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BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.
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Exoma , Pruebas Genéticas , Exoma/genética , Femenino , Pruebas Genéticas/métodos , Genómica , Humanos , Masculino , Fenotipo , Estudios ProspectivosRESUMEN
Current research on radionuclide disposal is mostly conducted in granite, clay, saltstone, or volcanic tuff formations. These rock types are not always available to host a geological repository in every nuclear waste-generating country, but carbonate rocks may serve as a potential alternative. To assess their feasibility, a forced gradient cross-borehole tracer experiment was conducted in a saturated fractured chalk formation. The mobility of stable Sr and Cs (as analogs for their radioactive counterparts), Ce (an actinide analog), Re (a Tc analog), bentonite particles, and fluorescent dye tracers through the flow path was analyzed. The migration of each of these radionuclide analogs (RAs) was shown to be dependent upon their chemical speciation in solution, their interactions with bentonite, and their sorption potential to the chalk rock matrix. The brackish groundwater resulted in flocculation and immobilization of most particulate RAs. Nevertheless, the high permeability of the fracture system allowed for fast overall transport times of all aqueous RAs investigated. This study suggests that the geochemical properties of carbonate rocks may provide suitable conditions for certain types of radionuclide storage (in particular, brackish, high-porosity, and low-permeability chalks). Nevertheless, careful consideration should be given to high-permeability fracture networks that may result in high radionuclide mobility.
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Agua Subterránea , Residuos Radiactivos , Geología , Modelos Teóricos , Porosidad , RadioisótoposRESUMEN
PURPOSE OF REVIEW: Glycogen storage disease Ib (GSD Ib) is characterized by hepatomegaly, hypoglycemia, neutropenia, enterocolitis and recurrent bacterial infections. It is attributable to mutations in G6PT1, the gene for the glucose-6-phosphate transporter responsible for transport of glucose into the endoplasmic reticulum. Neutropenia in GSD Ib is now frequently treated with granulocyte colony-stimulating factor (G-CSF). We formed a cooperative group to review outcomes of the long-term treatment of GSD Ib patients treated with G-CSF. RECENT FINDINGS: The study enrolled 103 patients (48 men and 55 women), including 47 currently adult patients. All of these patients were treated with G-CSF, starting at a median age of 3.8 years (range 0.04-33.9 years) with a median dose of 3.0âmcg/kg/day (range 0.01-93.1âmcg/kg/day) for a median of 10.3 years (range 0.01-29.3 years). Neutrophils increased in response to G-CSF in all patients (median values before G-CSF 0.2 × 10/l, on G-CSF 1.20 x 10/l). Treatment increased spleen size (before G-CSF, 47%, on treatment on G-CSF 76%), and splenomegaly was the dose-limiting adverse effect of treatment (pain and early satiety). Clinical observations and records attest to reduce frequency of infectious events and the severity of inflammatory bowel symptoms, but fever and recurrent infections remain a significant problem. In the cohort of patients followed carefully through the Severe Chronic Neutropenia International Registry, four patients have developed myelodysplasia or acute myeloid leukemia and we are aware of four other cases, (altogether seven on G-CSF, one never treated with G-CSF). Liver transplantation in five patients did not correct neutropenia. Four patients had hematopoietic stem cell transplantation; two adults and two children were transplanted; one adult and one child survived. SUMMARY: GSD Ib is a complex disorder of glucose metabolism causing severe chronic neutropenia. G-CSF is effective to raise blood neutrophil counts and reduce fevers and infections in most patients. In conjunction with other therapies (salicylates, mesalamine sulfasalazine and prednisone), G-CSF ameliorates inflammatory bowel symptoms, but doses must be limited because it increases spleen size associated with abdominal pain.
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Enfermedad del Almacenamiento de Glucógeno Tipo I/tratamiento farmacológico , Enfermedad del Almacenamiento de Glucógeno Tipo I/mortalidad , Factor Estimulante de Colonias de Granulocitos/administración & dosificación , Neutropenia/tratamiento farmacológico , Neutropenia/mortalidad , Sistema de Registros , Adolescente , Adulto , Niño , Preescolar , Supervivencia sin Enfermedad , Femenino , Enfermedad del Almacenamiento de Glucógeno Tipo I/sangre , Enfermedad del Almacenamiento de Glucógeno Tipo I/patología , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/sangre , Neutropenia/patología , Neutrófilos/metabolismo , Neutrófilos/patología , Tasa de SupervivenciaAsunto(s)
COVID-19 , Neutropenia , SARS-CoV-2 , Humanos , COVID-19/complicaciones , COVID-19/diagnóstico , COVID-19/epidemiología , Neutropenia/diagnóstico , Neutropenia/terapia , Neutropenia/etiología , Europa (Continente)/epidemiología , Masculino , Femenino , Enfermedad Crónica , Persona de Mediana Edad , Adulto , AncianoRESUMEN
Migration of colloids may facilitate the transport of radionuclides leaked from near surface waste sites and geological repositories. Intrinsic colloids are favorably formed by precipitation with carbonates in bicarbonate-rich environments, and their migration may be enhanced through fractured bedrock. The mobility of Ce(III) as an intrinsic colloid was studied in an artificial rainwater solution through a natural discrete chalk fracture. The results indicate that at variable injection concentrations (between 1 and 30 mg/L), nearly all of the recovered Ce takes the form of an intrinsic colloid of >0.45 µm diameter, including in those experiments in which the inlet solution was first filtered via 0.45 µm. In all experiments, these intrinsic colloids reached their maximum relative concentrations prior to that of the Br conservative tracer. Total Ce recovery from experiments using 0.45 µm filtered inlet solutions was only about 0.1%, and colloids of >0.45 µm constituted the majority of recovered Ce. About 1% of Ce was recovered when colloids of >0.45 µm were injected, indicating the enhanced mobility and recovery of Ce in the presence of bicarbonate.
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Cerio/química , Coloides/química , Carbonato de Calcio/química , Geología/métodos , Radioisótopos , Lluvia , Soluciones , Instalaciones de Eliminación de ResiduosRESUMEN
Internationally, it has been agreed that geologic repositories for spent fuel and radioactive waste are considered the internationally agreed upon solution for intermediate and long-term disposal. In countries where traditional nuclear waste repository host rocks (e.g., clay, salt, granite) are not available, other low permeability lithologies must be studied. Here, chalk is considered to determine its viability for disposal. Despite chalk's low bulk permeability, it may contain fracture networks that can facilitate radionuclide transport. In arid areas, groundwater salinity may change seasonally due to the mixing between brackish groundwater and fresh meteoric water. Such salinity changes may impact the radionuclides' mobility. In this study, radioactive U(VI) and radionuclide simulant tracers (Sr, Ce and Re) were injected into a naturally fractured chalk core. The mobility of tracers was investigated under abrupt salinity variations. Two solutions were used: a low ionic strength (IS) artificial rainwater (ARW; IS â¼0.002) and a high IS artificial groundwater (AGW; IS â¼0.2). During the experiments, the tracers were added to ARW, then the carrier was changed to AGW, and vice versa. Ce was mobile only in colloidal form, while Re was transported as a conservative tracer. Both Re and Ce demonstrated no change in mobility due to salinity changes. In contrast, U and Sr showed increased mobility when AGW was introduced and decreased mobility when ARW was introduced into the core. These experimental results, supported by reactive transport modeling, suggest that saline groundwater solutions promote U and Sr release via ion-exchange and enhance their migration in fractured chalk. The study emphasizes the impact of salinity variations near spent fuel repositories and their possible impact on radionuclide mobility.
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Lung exposures to dusts, pollutants, and other aerosol particulates are known to be associated with pulmonary diseases such as asthma and Chronic Obstructive Pulmonary Disease. These health impacts are attributed to the ability of aerosol components to induce pulmonary inflammation, which promotes tissue remodeling, including fibrosis, tissue degradation, and smooth muscle proliferation. Consequently, the distribution of these effects can have a significant impact on the physiologic function of the lung. In order to study the impact of distribution of inhaled particulates on lung pathogenesis, we compared the effect of different methods of particle delivery. By comparing intranasal versus aerosol delivery of fluorescent microspheres, we observed strikingly distinct patterns of particle deposition; intranasal delivery provided focused deposition concentrated on larger airways, while aerosol delivery showed unform deposition throughout the lung parenchyma. Recognizing that the impacts of inflammatory cells are contingent upon their recruitment and behavior, we postulate that these variations in distribution patterns can result in significant alterations in biological responses. To elucidate the relevance of these findings in terms of biological representation, we subsequently conducted an investigation into the responses elicited by the administration of endotoxin (bacterial Lipopolysaccharide, or LPS) in a transgenic neutrophil reporter mouse model. As with the microsphere results, patterns of recruited neutrophil inflammatory responses matched the delivery method; that is, despite the active migratory behavior of neutrophils, inflammatory histopathology patterns were either focused on large airways (intranasal administration) or diffusely throughout the parenchyma (aerosol). These results demonstrate the importance of modes of aerosol delivery as different patterns of inflammation and tissue remodeling will have distinct impacts on lung physiology.
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Pulmón , Aerosoles y Gotitas Respiratorias , Ratones , Animales , Administración por Inhalación , Tamaño de la Partícula , Pulmón/metabolismo , AerosolesRESUMEN
BACKGROUND: The nail salon industry in the US comprises mostly immigrant-owned, small mom-and-pop salons that employ primarily first-generation immigrant workers from Asia. Because of the cultural and language barriers, both owners and workers may not avail themselves of the occupational safety resources. We formed an academic-community partnership to co-design a feasibility study and multi-level occupational health intervention for Vietnamese-speaking salon owners, workers, and community-based organization. METHODS: The intervention for each salon included (i) 2-h in-person training covering chemical safety, infection control, musculoskeletal prevention, and workers' rights for both the owners and their employees, (ii) a tailored recommendation report for the owner, and (iii) check-ins with the owner during the 3-month follow-up. Community partner was trained to deliver the in-language training with technical assistance from the research team. Baseline and post-intervention individual data about health symptoms and behaviors, as well as personal chemical exposures were collected and analyzed. RESULTS: A total of 44 participants from 12 consented salons enrolled in the study. One salon dropped out at follow-up due to change of ownership. Analysis of the differences between post-and pre-intervention showed a tendency toward reduction in some self-reported symptoms in the respiratory system, skin, and eyes, neurotoxicity score, as well as chemical exposures. We could not rule out seasonality as an explanation for these trends. Increase in self-efficacy in some areas was observed post-intervention. CONCLUSIONS: Our study demonstrated a successful academic-community partnership to engage community members in the intervention study. While the intervention effects from this feasibility study should be interpreted with caution, our preliminary results indicated that our community-based intervention is a promising approach to reduce work-related exposures among Asian American nail salon workers.
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Exposición Profesional , Salud Laboral , Humanos , Exposición Profesional/análisis , Philadelphia , Industria de la Belleza , AsiáticoRESUMEN
With the clinical approval of T-cell-dependent immune checkpoint inhibitors for many cancers, therapeutic cancer vaccines have re-emerged as a promising immunotherapy. Cancer vaccines require the addition of immunostimulatory adjuvants to increase vaccine immunogenicity, and increasingly multiple adjuvants are used in combination to bolster further and shape cellular immunity to tumor antigens. However, rigorous quantification of adjuvants' synergistic interactions is challenging due to partial redundancy in costimulatory molecules and cytokine production, leading to the common assumption that combining both adjuvants at the maximum tolerated dose results in optimal efficacy. Herein, we examine this maximum dose assumption and find combinations of these doses are suboptimal. Instead, we optimized dendritic cell activation by extending the Multidimensional Synergy of Combinations (MuSyC) framework that measures the synergy of efficacy and potency between two vaccine adjuvants. Initially, we performed a preliminary in vitro screening of clinically translatable adjuvant receptor targets (TLR, STING, NLL, and RIG-I). We determined that STING agonist (CDN) plus TLR4 agonist (MPL-A) or TLR7/8 agonist (R848) as the best pairwise combinations for dendritic cell activation. In addition, we found that the combination of R848 and CDN is synergistically efficacious and potent in activating both murine and human antigen-presenting cells (APCs) in vitro. These two selected adjuvants were then used to estimate a MuSyC-dose optimized for in vivo T-cell priming using ovalbumin-based peptide vaccines. Finally, using B16 melanoma and MOC1 head and neck cancer models, MuSyC-dose-based adjuvating of cancer vaccines improved the antitumor response, increased tumor-infiltrating lymphocytes, and induced novel myeloid tumor infiltration changes. Further, the MuSyC-dose-based adjuvants approach did not cause additional weight changes or increased plasma cytokine levels compared to CDN alone. Collectively, our findings offer a proof of principle that our MuSyC-extended approach can be used to optimize cancer vaccine formulations for immunotherapy.
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Vacunas contra el Cáncer , Neoplasias , Adyuvantes Inmunológicos/farmacología , Adyuvantes Farmacéuticos/farmacología , Animales , Vacunas contra el Cáncer/uso terapéutico , Citocinas , Humanos , Inmunoterapia/métodos , Ratones , Ratones Endogámicos C57BL , Neoplasias/terapia , Eficacia de las VacunasRESUMEN
The influence of montmorillonite colloids on the mobility of 238Pu, 233U and 137Cs through a chalk fracture was investigated to assess the transport potential for radioactive waste. Radioisotopes of each element, along with the conservative tracer tritium, were injected in the presence and absence of montmorillonite colloids into a naturally fractured chalk core. In parallel, batch experiments were conducted to obtain experimental sorption coefficients (Kd, mL/g) for both montmorillonite colloids and the chalk fracture material. Breakthrough curves were modelled to determine diffusivity and sorption of each radionuclide to the chalk and the colloids under advective conditions. Uranium sorbed sparingly to chalk (log Kd = 0.7 ± 0.2) in batch sorption experiments. 233U(VI) breakthrough was controlled primarily by the matrix diffusion and sorption to chalk (15 and 25% recovery with and without colloids, respectively). Cesium, in contrast, sorbed strongly to both the montmorillonite colloids and chalk (batch log Kd = 3.2 ± 0.01 and 3.9 ± 0.01, respectively). The high affinity to chalk and low colloid concentrations overwhelmed any colloidal Cs transport, resulting in very low 137Cs breakthrough (1.1-5.5% mass recovery). Batch and fracture transport results, and the associated modelling revealed that Pu migrates both as Pu (IV) sorbed to montmorillonite colloids and as dissolved Pu(V) (7% recovery). Transport experiments revealed differences in Pu(IV) and Pu(V) transport behavior that could not be quantified in simple batch experiments but are critical to effectively predict transport behavior of redox-sensitive radionuclides. Finally, a brackish groundwater solution was injected after completion of the fracture flow experiments and resulted in remobilization and recovery of 2.2% of the total sorbed radionuclides which remained in the core from previous experiments. In general, our study demonstrates consistency in sorption behavior between batch and advective fracture transport. The results suggest that colloid-facilitated radionuclide transport will enhance radionuclide migration in fractured chalk for those radionuclides with exceedingly high affinity for colloids.
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Purpose To better define the epidemiology of discoid meniscus by analyzing a large, national database for incidence rates and associations with demographic variables. Methods From Optum's Clinformatics® Data Mart Database, incidence rates and proportions of reported racial categories - Asian, Black, Hispanic, and Caucasian - of diagnosed discoid meniscus cases (n = 198) in the study population of patients receiving arthroscopic meniscectomy or repair procedures (n = 60,042) were calculated and compared via chi-square tests to the total population. To control for age, sex, and socioeconomic factors such as income, multivariable logistic regression analysis was performed. Results Proportions of discoid meniscus patients who were Asian, Black, Hispanic, or Caucasian were <6%, <7%, 15.7%, and 73.7%, respectively; proportions of each racial category in the study population were 2.2%, 7.4%, 9.9%, and 80.5%, respectively. Incidence rates per 1000 for these were 5.95, 2.92, 5.19, and 3.01, respectively. After adjusting for age, sex, and income, race was not a statistically significant predictor. Odds of a discoid meniscus diagnosis decreased by 6% for each increment in age (p <0.001) and by 40% if male (p <0.001) in our total study population. In patients <=20 years old, sex was not a significant risk factor. Conclusions Younger age and female sex were identified as significant predictors for symptomatic discoid meniscus in the total study population. Unlike prior studies, this investigation did not show a significant association between this condition and race in the US, potentially increasing the diagnostic accuracy and estimated pretest probabilities for this condition based on patient demographics. What this study adds to existing knowledge This study provides new data on the role racial category plays in estimating the risk of having a symptomatic discoid meniscus requiring arthroscopic management, finding that it is unlikely to be a significant factor when controlling for other demographic variables. Furthermore, we report incidence statistics for this pathology in Black and Latinx populations, which so far have had little representation in peer-reviewed published literature on discoid meniscus epidemiology. In addition, this study suggests that age and sex possess statistically significant associations with a diagnosis of discoid meniscus requiring arthroscopic management, with the risk of diagnosis decreasing with age and increasing if female.
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The objective of this paper is to describe the development of a minimally invasive cochlear implant surgery (MICIS) electrode array insertion tool concept to enable clinical translation. First, analysis of the geometric parameters of potential MICIS patients (N = 97) was performed to inform tool design, inform MICIS phantom model design, and provide further insight into MICIS candidacy. Design changes were made to the insertion tool based on clinical requirements and parameter analysis results. A MICIS phantom testing model was built to evaluate insertion force profiles in a clinically realistic manner, and the new tool design was evaluated in the model and in cadavers to test clinical viability. Finally, after regulatory approval, the tool was used for the first time in a clinical case. Results of this work included first, in the parameter analysis, approximately 20% of the population was not considered viable MICIS candidates. Additionally, one 3D printed tool could accommodate all viable candidates with polyimide sheath length adjustments accounting for interpatient variation. The insertion tool design was miniaturized out of clinical necessity and a disassembly method, necessary for removal around the cochlear implant, was developed and tested. Phantom model testing revealed that the force profile of the insertion tool was similar to that of traditional forceps insertion. Cadaver testing demonstrated that all clinical requirements (including complete disassembly) were achieved with the tool, and the new tool enabled 15% deeper insertions compared to the forceps approach. Finally, and most importantly, the tool helped achieve a full insertion in its first MICIS clinical case. In conclusion, the new insertion tool provides a clinically viable solution to one of the most difficult aspects of MICIS.
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BACKGROUND: As regards anterior cruciate ligament (ACL) reconstruction (ACLR), graft diameter has been identified as a major predictor of failure in skeletally mature patients; however, this topic has not been well-studied in the higher risk pediatric population. Hamstring tendon autograft configuration can be adjusted to increase graft diameter, but tendon length must be adequate for ACLR. Historical parameters of expected tendon length have been variable, and no study has quantified pediatric ACL morphology with other osseous parameters. PURPOSE: To develop magnetic resonance imaging (MRI)-derived predictors of native ACL graft length in pediatric patients so as to enhance preoperative planning for graft preparation in this skeletally immature patient population. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: MRI scans of 110 patients were included (64 girls, 46 boys; median age, 10 years; range, 1-13 years). Patients with musculoskeletal diseases or prior knee injuries were excluded. The following measurements were taken on MRI: ACL length; sagittal and coronal ACL inclination; intercondylar notch width and inclination; and femoral condyle depth and width. Associations between these measurements and patient sex and age were investigated. Univariate linear regression and multivariable regression models were created for each radiographic ACL measure to compare R 2. RESULTS: Female ACL length was most strongly associated with the depth of the lateral femoral condyle as viewed in the sagittal plane (R 2 = 0.65; P < .001). Other statistically significant covariates of interest included distal femoral condylar width, age, and coronal notch width (P < .05). For males, the ACL length was most strongly associated with the distal femoral condyle width as viewed in the coronal plane (R 2 = 0.70; P < .001). Other statistically significant covariates of interest for male ACL lengths were lateral femoral condyle depth, age, and coronal notch width (P < .05). CONCLUSION: In pediatric populations, femoral condylar depth/width and patient age may be valuable in assessing ACL size and determining appropriate graft dimensions and configuration for ACLRs. The use of this information to optimize graft diameter may lower the rates of ACL graft failure in this high-risk group.
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Despite the widespread study of how injured nerves contribute to chronic pain, there are still major gaps in our understanding of pain mechanisms. This is particularly true of pain resulting from nerve injury, or neuropathic pain, wherein tactile or thermal stimuli cause painful responses that are particularly difficult to treat with existing therapies. Curiously, this stimulus-driven pain relies upon intact, uninjured sensory neurons that transmit the signals that are ultimately sensed as painful. Studies that interrogate uninjured neurons in search of cell-specific mechanisms have shown that nerve injury alters intact, uninjured neurons resulting in an activity that drives stimulus-evoked pain. This review of neuropathic pain mechanisms summarizes cell-type-specific pathology of uninjured sensory neurons and the sensory ganglia that house their cell bodies. Uninjured neurons have demonstrated a wide range of molecular and neurophysiologic changes, many of which are distinct from those detected in injured neurons. These intriguing findings include expression of pain-associated molecules, neurophysiological changes that underlie increased excitability, and evidence that intercellular signaling within sensory ganglia alters uninjured neurons. In addition to well-supported findings, this review also discusses potential mechanisms that remain poorly understood in the context of nerve injury. This review highlights key questions that will advance our understanding of the plasticity of sensory neuron subpopulations and clarify the role of uninjured neurons in developing anti-pain therapies.
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Mobility of radionuclides originating from geological repositories in the subsurface has been shown to be facilitated by clay colloids. In brackish water, however, colloids may flocculate and act to immobilize radionuclides associated with them. Furthermore, little research has been conducted on radionuclide interactions with carbonate rocks. Here, the impact of bentonite colloid presence on the transport of a cocktail of U(VI), Cs, Ce and Re through fractured chalk was investigated. Flow-through experiments were conducted with and without bentonite colloids, present as a mixture of bentonite and Ni-altered montmorillonite colloids. Ce was used as an analogue for reactive actinides in the (III) and (VI) redox states, and Re was considered an analogue for Tc. Filtered brackish groundwater (ionic strengthâ¯=â¯170â¯mM) pumped from a fractured chalk aquitard in the northern Negev Desert of Israel, was used as a solution matrix. Rhenium transport was identical to that of the conservative tracer, uranine. The sorption coefficient (Kd) of U(VI), Cs and Re, calculated from batch experiments with crushed chalk, proved to be a good predictor of mass recovery in transport experiments conducted without bentonite colloids. A meaningful Kd value for Ce could not be calculated due to its precipitation as a Ce-carbonate colloids. Transport of both U(VI) and Cs was indifferent to the presence of bentonite colloids. However, the addition of bentonite in the injection solution effectively immobilized Ce, decreasing its recovery from 17-41% to 0.8-1.4%. This indicates that radionuclides which interact with clay colloids that undergo flocculation and deposition may effectively be immobilized in brackish aquifers. The results of this study have implications for the prediction of potential mobility of radionuclides in safety assessments for future geological repositories to be located in fractured carbonate rocks in general and in brackish groundwater in particular.
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Carbonato de Calcio , Contaminantes Radiactivos del Agua , Coloides , Israel , Radioisótopos , Aguas SalinasRESUMEN
OBJECTIVES: Mammalian targets of rapamycin inhibitors (mTORi) are considered second-line immunosuppression agents because of associated increases in rejection and impaired wound healing. Recent reports indicate mTORi have been linked to improved survival, decreased inflammatory response in pancreatitis, and antiproliferative and antiangiogenic activity. Mammalian targets of rapamycin inhibitors have not been extensively analyzed in pancreas transplant recipients. METHODS: Adults with pancreas and kidney-pancreas transplants from 1987 to 2016 in the United Network for Organ Sharing database were analyzed (N = 25,837). Subjects were stratified into 2 groups: use of mTORi (n = 4174) and use of non-mTORi-based immunosuppression (n = 21,663). The log-rank test compared survival rates. Univariate and multivariate Cox regression analyses assessed patient and graft survival. RESULTS: Mammalian targets of rapamycin inhibitors were associated with a 7% risk reduction in allograft failure (hazard ratio, 0.931; P = 0.006). Allograft survival rates were significantly different between mTORi versus non-mTORi (P < 0.0001).The mTORi group showed a significantly higher patient survival rate 1, 3, 5, and 10 years posttransplant compared. Patient survival at 15 years was not significantly different. CONCLUSIONS: The use of mTORi for immunosuppression in pancreas transplant is associated with improved allograft survival and early patient survival posttransplant (up to 10 years).
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Supervivencia de Injerto/efectos de los fármacos , Inmunosupresores/farmacología , Trasplante de Riñón/métodos , Trasplante de Páncreas/métodos , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Adolescente , Adulto , Aloinjertos , Everolimus/farmacología , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Sirolimus/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Adulto JovenRESUMEN
In the context of geological disposal of radioactive waste, one of the controlling mechanisms for radionuclide migration through subsurface strata is sorption to mobile colloidal bentonite particles. Such particles may erode from the repository backfill or bentonite buffer and yield measurable (0.01-0.1â¯g/L) concentrations in natural groundwater. The extent of sorption is influenced by colloid concentration, ionic strength, radionuclide concentration, and the presence of competing metals. Uranium (VI) and cesium sorption to bentonite colloids was investigated both separately and together in low ionic strength (2.20â¯mM) artificial rainwater (ARW) and high ionic strength (169â¯mM) artificial groundwater (AGW; representative of a fractured carbonate rock aquitard). Sorption experiments were conducted as a factor of colloid concentration, initial metal concentration and opposing metal presence. It was shown that both U(VI) and Cs sorption were significantly reduced in AGW in comparison to ARW. Additionally, the sorption coefficient Kd of both metals was found to decrease with increasing colloid concentration. Competitive sorption experiments indicated that at high colloid concentration (1-2â¯g/L), Cs sorption was reduced in the presence of U(VI), and at low colloid concentration (0.01-0.5â¯g/L), both Cs and U(VI) Kds were reduced when they were present together due to competition for similar sorption sites. The results from this study imply that in brackish carbonate rock aquifers, typical of the Israeli northern Negev Desert, both U(VI) and Cs are more likely to be mobile as dissolved species rather than as colloid-associated solids.
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BACKGROUND: Helmets are known to reduce the incidence of traumatic brain injury (TBI) after bicycle-related accidents. The aim of this study was to assess the association of helmets with severity of TBI and facial fractures after bicycle-related accidents. METHODS: We performed an analysis of the 2012 National Trauma Data Bank abstracted information of all patients with an intracranial hemorrhage after bicycle-related accidents. Regression analysis was also performed. RESULTS: A total of 6,267 patients were included. About 25.1% (n = 1,573) of bicycle riders were helmeted. Overall, 52.4% (n = 3,284) of the patients had severe TBI, and the mortality rate was 2.8% (n = 176). Helmeted bicycle riders had 51% reduced odds of severe TBI (odds ratio [OR] .49, 95% confidence interval [CI] .43 to .55, P < .001) and 44% reduced odds of mortality (OR .56, 95% CI .34 to .78, P = .010). Helmet use also reduced the odds of facial fractures by 31% (OR .69, 95% CI .58 to .81, P < .001). CONCLUSION: Bicycle helmet use provides protection against severe TBI, reduces facial fractures, and saves lives even after sustaining an intracranial hemorrhage.
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Ciclismo/lesiones , Dispositivos de Protección de la Cabeza/estadística & datos numéricos , Adolescente , Adulto , Anciano , Lesiones Traumáticas del Encéfalo/epidemiología , Niño , Bases de Datos Factuales , Traumatismos Faciales/epidemiología , Femenino , Fracturas Óseas/epidemiología , Humanos , Puntaje de Gravedad del Traumatismo , Hemorragias Intracraneales/epidemiología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Estados Unidos/epidemiología , Adulto JovenRESUMEN
The 5-year survival rate for patients with oral cancer remains low, in part because diagnosis often occurs at a late stage. Early and accurate identification of oral high-grade dysplasia and cancer can help improve patient outcomes. Multimodal optical imaging is an adjunctive diagnostic technique in which autofluorescence imaging is used to identify high-risk regions within the oral cavity, followed by high-resolution microendoscopy to confirm or rule out the presence of neoplasia. Multimodal optical images were obtained from 206 sites in 100 patients. Histologic diagnosis, either from a punch biopsy or an excised surgical specimen, was used as the gold standard for all sites. Histopathologic diagnoses of moderate dysplasia or worse were considered neoplastic. Images from 92 sites in the first 30 patients were used as a training set to develop automated image analysis methods for identification of neoplasia. Diagnostic performance was evaluated prospectively using images from 114 sites in the remaining 70 patients as a test set. In the training set, multimodal optical imaging with automated image analysis correctly classified 95% of nonneoplastic sites and 94% of neoplastic sites. Among the 56 sites in the test set that were biopsied, multimodal optical imaging correctly classified 100% of nonneoplastic sites and 85% of neoplastic sites. Among the 58 sites in the test set that corresponded to a surgical specimen, multimodal imaging correctly classified 100% of nonneoplastic sites and 61% of neoplastic sites. These findings support the potential of multimodal optical imaging to aid in the early detection of oral cancer. Cancer Prev Res; 10(10); 563-70. ©2017 AACR.
Asunto(s)
Detección Precoz del Cáncer/métodos , Procesamiento de Imagen Asistido por Computador/métodos , Neoplasias de la Boca/diagnóstico por imagen , Boca/diagnóstico por imagen , Imagen Multimodal/métodos , Imagen Óptica/métodos , Algoritmos , Biopsia , Medios de Contraste/administración & dosificación , Humanos , Hiperplasia/diagnóstico por imagen , Hiperplasia/patología , Boca/patología , Boca/cirugía , Neoplasias de la Boca/patología , Neoplasias de la Boca/cirugía , Lesiones Precancerosas/diagnóstico por imagen , Lesiones Precancerosas/patología , Proflavina/administración & dosificación , Estudios Prospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
Colloid facilitated transport of radionuclides has been implicated as a major transport vector for leaked nuclear waste in the subsurface. Sorption of radionuclides onto mobile carrier colloids such as bentonite and humic acid often accelerates their transport through saturated rock fractures. Here, we employ column studies to investigate the impact of intrinsic, bentonite and humic acid colloids on the transport and recovery of Ce(III) through a fractured chalk core. Ce(III) recovery where either bentonite or humic colloids were added was 7.7-26.9% Ce for all experiments. Greater Ce(III) recovery was observed when both types of carrier colloids were present (25.4-37.4%). When only bentonite colloids were present, Ce(III) appeared to be fractionated between chemical sorption to the bentonite colloid surfaces and heteroaggregation of bentonite colloids with intrinsic carbonate colloids, precipitated naturally in solution. However, scanning electron microscope (SEM) images and colloid stability experiments reveal that in suspensions of humic acid colloids, colloid-facilitated Ce(III) migration results only from the latter attachment mechanism rather than from chemical sorption. This observed heteroaggregation of different colloid types may be an important factor to consider when predicting potential mobility of leaked radionuclides from geological repositories for spent fuel located in carbonate rocks.