, impedance, vibration, and temperature sensing from the recent literature are also reviewed. From this bird-eye view, key paradigms emerge, such as the blurring of boundaries between digital platforms and the pervasiveness of machine learning algorithms, significantly fostered by the possibility to be run in embedded devices for distributing intelligence in the environment.

Advances in measurements and instrumentation leveraging embedded systems.

The expression "embedded systems" is used in different contexts and with broad meanings, but in electronics, it refers to systems that contain peripherals and a firmware for local digital data processing, often on a single board. Embedded systems are often associated with the field of computer science, emphasizing the software and programming aspects of systems. However, the progress made on the hardware side cannot be ignored, and without such technological advances, embedded systems would not exist. In fact, the progress in the field of microelectronics drives a constant evolution of variegated digital platforms, which gradually become easier to program and configure, thus reducing the development and prototyping phase and causing a strong impact on different research and application fields.

Finger-counting observation interferes with number processing.

Aim of this study was to investigate the association between finger and number representation in a task in which students had to perform arithmetic calculations and decide whether the provided solution was correct or incorrect, while a pair of task-irrelevant hands gesturally expressed the same or a different number. In particular we aimed at investigating whether irrelevant finger-counting might interfere with arithmetic computing, thus showing the existence of a strict neural association between the two processes. 20 volunteers took part to the investigation and EEG/ERPs were recorded from 128 scalp sites. P300 amplitude was greater to correct than incorrect solutions. Accuracy was higher when there was no conflict between the two sets of information A numerical error-related negativity (nERN) was elicited by incorrect solutions, and also by correct solutions when the finger-counting was incongruent. Source analysis applied to the incongruent minus congruent difference showed that when finger-counting was incorrect nERN mostly derived from medial and superior prefrontal cortex activity (supporting action monitoring and suppression). Conversely, when finger-counting indicated the correct solution brain activation included occipital areas, somatosensory regions and visuomotor mirror areas, inferior and superior temporal cortex, reflecting attentional orienting toward the hands. In both cases, the left angular gyrus (BA39) was found active during conjoined digit/number processing, suggesting a strict neural association between finger and digit processing. The present findings help explaining why a lesion in the left parietal cortex may simultaneously lead to finger apraxia and acalculia (Gertsmann syndrome).

A statistical shape model of the left ventricle from real-time 3D echocardiography and its application to myocardial segmentation of cardiac magnetic resonance images.

OBJECT: We present in this paper the application of a statistical shape model of the left ventricle (LV) built from transthoracic real time 3D echocardiography (3DE) to segment the LV endocardium and epicardium in cardiac magnetic resonance (CMR) images. MATERIAL AND METHODS: The LV model was built from a training database constituted by over 9000 surfaces obtained from retrospectively selected 3DE examination of 435 patients with various pathologies. Three-dimensional segmentation of the endocardium and the epicardium was obtained by processing CMR images acquired in 30 patients with a dedicated active shape modelling (ASM) algorithm using the proposed LV model. RESULTS: The segmentation results obtained with the proposed method were compared with those obtained by the manual reference technique; similarity was proven by computing: i) point to surface distance (<2 mm), ii) Dice similarity coefficient (>89%), iii) Hausdorff distance (∼5 mm). This was furthermore confirmed by equivalence testing, linear regression and Bland Altman analysis applied on derived clinical parameters, such as LV volumes and mass. CONCLUSIONS: This study showed the potential usefulness of the proposed inter-modal ASM approach featuring a 3DE-based LV model for the 3D segmentation of the LV myocardium in CMR images.

Switched ratiometric lock-in amplifier enabling sub-ppm measurements in a wide frequency range.

Lock-in amplifiers (LIAs) are extensively used to perform high-resolution measurements. Ideally, when using LIAs, it would be possible to measure a minimum signal variation limited by the instrument input equivalent noise at the operating frequency and the chosen filtering bandwidth. Instead, digital LIAs show an unforeseen 1/f noise at the instrument demodulated output, proportional to the signal amplitude that poses a fundamental limit to the minimum detectable signal variation using the lock-in technique. In particular, the typical resolution limit of fast operating LIAs (>1 MHz) is of tens of ppm, orders of magnitude worse than the expected value. A detailed analysis shows that the additional noise is due to slow fluctuations of the signal gain from the generation stage to the acquisition one, mainly due to the digital-to-analog and analog-to-digital converters. To compensate them, a switched ratiometric technique based on two analog-to-digital converters alternately acquiring the signal coming from the device under test and the stimulus signal has been conceived. A field-programmabale gate array-based LIA working up to 10 MHz and implementing the technique has been realized, and results demonstrate a resolution improvement of more than an order of magnitude (from tens of ppm down to sub-ppm values) compared to standard implementations working up to similar frequencies. The technique is generally applicable without requiring calibration nor ad hoc experimental arrangements.

Physical and mental health burden in cases of bipolar disorder classified as current, former, or non-tobacco smokers.

BACKGROUND: Tobacco smoking increases the global burden of bipolar disorder (BD). We examined markers of physical and mental health that are associated with tobacco smoking, controlling for confounders that have not always been considered in previous studies of BD. METHODS: Over 600 individuals with BD I or II referred to the French Network for bipolar disorder (FACE-BD) who completed standardized assessments, and could be reliably classified as current (CS) or former smokers (FS), were compared with those who were never smokers (NS) on: BD symptom load and psychiatric comorbidities; prevalence of alcohol and substance use disorders (ASUD); medication usage; functioning and physical health parameters. The bivariate and multivariate analyses took into account age and gender. RESULTS: 300 cases (49%) were CS, 78 (13%) FS and 238 (39%) had never smoked. Rates were similar across genders regardless of BD subtype. Compared with NS, CS were more likely to have an ASUD (Odds Ratio (OR) 5.18), BD I (OR 2.09), and lower abdominal obesity (OR 0.97), and FS were more likely to have an ASUD (OR 6.32) and higher abdominal obesity (OR 1.03). LIMITATIONS: The sample comprised of white Europeans; the FS subgroup was relatively small and we did not apply any statistical correction for the bivariate analyses. CONCLUSIONS: The increased risk of physical and mental health burden in CS and FS compared to NS represents avoidable morbidity in BD. This study offers support to the argument that individuals with BD should be routinely offered support to prevent or stop tobacco smoking.

Segmentation of the left ventricular endocardium from magnetic resonance images by using different statistical shape models.

We evaluate in this paper different strategies for the construction of a statistical shape model (SSM) of the left ventricle (LV) to be used for segmentation in cardiac magnetic resonance (CMR) images. From a large database of LV surfaces obtained throughout the cardiac cycle from 3D echocardiographic (3DE) LV images, different LV shape models were built by varying the considered phase in the cardiac cycle and the registration procedure employed for surface alignment. Principal component analysis was computed to describe the statistical variability of the SSMs, which were then deformed by applying an active shape model (ASM) approach to segment the LV endocardium in CMR images of 45 patients. Segmentation performance was evaluated by comparing LV volumes derived by ASM segmentation with different SSMs and those obtained by manual tracing, considered as a reference. A high correlation (r(2)>0.92) was found in all cases, with better results when using the SSM models comprising more than one frame of the cardiac cycle.

Comparison of Image Processing Techniques for Nonviable Tissue Quantification in Late Gadolinium Enhancement Cardiac Magnetic Resonance Images.

PURPOSE: The aim of this study was to compare the performance of quantitative methods, either semiautomated or automated, for left ventricular (LV) nonviable tissue analysis from cardiac magnetic resonance late gadolinium enhancement (CMR-LGE) images. MATERIALS AND METHODS: The investigated segmentation techniques were: (i) n-standard deviations thresholding; (ii) full width at half maximum thresholding; (iii) Gaussian mixture model classification; and (iv) fuzzy c-means clustering. These algorithms were applied either in each short axis slice (single-slice approach) or globally considering the entire short-axis stack covering the LV (global approach). CMR-LGE images from 20 patients with ischemic cardiomyopathy were retrospectively selected, and results from each technique were assessed against manual tracing. RESULTS: All methods provided comparable performance in terms of accuracy in scar detection, computation of local transmurality, and high correlation in scar mass compared with the manual technique. In general, no significant difference between single-slice and global approach was noted. The reproducibility of manual and investigated techniques was confirmed in all cases with slightly lower results for the nSD approach. CONCLUSIONS: Automated techniques resulted in accurate and reproducible evaluation of LV scars from CMR-LGE in ischemic patients with performance similar to the manual technique. Their application could minimize user interaction and computational time, even when compared with semiautomated approaches.

Serum NT-proBNP Levels Are Not Related to Vitamin D Status in Young Patients with Congenital Heart Defects.

CONTEXT: Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has been suggested to influence cardiac performance and N-terminal-pro-type B natriuretic peptide (NT-proBNP) release in adults with heart failure. OBJECTIVES: To assess the vitamin D status and the impact of hypovitaminosis D on circulating NT-proBNP levels in young patients with congenital heart defects (CHD). DESIGN AND PATIENTS: This cross-sectional study included the assessment of serum 25-hydroxyvitamin D (25OHD), parathyroid function markers, and NT-proBNP levels in a series of 230 young in-patients (117 females, 113 males; 6.4 (4.0-9.1) years (median, interquartile range)) with CHD. RESULTS: Serum 25OHD levels <20 ng/mL were detected in 55.3% of patients. Optimal 25OHD levels (>30 ng/mL) occurred in 25% of patients. Serum 25OHD levels inversely correlated with age (r = -0.169, P = 0.013) and height standard deviation score (r = -0.269, P = 0.001). After correction for age, 25OHD negatively correlated with serum PTH levels (ß = -0.200, P = 0.002). PTH levels above the upper quartile (44 pg/mL) occurred in 32% of hypovitaminosis D patients. Serum NT-proBNP levels were not correlated with 25OHD and PTH levels. CONCLUSIONS: Half of the young CHD patients were diagnosed with 25OHD deficiency and a third of hypovitaminosis D patients experienced hyperparathyroidism. Nonetheless, serum NT-proBNP levels were not associated with hypovitaminosis D as well as hyperparathyroidism.

Note: Differential configurations for the mitigation of slow fluctuations limiting the resolution of digital lock-in amplifiers.

The resolution of digital lock-in amplifiers working with a narrow bandwidth (<100 Hz) is limited by slow fluctuations, which can be two orders of magnitude larger (µV range) than the noise of the input amplifier (tens of nV). In order to tackle this issue, affecting state-of-the-art laboratory instrumentation and here systematically quantified, three differential sensing configurations are presented. They adapt to different setup conditions and are based on manual and automatic tuning of dummy references, allowing a 25-fold resolution improvement for enhanced long-term tracking of impedance sensors.

Interdependence of initial cell density, drug concentration and exposure time revealed by real-time impedance spectroscopic cytotoxicity assay.

We investigated the combined effect of the initial cell density (12,500, 35,000, 75,000, and 100,000 cells cm(-2)) and concentration of the anti-cancer drug doxorubicin on HeLa cells by performing time-dependent cytotoxicity assays using real-time electrochemical impedance spectroscopy. A correlation between the rate of cell death and the initial cell seeding density was found at 2.5 µM doxorubicin concentration, whereas this was not observed at 5 or 100 µM. By sensing the changes in the cell-substrate interaction using impedance spectroscopy under static conditions, the onset of cytotoxicity was observed 5 h earlier than when using a standard colorimetric end-point assay (MTS) which measures changes in the mitochondrial metabolism. Furthermore, with the MTS assay no cytotoxicity was observed after 15 h of incubation with 2.5 µM doxorubicin, whereas the impedance showed at this time point cell viability that was below 25%. These results indicate that impedance detection reveals cytotoxic events undetectable when using the MTS assay, highlighting the importance of combining impedance detection with traditional drug toxicity assays towards a more in depth understanding of the effect of anti-cancer drugs on in vitro assays. Moreover, the detection of doxorubicin induced toxicity determined with impedance under static conditions proved to be 6 times faster than in perfusion culture.

Positive compared with negative margins in a single-centre retrospective study on 3957 consecutive excisions of basal cell carcinomas. Associated risk factors and preferred surgical management.

The rate of margins involvement and the associated recurrence risk in basal cell carcinomas (BCCs) varies widely in published works (7%-25% and 26%-67%, respectively). This study investigated the risk factors associated with incomplete excision and their relevance in surgical management when positive margins occur in 3957 BCCs excised in 2358 patients. This study performed a multivariate analysis on the database collected from all patients operated for BCCs in the Plastic Surgery Department between 1 January 1992 and 1 September 2007. All data collected (3957 excisions; 2358 individuals) were divided into complete and incomplete excisions groups and analyzed according to 14 variables. The overall rate of incomplete excisions was 14%. Mean age (68), size of the lesion (< 0.5 cm), BCC subtype (nodular with sclerosant aspects, sclerosant and basosquamous), location (face), infiltration depth (hypodermis and deep tissues), recurrent BCC and re-excised BCC were significantly associated with a higher rate of incomplete excision. The recurrence rate for incompletely excised tumours was 26.8%, while only 5.9% for completely excised tumours. Most of the risk factors associated to incomplete excision can be identified before surgery (by simple anamnesis and clinical examination) and successfully overcome by appropriate surgical margins. The high recurrence rate after incomplete excision and the low patient compliance towards follow-up should lead the surgeon to early re-excise residual cancer.

Structure-dependent optical and electrical transport properties of nanostructured Al-doped ZnO.

The structure-property relation of nanostructured Al-doped ZnO thin films has been investigated in detail through a systematic variation of structure and morphology, with particular emphasis on how they affect optical and electrical properties. A variety of structures, ranging from compact polycrystalline films to mesoporous, hierarchically organized cluster assemblies, are grown by pulsed laser deposition at room temperature at different oxygen pressures. We investigate the dependence of functional properties on structure and morphology and show how the correlation between electrical and optical properties can be studied to evaluate energy gap, conduction band effective mass and transport mechanisms. Understanding these properties opens up opportunities for specific applications in photovoltaic devices, where optimized combinations of conductivity, transparency and light scattering are required.

Pattern of cerebral ultrasound in neonatal heart surgery.

AIM: No study described reliably the changes in cerebral ultrasound (CUS) findings in neonatal heart surgery. We tried to define the modifications of CUS before and after heart surgery in neonates. PATIENTS: We studied 48 neonates with congenital heart defects were studied. Of these, 33 had correction of the malformation with cardiopulmonary bypass (CPB group); 15 underwent coarctation repair/shunting procedures (no-CPB group). Patients had CUS pre-operatively, 48-72 hours after surgery, and at discharge. RESULTS: Pre-operative studies did not show significant differences between the groups. In CPB group, preoperatively, 6/33 infants showed echogenicity of basal ganglia and 1/33 grade I IVH. In the early postoperative evaluation, 24/33 infants had abnormal scans: increased echogenicity of basal ganglia in 24 and grade I IVH in 14. At discharge, abnormal scans persisted in 20/33 (basal ganglia echogenicity in 20, grade I IVH in 12). In the no-CPB group, preoperatively, 1/15 infant showed echogenicity of basal ganglia. In the early postoperative evaluation, 6/15 had abnormal scans: increased echogenicity of basal ganglia in 6, grade I IVH in 4. At discharge, abnormal scans persisted in 3/15. CONCLUSIONS: CUS after neonatal heart surgery shows a definite pattern of increased echogenicity of the basal ganglia, more consistent after CPB. These changes may reflect disturbances of deep grey matter, and last 10-15 days at least.

Cardiac magnetic resonance: impact on diagnosis and management of patients with congenital cardiovascular disease.

AIM: To estimate the clinical impact of cardiac magnetic resonance (CMR) in patients with congenital cardiovascular disease (CCD). MATERIALS AND METHODS: Since 2003, 1.5T CMR was used at our university hospital to evaluate morphology, cardiac kinetics, aortic and pulmonary flow, and vascular anatomy in patients with CCD. The present study considered a consecutive series of these patients from 2003 to 2006. A paediatric cardiologist judged our reports as expected or unexpected and, secondarily, as not reliable (level 0), describing findings already known (level 1), not changing therapy/suggested lifestyle (level 2), changing therapy/suggested lifestyle (level 3) or changing diagnosis (level 4). RESULTS: CMR reports were judged to be expected in 187/214 (87%) and unexpected in 27/214 (13%). Less than 2% of CMRs were judged as levels 0 or 1, 66% as level 2, and 5% as level 4. During 2005-2006 the clinical impact improved toward higher impact levels (p<0.001, chi-square test). CONCLUSIONS: In patients with CCD, more than one in 10 CMR reports were unexpected to cardiologists and over seven in 10 prompted a change of diagnosis or therapy.

Increased risk for non-autoimmune hypothyroidism in young patients with congenital heart defects.

CONTEXT: Newborns with congenital hypothyroidism (CH) have an increased risk for congenital heart defects (CHD) due to a common embryonic developmental program between thyroid gland and heart and great vessels. OBJECTIVE: Our objective was to investigate the prevalence and origin of thyroid disorders in young patients with CHD. DESIGN AND SETTING: We conducted a prospective observational study between January 2007 and January 2009 in academic Pediatric Cardiosurgery and Endocrinology. PATIENTS: Patients included 324 children (164 males, 160 females, aged 0.2-15.4 yrs) with CHD. INTERVENTION: Subjects underwent hormonal and genetic screening. MAIN OUTCOME MEASURES: Serum TSH and thyroid hormone levels were assessed. RESULTS: Two CHD patients were diagnosed with CH at the neonatal screening (1:162). Mild hypothyroidism (serum TSH > 4.0 µU/ml) was diagnosed and confirmed 6 months later [TSH = 5.4 ± 1.5 µU/ml; free T(4) = 1.3 ± 0.2 ng/dl (normal values 0.8-1.9)] in 37 children (11.5%) who were negative at neonatal screening. Hypothyroidism was not related to type of CHD, whereas TSH levels positively correlated with serum N-terminal pro-type B natriuretic peptide levels. Biochemical and ultrasound findings consistent with thyroid autoimmunity were present in three of 37 hypothyroid children (8.1%). One patient had hemiagenesis (2.7%). Variations in candidate genes were screened in CHD patients. NKX2.5 coding sequence was normal in all samples. A 3-Mb microdeletion in 22q11.2 was detected in three patients (8.3%), whereas only known polymorphisms were identified in TBX1 coding sequence. CONCLUSIONS: CHD patients have an increased risk for both CH (10-fold higher) and acquired mild hypothyroidism (3-fold higher). Unrecognized mild hypothyroidism may negatively affect the outcome of CHD children, suggesting that thyroid function should be repeatedly checked. Thyroid autoimmunity and 22q11.2 microdeletions account for small percentages of these cases, and still unknown mechanisms underline such a strong association.

[Infective endocarditis in patients with congenital heart disease]. / Endocardite infettiva nei cardiopatici congeniti.

The incidence of infective endocarditis (IE) in patients with congenital heart disease (CHD) is higher than in general population; this is a major problem considering the continuous expansion of such group of patients. Generally the more complex is the congenital heart disease the higher is the risk of IE. The aetiology, clinical features, complications, basis for diagnosis and treatment of IE in CHD patients don't differ from those in acquired cardiac disease; however, right-sided IE is more frequent in CHD patients. Due to the complex anatomy or presence of artificial material in many CHD, the transesophageal echocardiogram is extremely useful although echocardiographic assessment remains difficult. Prognosis is better than in other forms of IE with a mortality rate <10%. Primary prevention is crucial: a good oral-dental hygiene and regular dental review are as important as antibiotic prophylaxis; however this awareness in the CHD population is still not satisfactorily spread due to an educational problem. New IE guidelines from International Cardiology Societies emphasize the role of primary prevention and limit antibiotic prophylaxis to the highest risk patients undergoing the highest risk procedures. This article reviews the main reasons justifying the revision of previous IE guidelines, focuses on criteria to select CHD patients requiring antibiotic prophylaxis and gives information about antibiotic therapy to use.