ABSTRACT
Predator-induced changes in prey foraging can influence community dynamics by increasing the abundance of basal resources via a trait-mediated trophic cascade. The strength of these cascades may be altered by eco-evolutionary relationships between predators and prey, but the role of basal resources has received limited attention. We hypothesized that trait-mediated trophic cascade strength may be shaped by selection from trophic levels above and below prey. Field and laboratory experiments used snails (Nucella lapillus) from two regions in the Gulf of Maine (GoM) that vary in basal resource availability (e.g. mussels), seawater temperature, and contact history with the invasive green crab, Carcinus maenas. In field and laboratory experiments, Nucella from both regions foraged on mussels in the presence or absence of green crab risk cues. In the field, Nucella from the northern GoM, where mussels are scarce, were less responsive to risk cues and more responsive to seawater temperature than southern Nucella. In the lab, however, northern Nucella foraged and grew more than southern snails in the presence of risk, but foraging and growth were similar in the absence of risk. We suggest that adaptation to basal resource availability may shape geographical variation in the strength of trait-mediated trophic cascades.
Subject(s)
Gastropoda , Animals , Biological Evolution , Cues , Geography , LaboratoriesABSTRACT
Invasive predators can cause substantial evolutionary change in native prey populations. Although invasions by predators typically occur over large scales, their distributions are usually characterized by substantial spatiotemporal heterogeneity that can lead to patchiness in the response of native prey species. Our ability to understand how local variation shapes patterns of inducible defense expression has thus far been limited by insufficient replication of populations within regions. Here, we examined local and regional variation in the inducible defenses of 12 native marine snail (Littorina obtusata) populations within two geographic regions in the Gulf of Maine that are characterized by vastly different contact histories with the invasive predatory green crab (Carcinus maenas). When exposed in the field to waterborne risk cues from the green crab for 90 days, snails expressed plastic increases in shell thickness that reduced their vulnerability to this shell-crushing predator. Despite significant differences in contact history with this invasive predator, snail populations from both regions produced similar levels of shell thickness and shell thickness plasticity in response to risk cues. Such phenotypic similarity emerged even though there were substantial geographic differences in the shell thickness of juvenile snails at the beginning of the experiment, and we suggest that it may reflect the effects of warming ocean temperatures and countergradient variation. Consistent with plasticity theory, a trend in our results suggests that southern snail populations, which have a longer contact history with the green crab, paid less in the form of reduced tissue mass for thicker shells than northern populations.
Subject(s)
Brachyura , Snails , Animals , Snails/genetics , Brachyura/physiology , Predatory Behavior/physiology , Biological Evolution , CuesABSTRACT
BACKGROUND: The Coronal Plane Alignment of the Knee (CPAK) classification categorizes knee phenotypes based on constitutional limb alignment (arithmetic hip-knee-ankle angle or aHKA) and joint line obliquity (JLO). This study aimed to determine if sagittal and rotational knee alignments vary among CPAK types in order to establish whether this classification should be expanded beyond coronal plane assessment. METHODS: Coronal, sagittal, and rotational alignment measurements were made and CPAK types were calculated from computed tomographic data of 437 patients (509 knees) who underwent robotic-assisted total knee arthroplasty (TKA). Differences in femoral, tibial, and tibio-femoral angular measurements were compared across CPAK types, and correlations were made to aHKA and JLO. Nonparametric and linear regression tests were used to analyze between-type differences. RESULTS: There were no differences in tibial slope or femoral rotational measures across CPAK phenotypes. However, CPAK Type III knees had a greater tibio-femoral rotation mean difference than CPAK Type I, II, IV, and V knees (P < .05). We also found increased femoral flexion in Type I knees when compared to Type VI knees (P = .01). The aHKA had a weak correlation with femoral flexion angle, and JLO had a weak correlation with femoral posterior condylar axis to tibial antero-posterior axis angle. CONCLUSION: Few clinically important differences in sagittal and rotational alignments were found between CPAK types, indicating that CPAK phenotype has little correlation to 3-dimensional alignment characteristics. Need for an expansion of the CPAK classification beyond coronal plane alignment is not supported from these results.
Subject(s)
Arthroplasty, Replacement, Knee , Fractures, Bone , Osteoarthritis, Knee , Humans , Knee Joint/diagnostic imaging , Knee Joint/surgery , Knee/surgery , Arthroplasty, Replacement, Knee/methods , Tibia/diagnostic imaging , Tibia/surgery , Femur/diagnostic imaging , Femur/surgery , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/surgery , Fractures, Bone/surgery , Retrospective StudiesABSTRACT
BACKGROUND: As surgical technologies and alignment strategies develop, accuracy of lower limb alignment assessment gains increasing importance. The current gold standard remains long leg (4ft) radiographs. Other measures include computed tomography (CT) and EOS scans. This study aimed to compare CT and EOS long leg views to determine the reliability of assessment of hip-knee-angle (HKA) in arthritic knees. MATERIALS AND METHODS: A retrospective study of 96 knees in patients undergoing total knee arthroplasty (TKA) was performed comparing HKA alignment data from EOS and CT. Coronal HKA and sagittal flexion angle were assessed by two independent observers. Inter-observer correlation was calculated. RESULTS: The coronal alignment on EOS was strongly positively correlated to coronal alignment on CT (r = 0.927, p = 0.001). 12 knees (13 %) exceeded CT vs EOS difference of 3°. Inter-rater reliability was excellent (intra-class coefficients >0.9). The mean difference between CT and EOS was significantly greater for patients with fixed flexion >10° (0.68) vs <10° (-0.2) p = 0.004. Mean difference in HKA did not differ between those 0-10° varus and >10° varus (p = 0.273). Valgus HKA had a higher mean difference (1.9°) compared to varus knees (-0.4°) (p = 0.001). CONCLUSION: CT and EOS showed excellent inter-rater reliability and correlated well. Increased sagittal plane deformity does effect coronal HKA assessment. Extreme varus did not affect the mean difference significantly, while valgus did. For the majority of patients either CT or EOS will give a reliable assessment of HKA but beware those with significant valgus or sagittal deformity where both modalities may be necessary to plan TKA.
Subject(s)
Arthroplasty, Replacement, Knee , Osteoarthritis, Knee , Humans , Arthroplasty, Replacement, Knee/methods , Tibia/surgery , Retrospective Studies , Femur/diagnostic imaging , Femur/surgery , Reproducibility of Results , Lower Extremity/diagnostic imaging , Knee Joint/diagnostic imaging , Knee Joint/surgery , Tomography, X-Ray Computed/methods , Osteoarthritis, Knee/diagnostic imaging , Osteoarthritis, Knee/surgeryABSTRACT
The spread of nonindigenous species by shipping is a large and growing global problem that harms coastal ecosystems and economies and may blur coastal biogeographical patterns. This study coupled eukaryotic environmental DNA (eDNA) metabarcoding with dissimilarity regression to test the hypothesis that ship-borne species spread homogenizes port communities. We first collected and metabarcoded water samples from ports in Europe, Asia, Australia and the Americas. We then calculated community dissimilarities between port pairs and tested for effects of environmental dissimilarity, biogeographical region and four alternative measures of ship-borne species transport risk. We predicted that higher shipping between ports would decrease community dissimilarity, that the effect of shipping would be small compared to that of environment dissimilarity and shared biogeography, and that more complex shipping risk metrics (which account for ballast water and stepping-stone spread) would perform better. Consistent with our hypotheses, community dissimilarities increased significantly with environmental dissimilarity and, to a lesser extent, decreased with ship-borne species transport risks, particularly if the ports had similar environments and stepping-stone risks were considered. Unexpectedly, we found no clear effect of shared biogeography, and that risk metrics incorporating estimates of ballast discharge did not offer more explanatory power than simpler traffic-based risks. Overall, we found that shipping homogenizes eukaryotic communities between ports in predictable ways, which could inform improvements in invasive species policy and management. We demonstrated the usefulness of eDNA metabarcoding and dissimilarity regression for disentangling the drivers of large-scale biodiversity patterns. We conclude by outlining logistical considerations and recommendations for future studies using this approach.
Subject(s)
DNA, Environmental , Ecosystem , DNA, Environmental/genetics , Ships , Biodiversity , Water , Environmental Monitoring , DNA Barcoding, TaxonomicABSTRACT
Background: The optimal cardiovascular (CV) risk stratification in liver transplant (LT) candidates remains unclear. The aim of this study was to evaluate concordance of findings between dobutamine stress echocardiography (DSE), positron emission tomography/computed tomography myocardial perfusion imaging (PET/CT MPI), and left heart catheterization in adult LT candidates. Methods: Data on 234 consecutive adult LT candidates from February 2015 to June 2018 with PET/CT MPI were reviewed. Adverse CV outcomes were adjudicated via chart review by a board-certified cardiologist. Results: Median age was 60.8, body mass index 30.2 kg/m2, and model of end-stage liver disease-sodium 14; 61% were male, and 54% had diabetes. Thirty-seven percent had nonalcoholic steatohepatitis and 29% alcohol-related liver disease. Sixty-five percent of patients had a DSE, of which 41% were nondiagnostic. No factors were independently associated with having a nondiagnostic DSE. The median global myocardial flow reserve correlated positively with hemoglobin and negatively with model of end-stage liver disease-sodium, age, ejection fraction, and body mass index. Moderate/high-risk MPIs were associated with older age and known CV disease. In patients with 2 cardiac testing modalities, findings were concordant in 87%. Eleven of 53 LT recipients experienced an adverse CV outcome, but no independent predictors were identified for this outcome. Conclusions: Results of different cardiac risk-stratification modalities were concordant across modalities the majority of the time in LT candidates, although these findings were not independently correlated with risk of post-LT CV outcomes. Given the high rates of nondiagnostic DSEs in this population, PET/CT MPI may be the preferred CV risk-stratification modality in older patients and those with known CV disease.
ABSTRACT
This study helps understand the ballast water-mediated species spread risk dynamics in the Mediterranean and examine potential policy options for ballast water management to further reduce species spread risk in the region. Results show that Gibraltar, Suez, and Istanbul remained high-risk ports from 2012 to 2018, and they are hub ports connecting several clusters. We reveal ballast water management implications for both the Mediterranean region and individual hub ports respectively. To further reduce the risks of individual Mediterranean hub ports beyond the IMO standards, the most effective (cost-effective) regulatory method is to set more stringent regulation towards such hub ports besides the IMO regulation. To further reduce the risks of the Mediterranean as a whole, the most effective (cost-effective) regulatory scenario is to set more stringent regulation towards all Mediterranean ports besides the IMO regulation. The barge-based method is the most cost-effective technology to achieve stricter regulations.
Subject(s)
Ships , Water , Mediterranean Sea , PolicyABSTRACT
The Ballast Water Management Convention can decrease the introduction risk of harmful aquatic organisms and pathogens, yet the Convention increases shipping costs and causes subsequent economic impacts. This paper examines whether the Convention generates disproportionate invasion risk reduction results and economic impacts on Small Island Developing States (SIDS) and Least Developed Countries (LDCs). Risk reduction is estimated with an invasion risk assessment model based on a higher-order network, and the effects of the regulation on national economies and trade are estimated with an integrated shipping cost and computable general equilibrium modeling framework. Then we use the Lorenz curve to examine if the regulation generates risk or economic inequality among regions. Risk reduction ratios of all regions (except Singapore) are above 99%, which proves the effectiveness of the Convention. The Gini coefficient of 0.66 shows the inequality in risk changes relative to income levels among regions, but risk reductions across all nations vary without particularly high risks for SIDS and LDCs than for large economies. Similarly, we reveal inequality in economic impacts relative to income levels (the Gini coefficient is 0.58), but there is no evidence that SIDS and LDCs are disproportionately impacted compared to more developed regions. Most changes in GDP, real exports, and real imports of studied regions are minor (smaller than 0.1%). However, there are more noteworthy changes for select sectors and trade partners including Togo, Bangladesh, and Dominican Republic, whose exports may decrease for textiles and metal and chemicals. We conclude the Convention decreases biological invasion risk and does not generate disproportionate negative impacts on SIDS and LDCs.
Subject(s)
Developing Countries , Water , Introduced Species , Ships , Water SupplyABSTRACT
This work evaluates efficacies of plausible ballast water management strategies and standards by integrating a global species spread risk assessment with a policy cost-effectiveness analysis. Specifically, we consider species spread risks and costs of port- and vessel-based strategies under both current organism concentration standards and stricter standards proposed by California. For each scenario, we estimate species spread risks and patterns using a higher-order analysis of a global ship-borne species spread model and estimate fleet costs for vessel- and barge-based ballast water treatment systems for each standard. We find that stricter standards may reduce species spread risk by a factor of 17 globally and would greatly simplify the complex network of ship-borne species spread. The current policy of IMO standards is most cost-effectively achieved through ship-based treatment, and that any additional risk reduction will be most cost-effectively achieved by port-based (or barge-based) technologies, particularly if these are strategically implemented at the top ports within the largest clusters. Barge-based ballast water management would require a shift in governance, and we suggest that this next level of policymaking could be feasible for special areas designated by the IMO, by State or multistate authorities, or by voluntary port applications.
Subject(s)
Introduced Species , Water Purification , Ships , Water , Water SupplyABSTRACT
AIMS: The Exeter V40 cemented polished tapered stem system has demonstrated excellent long-term outcomes. This paper presents a systematic review of the existing literature and reports on a large case series comparing implant fractures between the Exeter V40 series; 125 mm and conventional length stem systems. METHODS: A systematic literature search was performed adhering to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. In parallel, we performed a retrospective single centre study of Exeter V40 femoral stem prosthetic fractures between April 2003 and June 2020. RESULTS: There are 25 reported cases of such prosthetic fractures confined to small case series and case reports within the literature. We report an additional 19 cases to the literature (mean age 66.3 years (SD 11.7); 12 (63%) females; BMI 32.9 kg/m2 (SD 5.9)). The mean time from index procedure to fracture was 7.8 years (SD 3.6; 2.5 to 16.3). Exeter V40 stem fracture incidence was 0.15% and 1.21% for primary and revision arthroplasty, respectively. Incidence was significantly higher in revision arthroplasty (p < 0.001) and 125 mm length stems compared to ≥ 150 mm length stems (1.25% vs 0.13%, respectively; p < 0.001). When comparing different stem length cohorts, 125 mm short-stems were associated with stem-body fractures (92% vs 29%; p = 0.0095), earlier time to fracture (6.2 years vs 11.0 years; p = 0.0018), younger patient age at time of fracture (62.7 years vs 72.6 years; p = 0.037), and female sex (75% vs 43%; p = 0.326). CONCLUSION: This complication remains rare, although we report a significantly higher incidence at up to 17 years follow-up than in the literature. Short 125 mm length Exeter V40 stems undoubtedly have a role in restoring anatomy and biomechanics in smaller femoral geometries, although the surgeon has to appreciate the higher risk of stem fracture and the associated predisposing factors which may necessitate particular attention to surgical technique and planning. Cite this article: Bone Jt Open 2021;2(6):443-456.
ABSTRACT
INTRODUCTION: Hip fractures are the most common traumatic injury in the UK's elderly population. Patients are often extremely frail with multiple comorbidities and so are at high risk of death should they contract COVID-19. This study aims to quantify the effects of COVID-19 on patients presenting with hip fractures to the Norfolk and Norwich University Hospital (NNUH). METHODS: This is a single centre, prospective, observational cohort study of patients over the age of sixty admitted with a hip fracture to NNUH between March 24th and April 22nd, 2020 and comparing them retrospectively with controls in April 2019. Patients were followed up for 30 days; data collected includes demographics, COVID-19 PCR results, date/cause of death and other prognostic indicators. RESULTS: 66 consecutive patients managed for hip fractures were included in the study. 30-day mortality increased from 8.5% in April 2019 to 18.2% in April 2020. The 30-day mortality rate was 80% for those patients who test positive for COVID-19 as an inpatient, and was 13.8% for patients COVID-19 negative and for those who were untested. Those admitted from a healthcare institution were more likely to test positive for COVID-19 and had a higher 30-day mortality (p = 0.04 & p = 0.006, respectively). Suspected COVID-19-positive patients at time of admission had a delayed time to theatre, 46.7 h versus 27.1 h (p = 0.007), however this had no significant effect on mortality (p = 0.7). CONCLUSIONS: The combination of fragility hip fracture and COVID-19 is associated with poor outcomes. COVID-19 has also indirectly increased mortality in this patient group.
Subject(s)
COVID-19 , Hip Fractures , Aged , Humans , Pandemics , Prospective Studies , Retrospective Studies , SARS-CoV-2 , United Kingdom/epidemiologyABSTRACT
BACKGROUND: The aim of this study is to assess the Forgotten Joint Score (FJS) for total knee arthroplasty (TKA) and unicondylar knee arthroplasty (UKA) with both short- and long-term follow-up. METHODS: For a consecutive period of eight months, the FJS was sent to all patients who had undergone either a primary TKA or UKA either one, five or ten years previously at our institution. Patient demographics and operative details were recorded retrospectively. FJS were collected for three different TKA prosthesis and two different UKA prosthesis. RESULTS: A total of 588 FJS questionnaires were completed consisting of 482 TKA and 106 UKA procedures. The mean FJS for patients with TKA and UKA were 50.2 and 65.4 respectively (p < 0.001). Mean FJS for the ZUK were statistically superior to the Oxford UKA, 73.1 versus 60.1 (p = 0.020). For TKA mean FJS were statistically better at five compared to one year follow up, 53.8 versus 44.8 (p = 0.007). For UKA the mean FJJs were greatest at 10 year follow up (69.0), but the difference between scores at one (60.4) and five (68.4) years was not statistically significant (p = 0.243). CONCLUSION: This cross-sectional study has shown; superior FJSs for UKA compared to TKA and superior FJSs for a fixed bearing compared to a mobile bearing UKA and therefore supports the use of UKA opposed to TKA where the indications for UKA are satisfied. For TKA the FJS in the five-year post-operative group were significantly superior to those in the one-year post-operative group.
Subject(s)
Arthroplasty, Replacement, Knee , Osteoarthritis, Knee/surgery , Adult , Aged , Aged, 80 and over , Cross-Sectional Studies , Female , Humans , Knee Joint/physiopathology , Knee Joint/surgery , Knee Prosthesis , Male , Middle Aged , Osteoarthritis, Knee/etiology , Osteoarthritis, Knee/physiopathology , Recovery of Function , Retrospective Studies , Surveys and Questionnaires , Treatment OutcomeABSTRACT
BACKGROUND: Although N13-ammonia has favorable properties among FDA approved radiotracers, complexity of implementation has limited its use. We describe the initial patient experience of N13-ammonia PET imaging using a compact N13-ammonia production system. METHODS: N13 was produced using the ION-12SC, a 12MeV, 10uA superconducting minimally shielded cyclotron, and reduced to N13-ammonia in an automated multi-use purification unit. Patients were power injected with 9.3 ± 1.1 mCi (344.1 ± 40.7 MBq) of N13-ammonia for rest imaging, and 18.8 ± 0.9 mCi (695.6 ± 33.3 MBq) of N13-ammonia was injected at peak hyperemia for stress testing. Images were interpreted for relative perfusion, left ventricular volumes/function, blood flow quantification, and scored for image quality. RESULTS: In total 97 patients underwent 98 N13-ammonia PET scans (32 rest only/65 rest-stress/1 stress only). Image quality was 91.8% good or excellent. None were poor/non-diagnostic. Study durations were acceptable. Tracer related radiation dosimetry to patients was 0.7 ± 0.1 mSv (rest only), and 2.1 ± 0.1 mSv (rest-stress). CONCLUSION: Clinical N13-ammonia production by the Ionetix ION-12SC delivers high quality myocardial PET perfusion images in a rapid protocol.
Subject(s)
Ammonia , Coronary Artery Disease/diagnostic imaging , Myocardial Perfusion Imaging , Nitrogen Radioisotopes , Positron Emission Tomography Computed Tomography , Aged , Cyclotrons , Drug Compounding/instrumentation , Female , Humans , Male , Middle Aged , SuperconductivityABSTRACT
BACKGROUND: 18F-Flurpiridaz is a promising investigational radiotracer for PET myocardial perfusion imaging with favorable properties for quantification of myocardial blood flow (MBF). We sought to validate the incremental diagnostic value of absolute MBF quantification in a large multicenter trial against quantitative coronary angiography. METHODS: We retrospectively analyzed a subset of patients (N = 231) from the first phase 3 flurpiridaz trial (NCT01347710). Dynamic PET data at rest and pharmacologic stress were fit to a previously validated 2-tissue-compartment model. Absolute MBF and myocardial flow reserve (MFR) were compared with coronary artery disease severity quantified by invasive coronary angiography on a per-patient and per-vessel basis. RESULTS: Stress MBF per-vessel accurately identified obstructive disease (c-index 0.79) and progressively declined with increasing stenosis severity (2.35 ± 0.71 in patients without CAD; 1.92 ± 0.49 in non-obstructed territories of CAD patients; and 1.54 ± 0.50 in diseased territories, P < 0.05). MFR similarly declined with increasing stenosis severity (3.03 ± 0.94; 2.69 ± 0.95; and 2.33 ± 0.86, respectively, P < 0.05). In multivariable logistic regression modeling, stress MBF and MFR provided incremental diagnostic value beyond patient characteristics and relative perfusion analysis. CONCLUSIONS: Clinical myocardial blood flow measurement with 18F-flurpiridaz cardiac PET shows promise for routine application.
Subject(s)
Coronary Artery Disease/diagnostic imaging , Myocardial Perfusion Imaging , Positron-Emission Tomography , Pyridazines , Aged , Coronary Angiography , Coronary Artery Disease/physiopathology , Female , Fractional Flow Reserve, Myocardial , Humans , Logistic Models , Male , Middle Aged , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , Severity of Illness IndexABSTRACT
Global ballast water management regulations aiming to decrease aquatic species invasion require actions that can increase shipping costs. We employ an integrated shipping cost and global economic modeling approach to investigate the impacts of ballast water regulations on bilateral trade, national economies, and shipping patterns. Given the potential need for more stringent regulation at regional hotspots of species invasions, this work considers two ballast water treatment policy scenarios: implementation of current international regulations, and a possible stricter regional regulation that targets ships traveling to and from the United States while other vessels continue to face current standards. We find that ballast water management compliance costs under both scenarios lead to modest negative impacts on international trade and national economies overall. However, stricter regulations applied to U.S. ports are expected to have large negative impacts on bilateral trade of several specific commodities for a few countries. Trade diversion causes decreased U.S. imports of some products, leading to minor economic welfare losses.
Subject(s)
Ships , Water , Commerce , Internationality , Introduced Species , United StatesABSTRACT
More than 47 million Americans experience mental illness each year, and more than 9.2 million suffer from mental health and substance use disorders. More than 60% of adults with mental illness and 81% of those with substance use disorders do not receive treatment. As the human and financial costs from our nation's mental health and substance use disorders crisis escalate, a strong business case to better address this crisis has emerged. This article describes the root causes and cost of disparities and offers an innovative perspective on aligning stakeholders to make the business case for equity in treatment and outcomes.
Subject(s)
Health Equity/economics , Mental Health Services/economics , Substance-Related Disorders/economics , Healthcare Disparities , Humans , Mental Health , United StatesABSTRACT
The introduction and establishment of nonindigenous species (NIS) through global ship movements poses a significant threat to marine ecosystems and economies. While ballast-vectored invasions have been partly addressed by some national policies and an international agreement regulating the concentrations of organisms in ballast water, biofouling-vectored invasions remain largely unaddressed. Development of additional efficient and cost-effective ship-borne NIS policies requires an accurate estimation of NIS spread risk from both ballast water and biofouling. We demonstrate that the first-order Markovian assumption limits accurate modeling of NIS spread risks through the global shipping network. In contrast, we show that higher-order patterns provide more accurate NIS spread risk estimates by revealing indirect pathways of NIS transfer using Species Flow Higher-Order Networks (SF-HON). Using the largest available datasets of non-indigenous species for Europe and the United States, we then compare SF-HON model predictions against those from networks that consider only first-order connections and those that consider all possible indirect connections without consideration of their significance. We show that not only SF-HONs yield more accurate NIS spread risk predictions, but there are important differences in NIS spread via the ballast and biofouling vectors. Our work provides information that policymakers can use to develop more efficient and targeted prevention strategies for ship-borne NIS spread management, especially as management of biofouling is of increasing concern.
Subject(s)
Aquatic Organisms/physiology , Introduced Species , Biofouling , Cluster Analysis , Risk Assessment , ShipsABSTRACT
Genome editing in human induced pluripotent stem cells (iPSCs) provides the potential for disease modeling and cell therapy. By generating iPSCs with specific mutations, researchers can differentiate the modified cells to their lineage of interest for further investigation. However, the low efficiency of targeting in iPSCs has hampered the application of genome editing. In this study we used a CRISPR-Cas9 system that introduces a specific point substitution into the sequence of the Na+/K+-ATPase subunit ATP1A1. The introduced mutation confers resistance to cardiac glycosides, which can then be used to select successfully targeted cells. Using this system, we introduced different formats of donor DNA for homology-directed repair (HDR), including single-strand DNAs, double-strand DNAs, and plasmid donors. We achieved a 35-fold increase in HDR when using plasmid donor with a 400 bp repair template. We further co-targeted ATP1A1 and a second locus of interest to determine the enrichment of mutagenesis after cardiac glycoside selection. Through this approach, INDEL rate was increased after cardiac glycoside treatment, while HDR enrichment was only observed at certain loci. Collectively, these results suggest that a plasmid donor with a 400 bp repair template is an optimal donor DNA for targeted substitution and co-targeting ATP1A1 with the second locus enriches for mutagenesis events through cardiac glycoside selection in human iPSCs.
ABSTRACT
OBJECTIVES: The purpose of this study was to describe our experience with fluorine-18 fluorodeoxyglucose (FDG) positron emission tomography computed tomography (PET/CT) in diagnosing left ventricular assist device (LVAD) infections and perform a meta-analysis of published studies to determine overall diagnostic accuracy. BACKGROUND: Device-related infections are a common complication of LVADs and are linked to worse outcomes. Diagnosis of LVAD infections remains challenging. FDG PET/CT has demonstrated good diagnostic accuracy in several other infectious conditions. METHODS: This was a single-center, retrospective case series of FDG PET/CT scans in suspected LVAD infection between September 2015 and February 2018. A systematic review of PubMed from database inception through March 2018 was also conducted to identify additional studies. RESULTS: Nineteen FDG PET/CT scans were identified for the retrospective case series. The systematic review identified an additional 3 publications, for a total of 4 studies involving 119 scans assessing diagnostic performance. Axial (n = 36) and centrifugal (n = 83) flow LVADs were represented. Pooled sensitivity was 92% (95% confidence interval [CI]: 82% to 97%) and specificity was 83% (95% CI: 24% to 99%) for FDG PET/CT in diagnosing LVAD infections. Summary receiver-operating characteristic curve analysis demonstrated an AUC of 0.94 (95% CI: 0.91 to 0.95). CONCLUSIONS: FDG PET/CT for suspected LVAD infections demonstrates good diagnostic accuracy, with overall high sensitivity but variable specificity.
Subject(s)
Fluorodeoxyglucose F18/administration & dosage , Heart-Assist Devices/adverse effects , Positron Emission Tomography Computed Tomography , Prosthesis-Related Infections/diagnostic imaging , Radiopharmaceuticals/administration & dosage , Aged , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Prosthesis-Related Infections/microbiology , Reproducibility of Results , Retrospective StudiesABSTRACT
BACKGROUND: Left atrial (LA) remodeling is associated with structural, electric, and metabolic LA changes. Integrated evaluation of these features in vivo is lacking. METHODS: Patients undergoing 18F-fluorodeoxyglucose (FDG) PET-CT during a hyperinsulinemic-euglycemic clamp were classified into sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PerAF). The LA was semiautomatically segmented, and global FDG uptake was quantified using standardized uptake values (SUVmax and SUVmean) in gated, attenuation-corrected images and normalized to LA blood pool activity. Regression was used to relate FDG data to AF burden and critical patient factors. Continuous variables were compared using t-tests or Mann-Whitney tests. RESULTS: 117 patients were included (76% men, age 66.4 ± 11.0, ejection fraction (EF) 25[22-35]%) including those with SR (n = 48), PAF (n = 55), and PerAF (n = 14). Patients with any AF had increased SUVmean (2.3[1.5-2.4] vs 2.0[1.5-2.5], P = 0.006), SUVmax (4.4[2.8-6.7] vs 3.2[2.3-4.3], P < 0.001), uptake coefficient of variation (CoV) 0.28[0.22-0.40] vs 0.25[0.2-0.33], P < 0.001), and hypometabolic scar (32%[14%-53%] vs 16.5%[0%-38.5%], P = 0.01). AF burden correlated with increased SUVmean, SUVmax, CoV, and scar independent of age, gender, EF, or LA size (P < 0.03 for all). CONCLUSIONS: LA structure and metabolism can be assessed using FDG PET/CT. Greater AF burden correlates with the increased LA metabolism and scar.