Publications by authors named "Christopher Williams"

763 Publications

All of the accuracy in half of the time: assessing abbreviated versions of the Test of Memory Malingering in the context of verbal and visual memory impairment.

Clin Neuropsychol 2021 Apr 9:1-17. Epub 2021 Apr 9.

Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL, USA.

Objective: The Test of Memory Malingering (TOMM) Trial 1 (T1) and errors on the first 10 items of T1 (T1-e10) were developed as briefer versions of the TOMM to minimize evaluation time and burden, although the effect of genuine memory impairment on these indices is not well established. This study examined whether increasing material-specific verbal and visual memory impairment affected T1 and T1-e10 performance and accuracy for detecting invalidity. Data from 155 neuropsychiatric patients administered the TOMM, Rey Auditory Verbal Learning Test (RAVLT), and Brief Visuospatial Memory Test-Revised (BVMT-R) during outpatient evaluation were examined. Valid ( = 125) and invalid ( = 30) groups were established by four independent criterion performance validity tests. Verbal/visual memory impairment was classified as ≥37 T (normal memory); 30 T-36T (mild impairment); and ≤29 T (severe impairment). Overall, T1 had outstanding accuracy, with 77% sensitivity/90% specificity. T1-e10 was less accurate but had excellent discriminability, with 60% sensitivity/87% specificity. T1 maintained excellent accuracy regardless of memory impairment severity, with 77% sensitivity/≥88% specificity and a relatively invariant cut-score even among those with severe verbal/visual memory impairment. T1-e10 had excellent classification accuracy among those with normal memory and mild impairment, but accuracy and sensitivity dropped with severe impairment and the optimal cut-score had to be increased to maintain adequate specificity. TOMM T1 is an effective performance validity test with strong psychometric properties regardless of material-specificity and severity of memory impairment. By contrast, T1-e10 functions relatively well in the context of mild memory impairment but has reduced discriminability with severe memory impairment.
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http://dx.doi.org/10.1080/13854046.2021.1908596DOI Listing
April 2021

Self-sampling of capillary blood for SARS-CoV-2 serology.

Sci Rep 2021 04 8;11(1):7754. Epub 2021 Apr 8.

Centre for Drugs and Diagnostics, Liverpool School of Tropical Medicine, Liverpool, L3 5QA, UK.

Serological testing is emerging as a powerful tool to progress our understanding of COVID-19 exposure, transmission and immune response. Large-scale testing is limited by the need for in-person blood collection by staff trained in venepuncture, and the limited sensitivity of lateral flow tests. Capillary blood self-sampling and postage to laboratories for analysis could provide a reliable alternative. Two-hundred and nine matched venous and capillary blood samples were obtained from thirty nine participants and analysed using a COVID-19 IgG ELISA to detect antibodies against SARS-CoV-2. Thirty eight out of thirty nine participants were able to self-collect an adequate sample of capillary blood (≥ 50 µl). Using plasma from venous blood collected in lithium heparin as the reference standard, matched capillary blood samples, collected in lithium heparin-treated tubes and on filter paper as dried blood spots, achieved a Cohen's kappa coefficient of > 0.88 (near-perfect agreement, 95% CI 0.738-1.000). Storage of capillary blood at room temperature for up to 7 days post sampling did not affect concordance. Our results indicate that capillary blood self-sampling is a reliable and feasible alternative to venepuncture for serological assessment in COVID-19.
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http://dx.doi.org/10.1038/s41598-021-86008-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8032656PMC
April 2021

Cell-programmed nutrient partitioning in the tumour microenvironment.

Nature 2021 Apr 7. Epub 2021 Apr 7.

Department of Medicine, Vanderbilt University Medical Center (VUMC), Nashville, TN, USA.

Cancer cells characteristically consume glucose through Warburg metabolism, a process that forms the basis of tumour imaging by positron emission tomography (PET). Tumour-infiltrating immune cells also rely on glucose, and impaired immune cell metabolism in the tumour microenvironment (TME) contributes to immune evasion by tumour cells. However, whether the metabolism of immune cells is dysregulated in the TME by cell-intrinsic programs or by competition with cancer cells for limited nutrients remains unclear. Here we used PET tracers to measure the access to and uptake of glucose and glutamine by specific cell subsets in the TME. Notably, myeloid cells had the greatest capacity to take up intratumoral glucose, followed by T cells and cancer cells, across a range of cancer models. By contrast, cancer cells showed the highest uptake of glutamine. This distinct nutrient partitioning was programmed in a cell-intrinsic manner through mTORC1 signalling and the expression of genes related to the metabolism of glucose and glutamine. Inhibiting glutamine uptake enhanced glucose uptake across tumour-resident cell types, showing that glutamine metabolism suppresses glucose uptake without glucose being a limiting factor in the TME. Thus, cell-intrinsic programs drive the preferential acquisition of glucose and glutamine by immune and cancer cells, respectively. Cell-selective partitioning of these nutrients could be exploited to develop therapies and imaging strategies to enhance or monitor the metabolic programs and activities of specific cell populations in the TME.
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http://dx.doi.org/10.1038/s41586-021-03442-1DOI Listing
April 2021

Efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine against SARS-CoV-2 variant of concern 202012/01 (B.1.1.7): an exploratory analysis of a randomised controlled trial.

Lancet 2021 04 30;397(10282):1351-1362. Epub 2021 Mar 30.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Background: A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant.

Methods: Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 - relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137.

Findings: Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18-55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2-11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6-84·5) for B.1.1.7 and 81·5% (67·9-89·4) for non-B.1.1.7 lineages.

Interpretation: ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2.

Funding: UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(21)00628-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009612PMC
April 2021

Tetherin/BST2, a physiologically and therapeutically relevant regulator of platelet receptor signalling.

Blood Adv 2021 Apr;5(7):1884-1898

School of Physiology, Pharmacology, and Neuroscience, and.

The reactivity of platelets, which play a key role in the pathogenesis of atherothrombosis, is tightly regulated. The integral membrane protein tetherin/bone marrow stromal antigen-2 (BST-2) regulates membrane organization, altering both lipid and protein distribution within the plasma membrane. Because membrane microdomains have an established role in platelet receptor biology, we sought to characterize the physiological relevance of tetherin/BST-2 in those cells. To characterize the potential importance of tetherin/BST-2 to platelet function, we used tetherin/BST-2-/- murine platelets. In the mice, we found enhanced function and signaling downstream of a subset of membrane microdomain-expressing receptors, including the P2Y12, TP thromboxane, thrombin, and GPVI receptors. Preliminary studies in humans have revealed that treatment with interferon-α (IFN-α), which upregulates platelet tetherin/BST-2 expression, also reduces adenosine diphosphate-stimulated platelet receptor function and reactivity. A more comprehensive understanding of how tetherin/BST-2 negatively regulates receptor function was provided in cell line experiments, where we focused on the therapeutically relevant P2Y12 receptor (P2Y12R). Tetherin/BST-2 expression reduced both P2Y12R activation and trafficking, which was accompanied by reduced receptor lateral mobility specifically within membrane microdomains. In fluorescence lifetime imaging-Förster resonance energy transfer (FLIM-FRET)-based experiments, agonist stimulation reduced basal association between P2Y12R and tetherin/BST-2. Notably, the glycosylphosphatidylinositol (GPI) anchor of tetherin/BST-2 was required for both receptor interaction and observed functional effects. In summary, we established, for the first time, a fundamental role of the ubiquitously expressed protein tetherin/BST-2 in negatively regulating membrane microdomain-expressed platelet receptor function.
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http://dx.doi.org/10.1182/bloodadvances.2020003182DOI Listing
April 2021

Data Sharing Goals for Nonprofit Funders of Clinical Trials.

J Particip Med 2021 Mar 29;13(1):e23011. Epub 2021 Mar 29.

Pancreatic Cancer Action Network, Washington, DC, United States.

Sharing clinical trial data can provide value to research participants and communities by accelerating the development of new knowledge and therapies as investigators merge data sets to conduct new analyses, reproduce published findings to raise standards for original research, and learn from the work of others to generate new research questions. Nonprofit funders, including disease advocacy and patient-focused organizations, play a pivotal role in the promotion and implementation of data sharing policies. Funders are uniquely positioned to promote and support a culture of data sharing by serving as trusted liaisons between potential research participants and investigators who wish to access these participants' networks for clinical trial recruitment. In short, nonprofit funders can drive policies and influence research culture. The purpose of this paper is to detail a set of aspirational goals and forward thinking, collaborative data sharing solutions for nonprofit funders to fold into existing funding policies. The goals of this paper convey the complexity of the opportunities and challenges facing nonprofit funders and the appropriate prioritization of data sharing within their organizations and may serve as a starting point for a data sharing toolkit for nonprofit funders of clinical trials to provide the clarity of mission and mechanisms to enforce the data sharing practices their communities already expect are happening.
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http://dx.doi.org/10.2196/23011DOI Listing
March 2021

Assessment of differential neurocognitive performance based on the number of performance validity tests failures: A cross-validation study across multiple mixed clinical samples.

Clin Neuropsychol 2021 Mar 24:1-19. Epub 2021 Mar 24.

Department of Psychiatry, University of Illinois College of Medicine, Chicago, IL, USA.

This cross-sectional study examined the effect of number of Performance Validity Test (PVT) failures on neuropsychological test performance among a demographically diverse Veteran (VA) sample ( = 76) and academic medical sample (AMC;  = 128). A secondary goal was to investigate the psychometric implications of including versus excluding those with one PVT failure when cross-validating a series of embedded PVTs. All patients completed the same six criterion PVTs, with the AMC sample completing three additional embedded PVTs. Neurocognitive test performance differences were examined based on number of PVT failures (0, 1, 2+) for both samples, and effect of number of criterion failures on embedded PVT performance was analyzed among the AMC sample. Both groups with 0 or 1 PVT failures performed better than those with ≥2 PVT failures across most cognitive tests. There were nonsignificant differences between those with 0 or 1 PVT failures except for one test in the AMC sample. Receiver operator characteristic curve analyses found no differences in optimal cut score based on number of PVT failures when retaining/excluding one PVT failure. Findings support the use of ≥2 PVT failures as indicative of performance invalidity. These findings strongly support including those with one PVT failure with those with zero PVT failures in diagnostic accuracy studies, given that their inclusion reflects actual clinical practice, does not reduce sample sizes, and does not artificially deflate neurocognitive test results or inflate PVT classification accuracy statistics.
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http://dx.doi.org/10.1080/13854046.2021.1900398DOI Listing
March 2021

Structural resolution of switchable states of a de novo peptide assembly.

Nat Commun 2021 03 9;12(1):1530. Epub 2021 Mar 9.

School of Chemistry, University of Bristol, Cantock's Close, Bristol, UK.

De novo protein design is advancing rapidly. However, most designs are for single states. Here we report a de novo designed peptide that forms multiple α-helical-bundle states that are accessible and interconvertible under the same conditions. Usually in such designs amphipathic α helices associate to form compact structures with consolidated hydrophobic cores. However, recent rational and computational designs have delivered open α-helical barrels with functionalisable cavities. By placing glycine judiciously in the helical interfaces of an α-helical barrel, we obtain both open and compact states in a single protein crystal. Molecular dynamics simulations indicate a free-energy landscape with multiple and interconverting states. Together, these findings suggest a frustrated system in which steric interactions that maintain the open barrel and the hydrophobic effect that drives complete collapse are traded-off. Indeed, addition of a hydrophobic co-solvent that can bind within the barrel affects the switch between the states both in silico and experimentally.
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http://dx.doi.org/10.1038/s41467-021-21851-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943578PMC
March 2021

Complete lung collapse as a rare complication of sarcoidosis-associated mediastinal lymphadenopathy.

Respirol Case Rep 2021 Apr 10;9(4):e00739. Epub 2021 Mar 10.

Department of Pulmonology, Critical Care, and Sleep Medicine Mayo Clinic health System Eau Claire WI USA.

Complete lung collapse associated with sarcoidosis is exceedingly rare. Although lymphoma should be ruled out when patients with mediastinal lymphadenopathy develop lung collapse, sarcoidosis should be considered in the differential, especially when associated with fibrosing mediastinitis.
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http://dx.doi.org/10.1002/rcr2.739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946853PMC
April 2021

People with HIV-1 demonstrate type 1 interferon refractoriness associated with upregulated USP18.

J Virol 2021 Mar 3. Epub 2021 Mar 3.

Department of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

HIV-1 infection persists in humans despite expression of antiviral type 1 interferons (IFN). Even exogenous administration of IFNα only marginally reduces HIV-1 abundance, raising the hypothesis that people living with HIV-1 (PLWH) are refractory to type 1 IFN. We demonstrated type 1 IFN refractoriness in CD4+ and CD8+ T cells isolated from HIV-1 infected persons by detecting diminished STAT1 phosphorylation (pSTAT1) and interferon-stimulated gene (ISG) induction upon type 1 IFN stimulation compared to healthy controls. Importantly, HIV-1 infected people who were virologically suppressed with antiretrovirals also showed type 1 IFN refractoriness. We found that USP18 levels were elevated in people with refractory pSTAT1 and ISG induction and confirmed this finding in CD4+ T cells from another cohort of HIV-HCV coinfected persons who received exogenous pegylated interferon-α2b in a clinical trial. We used a cell culture model to recapitulate type 1 IFN refractoriness in uninfected CD4+ T cells that were conditioned with media from HIV-1 inoculated PBMCs, inhibiting infection with antiretroviral agents. In this model, RNA interference against USP18 partly restored type 1 IFN responses in CD4+ T cells. We found evidence of type 1 IFN refractoriness in PLWH irrespective of virologic suppression that was associated with upregulated USP18, a process that might be therapeutically targeted to improve endogenous control of infection.People living with HIV-1 (PLWH) have elevated constitutive expression of type 1 interferons (IFN). However, it is unclear whether this impacts downstream innate immune responses. We identified refractory responses to type 1 IFN stimulation in T cells from PLWH, independent of antiretroviral treatment. Type 1 IFN refractoriness was linked to elevated USP18 levels in the same cells. Moreover, we found that USP18 levels predicted the anti-HIV-1 effect of type 1 IFN-based therapy on PLWH. , we demonstrated that refractory type 1 IFN responses were transferrable to HIV-1 uninfected target CD4+ T cells, and this phenomenon was mediated by type 1 IFN from HIV-1 infected cells. Type 1 IFN responses were partially restored by USP18 knockdown. Our findings illuminate a new mechanism by which HIV-1 contributes to innate immune dysfunction in PLWH, through the continuous production of type 1 IFN that induces a refractory state of responsiveness.
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http://dx.doi.org/10.1128/JVI.01777-20DOI Listing
March 2021

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

Lancet 2021 03 19;397(10277):881-891. Epub 2021 Feb 19.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK. Electronic address:

Background: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.

Methods: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 10 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 10 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005).

Findings: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]).

Interpretation: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose.

Funding: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(21)00432-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7894131PMC
March 2021

Interventions to reduce social isolation and loneliness during COVID-19 physical distancing measures: A rapid systematic review.

PLoS One 2021 17;16(2):e0247139. Epub 2021 Feb 17.

The Primary Care Unit, Department of Public Health and Primary Care, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.

Background: A significant proportion of the worldwide population is at risk of social isolation and loneliness as a result of the COVID-19 pandemic. We aimed to identify effective interventions to reduce social isolation and loneliness that are compatible with COVID-19 shielding and social distancing measures.

Methods And Findings: In this rapid systematic review, we searched six electronic databases (Medline, Embase, Web of Science, PsycINFO, Cochrane Database of Systematic Reviews and SCOPUS) from inception to April 2020 for systematic reviews appraising interventions for loneliness and/or social isolation. Primary studies from those reviews were eligible if they included: 1) participants in a non-hospital setting; 2) interventions to reduce social isolation and/or loneliness that would be feasible during COVID-19 shielding measures; 3) a relevant control group; and 4) quantitative measures of social isolation, social support or loneliness. At least two authors independently screened studies, extracted data, and assessed risk of bias using the Downs and Black checklist. Study registration: PROSPERO CRD42020178654. We identified 45 RCTs and 13 non-randomised controlled trials; none were conducted during the COVID-19 pandemic. The nature, type, and potential effectiveness of interventions varied greatly. Effective interventions for loneliness include psychological therapies such as mindfulness, lessons on friendship, robotic pets, and social facilitation software. Few interventions improved social isolation. Overall, 37 of 58 studies were of "Fair" quality, as measured by the Downs & Black checklist. The main study limitations identified were the inclusion of studies of variable quality; the applicability of our findings to the entire population; and the current poor understanding of the types of loneliness and isolation experienced by different groups affected by the COVID-19 pandemic.

Conclusions: Many effective interventions involved cognitive or educational components, or facilitated communication between peers. These interventions may require minor modifications to align with COVID-19 shielding/social distancing measures. Future high-quality randomised controlled trials conducted under shielding/social distancing constraints are urgently needed.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247139PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7888614PMC
March 2021

Climate impacts of U.S. forest loss span net warming to net cooling.

Sci Adv 2021 Feb 12;7(7). Epub 2021 Feb 12.

Graduate School of Geography, Clark University, Worcester, MA 01610, USA.

Storing carbon in forests is a leading land-based strategy to curb anthropogenic climate change, but its planetary cooling effect is opposed by warming from low albedo. Using detailed geospatial data from Earth-observing satellites and the national forest inventory, we quantify the net climate effect of losing forest across the conterminous United States. We find that forest loss in the intermountain and Rocky Mountain West causes net planetary cooling but losses east of the Mississippi River and in Pacific Coast states tend toward net warming. Actual U.S. forest conversions from 1986 to 2000 cause net cooling for a decade but then transition to a large net warming over a century. Avoiding these forest conversions could have yielded a 100-year average annual global cooling of 0.00088°C. This would offset 17% of the 100-year climate warming effect from a single year of U.S. fossil fuel emissions, underscoring the scale of the mitigation challenge.
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http://dx.doi.org/10.1126/sciadv.aax8859DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880589PMC
February 2021

Neuropathologic Findings in Chronic Kidney Disease (CKD).

J Stroke Cerebrovasc Dis 2021 Feb 9:105657. Epub 2021 Feb 9.

Department of Pathology & Laboratory Medicine. Electronic address:

Studying the neuropathologic autopsy findings in subjects with chronic kidney disease (CKD) or chronic renal failure (CRF) is difficult for several reasons: etiology of the CKD may be heterogeneous, affected patients may have one or more major co-morbidities that themselves can cause significant neurologic disease, and agonal events may result in significant findings that were of minimal significance earlier in a patient's life. We studied the constellation of neuropathologic abnormalities in 40 autopsy brains originating from subjects of ages 34-95 years (no children in the study). The most common pathologic change was that of ischemic infarcts (cystic, lacunar and/or microinfarcts), which were seen in over half of subjects. These were associated with both large artery atherosclerosis and arteriolosclerosis (A/S), the latter finding being present in 29/40 subjects. Charcot-Bouchard microaneurysms were present in the brains of three subjects, in one case associated with severe amyloid angiopathy. Microvascular calcinosis (medial sclerosis in the case of arterioles) was seen in the basal ganglia (n=8) and/or endplate region of the hippocampus (n=7) and occasional ischemic infarcts in one brain showed severe calcification. Sequelae of cerebrovascular disease (especially A/S or microvascular disease) are a common neuropathologic substrate for neurologic disability and brain lesions in this complex group of patients. Regulation of calcium metabolism within brain microvessel walls may be worthy of further research in both human brain specimens and animal models.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105657DOI Listing
February 2021

Loss of the exocyst complex component EXOC3 promotes hemostasis and accelerates arterial thrombosis.

Blood Adv 2021 Feb;5(3):674-686

School of Physiology, Pharmacology & Neuroscience, University of Bristol, Bristol, United Kingdom; and.

The exocyst is an octameric complex comprising 8 distinct protein subunits, exocyst complex components (EXOC) 1 to 8. It has an established role in tethering secretory vesicles to the plasma membrane, but its relevance to platelet granule secretion and function remains to be determined. Here, EXOC3 conditional knockout (KO) mice in the megakaryocyte/platelet lineage were generated to assess exocyst function in platelets. Significant defects in platelet aggregation, integrin activation, α-granule (P-selectin and platelet factor 4), dense granule, and lysosomal granule secretion were detected in EXOC3 KO platelets after treatment with a glycoprotein VI (GPVI)-selective agonist, collagen-related peptide (CRP). Except for P-selectin exposure, these defects were completely recovered by maximal CRP concentrations. GPVI surface levels were also significantly decreased by 14.5% in KO platelets, whereas defects in proximal GPVI signaling responses, Syk and LAT phosphorylation, and calcium mobilization were also detected, implying an indirect mechanism for these recoverable defects due to decreased surface GPVI. Paradoxically, dense granule secretion, integrin activation, and changes in surface expression of integrin αIIb (CD41) were significantly increased in KO platelets after protease-activated receptor 4 activation, but calcium responses were unaltered. Elevated integrin activation responses were completely suppressed with a P2Y12 receptor antagonist, suggesting enhanced dense granule secretion of adenosine 5'-diphosphate as a critical mediator of these responses. Finally, arterial thrombosis was significantly accelerated in KO mice, which also displayed improved hemostasis determined by reduced tail bleeding times. These findings reveal a regulatory role for the exocyst in controlling critical aspects of platelet function pertinent to thrombosis and hemostasis.
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http://dx.doi.org/10.1182/bloodadvances.2020002515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7876885PMC
February 2021

YouTube as a source of information on the COVID-19 pandemic.

J Community Hosp Intern Med Perspect 2021 Jan 26;11(1):39-41. Epub 2021 Jan 26.

Department of Behavioral and Community Health, University of Maryland School of Public Health, Rochester, NY, USA.

: YouTube is a popular website where public can access and gain information from videos related to COVID-19. This paper seeks to assess the quality and validity of information available on YouTube, based on the current Center for Disease Control (CDC) and World Health Organization (WHO) guidelines. : We identified the 250 most-viewed videos from 1 January 2020 to 12 May 2020 on YouTube using keyword 'COVID 19'. Two independent reviewers analyzed the English-language videos as useful, misleading, or news updates. : After excluding non-English and irrelevant videos, 100 videos were analyzed. Forty-four videos were classified as useful, 33 videos were classified as news updates, and 23 videos were classified as misleading. Independent users had five times increased odds of posting misleading videos (40% vs. 12%, OR = 5.05, 95% CI = 1.84-13.9, P = 0.001), whereas news agencies have 2.8 greater odds of posting useful or update videos (87% vs 44%, OR = 2.85, 95% CI = 0.959-8.45, P = 0.087). : YouTube is an increasingly important source of medical information during the COVID-19 pandemic. Most of the videos were useful, however due to the public nature of the platform, misleading information may also be easily disseminated. Independent users are more likely to post-misleading videos.
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http://dx.doi.org/10.1080/20009666.2020.1837412DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850399PMC
January 2021

Additively manufactured respirators: quantifying particle transmission and identifying system-level challenges for improving filtration efficiency.

J Manuf Syst 2021 Jan 30. Epub 2021 Jan 30.

Department of Mechanical Engineering, Virginia Tech, Blacksburg, VA, 24061, United States.

The COVID-19 pandemic has disrupted the supply chain for personal protective equipment (PPE) for medical professionals, including N95-type respiratory protective masks. To address this shortage, many have looked to the agility and accessibility of additive manufacturing (AM) systems to provide a democratized, decentralized solution to producing respirators with equivalent protection for last-resort measures. However, there are concerns about the viability and safety in deploying this localized download, print, and wear strategy due to a lack of commensurate quality assurance processes. Many open-source respirator designs for AM indicate that they do not provide N95-equivalent protection (filtering 95% of SARS-CoV-2 particles) because they have either not passed aerosol generation tests or not been tested. Few studies have quantified particle transmission through respirator designs outside of the filter medium. This is concerning because several polymer-based AM processes produce porous parts, and inherent process variation between printers and materials also threaten the integrity of tolerances and seals within the printed respirator assembly. No study has isolated these failure mechanisms specifically for respirators. The goal of this paper is to measure particle transmission through printed respirators of different designs, materials, and AM processes. The authors compare the performance of printed respirators to N95 respirators and cloth masks. Respirators in this study printed using desktop- and industrial-scale fused filament fabrication processes and industrial-scale powder bed fusion processes were not sufficiently reliable for widespread distribution and local production of N95-type respiratory protection. Even while assuming a perfect seal between the respirator and the user's face, although a few respirators provided >90% efficiency at the 100-300 nm particle range, almost all printed respirators provided <60% filtration efficiency. Post-processing procedures including cleaning, sealing surfaces, and reinforcing the filter cap seal generally improved performance, but the printed respirators showed similar performance to various cloth masks. The authors further explore the process-driven aspects leading to low filtration efficiency. Although the design/printer/material combination dictates the AM respirator performance, the identified failure modes originate from system-level constraints and are therefore generalizable across multiple AM processes. Quantifying the limitations of AM in producing N95-type respiratory protective masks advances understanding of AM systems toward the development of better part and machine designs to meet the needs of reliable, functional, end-use parts.
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http://dx.doi.org/10.1016/j.jmsy.2021.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846466PMC
January 2021

Herbal Supplements: Precautions and Safe Use.

Nurs Clin North Am 2021 03 29;56(1):1-21. Epub 2020 Dec 29.

School of Nursing, Vanderbilt University, 461 21st Avenue South, Nashville, TN 37240, USA. Electronic address:

The Food and Drug Administration (FDA) classifies herbal preparations as food supplements. New herbal supplements and products are not governed by the strict FDA drug approval process and there is no premarket approval required. The FDA prohibits manufacturers and distributors from marketing adulterated or misbranded products but does not rigorously define safe practices. Scientific evidence related to herbal supplements is limited. Herbal supplements have been associated with adverse reactions and herbal-drug interactions. Information and precautions for 20 common herbal supplements, including St. John's wort, ginseng, echinacea, and ginkgo, are reviewed. Resources for consumers and health care professionals are highlighted.
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http://dx.doi.org/10.1016/j.cnur.2020.10.001DOI Listing
March 2021

Cryo-EM model validation recommendations based on outcomes of the 2019 EMDataResource challenge.

Nat Methods 2021 02 4;18(2):156-164. Epub 2021 Feb 4.

Department of Bioengineering, Stanford University, Stanford, CA, USA.

This paper describes outcomes of the 2019 Cryo-EM Model Challenge. The goals were to (1) assess the quality of models that can be produced from cryogenic electron microscopy (cryo-EM) maps using current modeling software, (2) evaluate reproducibility of modeling results from different software developers and users and (3) compare performance of current metrics used for model evaluation, particularly Fit-to-Map metrics, with focus on near-atomic resolution. Our findings demonstrate the relatively high accuracy and reproducibility of cryo-EM models derived by 13 participating teams from four benchmark maps, including three forming a resolution series (1.8 to 3.1 Å). The results permit specific recommendations to be made about validating near-atomic cryo-EM structures both in the context of individual experiments and structure data archives such as the Protein Data Bank. We recommend the adoption of multiple scoring parameters to provide full and objective annotation and assessment of the model, reflective of the observed cryo-EM map density.
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http://dx.doi.org/10.1038/s41592-020-01051-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864804PMC
February 2021

Tsetse salivary glycoproteins are modified with paucimannosidic N-glycans, are recognised by C-type lectins and bind to trypanosomes.

PLoS Negl Trop Dis 2021 Feb 2;15(2):e0009071. Epub 2021 Feb 2.

Department of Vector Biology, Liverpool School of Tropical Medicine, Liverpool, United Kingdom.

African sleeping sickness is caused by Trypanosoma brucei, a parasite transmitted by the bite of a tsetse fly. Trypanosome infection induces a severe transcriptional downregulation of tsetse genes encoding for salivary proteins, which reduces its anti-hemostatic and anti-clotting properties. To better understand trypanosome transmission and the possible role of glycans in insect bloodfeeding, we characterized the N-glycome of tsetse saliva glycoproteins. Tsetse salivary N-glycans were enzymatically released, tagged with either 2-aminobenzamide (2-AB) or procainamide, and analyzed by HILIC-UHPLC-FLR coupled online with positive-ion ESI-LC-MS/MS. We found that the N-glycan profiles of T. brucei-infected and naïve tsetse salivary glycoproteins are almost identical, consisting mainly (>50%) of highly processed Man3GlcNAc2 in addition to several other paucimannose, high mannose, and few hybrid-type N-glycans. In overlay assays, these sugars were differentially recognized by the mannose receptor and DC-SIGN C-type lectins. We also show that salivary glycoproteins bind strongly to the surface of transmissible metacyclic trypanosomes. We suggest that although the repertoire of tsetse salivary N-glycans does not change during a trypanosome infection, the interactions with mannosylated glycoproteins may influence parasite transmission into the vertebrate host.
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http://dx.doi.org/10.1371/journal.pntd.0009071DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880456PMC
February 2021

Testing an evidence-based drug abuse and violence preventive approach adapted for youth in juvenile justice diversionary settings.

Health Justice 2021 Feb 2;9(1). Epub 2021 Feb 2.

National Health Promotion Associates, White Plains, New York, USA.

Background: Universal school-based prevention programs for alcohol, tobacco, and other drug use are typically designed for all students within a particular school setting. However, it is unclear whether such broad-based programs are effective for youth at risk for substance use and violence in juvenile justice settings.

Method: The present study tested the feasibility, appropriateness, and efficacy of a preventive intervention to reduce risk factors for substance use and delinquency among youth in juvenile justice diversionary settings by promoting positive youth development and building personal strengths and prosocial relationships. Participants in the study (N = 288) were predominantly male (69%) and in the 9th grade (14 years old) or higher (91%), received the preventive intervention, and completed confidential questionnaires at the pre-test and post-test.

Results: The majority of youth who participated in the intervention rated the program topics (77.9%) and activities (72%) as appropriate for their age, would recommend it to their peers (73.6%), and would use the skills learned in the future (85.4%). Comparison of post-test adjusted means revealed that the prevention program had a significant positive impact on key knowledge, attitudes, and skills including goal-setting, stress-management, and communication skills.

Conclusions: The findings indicate that an evidence-based prevention approach adapted for youth diversionary settings can be effectively implemented and well-received by participating youth, and can produce positive changes in psychosocial skills and protective factors known to prevent multiple risk behaviors among youth. Future efforts to implement substance use prevention in community juvenile justice settings may benefit from highlighting a positive youth development, skills-based approach.
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http://dx.doi.org/10.1186/s40352-021-00128-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856753PMC
February 2021

Breast Cancer Reconstruction: Design Criteria for a Humanized Microphysiological System.

Tissue Eng Part A 2021 Mar 10. Epub 2021 Mar 10.

Obatala Sciences, Inc., New Orleans, Louisiana, USA.

International regulatory agencies such as the Food and Drug Administration have mandated that the scientific community develop humanized microphysiological systems (MPS) as an alternative to animal models in the near future. While the breast cancer research community has long appreciated the importance of three-dimensional growth dynamics in their experimental models, there are remaining obstacles preventing a full conversion to humanized MPS for drug discovery and pathophysiological studies. This perspective evaluates the current status of human tissue-derived cells and scaffolds as building blocks for an "idealized" breast cancer MPS based on bioengineering design principles. It considers the utility of adipose tissue as a potential source of endothelial, lymphohematopoietic, and stromal cells for the support of breast cancer epithelial cells. The relative merits of potential MPS scaffolds derived from adipose tissue, blood components, and synthetic biomaterials is evaluated relative to the current "gold standard" material, Matrigel, a murine chondrosarcoma-derived basement membrane-enriched hydrogel. The advantages and limitations of a humanized breast cancer MPS are discussed in the context of in-process and destructive read-out assays.
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http://dx.doi.org/10.1089/ten.TEA.2020.0372DOI Listing
March 2021

The Effect of Class Imbalance on Precision-Recall Curves.

Neural Comput 2021 Jan 29:1-5. Epub 2021 Jan 29.

School of Informatics, University of Edinburgh, Edinburgh EH8 9AB, U.K.

In this note, I study how the precision of a binary classifier depends on the ratio of positive to negative cases in the test set, as well as the classifier's true and false-positive rates. This relationship allows prediction of how the precision-recall curve will change with , which seems not to be well known. It also allows prediction of how and the precision gain and recall gain measures of Flach and Kull (2015) vary with .
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http://dx.doi.org/10.1162/neco_a_01362DOI Listing
January 2021

Frequency-dependent optimal weighting approach for megavoltage multilayer imagers.

Phys Med Biol 2021 Jan 27. Epub 2021 Jan 27.

Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, Massachusetts, UNITED STATES.

We developed and validated a method for optimally combining the sub-images of mega-voltage (MV) multi-layer imager (MLI) devices that are built with heterogeneous layers. Two MLI configurations were modeled within the GATE Monte Carlo package by stacking different layers of a GdOS:Tb (GOS) phosphor and a LKH-5 glass scintillator. Detector response was characterized in terms of the modulation transfer function (MTF), normalized noise power spectrum (NNPS) and detective quantum efficiency (DQE). Spatial frequency-dependent weighting factors were then analytically derived for each layer such that the total DQE of the summed combination image would be maximized across all spatial modes. The final image is obtained as the weighted sum of the sub-images from each layer. Optimal weighting factors that maximize the DQE were found to be the quotient of MTF and NNPS of each layer in the heterogeneous MLI detector. Results validated the improvement of the DQE across the entire frequency domain. For the LKH-5 slab configuration, DQE(0) increases between 2-3%, while the corresponding improvement for the LKH-5 pixelated configuration was around 7%. The performance of the weighting method was quantitatively evaluated with respect to spatial resolution, contrast-to-noise ratio (CNR) and signal-to-noise ratio (SNR) of simulated planar images of phantoms at 2.5 and 6 MV. The line pair phantom acquisition exhibit two fold increases in CNR and SNR, however MTF was degraded at spatial frequencies greater than 0.2 lp/mm. For the Las Vegas phantom, the weighting improved the CNR by around 30% depending on the contrast region while the SNR values are higher by a factor of 2.5. These results indicate that the imaging performance of MLI systems can be enhanced using the proposed frequency-dependent weighting scheme. The CNR and SNR of the weighted combined image is improved across all spatial scales independent of the detector combination or photon beam energy.
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http://dx.doi.org/10.1088/1361-6560/abe051DOI Listing
January 2021

Statin Use, Heart Radiation Dose, and Survival in Locally Advanced Lung Cancer.

Pract Radiat Oncol 2021 Jan 18. Epub 2021 Jan 18.

Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts. Electronic address:

Purpose: Patients with locally advanced non-small cell lung cancer (LA-NSCLC) have a high prevalence of pre-existing coronary heart disease and face excess cardiac risk after thoracic radiation therapy. We sought to assess whether statin therapy is a predictor of overall survival (OS) after thoracic radiation therapy.

Methods And Materials: We performed a retrospective analysis of 748 patients with LA-NSCLC treated with thoracic radiation therapy, using Kaplan-Meier OS estimates and Cox regression.

Results: Statin use among high cardiac risk patients (Framingham risk ≥20% or pre-existing coronary heart disease; n = 496) was 51.2%. After adjustment for baseline cardiac risk and other prognostic factors, statin therapy was associated with a significantly increased risk of all-cause mortality (adjusted hazard ratio, 1.39; 95% confidence interval [CI], 1.00-1.91; P = .048) but not major adverse cardiac events (adjusted hazard ratio, 1.18; 95% CI, 0.52-2.68; P = .69). Among statin-naïve patients, mean heart dose ≥10 Gy versus <10 Gy was associated with a significantly increased risk of all-cause mortality (hazard ratio, 1.32; 95% CI, 1.04-1.68; P = .022), with 2-year OS estimates of 46.9% versus 60.0%, respectively. However, OS did not differ by heart dose among patients on statin therapy (hazard ratio, 1.00; 95% CI, 0.76-1.32; P = 1.00; P-interaction = .031), with 2-year OS estimates of 46.9% versus 50.3%, respectively.

Conclusions: Among patients with LA-NSCLC, only half of statin-eligible high cardiac risk patients were on statin therapy, reflecting the highest cardiac risk level of our cohort. Statin use was an independent predictor of all-cause mortality but not major adverse cardiac events. Elevated mean heart dose (≥10 Gy) was associated with increased risk of all-cause mortality in statin-naïve patients but not among those on statin therapy, identifying a group of patients in which early intervention with statins may mitigate the deleterious effects of high heart radiation therapy dose. This warrants evaluation in prospective trials.
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http://dx.doi.org/10.1016/j.prro.2020.12.006DOI Listing
January 2021

Prevention of Unwanted Sexual Contact Among Cadets at the United States Air Force Academy: A Brief Small-Group Intervention.

Am J Public Health 2021 04 21;111(4):672-674. Epub 2021 Jan 21.

Kenneth W. Griffin is with the Department of Global and Community Health, College of Health and Human Services, George Mason University, Fairfax, VA. Christopher Williams is with National Health Promotion Associates, White Plains, NY, and the Department of Psychology, SUNY Purchase, Purchase, NY. At the time of the study, Wendy Travis was with the Department of Behavioral Sciences & Leadership, US Air Force Academy, Colorado Springs, CO. Andra Tharp was with Integrated Resilience Office, Headquarters Air Force, US Air Force, Washington, DC.

This study tested the effectiveness of a small-group preventive intervention designed to prevent unwanted sexual contact among cadets at the US Air Force Academy. Among cadets in the incoming class of 2021, unwanted sexual contact was cut by nearly half in the intervention group relative to the control group. This study is one of the first rigorously designed trials to demonstrate a significant impact on unwanted sexual contact among students attending a US military service academy.. ClinicalTrials.gov identifier: NCT03839797.
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http://dx.doi.org/10.2105/AJPH.2020.306050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958058PMC
April 2021

Abbreviated on-treatment CBCT using roughness penalized mono-energization of kV-MV data and a multi-layer MV imager.

Phys Med Biol 2021 Jan 20. Epub 2021 Jan 20.

Dana Farber Cancer Institute, Boston, Massachusetts, UNITED STATES.

Simultaneous acquisition of cone beam CT (CBCT) projections using both the kV and MV imagers of an image guided radiotherapy (IGRT) system reduces set-up scan times -- a benefit to lung cancer radiation oncology patients -- but increases noise in the 3D reconstruction. In this article, we present a kV-MV scan time reduction technique that uses two noise-reducing measures to achieve superior performance. The first is a high DQE multi-layer MV imager prototype. The second is a beam hardening correction algorithm which combines poly-energetic modeling with edge-preserving, regularized smoothing of the projections. Performance was tested in real acquisitions of the Catphan 604 and a thorax phantom. Percent noise was quantified from voxel values in a soft tissue volume of interest (VOI) while edge blur was quantified from a VOI straddling a boundary between air and soft material. Comparisons in noise/resolution performance trade-off were made between our proposed approach, a dose-equivalent kV-only scan, and a kV-MV reconstruction technique previously published by Yin et al. (2005 Med. Phys. (32) 9). The proposed technique demonstrated lower noise as a function of spatial resolution than the baseline kV-MV method, notably a 50% noise reduction at typical edge blur levels. Our proposed method also exhibited fainter non-uniformity artifacts and in some cases superior contrast. Overall, we find that the combination of a multi-layer MV imager, acquiring at a LINAC source energy of 2.5 MV, and a denoised beam hardening correction algorithm enables noise, resolution, and dose performance comparable to standard kV-imager only set-up CBCT, but with nearly half the gantry rotation time.
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http://dx.doi.org/10.1088/1361-6560/abddd2DOI Listing
January 2021

Improving SARS-CoV-2 structures: Peer review by early coordinate release.

Biophys J 2021 03 16;120(6):1085-1096. Epub 2021 Jan 16.

Department of Biochemistry, Duke University, Durham, North Carolina. Electronic address:

This work builds upon the record-breaking speed and generous immediate release of new experimental three-dimensional structures of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and complexes, which are crucial to downstream vaccine and drug development. We have surveyed those structures to catch the occasional errors that could be significant for those important uses and for which we were able to provide demonstrably higher-accuracy corrections. This process relied on new validation and correction methods such as CaBLAM and ISOLDE, which are not yet in routine use. We found such important and correctable problems in seven early SARS-CoV-2 structures. Two of the structures were soon superseded by new higher-resolution data, confirming our proposed changes. For the other five, we emailed the depositors a documented and illustrated report and encouraged them to make the model corrections themselves and use the new option at the worldwide Protein Data Bank for depositors to re-version their coordinates without changing the Protein Data Bank code. This quickly and easily makes the better-accuracy coordinates available to anyone who examines or downloads their structure, even before formal publication. The changes have involved sequence misalignments, incorrect RNA conformations near a bound inhibitor, incorrect metal ligands, and cis-trans or peptide flips that prevent good contact at interaction sites. These improvements have propagated into nearly all related structures done afterward. This process constitutes a new form of highly rigorous peer review, which is actually faster and more strict than standard publication review because it has access to coordinates and maps; journal peer review would also be strengthened by such access.
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http://dx.doi.org/10.1016/j.bpj.2020.12.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7834719PMC
March 2021

Identification and characterization of novel variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.

Cold Spring Harb Mol Case Stud 2021 Feb 19;7(1). Epub 2021 Feb 19.

Baylor College of Medicine, Integrated Molecular and Biomedical Sciences Graduate Program, Houston, Texas 77030, USA.

Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, , which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing : arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous c.619delG, p.(Asp207Thrfs*22), or the -encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.
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http://dx.doi.org/10.1101/mcs.a005454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903889PMC
February 2021