73 research outputs found
Brueckner-Hartree-Fock study of circular quantum dots
We calculate ground state energies in the Brueckner-Hartree-Fock theory for
electrons (with ) confined to a circular quantum dot and in
presence of a static magnetic field. Comparison with the predictions of
Hartree-Fock, local-spin-density and exact configuration-interaction theories
is made. We find that the correlations taken into account in
Brueckner-Hartree-Fock calculations give an important contribution to the
ground state energies, specially in strongly confined dots. In this
high-density range, corresponding in practice to self-assembled quantum dots,
the results of Brueckner-Hartree-Fock calculations are close to the exact
values and better than those obtained in the local-spin-density approximation.Comment: Regular articl
Magnetoplasmons in quantum rings
We have studied the structure and dipole charge density response of nanorings
as a function of the magnetic field using local-spin density functional theory.
Two small rings consisting of 12 and 22 electrons confined by a positively
charged background are used to represent the cases of a narrow and a wide ring.
The results are qualitatively compared with experimental data existing on
microrings and on antidots. A smaller ring containing 5 electrons is also
analyzed to allow for a closer comparison with a recent experiment on a two
electron quantum ring.Comment: Typeset using Revtex, 13 pages and 11 Postscript figure
Influence of shape of quantum dots on their far-infrared absorption
We investigate the effects of the shape of quantum dots on their far-infrared
absorption in an external magnetic field by a model calculation. We focus our
attention on dots with a parabolic confinement potential deviating from the
common circular symmetry, and dots having circular doughnut shape. For a
confinement where the generalized Kohn theorem does not hold we are able to
interprete the results in terms of a mixture of a center-of-mass mode and
collective modes reflecting an excitation of relative motion of the electrons.
The calculations are performed within the time-dependent Hartree approximation
and the results are compared to available experimental results.Comment: RevTeX, 16 pages with 10 postscript figures included. Submitted to
Phys. Rev.
Dissociation of vertical semiconductor diatomic artificial molecules
We investigate the dissociation of few-electron circular vertical
semiconductor double quantum dot artificial molecules at 0 T as a function of
interdot distance. Slight mismatch introduced in the fabrication of the
artificial molecules from nominally identical constituent quantum wells induces
localization by offsetting the energy levels in the quantum dots by up to 2
meV, and this plays a crucial role in the appearance of the addition energy
spectra as a function of coupling strength particularly in the weak coupling
limit.Comment: Accepted for publication in Phys. Rev. Let
Current-spin-density functional study of persistent currents in quantum rings
We present a numerical study of persistent currents in quantum rings using
current spin density functional theory (CSDFT). This formalism allows for a
systematic study of the joint effects of both spin, interactions and impurities
for realistic systems. It is illustrated that CSDFT is suitable for describing
the physical effects related to Aharonov-Bohm phases by comparing energy
spectra of impurity-free rings to existing exact diagonalization and
experimental results. Further, we examine the effects of a symmetry-breaking
impurity potential on the density and current characteristics of the system and
propose that narrowing the confining potential at fixed impurity potential will
suppress the persistent current in a characteristic way.Comment: 7 pages REVTeX, including 8 postscript figure
Current Density Functional approach to large quantum dots in intense magnetic fields
Within Current Density Functional Theory, we have studied a quantum dot made
of 210 electrons confined in a disk geometry. The ground state of this large
dot exhibits some features as a function of the magnetic field (B) that can be
attributed in a clear way to the formation of compressible and incompressible
states of the system. The orbital and spin angular momenta, the total energy,
ionization and electron chemical potentials of the ground state, as well as the
frequencies of far-infrared edge modes are calculated as a function of B, and
compared with available experimental and theoretical results.Comment: Typeset using Revtex, 17 pages and 13 Postscript figure
Molecular characterization of new FBXL4 mutations in patients with mtDNA depletion syndrome
Encephalomyopathic mitochondrial DNA (mtDNA) depletion syndrome 13 (MTDPS13) is a rare genetic disorder caused by defects in F-box leucine-rich repeat protein 4 (FBXL4). Although FBXL4 is essential for the bioenergetic homeostasis of the cell, the precise role of the protein remains unknown. In this study, we report two cases of unrelated patients presenting in the neonatal period with hyperlactacidemia and generalized hypotonia. Severe mtDNA depletion was detected in muscle biopsy in both patients. Genetic analysis showed one patient as having in compound heterozygosis a splice site variant c.858+5G>C and a missense variant c.1510T>C (p.Cys504Arg) in FBXL4. The second patient harbored a frameshift novel variant c.851delC (p.Pro284LeufsTer7) in homozygosis. To validate the pathogenicity of these variants, molecular and biochemical analyses were performed using skin-derived fibroblasts. We observed that the mtDNA depletion was less severe in fibroblasts than in muscle. Interestingly, the cells harboring a nonsense variant in homozygosis showed normal mtDNA copy number. Both patient fibroblasts, however, demonstrated reduced mitochondrial transcript quantity leading to diminished steady state levels of respiratory complex subunits, decreased respiratory complex IV (CIV) activity, and finally, low mitochondrial ATP levels. Both patients also revealed citrate synthase deficiency. Genetic complementation assays established that the deficient phenotype was rescued by the canonical version of FBXL4, confirming the pathological nature of the variants. Further analysis of fibroblasts allowed to establish that increased mitochondrial mass, mitochondrial fragmentation, and augmented autophagy are associated with FBXL4 deficiency in cells, but are probably secondary to a primary metabolic defect affecting oxidative phosphorylation
A Didactic Model of Macromolecular Crowding Effects on Protein Folding
A didactic model is presented to illustrate how the effect of macromolecular crowding on protein folding and association is modeled using current analytical theory and discrete molecular dynamics. While analytical treatments of crowding may consider the effect as a potential of average force acting to compress a polypeptide chain into a compact state, the use of simulations enables the presence of crowding reagents to be treated explicitly. Using an analytically solvable toy model for protein folding, an approximate statistical thermodynamic method is directly compared to simulation in order to gauge the effectiveness of current analytical crowding descriptions. Both methodologies are in quantitative agreement under most conditions, indication that both current theory and simulation methods are capable of recapitulating aspects of protein folding even by utilizing a simplistic protein model
Rapid, pointâofâcare antigen and molecularâbased tests for diagnosis of SARSâCoVâ2 infection
Background
Accurate rapid diagnostic tests for SARSâCoVâ2 infection could contribute to clinical and public health strategies to manage the COVIDâ19 pandemic. Pointâofâcare antigen and molecular tests to detect current infection could increase access to testing and early confirmation of cases, and expediate clinical and public health management decisions that may reduce transmission.
Objectives
To assess the diagnostic accuracy of pointâofâcare antigen and molecularâbased tests for diagnosis of SARSâCoVâ2 infection. We consider accuracy separately in symptomatic and asymptomatic population groups.
Search methods
Electronic searches of the Cochrane COVIDâ19 Study Register and the COVIDâ19 Living Evidence Database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) were undertaken on 30 Sept 2020. We checked repositories of COVIDâ19 publications and included independent evaluations from national reference laboratories, the Foundation for Innovative New Diagnostics and the Diagnostics Global Health website to 16 Nov 2020. We did not apply language restrictions.
Selection criteria
We included studies of people with either suspected SARSâCoVâ2 infection, known SARSâCoVâ2 infection or known absence of infection, or those who were being screened for infection. We included test accuracy studies of any design that evaluated commercially produced, rapid antigen or molecular tests suitable for a pointâofâcare setting (minimal equipment, sample preparation, and biosafety requirements, with results within two hours of sample collection). We included all reference standards that define the presence or absence of SARSâCoVâ2 (including reverse transcription polymerase chain reaction (RTâPCR) tests and established diagnostic criteria).
Data collection and analysis
Studies were screened independently in duplicate with disagreements resolved by discussion with a third author. Study characteristics were extracted by one author and checked by a second; extraction of study results and assessments of risk of bias and applicability (made using the QUADASâ2 tool) were undertaken independently in duplicate. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and pooled data using the bivariate model separately for antigen and molecularâbased tests. We tabulated results by test manufacturer and compliance with manufacturer instructions for use and according to symptom status.
Main results
Seventyâeight study cohorts were included (described in 64 study reports, including 20 preâprints), reporting results for 24,087 samples (7,415 with confirmed SARSâCoVâ2). Studies were mainly from Europe (n = 39) or North America (n = 20), and evaluated 16 antigen and five molecular assays.
We considered risk of bias to be high in 29 (37%) studies because of participant selection; in 66 (85%) because of weaknesses in the reference standard for absence of infection; and in 29 (37%) for participant flow and timing. Studies of antigen tests were of a higher methodological quality compared to studies of molecular tests, particularly regarding the risk of bias for participant selection and the index test. Characteristics of participants in 35 (45%) studies differed from those in whom the test was intended to be used and the delivery of the index test in 39 (50%) studies differed from the way in which the test was intended to be used. Nearly all studies (97%) defined the presence or absence of SARSâCoVâ2 based on a single RTâPCR result, and none included participants meeting case definitions for probable COVIDâ19.
Antigen tests
Fortyâeight studies reported 58 evaluations of antigen tests. Estimates of sensitivity varied considerably between studies. There were differences between symptomatic (72.0%, 95% CI 63.7% to 79.0%; 37 evaluations; 15530 samples, 4410 cases) and asymptomatic participants (58.1%, 95% CI 40.2% to 74.1%; 12 evaluations; 1581 samples, 295 cases). Average sensitivity was higher in the first week after symptom onset (78.3%, 95% CI 71.1% to 84.1%; 26 evaluations; 5769 samples, 2320 cases) than in the second week of symptoms (51.0%, 95% CI 40.8% to 61.0%; 22 evaluations; 935 samples, 692 cases). Sensitivity was high in those with cycle threshold (Ct) values on PCR â€25 (94.5%, 95% CI 91.0% to 96.7%; 36 evaluations; 2613 cases) compared to those with Ct values >25 (40.7%, 95% CI 31.8% to 50.3%; 36 evaluations; 2632 cases). Sensitivity varied between brands. Using data from instructions for use (IFU) compliant evaluations in symptomatic participants, summary sensitivities ranged from 34.1% (95% CI 29.7% to 38.8%; Coris Bioconcept) to 88.1% (95% CI 84.2% to 91.1%; SD Biosensor STANDARD Q). Average specificities were high in symptomatic and asymptomatic participants, and for most brands (overall summary specificity 99.6%, 95% CI 99.0% to 99.8%).
At 5% prevalence using data for the most sensitive assays in symptomatic people (SD Biosensor STANDARD Q and Abbott Panbio), positive predictive values (PPVs) of 84% to 90% mean that between 1 in 10 and 1 in 6 positive results will be a false positive, and between 1 in 4 and 1 in 8 cases will be missed. At 0.5% prevalence applying the same tests in asymptomatic people would result in PPVs of 11% to 28% meaning that between 7 in 10 and 9 in 10 positive results will be false positives, and between 1 in 2 and 1 in 3 cases will be missed.
No studies assessed the accuracy of repeated lateral flow testing or selfâtesting.
Rapid molecular assays
Thirty studies reported 33 evaluations of five different rapid molecular tests. Sensitivities varied according to test brand. Most of the data relate to the ID NOW and Xpert Xpress assays. Using data from evaluations following the manufacturerâs instructions for use, the average sensitivity of ID NOW was 73.0% (95% CI 66.8% to 78.4%) and average specificity 99.7% (95% CI 98.7% to 99.9%; 4 evaluations; 812 samples, 222 cases). For Xpert Xpress, the average sensitivity was 100% (95% CI 88.1% to 100%) and average specificity 97.2% (95% CI 89.4% to 99.3%; 2 evaluations; 100 samples, 29 cases). Insufficient data were available to investigate the effect of symptom status or time after symptom onset.
Authors' conclusions
Antigen tests vary in sensitivity. In people with signs and symptoms of COVIDâ19, sensitivities are highest in the first week of illness when viral loads are higher. The assays shown to meet appropriate criteria, such as WHO's priority target product profiles for COVIDâ19 diagnostics (âacceptableâ sensitivity â„ 80% and specificity â„ 97%), can be considered as a replacement for laboratoryâbased RTâPCR when immediate decisions about patient care must be made, or where RTâPCR cannot be delivered in a timely manner. Positive predictive values suggest that confirmatory testing of those with positive results may be considered in low prevalence settings. Due to the variable sensitivity of antigen tests, people who test negative may still be infected.
Evidence for testing in asymptomatic cohorts was limited. Test accuracy studies cannot adequately assess the ability of antigen tests to differentiate those who are infectious and require isolation from those who pose no risk, as there is no reference standard for infectiousness. A small number of molecular tests showed high accuracy and may be suitable alternatives to RTâPCR. However, further evaluations of the tests in settings as they are intended to be used are required to fully establish performance in practice.
Several important studies in asymptomatic individuals have been reported since the close of our search and will be incorporated at the next update of this review. Comparative studies of antigen tests in their intended use settings and according to test operator (including selfâtesting) are required
Antibody tests for identification of current and past infection with SARS-CoV-2
Background
The diagnostic challenges associated with the COVIDâ19 pandemic resulted in rapid development of diagnostic test methods for detecting SARSâCoVâ2 infection. Serology tests to detect the presence of antibodies to SARSâCoVâ2 enable detection of past infection and may detect cases of SARSâCoVâ2 infection that were missed by earlier diagnostic tests. Understanding the diagnostic accuracy of serology tests for SARSâCoVâ2 infection may enable development of effective diagnostic and management pathways, inform public health management decisions and understanding of SARSâCoVâ2 epidemiology.
Objectives
To assess the accuracy of antibody tests, firstly, to determine if a person presenting in the community, or in primary or secondary care has current SARSâCoVâ2 infection according to time after onset of infection and, secondly, to determine if a person has previously been infected with SARSâCoVâ2. Sources of heterogeneity investigated included: timing of test, test method, SARSâCoVâ2 antigen used, test brand, and reference standard for nonâSARSâCoVâ2 cases.
Search methods
The COVIDâ19 Open Access Project living evidence database from the University of Bern (which includes daily updates from PubMed and Embase and preprints from medRxiv and bioRxiv) was searched on 30 September 2020. We included additional publications from the Evidence for Policy and Practice Information and Coâordinating Centre (EPPIâCentre) âCOVIDâ19: Living map of the evidenceâ and the Norwegian Institute of Public Health âNIPH systematic and living map on COVIDâ19 evidenceâ. We did not apply language restrictions.
Selection criteria
We included test accuracy studies of any design that evaluated commercially produced serology tests, targeting IgG, IgM, IgA alone, or in combination. Studies must have provided data for sensitivity, that could be allocated to a predefined time period after onset of symptoms, or after a positive RTâPCR test. Small studies with fewer than 25 SARSâCoVâ2 infection cases were excluded. We included any reference standard to define the presence or absence of SARSâCoVâ2 (including reverse transcription polymerase chain reaction tests (RTâPCR), clinical diagnostic criteria, and preâpandemic samples).
Data collection and analysis
We use standard screening procedures with three reviewers. Quality assessment (using the QUADASâ2 tool) and numeric study results were extracted independently by two people. Other study characteristics were extracted by one reviewer and checked by a second. We present sensitivity and specificity with 95% confidence intervals (CIs) for each test and, for metaâanalysis, we fitted univariate randomâeffects logistic regression models for sensitivity by eligible time period and for specificity by reference standard group. Heterogeneity was investigated by including indicator variables in the randomâeffects logistic regression models. We tabulated results by test manufacturer and summarised results for tests that were evaluated in 200 or more samples and that met a modification of UK Medicines and Healthcare products Regulatory Agency (MHRA) target performance criteria.
Main results
We included 178 separate studies (described in 177 study reports, with 45 as preâprints) providing 527 test evaluations. The studies included 64,688 samples including 25,724 from people with confirmed SARSâCoVâ2; most compared the accuracy of two or more assays (102/178, 57%). Participants with confirmed SARSâCoVâ2 infection were most commonly hospital inpatients (78/178, 44%), and preâpandemic samples were used by 45% (81/178) to estimate specificity. Over twoâthirds of studies recruited participants based on known SARSâCoVâ2 infection status (123/178, 69%). All studies were conducted prior to the introduction of SARSâCoVâ2 vaccines and present data for naturally acquired antibody responses. Seventyânine percent (141/178) of studies reported sensitivity by week after symptom onset and 66% (117/178) for convalescent phase infection. Studies evaluated enzymeâlinked immunosorbent assays (ELISA) (165/527; 31%), chemiluminescent assays (CLIA) (167/527; 32%) or lateral flow assays (LFA) (188/527; 36%).
Risk of bias was high because of participant selection (172, 97%); application and interpretation of the index test (35, 20%); weaknesses in the reference standard (38, 21%); and issues related to participant flow and timing (148, 82%). We judged that there were high concerns about the applicability of the evidence related to participants in 170 (96%) studies, and about the applicability of the reference standard in 162 (91%) studies.
Average sensitivities for current SARSâCoVâ2 infection increased by week after onset for all target antibodies. Average sensitivity for the combination of either IgG or IgM was 41.1% in week one (95% CI 38.1 to 44.2; 103 evaluations; 3881 samples, 1593 cases), 74.9% in week two (95% CI 72.4 to 77.3; 96 evaluations, 3948 samples, 2904 cases) and 88.0% by week three after onset of symptoms (95% CI 86.3 to 89.5; 103 evaluations, 2929 samples, 2571 cases). Average sensitivity during the convalescent phase of infection (up to a maximum of 100 days since onset of symptoms, where reported) was 89.8% for IgG (95% CI 88.5 to 90.9; 253 evaluations, 16,846 samples, 14,183 cases), 92.9% for IgG or IgM combined (95% CI 91.0 to 94.4; 108 evaluations, 3571 samples, 3206 cases) and 94.3% for total antibodies (95% CI 92.8 to 95.5; 58 evaluations, 7063 samples, 6652 cases). Average sensitivities for IgM alone followed a similar pattern but were of a lower test accuracy in every time slot.
Average specificities were consistently high and precise, particularly for preâpandemic samples which provide the least biased estimates of specificity (ranging from 98.6% for IgM to 99.8% for total antibodies).
Subgroup analyses suggested small differences in sensitivity and specificity by test technology however heterogeneity in study results, timing of sample collection, and smaller sample numbers in some groups made comparisons difficult. For IgG, CLIAs were the most sensitive (convalescentâphase infection) and specific (preâpandemic samples) compared to both ELISAs and LFAs (P < 0.001 for differences across test methods). The antigen(s) used (whether from the Spikeâprotein or nucleocapsid) appeared to have some effect on average sensitivity in the first weeks after onset but there was no clear evidence of an effect during convalescentâphase infection.
Investigations of test performance by brand showed considerable variation in sensitivity between tests, and in results between studies evaluating the same test. For tests that were evaluated in 200 or more samples, the lower bound of the 95% CI for sensitivity was 90% or more for only a small number of tests (IgG, n = 5; IgG or IgM, n = 1; total antibodies, n = 4). More test brands met the MHRA minimum criteria for specificity of 98% or above (IgG, n = 16; IgG or IgM, n = 5; total antibodies, n = 7). Seven assays met the specified criteria for both sensitivity and specificity.
In a lowâprevalence (2%) setting, where antibody testing is used to diagnose COVIDâ19 in people with symptoms but who have had a negative PCR test, we would anticipate that 1 (1 to 2) case would be missed and 8 (5 to 15) would be falsely positive in 1000 people undergoing IgG or IgM testing in week three after onset of SARSâCoVâ2 infection.
In a seroprevalence survey, where prevalence of prior infection is 50%, we would anticipate that 51 (46 to 58) cases would be missed and 6 (5 to 7) would be falsely positive in 1000 people having IgG tests during the convalescent phase (21 to 100 days postâsymptom onset or postâpositive PCR) of SARSâCoVâ2 infection.
Authors' conclusions
Some antibody tests could be a useful diagnostic tool for those in whom molecularâ or antigenâbased tests have failed to detect the SARSâCoVâ2 virus, including in those with ongoing symptoms of acute infection (from week three onwards) or those presenting with postâacute sequelae of COVIDâ19. However, antibody tests have an increasing likelihood of detecting an immune response to infection as time since onset of infection progresses and have demonstrated adequate performance for detection of prior infection for seroâepidemiological purposes. The applicability of results for detection of vaccinationâinduced antibodies is uncertain
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