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Background: Mechanical thrombectomy is a promising treatment option for deep vein thrombosis; however, long-term data are lacking. Here, we report for the first time the 1-year clinical outcomes from the completely enrolled ClotTriever Outcomes (CLOUT) registry evaluating mechanical thrombectomy with the ClotTriever System (Inari Medical). Methods: The CLOUT registry (NCT03575364) is a prospective, multicenter, single-arm study that enrolled 500 patients with proximal lower extremity deep vein thrombosis. Prespecified 1-year outcomes include Villalta score and corresponding postthrombotic syndrome (PTS) severity, duplex ultrasound findings of patency (defined as the presence of flow with normal or partial compressibility), Revised Venous Clinical Severity Score, and quality of life (QoL). Results: In CLOUT, the median age was 61.9 years and 50.5% of patients were women. A total of 310 patients completed the 1-year visit. The 1-year PTS rate (Villalta score ≥ 5) was 19.3% and the moderate-to-severe PTS rate (Villalta score ≥ 10) was 8.8%. Median Villalta score decreased from 9.0 (IQR, 5.0-14.0) at baseline to 1.0 (IQR, 0.0-4.0) at 1 year (P < .0001). Similar rates of PTS and moderate-to-severe PTS were observed among limbs assessed at all study time points. Patency was observed in 94.2% of limbs. Median Revised Venous Clinical Severity Score was 6.0 (IQR, 3.0-9.0) at baseline and 3.0 (IQR, 1.0-4.0) at 1 year (P < .0001). Additionally, 90.4% of patients experienced improvements in QoL. Conclusions: One-year outcomes from the CLOUT registry demonstrate low PTS rates and preserved patency accompanied by improved symptom relief and QoL. Study follow-up through 2 years is ongoing.
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Understanding and treating human diseases require valid animal models. Leveraging the genetic diversity in rhesus macaque populations across eight primate centers in the United States, we conduct targeted-sequencing on 1845 individuals for 374 genes linked to inherited human retinal and neurodevelopmental diseases. We identify over 47,000 single nucleotide variants, a substantial proportion of which are shared with human populations. By combining rhesus and human allele frequencies with established variant prediction methods, we develop a machine learning-based score that outperforms established methods in predicting missense variant pathogenicity. Remarkably, we find a marked number of loss-of-function variants and putative deleterious variants, which may lead to the development of rhesus disease models. Through phenotyping of macaques carrying a pathogenic OPA1:p.A8S variant, we identify a genetic model of autosomal dominant optic atrophy. Finally, we present a public website housing variant and genotype data from over two thousand rhesus macaques.
Subject(s)
Disease Models, Animal , Genetic Variation , Macaca mulatta , Animals , Macaca mulatta/genetics , Humans , Gene Frequency , Optic Atrophy, Autosomal Dominant/genetics , Polymorphism, Single Nucleotide , Phenotype , Machine Learning , Genotype , Mutation, MissenseABSTRACT
Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.
Subject(s)
Neoplasms , Whole Genome Sequencing , Humans , Neoplasms/genetics , Neoplasms/therapy , Neoplasms/diagnosis , Child , Male , Child, Preschool , Female , Adolescent , Infant , Genetic Testing/methods , Genome, Human/genetics , Genomics/methods , Infant, NewbornABSTRACT
Infection with clade I Mpox virus (MPXV) results in adverse pregnancy outcomes, yet the potential for vertical transmission resulting in fetal harm with clade IIb MPXV, the clade that is currently circulating in the Western Hemisphere, remains unknown. We established a rhesus macaque model of vertical MPXV transmission with early gestation inoculation. Three pregnant rhesus macaques were inoculated intradermally with 1.5 × 10^5 plaque forming units (PFU) of clade IIb MPXV near gestational day (GD) 30 and animals were monitored for viremia and maternal and fetal well-being. Animals were euthanized to collect tissues at 5, 14, or 25 days post-inoculation (dpi). Tissues were evaluated for viral DNA (vDNA) loads, infectious virus titers, histopathology, MPXV mRNA and protein localization, as well as MPXV protein co-localization with placental cells including, Hofbauer cells, mesenchymal stromal cells, endothelial cells, and trophoblasts. vDNA was detected in maternal blood and skin lesions by 5 dpi. Lack of fetal heartbeat was observed at 14 or 25 dpi for two dams indicating fetal demise; the third dam developed significant vaginal bleeding at 5 dpi and was deemed an impending miscarriage. vDNA was detected in placental and fetal tissue in both fetal demise cases. MPXV localized to placental villi by ISH and IHC. Clade IIb MPXV infection in pregnant rhesus macaques results in vertical transmission to the fetus and adverse pregnancy outcomes, like clade I MPXV. Further studies are needed to determine whether antiviral therapy with tecovirimat will prevent vertical transmission and improve pregnancy outcomes. One Sentence Summary: Clade IIb Mpox virus infection of pregnant rhesus macaques results in vertical transmission from mother to fetus and adverse pregnancy outcomes.
ABSTRACT
This research builds upon a previous study that explored the potential of the modified WIBS-4+ to selectively differentiate and detect different bioaerosol classes. The current work evaluates the influence of meteorological and air quality parameters on bioaerosol concentrations, specifically pollen and fungal spore dynamics. Temperature was found to be the most influential parameter in terms of pollen production and release, showing a strong positive correlation. Wind data analysis provided insights into the potential geographic origins of pollen and fungal spore concentrations. Fungal spores were primarily shown to originate from a westerly direction, corresponding to agricultural land use, whereas pollen largely originated from a North-easterly direction, corresponding to several forests. The influence of air quality was also analysed to understand its potential impact on the WIBS fluorescent parameters investigated. Most parameters had a negative association with fungal spore concentrations, whereas several anthropogenic influences showed notable positive correlations with daily pollen concentrations. This is attributed to similar driving forces (meteorological parameters) and geographical origins. In addition, the WIBS showed a significant correlation with anthropogenic pollutants originating from combustion sources, suggesting the potential for such modified spectroscopic instruments to be utilized as air quality monitors. By combining all meteorological and pollution data along with WIBS-4+ channel data, a set of Multiple Linear Regression (MLR) analyses were completed. Successful results with R2 values ranging from 0.6 to 0.8 were recorded. The inclusion of meteorological parameters was dependent on the spore or pollen type being examined.
Subject(s)
Aerosols , Air Pollutants , Environmental Monitoring , Pollen , Spores, Fungal , Environmental Monitoring/methods , Aerosols/analysis , Air Pollutants/analysis , Air Pollution/statistics & numerical data , Air Microbiology , Wind , Spectrum Analysis/methodsABSTRACT
BACKGROUND AND AIMS: Chronic stress associates with cardiovascular disease, but mechanisms remain incompletely defined. Advanced imaging was used to identify stress-related neural imaging phenotypes associated with atherosclerosis. METHODS: Twenty-seven individuals with post-traumatic stress disorder (PTSD), 45 trauma-exposed controls without PTSD, and 22 healthy controls underwent 18F-fluorodeoxyglucose positron emission tomography/magnetic resonance imaging (18F-FDG PET/MRI). Atherosclerotic inflammation and burden were assessed using 18F-FDG PET (as maximal target-to-background ratio, TBR max) and MRI, respectively. Inflammation was assessed using high-sensitivity C-reactive protein (hsCRP) and leucopoietic imaging (18F-FDG PET uptake in spleen and bone marrow). Stress-associated neural network activity (SNA) was assessed on 18F-FDG PET as amygdala relative to ventromedial prefrontal cortex (vmPFC) activity. MRI diffusion tensor imaging assessed the axonal integrity (AI) of the uncinate fasciculus (major white matter tract connecting vmPFC and amygdala). RESULTS: Median age was 37 years old and 54% of participants were female. There were no significant differences in atherosclerotic inflammation between participants with PTSD and controls; adjusted mean difference in TBR max (95% confidence interval) of the aorta 0.020 (-0.098, 0.138), and of the carotids 0.014 (-0.091, 0.119). Participants with PTSD had higher hsCRP, spleen activity, and aorta atherosclerotic burden (normalized wall index). Participants with PTSD also had higher SNA and lower AI. Across the cohort, carotid atherosclerotic burden (standard deviation of wall thickness) associated positively with SNA and negatively with AI independent of Framingham risk score. CONCLUSIONS: In this study of limited size, participants with PTSD did not have higher atherosclerotic inflammation than controls. Notably, impaired cortico-limbic interactions (higher amygdala relative to vmPFC activity or disruption of their intercommunication) associated with carotid atherosclerotic burden. Larger studies are needed to refine these findings.
Subject(s)
Carotid Artery Diseases , Positron-Emission Tomography , Stress Disorders, Post-Traumatic , Humans , Female , Male , Adult , Stress Disorders, Post-Traumatic/physiopathology , Stress Disorders, Post-Traumatic/diagnostic imaging , Carotid Artery Diseases/physiopathology , Carotid Artery Diseases/diagnostic imaging , Fluorodeoxyglucose F18 , Magnetic Resonance Imaging , Middle Aged , Prefrontal Cortex/diagnostic imaging , Prefrontal Cortex/physiopathology , Amygdala/diagnostic imaging , Amygdala/physiopathology , Radiopharmaceuticals , Case-Control Studies , Stress, Psychological/physiopathology , Stress, Psychological/complicationsABSTRACT
The prevalence in allergic diseases has increased considerably in the past decades. An important trigger of the symptoms of allergic rhinitis (hay fever) is the pollen of wind-pollinating plants. This pollen is developed by plants and is released into the air where it gets exposed to environmental influences and air pollution. We investigated the chemical changes to pollen that occur after release from the flower in a rural (Veluwe) and an urban (Amsterdam) site in the Netherlands using Fourier Transform Infrared (FTIR) spectroscopy. During the spring/summer of 2020 (during the COVID pandemic) the pollen of nine taxa (Alnus, Betula, Fagus, Fraxinus, Pinus, Plantago, Poaceae, Quercus and Salix) were collected directly from flowers and the air (using a mobile sampler). FTIR spectra were obtained for multiple individual pollen grains for each taxa. The spectra obtained from airborne pollen collected at the rural vs. urban sites did not show any statistical difference. This is possibly a result of a reduced difference in pollutant concentrations between the two sites due to the COVID-19-lockdown measures were in place. However, consistent differences in the FTIR spectra recovered from airborne vs. flower pollen were recorded for all pollen taxa. After the release from the flower the chemical composition of the pollen changed: (i) polysaccharides are converted to monosaccharides; (ii) protein concentration and/or nitration/oxidation level is altered; (iii) lipids are modified and/or reduced in concentration. These changes may alter the allergenicity of the pollen and suggest that further work on the allergenic nature of airborne pollen is required.
Subject(s)
Air Pollutants , Air Pollution , Allergens , Environmental Monitoring , Flowers , Pollen , Netherlands , Allergens/analysis , Air Pollutants/analysis , Air Pollution/statistics & numerical data , Spectroscopy, Fourier Transform Infrared , COVID-19ABSTRACT
Mauritian-origin cynomolgus macaques (MCMs) serve as a powerful nonhuman primate model in biomedical research due to their unique genetic homogeneity, which simplifies experimental designs. Despite their extensive use, a comprehensive understanding of crucial immune-regulating gene families, particularly killer Ig-like receptors (KIR) and NK group 2 (NKG2), has been hindered by the lack of detailed genomic reference assemblies. In this study, we employ advanced long-read sequencing techniques to completely assemble eight KIR and seven NKG2 genomic haplotypes, providing an extensive insight into the structural and allelic diversity of these immunoregulatory gene clusters. Leveraging these genomic resources, we prototype a strategy for genotyping KIR and NKG2 using short-read, whole-exome capture data, illustrating the potential for cost-effective multilocus genotyping at colony scale. These results mark a significant enhancement for biomedical research in MCMs and underscore the feasibility of broad-scale genetic investigations.
Subject(s)
Haplotypes , Macaca fascicularis , Receptors, KIR , Animals , Receptors, KIR/genetics , Macaca fascicularis/genetics , NK Cell Lectin-Like Receptor Subfamily C/genetics , Genomics/methods , GenotypeSubject(s)
Stress, Psychological , Humans , Europe/epidemiology , Stress, Psychological/epidemiology , BrainABSTRACT
Aim: Use long-term follow-up data from the IMPERIAL study to determine whether drug-eluting polymer-based nitinol stent treatment can delay the time to repeat intervention for femoropopliteal artery disease and how such a delay may result in cost savings in a value-based episode of care. Patients & methods: The IMPERIAL randomized controlled trial was an international study of a paclitaxel-eluting polymer-coated stent (Eluvia, Boston Scientific, MA, USA) versus a polymer-free paclitaxel-coated stent (Zilver PTX, Cook Corporation, IN, USA) for treating lesions of the femoropopliteal arterial segment. Study patients (n = 465) had symptomatic lower limb ischemia. Safety and efficacy assessments were performed through 5 years. Mean time to first reintervention was calculated in post-hoc analysis for patients who underwent a clinically driven target lesion revascularization (CD-TLR) through 3 or 5 years following the index procedure. To simulate potential cost savings associated with differential CD-TLR burden over time, a cost-avoidance analysis using input parameters from IMPERIAL and US 100% Medicare standard analytical files was developed. Results: Among patients with a first CD-TLR through 3 years of follow-up, mean time to reintervention was 5.5 months longer (difference 166 days, 95% CI: 51, 282 days; p = 0.0058) for patients treated with Eluvia (n = 56) than for those treated with Zilver PTX (n = 30). Through the 5-year study follow-up period, CD-TLR rates were 29.3% (68/232) for Eluvia and 34.2% (39/114) for Zilver PTX (p = 0.3540) and mean time to first reintervention exceeded 2 years for patients treated with Eluvia at 737 days versus 645 days for the Zilver PTX group (difference 92 days, 95% CI: -85, 269 days; p = 0.3099). Simulated savings considering reinterventions occurring over 1 and 5 years following initial use of Eluvia over Zilver PTX were US $1,395,635 and US $1,531,795, respectively, when IMPERIAL CD-TLR rates were extrapolated to 1000 patients. Conclusion: IMPERIAL data suggest initial treatment with Eluvia extends the time patients spend without undergoing reintervention. This extension may be associated with cost savings in relevant time frames.
Subject(s)
Drug-Eluting Stents , Femoral Artery , Paclitaxel , Peripheral Arterial Disease , Popliteal Artery , Humans , Drug-Eluting Stents/economics , Popliteal Artery/surgery , Peripheral Arterial Disease/economics , Peripheral Arterial Disease/therapy , Femoral Artery/surgery , Male , Female , Aged , Paclitaxel/therapeutic use , Paclitaxel/economics , Paclitaxel/administration & dosage , Time Factors , Middle Aged , Polymers/therapeutic use , Alloys/economics , Cost-Benefit Analysis , Cost SavingsABSTRACT
Genetically diverse simian arteriviruses (simarteriviruses) naturally infect geographically and phylogenetically diverse monkeys, and cross-species transmission and emergence are of considerable concern. Characterization of most simarteriviruses beyond sequence analysis has not been possible because the viruses fail to propagate in the laboratory. We attempted to isolate 4 simarteriviruses, Kibale red colobus virus 1, Pebjah virus, simian hemorrhagic fever virus, and Southwest baboon virus 1, by inoculating an immortalized grivet cell line (known to replicate simian hemorrhagic fever virus), primary macaque cells, macrophages derived from macaque induced pluripotent stem cells, and mice engrafted with macaque CD34+-enriched hematopoietic stem cells. The combined effort resulted in successful virus isolation; however, no single approach was successful for all 4 simarteriviruses. We describe several approaches that might be used to isolate additional simarteriviruses for phenotypic characterization. Our results will expedite laboratory studies of simarteriviruses to elucidate virus-host interactions, assess zoonotic risk, and develop medical countermeasures.
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Arterivirus , Animals , Mice , Arterivirus/genetics , Macaca , Macrophages , Cell LineABSTRACT
BACKGROUND: The origin of novel SARS-CoV-2 spike sequences found in wastewater, without corresponding detection in clinical specimens, remains unclear. We sought to determine the origin of one such cryptic wastewater lineage by tracking and characterising its persistence and genomic evolution over time. METHODS: We first detected a cryptic lineage, WI-CL-001, in municipal wastewater in Wisconsin, USA, in January, 2022. To determine the source of WI-CL-001, we systematically sampled wastewater from targeted sub-sewershed lines and maintenance holes using compositing autosamplers. Viral concentrations in wastewater samples over time were measured by RT digital PCR. In addition to using metagenomic 12s rRNA sequencing to determine the virus's host species, we also sequenced SARS-CoV-2 spike receptor binding domains, and, where possible, whole viral genomes to identify and characterise the evolution of this lineage. FINDINGS: We traced WI-CL-001 to its source at a single commercial building. There we detected the cryptic lineage at concentrations as high as 2·7 × 109 genome copies per L. The majority of 12s rRNA sequences detected in wastewater leaving the identified source building were human. Additionally, we generated over 100 viral receptor binding domain and whole-genome sequences from wastewater samples containing the cryptic lineage collected over the 13 consecutive months this virus was detectable (January, 2022, to January, 2023). These sequences contained a combination of fixed nucleotide substitutions characteristic of Pango lineage B.1.234, which circulated in humans in Wisconsin at low levels from October, 2020, to February, 2021. Despite this, mutations in the spike gene and elsewhere resembled those subsequently found in omicron variants. INTERPRETATION: We propose that prolonged detection of WI-CL-001 in wastewater indicates persistent shedding of SARS-CoV-2 from a single human initially infected by an ancestral B.1.234 virus. The accumulation of convergent omicron-like mutations in WI-CL-001's ancestral B.1.234 genome probably reflects persistent infection and extensive within-host evolution. People who shed cryptic lineages could be an important source of highly divergent viruses that sporadically emerge and spread. FUNDING: The Rockefeller Foundation, Wisconsin Department of Health Services, Centers for Disease Control and Prevention, National Institute on Drug Abuse, and the Center for Research on Influenza Pathogenesis and Transmission.
Subject(s)
COVID-19 , Wastewater , United States , Humans , SARS-CoV-2/genetics , COVID-19/epidemiology , Centers for Disease Control and Prevention, U.S.ABSTRACT
Skin volatile emissions offer a noninvasive insight into metabolic activity within the body as well as the skin microbiome and specific volatile compounds have been shown to correlate with age, albeit only in a few small studies. Building on this, here skin volatiles were collected and analyzed in a healthy participant study (n = 60) using a robust headspace-solid phase microextraction (HS-SPME) gas chromatography-mass spectrometry (GC-MS) workflow. Following processing, 18 identified compounds were deemed suitable for this study. These were classified according to gender influences and their correlations with age were investigated. Finally, 6 volatiles (of both endogenous and exogenous origin) were identified as significantly changing in abundance with participant age (p < 0.1). The potential origins of these dysregulations are discussed. Multiple linear regression (MLR) analysis was employed to model age based on these significant volatiles as independent variables, along with gender. Our analysis shows that skin volatiles show a strong predictive ability for age (explained variance of 68%), stronger than other biochemical measures collected in this study (skin surface pH, water content) which are understood to vary with chronological age. Overall, this work provides new insights into the impact of aging on the skin volatile profiles which comprises both endogenously and exogenously derived volatile compounds. It goes toward demonstrating the biological significance of skin volatiles and will help pave the way for more rigorous consideration of the healthy "baseline" skin volatile profile in volatilomics-based health diagnostics development going forward.
Subject(s)
Solid Phase Microextraction , Volatile Organic Compounds , Humans , Multivariate Analysis , Gas Chromatography-Mass Spectrometry/methods , Solid Phase Microextraction/methods , Volatile Organic Compounds/analysisABSTRACT
Mercury (Hg) is a global environmental concern that affects both humans and ecosystem. The comprehensive understanding of sources and dynamics is crucial for facilitating targeted and effective control strategies. Herein, a robust approach integrating Multivariate Statistics, Geostatistics, and Positive Matrix Factorization (PMF) was employed to quantitatively elucidate the distribution and sources of Hg in agricultural lands. Results indicated elevated Hg concentrations in the land with 74.46% of soils, including 84.85% of topsoil, 69.70% of subsoil, and 67.31% of deepsoil, exceeding risk screening value. Geoaccumulation Index of Hg in soil surpassed level â ¡ with more than 50% of Hg in the residual fraction regardless of the layer or location. The levels of Hg in surface water for irrigation exhibited a negative correlation with the distance from the mine and a positive correlation with that in sediment (R2>0.78, p < 0.01), suggesting the downstream migration and remobilization from sediment. Source apportion revealed that human activities as primary contributors despite high variability across locations and soil layers. Contributions to downstream soil Hg from Natural Background (NB), Primary Ore Mining (OM), Agricultural Practices (AP), and Wastewater Irrigation (WI) were 15.5%, 83.1%, 1.3%, and 0.1%, respectively. A reliable approach for source apportionment of Hg in soil was suggested, demonstrating potential applicability in the risk management of Hg-contaminated sites.
Subject(s)
Mercury , Metals, Heavy , Soil Pollutants , Humans , Mercury/analysis , Soil , Ecosystem , Soil Pollutants/analysis , Environmental Monitoring/methods , Mining , Risk Assessment , China , Metals, Heavy/analysisABSTRACT
Immunodominant and highly conserved flavivirus envelope proteins can trigger cross-reactive IgG antibodies against related flaviviruses, which shapes subsequent protection or disease severity. This study examined how prior dengue serotype 3 (DENV-3) infection affects subsequent Zika virus (ZIKV) plasmablast responses in rhesus macaques (n = 4). We found that prior DENV-3 infection was not associated with diminished ZIKV-neutralizing antibodies or magnitude of plasmablast activation. Rather, characterization of 363 plasmablasts and their derivative 177 monoclonal antibody supernatants from acute ZIKV infection revealed that prior DENV-3 infection was associated with a differential isotype distribution toward IgG, lower somatic hypermutation, and lesser B cell receptor variable gene diversity as compared with repeat ZIKV challenge. We did not find long-lasting DENV-3 cross-reactive IgG after a ZIKV infection but did find persistent ZIKV-binding cross-reactive IgG after a DENV-3 infection, suggesting non-reciprocal cross-reactive immunity. Infection with ZIKV after DENV-3 boosted pre-existing DENV-3-neutralizing antibodies by two- to threefold, demonstrating immune imprinting. These findings suggest that the order of DENV and ZIKV infections has impact on the quality of early B cell immunity which has implications for optimal immunization strategies. IMPORTANCE: The Zika virus epidemic of 2015-2016 in the Americas revealed that this mosquito-transmitted virus could be congenitally transmitted during pregnancy and cause birth defects in newborns. Currently, there are no interventions to mitigate this disease and Zika virus is likely to re-emerge. Understanding how protective antibody responses are generated against Zika virus can help in the development of a safe and effective vaccine. One main challenge is that Zika virus co-circulates with related viruses like dengue, such that prior exposure to one can generate cross-reactive antibodies against the other which may enhance infection and disease from the second virus. In this study, we sought to understand how prior dengue virus infection impacts subsequent immunity to Zika virus by single-cell sequencing of antibody producing cells in a second Zika virus infection. Identifying specific qualities of Zika virus immunity that are modulated by prior dengue virus immunity will enable optimal immunization strategies.
Subject(s)
Dengue Virus , Dengue , Flavivirus , Zika Virus Infection , Zika Virus , Animals , Macaca mulatta , Serogroup , Antibodies, Viral , Immunoglobulin G , Antibodies, Neutralizing , Cross ReactionsABSTRACT
Remediation of contaminated soil at industrial sites has become a challenge and an opportunity for sustainable urban land use, considering the substantial secondary impacts resulting from remediation activities. The design of soil remediation strategies for multi-site remediation from a regional perspective is of great significance for cities with a large number of brownfields. Centralized and decentralized facilities have been studied in different environmental fields, yet limited research has focused on centralized soil remediation, specifically the treatment of contaminated soil from different sites through the construction of shared soil treatment facilities. This study proposes a framework for comparing centralized and decentralized strategies for contaminated soil remediation based on the integration of life-cycle sustainability assessment and multi-objective optimization. With Zhuzhou, an industrial city in China, serving as an example, results show that after optimization, the centralized scenario can reduce total environmental impacts by 25 %-41 %. In addition, the centralized scenario can reduce economic costs by 27 %-39 %, saving up to 176 million USD. The advantages of the centralized soil remediation strategy include: (1) increased use of soil washing, (2) reduced use of off-site disposal, and (3) reduced construction and efficient utilization of soil treatment facilities. In conclusion, the centralized strategy is relatively suitable for cities or areas with a large number of medium or small-sized contaminated sites. The built framework can quantitatively evaluate multiple sites soil remediation at both the city and individual site level, allowing for a straightforward and objective comparison with the optimal remediation design.
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SARS-CoV-2 causes persistent infections in a subset of individuals, which is a major clinical and public health problem that should be prioritised for further investigation for several reasons. First, persistent SARS-CoV-2 infection often goes unrecognised, and therefore might affect a substantial number of people, particularly immunocompromised individuals. Second, the formation of tissue reservoirs (including in non-respiratory tissues) might underlie the pathophysiology of the persistent SARS-CoV-2 infection and require new strategies for diagnosis and treatment. Finally, persistent SARS-CoV-2 replication, particularly in the setting of suboptimal immune responses, is a possible source of new, divergent virus variants that escape pre-existing immunity on the individual and population levels. Defining optimal diagnostic and treatment strategies for patients with persistent virus replication and monitoring viral evolution are therefore urgent medical and public health priorities.
Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/epidemiology , Virus Replication , Immunocompromised HostABSTRACT
Mercury (Hg) contamination in aquatic environments presents a significant ecological and human health concern. This study explored the relationship between catchment land use and Hg concentrations within Qinghai Lake sediment, the largest lake in China, situated on the Qinghai-Tibet plateau. The study entailed detailed mapping of Hg sediment concentrations and a subsequent environmental risk assessment. Considering the complex nature of the plateau landform and surface vegetation, the study area was delineated at a 100 km radius centered on Qinghai Lake, which was divided into 30 sectors to quantify relationships between land use and the sediment Hg concentration. The results revealed a mean sediment Hg concentration of 29.91 µg/kg, which was elevated above the background level. Kendall's correlation analysis revealed significant but weak associations between sediment Hg concentrations and three land use types: grassland (rangeland and trees) (rs = 0.27, p < 0.05), crops (rs = -0.37, p < 0.05), and bare ground (rs = -0.25, p < 0.1), suggesting that growing areas of grassland correlated with higher Hg levels in the lake sediment, in contrast to bare ground or crops area, which correlated with lower Hg concentrations. Multiple linear regression models also observed weak negative relationships between bare ground and crops with sediment Hg concentration. This research methodology enhances our understanding of the impact of land use on Hg accumulation in lake sediments and underscores the need for integrated watershed management strategies to mitigate Hg pollution in Qinghai Lake.
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Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD ( App NL-G-F /hMapt ), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.
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ABSTRACT: T-ALL relapse usually occurs early but can occur much later, which has been suggested to represent a de novo leukemia. However, we conclusively demonstrate late relapse can evolve from a pre-leukemic subclone harbouring a non-coding mutation that evades initial chemotherapy.