Hepatitis B virus (HBV) reactivation has been documented in association with multiple immunotherapy regimens . These reactivations can be life-threatening and result in fulminant hepatic failure. ...There are currently no reports of HBV reactivation on nivolumab treatment. This is a case of a patient with known HIV infection and previous HBV workup that revealed him to be anti-hepatitis B core antibody positive, hepatitis B surface antigen negative, and HBV DNA negative. He experienced a HBV reactivation while on therapy with nivolumab for stage IIIa poorly differentiated carcinoma of the lung, which was a recurrence from a prior surgically resected stage Ia well differentiated adenocarcinoma of the lung. He is a long-term nonprogressor in regards to his HIV and had previously had a negative HBV DNA level and had declined antiretroviral therapy until just prior to starting nivolumab. This case is also of interest as antiprogrammed death-1 receptors are involved in CD4-related HIV control , and the effects of nivolumab in a patient who was an HIV long-term nonprogressor are unknown. There was concern that he would develop increased HIV viremia and CD4-related immune dysfunction without antiretroviral therapy, and thus, he agreed to treatment prior to starting antineoplastic immunotherapy.
Land application of biosolids is one potential source of pharmaceuticals and personal care products (PPCPs) into agricultural soils. Degradation is an important natural attenuation pathway that ...affects the fate and transport of PPCPs in the soil system and biosolids application could alter the process. The present study assessed the effect of individual and mixture compound environments on the biodegradation rate and half-life of three non-steroidal anti-inflammatory drugs (NSAIDs), naproxen (NPX), ibuprofen (IBF), and ketoprofen (KTF), in a loamy sand textured agricultural soil receiving an alkaline treated biosolid (ATB) amendment. A prolonged half-life of the target NSAIDs was determined for sterile soils and shorter half-lives in unsterile soils, indicating the loss of target compounds in all treatments was mainly attributed to biodegradation and followed first-order kinetics. IBF and NPX showed low to moderate persistence in soil and ATB amended soil, with half-lives ranging from 4.9 to 14.8 days, while KTF appeared to be highly persistent with an average half-life of 33 days. The order in which the target NSAIDs disappeared in both soil and ATB amended soil was: IBF > NPX > KTF, for both individual and mixture compound treatments. Soils that received the ATB amendment demonstrated inhibited degradation of NPX in all treatments, as well as IBF and KTF in individual compound treatment over the 14-day incubation study. We also observed an inhibition effect from the ATB amendment in sterile soil treatments. In mixture compound treatments, IBF degradation was inhibited in both soil and ATB amended soil. The degradation rate of KTF in mixture compound environment in soil was lower, while the opposite effects were observed in ATB amended soils. For NPX, the degradation was enhanced in mixture compound environment in ATB amended soil, while the same degradation rate of NPX was calculated in soil.
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•Degradation of three NSAIDs was evaluated as individual vs mixture compounds in soil with and without biosolids.•Biodegradation was a significant pathway for NSAID loss in soil.•Biodegradation accounted for 20 to 50% of losses for naproxen, ibuprofen, and ketoprofen•Biosolids addition inhibited degradation kinetics of NSAIDs in soil•NSAID loss from soil followed first-order kinetics
Invasion of natural ecosystems by exotic species is a major threat to biodiversity globally. We assessed two alternative (but not exclusive) hypotheses to explain the success of exotic species in ...urban bushland on low fertility sandstone-derived soils in Sydney, Australia. These were that success of exotic species is promoted by: (1) plant attributes in particular disturbance types; and (2) freedom from herbivores. We tested these at sites subject to different types of disturbance: nutrient and water enrichment (below stormwater outlets), nutrient enrichment (riparian zones of creeks with an urban catchment) and physical disturbance (tracks), and control sites. At each site we estimated percentage cover of all species and surveyed leaves for damage by herbivores. Species were classified as native, non-invasive exotic or invasive exotic. We found that sites without any disturbance did not support exotic plants. Physically disturbed sites on low fertility soils supported only one exotic species, suggesting that nutrient enrichment is a critical prerequisite for exotic species invasion on low fertility soils. Exotic species cover was highest and native species richness most reduced in areas of highest nutrient enrichment. Both invasive exotic and non-invasive exotic species had significantly lower levels of leaf herbivory than native species, implying that release from pests alone cannot account for the success of invasive species. Specific leaf area of invasive exotic species was consistently higher than specific leaf area of non-invasive exotic and native species, regardless of disturbance type. In physically disturbed sites of higher soil fertility, exotic species were small herbs and grasses of long flowering duration and with small unassisted or wind-dispersed seeds. In sites subject to nutrient-enrichment, exotic species were more likely to be climbers, able to propagate vegetatively, and with seeds dispersed by vertebrates. Thus different plant attributes contribute to exotic species success under different disturbance types. The clearest consistent difference we found between invasive exotic and non-invasive exotic species was in specific leaf area, suggesting that large specific leaf area facilitates invasiveness.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used globally to treat and prevent illness. Biosolids change physico-chemical characteristics of soil and can affect the mobility of NSAIDs. ...A field-based lysimeter study evaluated the effect of three rates (0, 7, and 28 Mg ha−1) of alkaline treated biosolids (ATB) on the leaching potential of naproxen (NPX), ibuprofen (IBF), and ketoprofen (KTF) over 34 days in a sandy loam textured soil. Although all three NSAIDs in the lysimeter cells vertically migrated to deeper soil depths after spiking, the sum of all NPX, IBF, and KTF detected in the leachate samples from all treatments were only 0.03%, 0.02%, and 0.04% of the initial spiking mass to the surface soil, respectively. A mass balance analysis indicated a low accumulation of these compounds in the soil at the end of the study (Day 34) from all treatments with only 4.8%, 0.5%, and 0.7% of initial spiked NPX, IBF, and KTF, respectively. Application of ATB significantly increased soil pH and organic matter (OM) content of the soils but did not impact retention of the compounds in the soil profile. Overall, all three NSAIDs in the present study presented low mobility in the loamy sand textured agricultural soil.
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•Biodegradation was the main mechanism of NSAIDs dissipation in the lysimeter cells.•Soil amended with biosolids did not impact the NSAIDs retention in the soil profile.•Naproxen, ibuprofen, and ketoprofen as parent compounds showed low mobility in the soil.•The low NSAIDs mass measured in leachate indicated a low risk to the environment.
Recently Bekker et al. Bekker G‐J et al. Protein Sci. 2019;28:429–438. described a computational strategy of applying molecular‐dynamics simulations to estimate the relative stabilities of ...single‐domain antibodies, and utilized their method to design changes with the aim of increasing the stability of a single‐domain antibody with a known crystal structure. The structure from which they generated potentially stabilizing mutations is an anti‐cholera toxin single domain antibody selected from a naïve library which has relatively low thermal stability, reflected by a melting point of 48°C. Their work was purely theoretical, so to examine their predictions, we prepared the parental and predicted stabilizing mutant single domain antibodies and examined their thermal stability, ability to refold and affinity. We found that the mutation that improved stability the most (~7°C) was one which changed an amino acid in CDR1 from an asparagine to an aspartic acid. This change unfortunately was also accompanied by a reduction in affinity. Thus, while their modeling did appear to successfully predict stabilizing mutations, introducing mutations in the binding regions is problematic. Of further interest, the mutations selected via their high temperature simulations, did improve refolding, suggesting that they were successful in stabilizing the structure at high temperatures and thereby decrease aggregation. Our result should permit them to reassess and refine their model and may one day lead to a usefulin silico approach to protein stabilization.
Rapid and accurate delineation of contaminated sediments in marine environments is critical for the effective assessment of site risks and the development of appropriate remedial action plans. In ...this study, a new application of the ultraviolet optical screening tool (UVOST) equipped with electrical conductivity measurement (UVOST-EC) is proposed to delineate a water-covered sediment contaminated with dioxins and furans in a decommissioned pulp and paper wastewater stabilization basin. Bench scale experiments are presented that were used to develop a UVOST-EC interpretation method for delineating between two different sediment types present in the basin: an anthropogenically derived organic rich contaminated sediment (“black sediment”) and a naturally occurring grey organic silt sediment with marine provenance (“grey sediment”). The method involves comparative analysis of fluorescence and electrical conductivity signatures between the two sediments. Results indicate that each sediment type presents unique “signatures” related to fluorescence and electrical signals which corresponds to variability in their physio-chemical structure. Almost 100 UVOST-EC tests performed at the study site were paired with ex situ physical gravity core measurements of the black sediment to test the accuracy of the UVOST-EC-based method. A statistical analysis at seven sample “cluster” sites (i.e. multiple sub-samples within a defined area) indicated that the mean of sediment thickness obtained by the UVOST-EC measurement technique at a given site were not significantly different (p = 0.05) from measurements derived from sediment gravity core measurements. The UVOST-EC-based sediment thickness delineation method reliably determined the thickness of the dioxin and furan contaminated sediments as compared to gravity core determination for the sediment in this study. Application of this approach to other studies should be assessed in a similar manner. The UVOST-EC method offers health and safety, cost, logistics, and data interpretation benefits.
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•New technique for delineating a contaminated organic sediment is presented.•Proposed technique can eliminate health and safety concerns and provide cost saving.•Proposed technique verified at field scale with close to 100 samples.
Single-domain antibodies (sdAb), recombinantly produced variable heavy domains derived from the unconventional heavy chain antibodies found in camelids, provide stable, well-expressed binding ...elements with excellent affinity that can be tailored for specific applications through protein engineering. Complex matrices, such as plasma and serum, can dramatically reduce assay sensitivity. Thus, to achieve highly sensitive detection in complex matrices a highly efficient assay is essential. We produced sdAb as genetically linked dimers, and trimers, each including SpyTag at their C-terminus. The constructs were immobilized onto dyed magnetic microspheres to which SpyCatcher had been coupled and characterized in terms of their performance as capture reagents in sandwich assays. Initial tests on the ability of oriented monomer, dimer, and trimer captures to improve detection versus unoriented constructs in an assay for staphylococcal enterotoxin B spiked into buffer showed the oriented dimer format provided the best sensitivity while offering robust protein production. Thus, this format was utilized to improve a sdAb-based assay for the detection of dengue virus (DENV) nonstructural protein 1 (NS1) in serum. Detection of NS1 from each of the four DENV serotypes spiked into 50% normal human serum was increased by at least a factor of 5 when using the oriented dimer capture. We then demonstrated the potential of using the oriented dimer capture to improve detection of NS1 in clinical samples. This general method should enhance the utility of sdAb incorporated into any diagnostic assay, including those for high consequence pathogens.
We demonstrate the viability of using ultra-thin sheets of microbially grown nanocellulose to build functional medical sensors. Microbially grown nanocellulose is an interesting alternative to ...plastics, as it is hydrophilic, biocompatible, porous, and hydrogen bonding, thereby allowing the potential development of new application routes. Exploiting the distinguishing properties of this material enables us to develop solution-based processes to create nanocellulose printed circuit boards, allowing a variety of electronics to be mounted onto our nanocellulose. As proofs of concept, we have demonstrated applications in medical sensing such as heart rate monitoring and temperature sensing-potential applications fitting the wide-ranging paradigm of a future where the Internet of Things is dominant.
Kraepelin said severe mental illness was due to 2 diseases subsequently characterized as disorders of thought vs disorders of mood, ie, the Kraepelinian dichotomy. Schizophrenia, traditionally ...considered the disorder of thought, has been defined by the presence of hallucinations, delusions, catatonia, and disorganization. Tangentiality, derailment, loose associations, and thought blocking are typically considered pathognomonic of schizophrenia. By contrast, the mood disorders have been characterized only as disorders of the emotions, though both depression and mania, when severe, are now recognized to include the same psychotic features traditionally considered diagnostic of schizophrenia. This article addresses disordered thinking in mania in order to clarify the relationship between schizophrenia and psychotic mood disorders. Normally, the brain's selective attention mechanism filters and prioritizes incoming stimuli by excluding from consciousness extraneous, low-priority stimuli and grading the importance of more relevant data. Because this "filter/prioritizer" becomes defective in mania, tangential stimuli are processed without appropriate prioritization. Observed as distractibility, this symptom is an index of the breakdown in selective attention and the severity of mania, accounting for the signs and symptoms of psychotic thinking. The zone of rarity between schizophrenia and psychotic mood disorders is blurred because severe disorders of mood are also disorders of thought. This relationship calls into question the tenet that schizophrenia is a disease separate from psychotic mood disorders. Patients whose case histories are discussed herein gave their written informed consent to participate in this institutional human subjects committee-approved protocol.
Electroanalytical techniques are useful for detection and identification because the instrumentation is simple and can support a wide variety of assays. One example is cyclic square wave voltammetry ...(CSWV), a practical detection technique for different classes of compounds including explosives, herbicides/pesticides, industrial compounds, and heavy metals. A key barrier to the widespread application of CSWV for chemical identification is the necessity of a high performance, generalizable classification algorithm. Here, machine and deep learning models were developed for classifying samples based on voltammograms alone. The highest performing models were Long Short-Term Memory (LSTM) and Fully Convolutional Networks (FCNs), depending on the dataset against which performance was assessed. When compared to other algorithms, previously used for classification of CSWV and other similar data, our LSTM and FCN-based neural networks achieve higher sensitivity and specificity with the area under the curve values from receiver operating characteristic (ROC) analyses greater than 0.99 for several datasets. Class activation maps were paired with CSWV scans to assist in understanding the decision-making process of the networks, and their ability to utilize this information was examined. The best-performing models were then successfully applied to new or holdout experimental data. An automated method for processing CSWV data, training machine learning models, and evaluating their prediction performance is described, and the tools generated provide support for the identification of compounds using CSWV from samples in the field.
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