Publications by authors named "David Young"

783 Publications

Barriers and enablers to influenza vaccination uptake in adults with chronic respiratory conditions: applying the behaviour change wheel to specify multi-levelled tailored intervention content.

Psychol Health 2021 Jul 30:1-20. Epub 2021 Jul 30.

School of Psychological Sciences & Health, University of Strathclyde, Scotland, UK.

Objective: To specify intervention content to enhance influenza vaccination uptake among adults with chronic respiratory conditions using the Behaviour Change Wheel (BCW).

Design: Cross-sectional, multi-modal data collection and theory-informed analysis and expert stakeholder engagement.

Methods: Content analysis was used to identify barriers and enablers to influenza vaccination from nine focus groups (n = 38), individual interviews (n = 21) and open-ended survey responses (n = 101). The Theoretical Domains Framework (TDF) and the BCW were used to specify evidence-based and theoretically-informed recommendations. Expert stakeholders refined recommendations using the Acceptability, Practicability, Effectiveness, Affordability, Side-effects, and Equity (APEASE) criteria to yield a range of potentially actionable ideas.

Results: TDF analysis identified perceptions of vaccine side effects (beliefs about consequences [BACons]) was the most common barrier to vaccination, followed by time constraints (environmental context and resources [ECR]) and fear of needles (Emotion). Enablers included protection from influenza (BACons), receiving reminders (ECR) and support from others (Social Influences). These factors mapped to seven BCW intervention functions and 22 behaviour change techniques.

Conclusions: Factors affecting vaccine uptake are multifaceted and multileveled. The study suggested a suite of complementary multi-level intervention components to enhance vaccination uptake involving a range of diverse actors, intervention recipients and settings.
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http://dx.doi.org/10.1080/08870446.2021.1957104DOI Listing
July 2021

A Photoluminescent Ag10Cu6 Cluster Stablized by a PNNP Ligand and Phenylacetylides Selectively and Reversibly Senses Ammonia in Air and Water.

Chem Asian J 2021 Jul 26. Epub 2021 Jul 26.

Soochow University, College of Chemistry, Chemical Engineering and Materials Science, 199 RenAi road, Suzhou Industrial Park, 215123, Suzhou, CHINA.

Photoluminescent bimetallic cluster [Ag10Cu6(bdppthi)2(C≡CPh)12(MeOH)2(H2O)](ClO4)4 (1) , bdppthi = N,N'-bis(diphenylphosphanylmethyl)-tetrahydroimidazole} was synthesized from the PNNP type ligand bdppthi generated in-situ . Upon excitation at 365 nm, 1 exhibited strong phosphorescent emission at 630 nm, which was selectively quenched by NH 3 in air or water. The sensing of NH3 was rapid and recoverable, with detection limits of 53 ppm (v/v) in N2 and 21 μM (0.36 ppm, w/w) for NH3 ·H2O in water. Cluster 1 could potentially serve as a bifunctional chemical sensor for the efficient detection of ammonia in waste-gas and waste-water.
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http://dx.doi.org/10.1002/asia.202100783DOI Listing
July 2021

Matrix metalloproteinase-13 is fully activated by neutrophil elastase, and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis.

FEBS J 2021 Jul 16. Epub 2021 Jul 16.

Skeletal Research Group, Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

Matrix metalloproteinase-13 is a uniquely important collagenase that promotes the irreversible destruction of cartilage collagen in osteoarthritis (OA). Collagenase activation is a key control point for cartilage breakdown to occur, yet our understanding of the proteinases involved in this process is limited. Neutrophil elastase is a well-described proteoglycan-degrading enzyme which is historically associated with inflammatory arthritis, but more recent evidence suggests a potential role in OA. In this study, we investigated the effect of neutrophil elastase on OA cartilage collagen destruction and collagenase activation. Neutrophil elastase induced significant collagen destruction from human OA cartilage ex vivo, in an MMP-dependent manner. In vitro, neutrophil elastase directly and robustly activated proMMP-13, and N-terminal sequencing identified cleavage close to the cysteine switch at MKKPR, ultimately resulting in the fully active form with the neo-N terminus of YNVFP. Mole-per-mole, activation was more potent than by MMP-3, a classical collagenase activator. Elastase was detectable in human OA synovial fluid, and OA synovia which displayed histologically graded evidence of synovitis. Bioinformatic analyses demonstrated that, compared with other tissues, control cartilage exhibited remarkably high transcript levels of the major elastase inhibitor, alpha-1 antitrypsin (AAT; gene name SERPINA1), but these were reduced in OA. AAT was located predominantly in superficial cartilage zones, and staining enhanced in regions of cartilage damage. Finally, active MMP-13 specifically inactivated AAT by removal of the serine proteinase cleavage/inhibition site. Taken together, this study identifies elastase as a novel activator of proMMP-13 that has relevance for cartilage collagen destruction in OA patients with synovitis.
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http://dx.doi.org/10.1111/febs.16127DOI Listing
July 2021

Cement-in-cement femoral component revision : a comparison of two different taper-slip designs with medium-term follow up.

Bone Joint J 2021 Jul;103-B(7):1215-1221

Queen Elizabeth University Hospital, Glasgow, UK.

Aims: Cement-in-cement revision of the femoral component represents a widely practised technique for a variety of indications in revision total hip arthroplasty. In this study, we compare the clinical and radiological outcomes of two polished tapered femoral components.

Methods: From our prospectively collated database, we identified all patients undergoing cement-in-cement revision from January 2005 to January 2013 who had a minimum of two years' follow-up. All cases were performed by the senior author using either an Exeter short revision stem or the C-Stem AMT high offset No. 1 prosthesis. Patients were followed-up annually with clinical and radiological assessment.

Results: A total of 97 patients matched the inclusion criteria (50 Exeter and 47 C-Stem AMT components). There were no significant differences between the patient demographic data in either group. Mean follow-up was 9.7 years. A significant improvement in Oxford Hip Score (OHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and 12-item Short-Form Survey (SF-12) scores was observed in both cohorts. Leg lengths were significantly shorter in the Exeter group, with a mean of -4 mm in this cohort compared with 0 mm in the C-Stem AMT group. One patient in the Exeter group had early evidence of radiological loosening. In total, 16 patients (15%) underwent further revision of the femoral component (seven in the C-Stem AMT group and nine in the Exeter group). No femoral components were revised for aseptic loosening. There were two cases of femoral component fracture in the Exeter group.

Conclusion: Our series shows promising mid-term outcomes for the cement-in-cement revision technique using either the Exeter or C-Stem AMT components. These results demonstrate that cement-in-cement revision using a double or triple taper-slip design is a safe and reliable technique when used for the correct indications. Cite this article:  2021;103-B(7):1215-1221.
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http://dx.doi.org/10.1302/0301-620X.103B7.BJJ-2020-1953.R2DOI Listing
July 2021

Prediction and Validation of Hematopoietic Stem and Progenitor Cell Off-Target Editing in Transplanted Rhesus Macaques.

Mol Ther 2021 Jun 23. Epub 2021 Jun 23.

Translational Stem Cell Biology Branch, NHLBI, NIH, Bethesda, MD 20892, USA. Electronic address:

The programmable nuclease technology CRISPR/Cas9 has revolutionized gene editing in the last decade. Due to the risk of off-target editing, accurate and sensitive methods for off-target characterization are crucial prior to applying CRISPR/Cas9 therapeutically. Here, we utilized a rhesus macaque model to compare the predictive values of CIRCLE-seq, an in vitro off-target prediction method, with in silico prediction (ISP) based solely on genomic sequence comparisons. We use AmpliSeq HD error-corrected sequencing to validate off-target sites predicted by CIRCLE-seq and ISP for a CD33 gRNA with thousands of off-target sites predicted by ISP and CIRCLE-seq. We found poor correlation between the sites predicted by the two methods. When almost 500 sites predicted by each method were analyzed by error-corrected sequencing of hematopoietic cells following transplantation, 19 off-target sites revealed insertion/deletion mutations. Of these sites, 8 were predicted by both methods, 8 by CIRCLE-seq only, and 3 by ISP only. The levels of cells with these off-target edits exhibited no expansion or abnormal behavior in vivo in animals followed for up to 2 years. In addition, we utilized an unbiased method termed CAST-Seq to search for translocations between the on-target site and off-target sites present in animals following transplantation, detecting one specific translocation that persisted in blood cells for at least one year following transplantation. In conclusion, neither CIRCLE-seq or ISP predicted all sites, and a combination of careful gRNA design, followed by screening for predicted off-target sites in target cells by multiple methods may be required for optimizing safety of clinical development.
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http://dx.doi.org/10.1016/j.ymthe.2021.06.016DOI Listing
June 2021

Osteoporosis, fracture, osteoarthritis & sarcopenia: A systematic review of circulating microRNA association.

Bone 2021 Nov 22;152:116068. Epub 2021 Jun 22.

Population Health Sciences Institute, Faculty of Medicine, Newcastle University, Sir James Spence Building, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, United Kingdom; Medical Research Council Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing, Newcastle University, Newcastle upon Tyne NE2 4HH, United Kingdom. Electronic address:

Circulating microRNAs (c-miRs) show promise as biomarkers. This systematic review explores their potential association with age-related fracture/osteoporosis (OP), osteoarthritis (OA) and sarcopenia (SP), as well as cross-disease association. Most overlap occurred between OA and OP, suggesting potentially shared microRNA activity. There was little agreement in results across studies. Few reported receiver operating characteristic analysis (ROC) and many identified significant dysregulation in disease, but direction of effect was commonly conflicting. c-miRs with most evidence for consistency in dysregulation included miR-146a, miR-155 and miR-98 for OA (upregulated). Area under the curve (AUC) for miR-146a biomarker performance was AUC 0.92, p = 0.028. miR-125b (AUC 0.76-0.89), miR-100, miR-148a and miR-24 were consistently upregulated in OP. Insufficient evidence exists for c-miRs in SP. Study quality was typically rated intermediate/high risk of bias. Wide study heterogeneity meant meta-analysis was not possible. We provide detailed critique and recommendations for future approaches in c-miR analyses based on this review.
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http://dx.doi.org/10.1016/j.bone.2021.116068DOI Listing
November 2021

Hybrid AI-assistive diagnostic model permits rapid TBS classification of cervical liquid-based thin-layer cell smears.

Nat Commun 2021 06 10;12(1):3541. Epub 2021 Jun 10.

Department of Pathology, Guangdong Provincial Women's and Children's Dispensary, Shenzhen, Guangdong Province, PR China.

Technical advancements significantly improve earlier diagnosis of cervical cancer, but accurate diagnosis is still difficult due to various factors. We develop an artificial intelligence assistive diagnostic solution, AIATBS, to improve cervical liquid-based thin-layer cell smear diagnosis according to clinical TBS criteria. We train AIATBS with >81,000 retrospective samples. It integrates YOLOv3 for target detection, Xception and Patch-based models to boost target classification, and U-net for nucleus segmentation. We integrate XGBoost and a logical decision tree with these models to optimize the parameters given by the learning process, and we develop a complete cervical liquid-based cytology smear TBS diagnostic system which also includes a quality control solution. We validate the optimized system with >34,000 multicenter prospective samples and achieve better sensitivity compared to senior cytologists, yet retain high specificity while achieving a speed of <180s/slide. Our system is adaptive to sample preparation using different standards, staining protocols and scanners.
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http://dx.doi.org/10.1038/s41467-021-23913-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8192526PMC
June 2021

Importance of Low-Fidelity Training on Personal Protective Equipment Use for Perioperative Workforce During COVID-19: Continuing Professional Development Imagination in Action.

J Contin Educ Health Prof 2021 Jun 8. Epub 2021 Jun 8.

Department of Anesthesiology, Perioperative and Pain Medicine, Baylor College of Medicine, Texas Children's Hospital, Houston, TX.

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http://dx.doi.org/10.1097/CEH.0000000000000369DOI Listing
June 2021

Risk factors for posterior capsule rupture in cataract surgery as reflected in the European Registry of Quality Outcomes for Cataract and Refractive Surgery.

J Cataract Refract Surg 2021 Jun 1. Epub 2021 Jun 1.

University Eye Clinic, Maastricht University Medical Center+, Maastricht, the Netherlands Department of Clinical Sciences, Ophthalmology, Umeå University, Umeå, Sweden European Society of Cataract and Refractive Surgeons (ESCRS), Dublin, Ireland Department of Ophthalmology, Amsterdam UMC, Amsterdam, the Netherlands Department of Ophthalmology, Oxford Eye Hospital, Oxford, United Kingdom Department of Ophthalmology, Antwerp University Hospital, Antwerp, Belgium Department of Mathematics and Statistics, University of Strathclyde, Glasgow, United Kingdom Department of Ophthalmology, Sahgrenska University Hospital, Mölndal, Sweden Department of Clinical Sciences, Ophthalmology, Lund University, Lund, Sweden.

Purpose: To analyze the incidence and risk factors of posterior capsule rupture (PCR) in cataract surgery.

Setting: European clinics affiliated with the European Registry of Quality Outcomes for Cataract and Refractive Surgery (EUREQUO).

Design: Retrospective cross-sectional register-based study.

Methods: Data was obtained from the EUREQUO. The database contains data on demographics, comorbidities, and intraoperative complications, including PCR for the study period from January 1, 2008, to December 31, 2018. Univariable and multivariable logistic regression analyses were performed to estimate the (adjusted) odds ratio (OR) and 95% confidence intervals (CI).

Results: Data was available of 2,853,376 patients and 31,749 (1.1%) cataract surgeries were complicated by a PCR. The PCR rate ranged from 0.60 to 1.65 percent throughout the years, with a decreasing trend (p <0.001). The mean age of the PCR cohort was 74.8 ± 10.5 years and 17,629 (55.5%) patients were female. Risk factors most significantly associated with PCR were corneal opacities (OR 3.21, 95% CI 3.02 - 3.41, p <0.001), diabetic retinopathy (OR 2.74, 95% CI 2.59 - 2.90, p <0.001), poor preoperative visual acuity (OR 1.98, 95% CI 1.88 - 2.07, p <0.001), and white cataract (OR 1.87, 95% CI 1.72 - 2.03, p <0.001).

Conclusion: Risk factors for PCR were identified based on the EUREQUO and the incidence of this complication is decreasing over time.
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http://dx.doi.org/10.1097/j.jcrs.0000000000000708DOI Listing
June 2021

Pearl Powder-An Emerging Material for Biomedical Applications: A Review.

Materials (Basel) 2021 May 24;14(11). Epub 2021 May 24.

Zhejiang Fenix Health Science and Technology Co., Ltd., Zhejiang 176849, China.

Pearl powder is a well-known traditional Chinese medicine for a variety of indications from beauty care to healthcare. While used for over a thousand years, there has yet to be an in-depth understanding and review in this area. The use of pearl powder is particularly growing in the biomedical area with various benefits reported due to the active ingredients within the pearl matrix itself. In this review, we focus on the emerging biomedical applications of pearl powder, touching on applications of pearl powder in wound healing, bone repairing, treatment of skin conditions, and other health indications.
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http://dx.doi.org/10.3390/ma14112797DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197316PMC
May 2021

Older adults' vaccine hesitancy: Psychosocial factors associated with influenza, pneumococcal, and shingles vaccine uptake.

Vaccine 2021 06 20;39(26):3520-3527. Epub 2021 May 20.

School of Psychological Sciences & Health, University of Strathclyde, 40 George Street, Glasgow G1 1QE, UK.

Influenza, pneumococcal disease, and shingles (herpes zoster) are more prevalent in older people. These illnesses are preventable via vaccination, but uptake is low and decreasing. Little research has focused on understanding the psychosocial reasons behind older adults' hesitancy towards different vaccines. A cross-sectional survey with 372 UK-based adults aged 65-92 years (M = 70.5) assessed awareness and uptake of the influenza, pneumococcal, and shingles vaccines. Participants provided health and socio-demographic data and completed two scales measuring the psychosocial factors associated with vaccination behaviour. Self-reported daily functioning, cognitive difficulties, and social support were also assessed. Participants were additionally given the opportunity to provide free text responses outlining up to three main reasons for their vaccination decisions. We found that considerably more participants had received the influenza vaccine in the last 12 months (83.6%), relative to having ever received the pneumococcal (60.2%) and shingles vaccines (58.9%). Participants were more aware of their eligibility for the influenza vaccine, and were more likely to have been offered it. Multivariate logistic regression analyses showed that a lower sense of collective responsibility independently predicted lack of uptake of all three vaccines. Greater calculation of disease and vaccination risk, and preference for natural immunity, also predicted not getting the influenza vaccine. For both the pneumococcal and shingles vaccines, concerns about profiteering further predicted lack of uptake. Analysis of the qualitative responses highlighted that participants vaccinated to protect their own health and that of others. Our findings suggest that interventions targeted towards older adults would benefit from being vaccine-specific and that they should emphasise disease risks and vaccine benefits for the individual, as well as the benefits of vaccination for the wider community. These findings can help inform intervention development aimed at increasing vaccination uptake in future.
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http://dx.doi.org/10.1016/j.vaccine.2021.04.062DOI Listing
June 2021

Assessing the Relative Importance of Estuarine Nursery Habitats - a Dungeness Crab () Case Study.

Estuaries Coast 2020 Aug;44(4):1062-1073

Pacific Coastal Ecology Branch, Pacific Ecological Systems Division, U.S. Environmental Protection Agency, Newport, OR 97365, USA.

Estuaries serve as important nurseries for many recreationally and commercially harvested fisheries species. Recent conceptual approaches (i.e., seascape) for assessing the value of estuaries to fisheries have advocated for complex habitat-scale assessments that integrate multiple life-history responses (e.g., abundance, growth, reproduction) and ecological processes across heterogeneous landscapes. Although ecologically compelling, implementing seascape approaches may not be feasible for resource-limited management agencies. In such cases, we propose that resource managers can enhance the identification of fishery-important estuarine habitats by integrating attainable aspects of the seascape approach into a more traditional single response (e.g., abundance) model. Using Dungeness crab () as a case study, we applied a spatially-explicit hybrid approach to assess the relative contribution of different estuarine habitats to that important fishery species within three Oregon estuaries (Tillamook, Yaquina, and Alsea bays). We measured the abundance of juvenile from low-tide trawls in estuarine channels and the mosaic of habitat characteristics within defined home-range distances for the crabs. After identifying and reducing strong intercorrelations among habitat variable data, we developed a best-fit model that associated crab abundance with the most influential habitat variables. We found that lower-estuary side channels supported the highest abundance of juvenile crabs; furthermore, crab abundance was positively associated with high salinity and burrowing shrimp () density on adjacent unvegetated tidal flats. This hybrid method produced a habitat-specific model that better predicted juvenile abundance than did a model based on generalized habitat categories.
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http://dx.doi.org/10.1007/s12237-020-00821-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128707PMC
August 2020

40S ribosome profiling reveals distinct roles for Tma20/Tma22 (MCT-1/DENR) and Tma64 (eIF2D) in 40S subunit recycling.

Nat Commun 2021 05 20;12(1):2976. Epub 2021 May 20.

Laboratory of Biochemistry and Genetics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.

The recycling of ribosomes at stop codons for use in further rounds of translation is critical for efficient protein synthesis. Removal of the 60S subunit is catalyzed by the ATPase Rli1 (ABCE1) while removal of the 40S is thought to require Tma64 (eIF2D), Tma20 (MCT-1), and Tma22 (DENR). However, it remains unclear how these Tma proteins cause 40S removal and control reinitiation of downstream translation. Here we used a 40S ribosome footprinting strategy to directly observe intermediate steps of ribosome recycling in cells. Deletion of the genes encoding these Tma proteins resulted in broad accumulation of unrecycled 40S subunits at stop codons, directly establishing their role in 40S recycling. Furthermore, the Tma20/Tma22 heterodimer was responsible for a majority of 40S recycling events while Tma64 played a minor role. Introduction of an autism-associated mutation into TMA22 resulted in a loss of 40S recycling activity, linking ribosome recycling and neurological disease.
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http://dx.doi.org/10.1038/s41467-021-23223-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137927PMC
May 2021

Increased hippocampal excitability in miR-324-null mice.

Sci Rep 2021 May 17;11(1):10452. Epub 2021 May 17.

Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.

MicroRNAs are non-coding RNAs that act to downregulate the expression of target genes by translational repression and degradation of messenger RNA molecules. Individual microRNAs have the ability to specifically target a wide array of gene transcripts, therefore allowing each microRNA to play key roles in multiple biological pathways. miR-324 is a microRNA predicted to target thousands of RNA transcripts and is expressed far more highly in the brain than in any other tissue, suggesting that it may play a role in one or multiple neurological pathways. Here we present data from the first global miR-324-null mice, in which increased excitability and interictal discharges were identified in vitro in the hippocampus. RNA sequencing was used to identify differentially expressed genes in miR-324-null mice which may contribute to this increased hippocampal excitability, and 3'UTR luciferase assays and western blotting revealed that two of these, Suox and Cd300lf, are novel direct targets of miR-324. Characterisation of microRNAs that produce an effect on neurological activity, such as miR-324, and identification of the pathways they regulate will allow a better understanding of the processes involved in normal neurological function and in turn may present novel pharmaceutical targets in treating neurological disease.
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http://dx.doi.org/10.1038/s41598-021-89874-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129095PMC
May 2021

Comparison of British Thyroid Association, American College of Radiology TIRADS and Artificial Intelligence TIRADS with histological correlation: diagnostic performance for predicting thyroid malignancy and unnecessary fine needle aspiration rate.

Br J Radiol 2021 Jul 9;94(1123):20201444. Epub 2021 Jun 9.

Department of Radiology, Glasgow Royal Infirmary, NHS GG&C, Glasgow, UK.

Objectives: To compare diagnostic performance of British Thyroid Association (BTA), American College of Radiology Thyroid Imaging Reporting and Data System (ACR-TIRADS) and Artificial Intelligence TIRADS (AI-TIRADS) for thyroid nodule malignancy. To determine comparative unnecessary fine needle aspiration (FNA) rates.

Methods: 218 thyroid nodules with definitive histology obtained during 2017 were included. Ultrasound images were reviewed retrospectively in consensus by two subspecialist radiologists, blinded to histopathology, and nodules assigned a BTA, ACR-TIRADS and AI-TIRADS grade. Nodule laterality and size were recorded to allow accurate histopathological correlation and determine which nodules met criteria for FNA.

Results: 77 (35.3%) nodules were malignant. Deeming ultrasound Grade 4-5 as test-positive and 1-2 as test-negative, sensitivity and specificity for BTA was 98.28 and 42.55%, for ACR-TIRADS: 95.24 and 40.57% and for AI-TIRADS: 93.44 and 45.71%. FNA was indicated in 101 (71.6%), 67 (47.5%) and 65 (46.1%) benign nodules utilising BTA, ACR-TIRADS and AI-TIRADS respectively. The unnecessary FNA rate was significantly higher with BTA (46.3%) compared to ACR-TIRADS (30.7%) and AI-TIRADS (29.8%) < 0.001.

Conclusion: BTA, ACR-TIRADS and AI-TIRADS had similar diagnostic performance for predicting thyroid nodule malignancy with sensitivity >93% for all systems when considering ultrasound Grade 4-5 as malignant and Grade 1-2 as benign. ACR-TIRADS and AI-TIRADS both had a significantly lower rate of recommended FNA in benign nodules compared to BTA.

Advances In Knowledge: BTA, ACR-TIRADS and AI-TIRADS have comparable diagnostic performance with high sensitivity but relatively low specificity for predicting thyroid nodule malignancy in this cohort using histology as gold-standard. Using Grade 1-2 as benign and 4-5 as malignant there were more false negatives with TIRADS but this improved when taking other features into account while BTA had a significantly higher rate of unnecessary FNA.
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http://dx.doi.org/10.1259/bjr.20201444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248201PMC
July 2021

A photoluminescent Au(I)/Ag(I)/PNN coordination complex for relatively rapid and reversible alcohol sensing.

Dalton Trans 2021 May;50(20):6773-6777

College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, Jiangsu, P. R. China.

Trinuclear complex [Au2Ag(dppmaphen)2(CN)2]PF6 photoluminesces on exposure to low molecular weight alcohols. This emission is likely due to C-Hπ interactions between the analyte and -PPh2 group, that inhibits non-radiative relaxation of the photoexcited state. Photoluminescene was quenched by removing the analyte under a stream of N2 or replacing it with H2O. This on/off switching was clearly visible, relatively rapid and recyclable.
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http://dx.doi.org/10.1039/d1dt00931aDOI Listing
May 2021

Deletions in FLT-3 juxtamembrane domain define a new class of pathogenic mutations: case report and systematic analysis.

Blood Adv 2021 05;5(9):2285-2293

Department of Oncology.

The FMS-like tyrosine kinase 3 (FLT-3) is the most frequently mutated gene in acute myeloid leukemia (AML), a high-risk feature, and now the target of tyrosine kinase inhibitors (TKIs), which are approved and in development. The most common mutation is the internal tandem duplication (ITD). We present a novel mutation, FLT-3/Q575Δ, identified in a patient with AML through next-generation sequencing (NGS). This mutation is activating, drives downstream signaling comparable to FLT-3/ITD, and can be targeted using available FLT-3 TKIs. We present the results of a systematic analysis that identified Y572Δ, E573Δ, and S574Δ as similarly activating and targetable deletions located in the FLT-3 juxtamembrane domain (JMD). These mutations target key residues in the JMD involved in the interactions within FLT-3 that regulate its activation. Our results suggest a new class of FLT-3 mutations that may have an impact on patient care and highlight the increasing importance of a systematic understanding of FLT-3 mutations other than ITD. It is likely that, as NGS becomes more commonly used in the diagnosis of patients with AML, these and other activating mutations will be discovered with increasing frequency.
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http://dx.doi.org/10.1182/bloodadvances.2020002876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114556PMC
May 2021

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel against Amblyomma americanum in cats.

Parasite 2021 2;28:25. Epub 2021 Apr 2.

Boehringer-Ingelheim Animal Health, 29 avenue Tony Garnier, 69007 Lyon, France.

Esafoxolaner, a purified enantiomer of afoxolaner with insecticidal and acaricidal properties, is combined with eprinomectin and praziquantel in NexGard Combo, a novel topical endectoparasiticide product for cats. The efficacy of this novel formulation was assessed in two experimental studies against induced infestations with Amblyomma americanum, a tick species of major importance, highly prevalent in a large southeastern quarter of the United States. In each study, 10 cats were randomly allocated to a placebo control group and 10 cats to a novel formulation treated group. Infested cats were treated topically once at the minimum recommended dose. Both studies were designed to test curative efficacy on existing infestation, 72 h after treatment, and to test preventive efficacy, 72 h after subsequent weekly (Study #1) or fortnightly (Study #2) infestations for one month. For each infestation, all cats were infested with 50 unfed adult A. americanum. At each tick count, in both studies, at least 8 in 10 placebo control cats were infested with 13 (26%) or more live ticks, demonstrating adequate infestation throughout the studies. Curative efficacy of the novel formulation was 99% in both studies; preventive efficacy was 92% and 100% for at least one month.
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http://dx.doi.org/10.1051/parasite/2021021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019551PMC
April 2021

Efficacy of a novel topical combination of esafoxolaner, eprinomectin and praziquantel against adult cat flea Ctenocephalides felis and flea egg production in cats.

Parasite 2021 2;28:21. Epub 2021 Apr 2.

Boehringer-Ingelheim Animal Health, Missouri Research Center, 6498 Jade Rd., Fulton, MO 65251, USA.

Esafoxolaner, a purified enantiomer of afoxolaner with insecticidal and acaricidal properties, is combined with eprinomectin and praziquantel in NexGard Combo, a novel topical endectoparasiticide formulation for cats. The efficacy of this novel formulation against adult and immature stages of Ctenocephalides felis fleas was tested in four experimental studies. Two studies were designed to test adulticide efficacy, one to test inhibition of immature stages, and one to test both adulticide efficacy and inhibition of immature stages. In each study, cats were randomly allocated to a placebo control group or to a novel formulation group treated once at the minimum recommended dose. Cats were experimentally infested weekly for one to two months with unfed C. felis originating from North America or Europe. For adulticide efficacy evaluations, live fleas were counted 24 h after treatment and after subsequent weekly infestations. For immature stages, flea eggs were collected and counted weekly for evaluation of egg production inhibition and incubated for larval hatching evaluation. In the three studies testing adult fleas, curative efficacies, 24 h after treatment, were 92.1%, 98.3% and 99.7%; preventive weekly efficacies, 24 h after weekly infestations, remained higher than 95.5% for at least one month. In the two studies testing immature stages, egg production and larval hatching was significantly reduced for at least one month. These studies provide robust evidence of efficacy of the novel formulation against experimental adult flea infestations and for the prevention of environmental contamination by immature flea stages, for at least one month.
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http://dx.doi.org/10.1051/parasite/2021017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019553PMC
April 2021

A mixed methods study of seasonal influenza vaccine hesitancy in adults with chronic respiratory conditions.

Influenza Other Respir Viruses 2021 Mar 27. Epub 2021 Mar 27.

School of Psychological Sciences and Health, University of Strathclyde, Glasgow, UK.

Background: Seasonal influenza vaccination is recommended for patients with chronic respiratory conditions, but uptake is suboptimal. We undertook a comprehensive mixed methods study in order to examine the barriers and enablers to influenza vaccination in patients with chronic respiratory conditions.

Methods: Mixed methods including a survey (n = 429) which assessed sociodemographics and the psychological factors associated with vaccine uptake (ie confidence, complacency, constraints, calculation and collective responsibility) with binary logistic regression analysis. We also undertook focus groups and interviews (n = 59) to further explore barriers and enablers to uptake using thematic analysis.

Results: The survey analysis identified that older participants were more likely to accept the vaccine, as were those with higher perceptions of collective responsibility around vaccination, lower levels of complacency and lower levels of constraints. Thematic analysis showed that concerns over vaccine side effects, lack of tailored information and knowledge, and a lack of trust and rapport with healthcare professionals were key barriers. In contrast, the importance of feeling protected, acceptance of being part of an at-risk group and feeling a reduced sense of vulnerability after vaccination were seen as key enablers.

Conclusions: Our findings showed that the decision to accept a vaccine against influenza is influenced by multiple sociodemographic and psychological factors. Future interventions should provide clear and transparent information about side effects and be tailored to patients with chronic respiratory conditions. Interactions between patients and their healthcare providers have a particularly important role to play in helping patients address their concerns and feel confident in vaccination.
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http://dx.doi.org/10.1111/irv.12856DOI Listing
March 2021

Reprogramming of translation in yeast cells impaired for ribosome recycling favors short, efficiently translated mRNAs.

Elife 2021 03 25;10. Epub 2021 Mar 25.

Division of Molecular and Cellular Biology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, United States.

In eukaryotes, 43S preinitiation complex (PIC) formation is a rate-determining step of translation. Ribosome recycling following translation termination produces free 40S subunits for re-assembly of 43S PICs. Yeast mutants lacking orthologs of mammalian eIF2D (Tma64), and either MCT-1 (Tma20) or DENR (Tma22), are broadly impaired for 40S recycling; however, it was unknown whether this defect alters the translational efficiencies (TEs) of particular mRNAs. Here, we conducted ribosome profiling of a yeast double mutant and observed a marked reprogramming of translation, wherein the TEs of the most efficiently translated ('strong') mRNAs increase, while those of 'weak' mRNAs generally decline. Remarkably, similar reprogramming was seen on reducing 43S PIC assembly by inducing phosphorylation of eIF2α or by decreasing total 40S subunit levels by depleting Rps26. Our findings suggest that strong mRNAs outcompete weak mRNAs in response to 43S PIC limitation achieved in various ways, in accordance with previous mathematical modeling.
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http://dx.doi.org/10.7554/eLife.64283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993997PMC
March 2021

Trends in socioeconomic inequalities in underweight and obesity in 5-year-old children, 2011-2018: a population-based, repeated cross-sectional study.

BMJ Open 2021 03 19;11(3):e042023. Epub 2021 Mar 19.

School of Dentistry, Medicine and Nursing, College of MVLS, University of Glasgow, Glasgow, UK.

Objective: To explore trends in prevalence and socioeconomic inequalities in underweight and obesity in 5-year-old schoolchildren in Scotland between 2011/2012 and 2017/2018.

Design: A population-based, repeated cross-sectional study.

Setting: Local authority primary schools in Scotland.

Participants: 373 189 5-year-old schoolchildren in Scotland between 2011/2012 and 2017/2018.

Methodology: Trends in prevalence and inequalities in underweight and obesity were examined across seven school years (2011/2012-2017/2018) for 373 189 5-year-old schoolchildren in Scotland. Body mass index SD scores were calculated, and epidemiological cut-offs relative to the UK 1990 references categorised underweight and obesity. Slope/relative indices of inequality (SII/RII) were calculated for underweight and obesity by school year using the area-based Scottish Index of Multiple Deprivation.

Results: The prevalence of obesity rose slightly overall during the study period (9.8% in 2011/2012; 10.1% in 2017/2018). However, this masked a widening of inequalities, with children from the most deprived areas experiencing a greater risk of obesity in 2017/2018 than in 2011/2012 (risk ratio=1.14, 95% CI 1.04 to 1.25) compared with an unchanged risk in children from the least deprived areas (risk ratio=0.95, 95% CI 0.82 to 1.11). SII and RII indicate widening inequalities for obesity, with RII rising from 1.95 (95% CI 1.71 to 2.22) in 2011/2012 to 2.22 (95% CI 1.93 to 2.56) in 2017/2018. The prevalence of underweight was consistently low (compared with the UK 1990 references) and remained unchanged over the study period (1.2% in 2011/2012; 1.1% in 2017/2018), with no consistent evidence of social patterning over time.

Conclusions: Inequalities in obesity in schoolchildren in Scotland are large and have widened from 2011, despite only a slight rise in overall prevalence. In contrast there has been little change in underweight prevalence or inequalities during the study period. Extra resources for policy implementation and measures which do not widen inequalities and focus on reaching the most deprived children are required to tackle the high prevalence and growing inequalities in childhood obesity in Scotland.
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http://dx.doi.org/10.1136/bmjopen-2020-042023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986667PMC
March 2021

State of the art in cystic fibrosis pharmacology optimization of antimicrobials in the treatment of cystic fibrosis pulmonary exacerbations: III. Executive summary.

Pediatr Pulmonol 2021 Jul 15;56(7):1825-1837. Epub 2021 Mar 15.

Department of Pharmacy, Intermountain Primary Children's Hospital, Salt Lake City, Utah, USA.

Acute pulmonary exacerbations are complications of cystic fibrosis (CF) and are associated with increased morbidity and mortality. Methicillin-resistant Staphylococcus aureus (MRSA) and Aspergillus fumigatus are organisms that have been detected in the lungs of CF patients. The focus of this review is to provide an overview of the classes of antimicrobials used for MRSA and allergic bronchopulmonary aspergillosis (ABPA), a hypersensitivity reaction caused by A. fumigatus. The current anti-MRSA antibiotics and medications for ABPA dosing recommendations are discussed. This article also reviews the findings from the MRSA utilization surveys and the pharmacokinetic and pharmacodynamic differences between CF and non-CF patients. Antimethicillin S. aureus antibiotics include ceftaroline, clindamycin, fluoroquinolone derivatives (ciprofloxacin, levofloxacin), glycopeptide derivatives (telavancin, vancomycin), linezolid, rifampin, sulfamethoxazole/trimethoprim, and tetracycline derivatives (doxycycline, minocycline, tigecycline). Medications used for ABPA include corticosteroids, amphotericin B, azole antifungals (isavuconazole, itraconazole, posaconazole, voriconazole), and a monoclonal antibody, omalizumab.
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http://dx.doi.org/10.1002/ppul.25353DOI Listing
July 2021

Patients' attitudes towards the potential use of stability tape to minimize head movements during cataract surgery.

Semin Ophthalmol 2021 Feb 27:1-5. Epub 2021 Feb 27.

Tennent Institute of Ophthalmology, Gartnavel General Hospital, Glasgow, UK.

: Head stabilization may reduce intra-operative risk during cataract surgery, but could be misinterpreted as "restraint." We wanted to establish patients' attitudes towards the potential use of stability-tape.: One-hundred consecutive patients attending for local-anaesthetic cataract surgery were asked to complete a pre-operative questionnaire. This explored patient concerns and views regarding intra-operative head movement and the potential use of stability-tape.: All 100-patients completed the questionnaire. The median head movement concern score was 2 out of 10 (range 1-9, IQR 1-5). Eighty-four percent felt stability tape should be offered to all patients and 97% would consent for its' use. Only 6% voiced concern about the use of stability-tape (95% CI 2.2%, 12.6%).: Patients had low concern for moving their head during surgery. The concept of stability-tape to minimize head movements during cataract surgery was viewed positively by most patients. This strategy may promote safer surgery in selected cases.
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http://dx.doi.org/10.1080/08820538.2021.1890783DOI Listing
February 2021

Constructing and optimizing 3D atlases from 2D data with application to the developing mouse brain.

Elife 2021 Feb 11;10. Epub 2021 Feb 11.

Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, United States.

3D imaging data necessitate 3D reference atlases for accurate quantitative interpretation. Existing computational methods to generate 3D atlases from 2D-derived atlases result in extensive artifacts, while manual curation approaches are labor-intensive. We present a computational approach for 3D atlas construction that substantially reduces artifacts by identifying anatomical boundaries in the underlying imaging data and using these to guide 3D transformation. Anatomical boundaries also allow extension of atlases to complete edge regions. Applying these methods to the eight developmental stages in the Allen Developing Mouse Brain Atlas (ADMBA) led to more comprehensive and accurate atlases. We generated imaging data from 15 whole mouse brains to validate atlas performance and observed qualitative and quantitative improvement (37% greater alignment between atlas and anatomical boundaries). We provide the pipeline as the MagellanMapper software and the eight 3D reconstructed ADMBA atlases. These resources facilitate whole-organ quantitative analysis between samples and across development.
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http://dx.doi.org/10.7554/eLife.61408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994002PMC
February 2021

Charge Interactions in a Highly Charge-Depleted Protein.

J Am Chem Soc 2021 02 2;143(6):2500-2508. Epub 2021 Feb 2.

Linderstrøm-Lang Centre for Protein Science, Department of Biology, University of Copenhagen, DK-2200 Copenhagen, Denmark.

Electrostatic forces are important for protein folding and are favored targets of protein engineering. However, interactions between charged residues are difficult to study because of the complex network of interactions found in most proteins. We have designed a purposely simple system to investigate this problem by systematically introducing individual and pairs of charged and titratable residues in a protein otherwise free of such residues. We used constant pH molecular dynamics simulations, NMR spectroscopy, and thermodynamic double mutant cycles to probe the structure and energetics of the interaction between the charged residues. We found that the partial burial of surface charges contributes to a shift in p value, causing an aspartate to titrate in the neutral pH range. Additionally, the interaction between pairs of residues was found to be highly context dependent, with some pairs having no apparent preferential interaction, while other pairs would engage in coupled titration forming a highly stabilized salt bridge. We find good agreement between experiments and simulations and use the simulations to rationalize our observations and to provide a detailed mechanistic understanding of the electrostatic interactions.
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http://dx.doi.org/10.1021/jacs.0c10789DOI Listing
February 2021

Annihilation and Control of Chiral Domain Walls with Magnetic Fields.

Nano Lett 2021 Feb 25;21(3):1205-1212. Epub 2021 Jan 25.

Department of Physics and Astronomy, Louisiana State University, Baton Rouge, Louisiana 70803, United States.

The control of domain walls is central to nearly all magnetic technologies, particularly for information storage and spintronics. Creative attempts to increase storage density need to overcome volatility due to thermal fluctuations of nanoscopic domains and heating limitations. Topological defects, such as solitons, skyrmions, and merons, may be much less susceptible to fluctuations, owing to topological constraints, while also being controllable with low current densities. Here, we present the first evidence for soliton/soliton and soliton/antisoliton domain walls in the hexagonal chiral magnet MnNbS that respond asymmetrically to magnetic fields and exhibit pair-annihilation. This is important because it suggests the possibility of controlling the occurrence of soliton pairs and the use of small fields or small currents to control nanoscopic magnetic domains. Specifically, our data suggest that either soliton/soliton or soliton/antisoliton pairs can be stabilized by tuning the balance between intrinsic exchange interactions and long-range magnetostatics in restricted geometries.
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http://dx.doi.org/10.1021/acs.nanolett.0c03199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883385PMC
February 2021

Synthetic mycobacterial diacyl trehaloses reveal differential recognition by human T cell receptors and the C-type lectin Mincle.

Sci Rep 2021 Jan 21;11(1):2010. Epub 2021 Jan 21.

Division of Rheumatology, Inflammation, and Immunity, Brigham and Women's Hospital and Harvard Medical School, Hale Building for Transformative Medicine, 60 Fenwood Road, Boston, MA, 02115, USA.

The cell wall of Mycobacterium tuberculosis is composed of diverse glycolipids which potentially interact with the human immune system. To overcome difficulties in obtaining pure compounds from bacterial extracts, we recently synthesized three forms of mycobacterial diacyltrehalose (DAT) that differ in their fatty acid composition, DAT, DAT, and DAT. To study the potential recognition of DATs by human T cells, we treated the lipid-binding antigen presenting molecule CD1b with synthetic DATs and looked for T cells that bound the complex. DAT- and DAT-treated CD1b tetramers were recognized by T cells, but DAT-treated CD1b tetramers were not. A T cell line derived using CD1b-DAT tetramers showed that there is no cross-reactivity between DATs in an IFN-γ release assay, suggesting that the chemical structure of the fatty acid at the 3-position determines recognition by T cells. In contrast with the lack of recognition of DAT by human T cells, DAT but not DAT or DAT, activates Mincle. Thus, we show that the mycobacterial lipid DAT can be both an antigen for T cells and an agonist for the innate Mincle receptor, and that small chemical differences determine recognition by different parts of the immune system.
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http://dx.doi.org/10.1038/s41598-021-81474-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820438PMC
January 2021

Understanding the expanding role of pharmacy services in outpatient cystic fibrosis care.

Pediatr Pulmonol 2021 Jun 1;56(6):1378-1385. Epub 2021 Feb 1.

Department of Pharmacy, University of Utah Adult Cystic Fibrosis Center, Salt Lake City, Utah, USA.

Cystic fibrosis (CF) patients utilize an average of 10 (±5) medications per day. Given the complexity of the medication regimen, the CF Foundation (CFF) recommends pharmacists as members of the CF care team. The areas of pharmacy services have been identified in the literature. "Limited access pharmacists" are consulted to answer questions, assist in evaluating serum drug concentrations, provide medication education, and monitor for drug-drug interactions. Reduction in hospital length of stay has been shown through this collaboration. "Full access pharmacists" provide comprehensive medication therapy management resulting in medication adherence and access improvements, sustainability of treatments, improved provider communication, reduced medication errors and costs, expedited medication refill authorization, increased utilization of respiratory therapists, enhanced discussion of medications with CF team members, and reduction in the number of pharmacies utilized by patients to fill CF medications. An integrated CF pharmacy team are essential members of the multidisciplinary CF care team that have been shown to improve in CF medication access, increases in body weight and body mass index, reduction in prior authorization submission times, reduction in medication delivery times, expedited medication refill authorizations, increased collaboration with respiratory therapists, augmented discussion of medication with CF team members, and reduction in the number of pharmacies utilized by CF patients. There is a need to further evaluate the impact of outpatient CF pharmacy services due to the improvements in the care on patients and families affected by CF, and as the number of CFF-accredited care centers integrates CF pharmacy teams throughout the country increases.
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http://dx.doi.org/10.1002/ppul.25283DOI Listing
June 2021

Preventing Recurrence in Clean and Contaminated Hernias Using Biologic Versus Synthetic Mesh in Ventral Hernia Repair: The PRICE Randomized Clinical Trial.

Ann Surg 2021 04;273(4):648-655

Department of Surgery, University of California, San Francisco, CA.

Objective: The aim of this study was to evaluate which mesh type yields lower recurrence and complication rates after ventral hernia repair.

Summary Background Data: More than 400,000 ventral hernia repairs are performed annually in the United States. Although the most effective method for repairing ventral hernias involves using mesh, whether to use biologic mesh versus synthetic mesh is controversial.

Methods: Single-blind, randomized, controlled, pragmatic clinical trial conducted from March 2014 through October 2018; 165 patients enrolled with an average follow up of 26 months. Patients were randomized 1:1 to have their ventral hernias repaired using either a biologic (porcine) or synthetic (polypropylene) mesh. The primary study outcome measure was hernia recurrence at 2 years.

Results: A total of 165 patients (68 men), mean age 55 years, were included in the study with a mean follow-up of 26 months. An intention-to-treat analysis noted that hernias recurred in 25 patients (39.7%) assigned to biologic mesh and in 14 patients (21.9%) assigned to synthetic mesh (P = 0.035) at 2 years. Subgroup analysis identified an increased rate of hernia recurrence in the biologic versus the synthetic mesh group under contaminated wound conditions (50.0% vs 5.9%; P for interaction = 0.041). Postoperative complication rates were similar for the 2 mesh types.

Conclusions: The risk of hernia recurrence was significantly higher for patients undergoing ventral hernia repair with biologic mesh compared to synthetic mesh, with similar rates of postoperative complications. These data indicate that the use of synthetic mesh over biologic mesh to repair ventral hernias is effective and can be endorsed, including under contaminated wound conditions.

Trial Registration: ClinicalTrials.gov Identifier: NCT02041494.
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http://dx.doi.org/10.1097/SLA.0000000000004336DOI Listing
April 2021
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