A power-efficient charge pump is proposed. The use of low-voltage transistors and of a simple two-phase clocking scheme permits the use of higher operating frequencies compared to conventional ...solutions, thus obtaining high current, high efficiency, and small area. Measurements show good results for frequencies around 100 MHz. Two test patterns have been fabricated, one with three stages and one with five stages, in a 1.8-V 0.18-/spl mu/m triple-well standard CMOS digital process (six metals). High-voltage capacitors have been implemented using metal to metal parasitic capacitance.
Analog In-Memory Computing (AiMC) based on Non-Volatile Memories (NVM) is a promising candidate to reduce latency and power consumption of neural network (NN) inference in edge-computing ...applications. This kind of computational accelerators allows both storing weights and performing in-situ analog computation inside the array. This tutorial explores trade-offs and strategies in the design of DACs and ADCs for this kind of systems, highlighting the strong interdependence between the two converters. Starting from an analysis of input and weights encoding techniques this tutorial will then propose a discussion aiming at exploring critical aspects that constrain the design of D-A and A-D converters drawing some co-design considerations.
Reliability and yield of CMOS integrated circuits are becoming more and more dependent on interconnect elements (contacts, vias, and metal lines). These are therefore considered to represent one of ...the main limits to the future scaling down of integration processes. Indeed, the continuous growth of semiconductor technology integration density has led to billions of transistorson a single chip and, hence, the evaluation of process yield asks for failure rate sensitivity in the order of 1 fault per billion. This paper presents a test structure which allows evaluating the contribution of interconnects to reliability and manufacturing yield degradation in high-density CMOS technologies. The test structure is based on a suitable array of contacts and vias, and has been conceived to measure the statistical distribution of interconnect failures. The main advantages of the proposed test structure are: the reduced number of test pads required measuring an extremely high amount of contacts and vias; the high sensitivity, which allows also resistive contacts or vias to be identified; and the possibility to determine the physical location of interconnect faults, thus simplifying the subsequent physical failure analysis. The test structure was integrated in 130 nm CMOS technology. Experimental results demonstrate the effectiveness of the proposed solution.
Objectives This study sought to examine the clinical performance of and theoretical basis for the instantaneous wave-free ratio (iFR) approximation to the fractional flow reserve (FFR). Background ...Recent work has proposed iFR as a vasodilation-free alternative to FFR for making mechanical revascularization decisions. Its fundamental basis is the assumption that diastolic resting myocardial resistance equals mean hyperemic resistance. Methods Pressure-only and combined pressure-flow clinical data from several centers were studied both empirically and by using pressure-flow physiology. A Monte Carlo simulation was performed by repeatedly selecting random parameters as if drawing from a cohort of hypothetical patients, using the reported ranges of these physiologic variables. Results We aggregated observations of 1,129 patients, including 120 with combined pressure-flow data. Separately, we performed 1,000 Monte Carlo simulations. Clinical data showed that iFR was +0.09 higher than FFR on average, with ±0.17 limits of agreement. Diastolic resting resistance was 2.5 ± 1.0 times higher than mean hyperemic resistance in patients. Without invoking wave mechanics, classic pressure-flow physiology explained clinical observations well, with a coefficient of determination of >0.9. Nearly identical scatter of iFR versus FFR was seen between simulation and patient observations, thereby supporting our model. Conclusions iFR provides both a biased estimate of FFR, on average, and an uncertain estimate of FFR in individual cases. Diastolic resting myocardial resistance does not equal mean hyperemic resistance, thereby contravening the most basic condition on which iFR depends. Fundamental relationships of coronary pressure and flow explain the iFR approximation without invoking wave mechanics.
Abstract
Objective. The relationship between metformin accumulation and lactate increase is still debated. This observational case series aims to evaluate the correlation of metformin plasma levels ...with the pH, lactate and creatinine levels, and with the mortality rate in selected patients with metformin accumulation confirmed through metformin plasma concentration detection at hospital admission. Material and methods. All cases of lactic acidosis (pH, ≤ 7.35; arterial lactate, ≥ 5 mmol/L) related to metformin accumulation (plasma level ≥ 4 mcg/mL) from 2007 to 2011 were retrospectively reviewed. Erroneous ingestion and voluntary overdoses were excluded. Epidemiological, medical history, clinical and laboratory data were evaluated in all cases. Results. Sixty-six patients were included. Thirty-one patients (47%) had contraindication to therapy with metformin. All patients showed severe lactic acidosis (pH, 6.91 ± 0.18; lactate, 14.36 ± 4.90 mmol/L) and acute renal failure (creatinine, 7.24 ± 3.29 mg/dL). The mean metformin plasma concentration was 40.68 ± 27.70 mcg/mL. Metformin plasma concentrations showed a correlation, statistically significant even if not strong, with creatinine (p = 0.002, R = 0.37), pH (p < 0.0001, R = − 0.43) and plasma lactate levels (p = 0.001, R = 0.41). Sixty-two (94%) underwent dialysis. Early mortality (before discharge from ICU) was 26% (17 cases). Lactate and metformin concentrations had mean levels not statistically different in surviving and deceased patients. Conclusions. Patients on chronic therapy with metformin may develop a mitochondrial-related toxicity that should be considered when patients present with lactic acidosis, renal failure, and frequently, a medical history of gastrointestinal manifestations during the days preceding the hospital admission. The correlation between metformin plasma concentrations and creatinine, pH, and lactate levels seems to be related to the mechanism of action (inhibition of complex I of the mitochondrial respiratory chain) and to the kinetic properties (high distribution volume and low protein binding) of the drug. The relevant early mortality seems not correlated with the levels of metformin or lactates: this could be due to the possible role of concurrent illness even if, such as for the relationships with lactate and creatinine, a more proper toxicological evaluation could be obtained by assessing metformin erythrocyte concentrations instead of the plasmatic ones.
A system-on-chip prototype implementing a full integration of a 64-minute digital voice recorder/player and embedding a 4-b/cell multilevel digital flash memory is presented in this paper. A ...hardwired adaptive-differential pulse-code modulation speech coder/decoder (8 to 40 kb/s) and a microcontroller are integrated into a bus-centric architecture. An 8-Mcell/32-Mb multilevel flash memory is used as an embedded mass storage media and a fully digital on-chip built-in-self-test solution is presented. This speech recording system features a modular architecture allowing full reuse and mix-and-match of its IP building blocks. The architecture of the system and solutions for implementing embedded multilevel flash memories are presented. System operation modes are described showing how the desired message editing functionality is implemented by a mixed hardware/software solution. The chip is 3-V-only and it counts 13 M transistors at 225 mm/sup 2/ area in a 0.5-/spl mu/m embedded flash technology.
Background
In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest.
...Objective
To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study).
Methods
A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid β peptide 1–42 (Aβ42), tau and p‐tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting‐state and auditory oddball event‐related potential (AO‐ERP) paradigm) biomarkers were evaluated.
Results
Prodromal AD was found in 55 aMCI patients defined by low Aβ42 in the cerebrospinal fluid (Aβ positive). Compared to the aMCI group with high Aβ42 levels (Aβ negative), Aβ positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO‐ERP (P = 0.03).
Conclusion
These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.
The Italian institute for nuclear physics (INFN) has financed the SIMP project (2019–2021) in order to strengthen its skills and technologies in the field of meV detectors with the ultimate aim of ...developing a single microwave photon detector. This goal will be pursued by improving the sensitivity and the dark-count rate of two types of photodetectors: current-biased Josephson junction (CBJJ) for the frequency range 10–50 GHz and transition-edge sensor (TES) for the frequency range 30–100 GHz. Preliminary results on materials and devices characterization are presented.
The Campanian Plain in southern Italy has been volcanically active for at least the last 300ka. The Campanian Ignimbrite (CI) erupted at 39.3ka, has a volume of ≥310km3 and a great areal extent. ...However, significant, but scattered deposits of older ignimbrites underlie the CI and document a long history of volcanism. We examined the mineralogy and geochemistry of 11 older ignimbrite strata by optical petrography, electron microprobe, scanning electron microscope, X-ray diffraction, and various whole-rock geochemical techniques. We have analyzed strata at Durazzano (116.1ka), Moschiano (184.7ka), Seiano Valley (245.9 and 289.6ka), and Taurano — Acqua Feconia (157.4, 183.8, 205.6, and 210.4ka) that have been previously dated on unaltered sanidine. The older ignimbrites are highly altered with loss on ignition (LOI) that ranges from 17 to 8wt%. Whole-rock compositions reflect variable element mobility during weathering; e.g., CaO is enriched and Na2O depleted relative to hydration. X-ray diffraction identified major chabazite, kaolinite, and illite alteration products in some samples. Rhabdophane-(Nd), usually intergrown with chabazite and Mn-carbonate, indicates that some LREE were also mobilized during weathering. The phenocryst mineralogy is typical for Campanian Plain (CP) magmas and consists of plagioclase (An88 Ab11 Or1 to An32 Ab63 Or5), potassium feldspar (Or40 Ab57 An3 to Or79 Ab18 An3), biotite (TiO2=~4–7wt%, BaO=up to 2wt%, F=up to 2wt%), diopside (Ca47Mg47Fe6 to Ca48Mg29Fe23), and titaniferous magnetite. Relatively immobile trace elements Zr, Hf, Th, Ta, V, and Nb were used to investigate element abundance and ratio compared to the Campanian Ignimbrite and other CP magmas. Zr/Hf of the older ignimbrites is similar to that of the CI, but Ta is depleted relative to Th and V is enriched compared to CI. Th/Ta and Nb/V distributions for most of the older ignimbrites are similar to those in the Neapolitan Yellow Tuff with the exception of the sample MS-1 from Moschiano that is more evolved and similar to Campanian Ignimbrite. All older ignimbrite Zr/Hf (w/w) and many Nb/Ta (w/w) ratios are superchondritic that suggests that the older ignimbrites represent fractional crystallization products of parental magmas generated from enriched mantle without significant addition of continental crust.
Amyloid and tau pathological accumulation should be considered for Alzheimer's disease (AD) definition and before subjects' enrollment in disease-modifying trials. Although age, APOEε4, and sex ...influence cerebrospinal fluid (CSF) biomarker levels, none of these variables are considered by current normality/abnormality cutoffs. Using baseline CSF data from 2 independent cohorts (PharmaCOG/European Alzheimer's Disease Neuroimaging Initiative and Alzheimer's Disease Neuroimaging Initiative), we investigated the effect of age, APOEε4 status, and sex on CSF Aβ42/P-tau distribution and cutoff extraction by applying mixture models with covariates. The Aβ42/P-tau distribution revealed the presence of 3 subgroups (AD-like, intermediate, control-like) and 2 cutoffs. The identification of the intermediate subgroup and of the higher cutoff was APOEε4 dependent in both cohorts. APOE-specific classification (higher cutoff for APOEε4+, lower cutoff for APOEε4-) showed higher diagnostic accuracy in identifying MCI due to AD compared to single Aβ42 and Aβ42/P-tau cutoffs. APOEε4 influences amyloid and tau CSF markers and AD progression in MCI patients supporting i) the use of APOE-specific cutoffs to identify MCI due to AD and ii) the utility of considering APOE genotype for early AD diagnosis.
•Cerebrospinal fluid Aβ42/P-tau ratio distribution revealed the presence of 3 subgroups.•APOEε4 status influenced cerebrospinal fluid Aβ42/P-tau ratio cutoff extraction and Alzheimer's progression.•Higher diagnostic accuracy of APOE-specific classification compared to single cutoffs.•Results were replicated in an independent cohort.
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