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Xylazine is in the unregulated drug supply at increasing rates, usually combined with fentanyl, necessitating understanding of its pharmacology. Despite commentary from politicians, and public health officials, it is unknown how xylazine impacts naloxone efficacy, and. few studies have examined it alone. Here, we examine the impact of xylazine alone and in combination with fentanyl on several behaviors in mice. Surprisingly, naloxone precipitates withdrawal from xylazine and fentanyl/xylazine coadministration, with enhanced sensitivity in females. Further, xylazine is a full agonist at kappa opioid receptors, a potential mechanism for its naloxone sensitivity. Finally, we demonstrate surprising effects of xylazine to kappa opioid antagonism, which are relevant for public health considerations. These data address an ongoing health crisis and will help inform critical policy and healthcare decisions. One-sentence summary: We present surprising new insights into xylazine and fentanyl pharmacology with immediate implications for clinical practice and frontline public health.

Diagnosing faults occurring in industrial equipment and monitoring its status is crucial for maintaining the continuous operation of the equipment. The conventional diagnostic approaches, such as model-based methods, need to model the dynamics of the physical process; however, obtaining an accurate dynamic model of complex interconnected industrial systems poses a significant challenge. Modern diagnostic methods based on data-driven using artificial intelligence models rely heavily on sensor data to perform fault detection and diagnosis. Conventional machine learning methods have low detection accuracy and rely on domain knowledge to extract meaningful features from data acquired from the equipment. On the other hand, deep learning models can automatically extract useful features from fault data with high diagnostic performance. This paper proposes a two-dimensional Convolutional Neural Network (2DCNN) diagnostic model to effectively improve the diagnostic accuracy of predicting faults on a tabular dataset with multiple fault classes. A simple sliding window approach is proposed to effectively transform and reshape the features in the dataset as inputs to the proposed model architecture. The method's feasibility was evaluated using data from an industrial robotic fuse quality test bench. Experimental results show high diagnostic performance with an average accuracy of 99.98% compared to conventional methods commonly used for diagnostics. Moreover, validation of the diagnostic model on the experimental dataset using raw multi-sensor fusion from a robot manipulator platform was carried out. The results demonstrate the model's outstanding diagnostic performance, with an average testing accuracy of 99.74% for four fault classes.

While birds and other vertebrates are well known hazards to aviation at airports, the threat posed by invertebrates is less well understood. Here we present an example of a serious risk to flight safety from the mud-nesting keyhole wasp (Pachodynerus nasidens) which views aircraft pitot probes as an attractive nesting opportunity at Brisbane Airport. Pitot probes measure airspeed, and obstructions can render measurements inaccurate, leading to serious and potentially catastrophic consequences. We undertook experiments over 39 months to determine rates of nesting in pitot probes and the associated risk of blocked probes. We also examined how this risk was reduced by covering probes. A bow-tie risk analysis was completed to assess the safety, reputation, one-off financial loss, and injury and illness costs of a range of incidents of increasing severity, and climate modelling was used to show the potential spread of the keyhole wasp in Australia. The reduction in risk from covering 33% to 75% of all probes on arrival is substantial and made more significant when the costs of incidents are set against those of wasp management. The prospects for eradicating the keyhole wasp and the prospect of it spreading to other parts of Australia with suitable climatic conditions are discussed in view of the substantial risk the species presents.

Gene editing with the CRISPR-Cas9 system could revolutionize hematopoietic stem cell (HSC)-targeted gene therapy for hereditary diseases, including sickle cell disease (SCD). Conventional delivery of editing tools by electroporation limits HSC fitness due to its toxicity; therefore, efficient and non-toxic delivery remains crucial. Integrating lentiviral vectors are established for therapeutic gene delivery to engraftable HSCs in gene therapy trials; however, their sustained expression and size limitation preclude their use for CRISPR-Cas9 delivery. Here, we developed a Cas9 protein delivery non-integrating lentiviral system encoding guide RNA and donor DNA, allowing for transient endonuclease function and inclusion of all editing tools in a single vector (all-in-one). We demonstrated efficient one-time correction of the SCD mutation in the endogenous βs-globin gene up to 42% at the protein level (p < 0.01) with the Cas9 protein delivery non-integrating lentiviral all-in-one system without electroporation. Our findings improve prospects for efficient and safe genome editing.

Lentiviral addition of βT87Q-globin, a modified β-globin with an anti-sickling mutation, is currently being used in gene therapy trials for sickle cell disease (SCD) and β-thalassemia patients. βT87Q-globin interferes with sickle hemoglobin (HbS) polymerization. Here, we generated the SCD mutation in an immortalized human erythroid cell line (HUDEP-2) to investigate the anti-sickling activity of βT87Q-globin. Sickle HUDEP-2 (sHUDEP-2) cells produced robust HbS after differentiation and sickled under deoxygenated conditions, comparable with SCD CD34+ progeny. Lentiviral transduction provided 9.5–26.8 pg/cell βT87Q-globin (R2 = 0.83) in a vector copy number (VCN)-dependent manner, resulting in a significant reduction of sickling ratios (R2 = 0.92). Interestingly, βT87Q-globin transduction markedly reduced endogenous βS-globin (R2 = 0.84) to an undetectable level (0.4–16.8 pg/cell) in sHUDEP-2 cells, as well as endogenous β-globin in human CD34+ cell-derived erythroid cells. RNA sequencing (RNA-seq) analysis with βT87Q-transduced sHUDEP-2 and human CD34+-derived cells revealed activation of inflammation- and proliferation-related programs, suggesting minimal changes in background gene expression except for βT87Q-globin expression and endogenous β/βS-globin suppression. In summary, using sHUDEP-2 and CD34+-derived cells, we demonstrated that lentiviral addition of βT87Q-globin strongly reduced endogenous β-/βS-globin expression, resulting in an anti-sickling effect. Our findings should be helpful to understand the anti-sickling effects of therapeutic genes in SCD gene therapy.

Humanized animal models are central to efforts aimed at improving hematopoietic stem cell (HSC) transplantation with or without genetic modification. Human cell engraftment is feasible in immunodeficient mice; however, high HSC doses and conditioning limit broad use of xenograft models. We assessed human CD45+ chimerism after transplanting varying doses of human CD34+ HSCs (2 × 105 to 2 × 106 cells/mouse) with or without busulfan (BU) pretransplant conditioning in c-kit mutant mice that do not require conditioning (non-obese diabetic [NOD]/B6/severe combined immunodeficiency [SCID]/ interleukin-2 receptor gamma chain null (IL-2rγ−/−) KitW41/W41 [NBSGW]). We then tested a range of BU (5–37.5 mg/kg) using 2 × 105 human CD34+ cells. Glycophorin-A erythrocyte chimerism was assessed after murine macrophage depletion using clodronate liposomes. We demonstrated successful long-term engraftment of human CD34+ cells at all cell doses in this model, and equivalent engraftment using 10-fold less CD34+ cells with the addition of BU conditioning. Low-dose BU (10 mg/kg) was sufficient to allow human engraftment using 2 × 105 CD34+ cells, whereas higher doses (≥37.5 mg/kg) were toxic. NBSGW mice support human erythropoiesis in the bone marrow; however, murine macrophage depletion provided only minimal and transient increases in peripheral blood human erythrocytes. Our xenograft model is therefore useful in HSC gene therapy and genome-editing studies, especially for modeling in disorders, such as sickle cell disease, where access to HSCs is limited. Keywords: busulfan, c-kit, erythropoiesis, gene therapy, hematopoietic stem cell transplantation, immunodeficient mice, xenograft transplantation

Summary: Sickle cell disease (SCD) is caused by a 20A > T mutation in the β-globin gene. Genome-editing technologies have the potential to correct the SCD mutation in hematopoietic stem cells (HSCs), producing adult hemoglobin while simultaneously eliminating sickle hemoglobin. Here, we developed high-efficiency viral vector-free non-footprint gene correction in SCD CD34+ cells with electroporation to deliver SCD mutation-targeting guide RNA, Cas9 endonuclease, and 100-mer single-strand donor DNA encoding intact β-globin sequence, achieving therapeutic-level gene correction at DNA (∼30%) and protein (∼80%) levels. Gene-edited SCD CD34+ cells contributed corrected cells 6 months post-xenograft mouse transplant without off-target δ-globin editing. We then developed a rhesus β-to-βs-globin gene conversion strategy to model HSC-targeted genome editing for SCD and demonstrate the engraftment of gene-edited CD34+ cells 10–12 months post-transplant in rhesus macaques. In summary, gene-corrected CD34+ HSCs are engraftable in xenograft mice and non-human primates. These findings are helpful in designing HSC-targeted gene correction trials.

Hematopoietic stem cell (HSC) gene therapy is curative for various hereditary diseases; however, high-efficiency transduction in HSCs remains crucial to improve the prospects for hemoglobinopathies. We previously optimized lentiviral transduction in human CD34+ cells with serum-free medium containing minimal cytokines, allowing efficient transduction (∼50%) and robust xenograft engraftment. In this study, we further improved lentiviral transduction in human CD34+ cells. High-density culture conditions (4e6/mL) resulted in ∼5-fold more efficient transduction in CD34+ cells (p < 0.01) compared with standard cell density (1e5/mL). After co-culturing vector-exposed CD34+ cells with non-transduced CD34+ cells, high-density culture conditions enhanced lentiviral gene marking in the non-transduced population (p < 0.01) compared with low-density conditions, suggesting that increasing cell-to-cell contact allows more efficient transduction. Two adjuvants, poloxamer 407 (100 μg/mL) and prostaglandin E2 (10 μM), were added to high-density CD34+ cells, resulting in ∼4-fold more efficient transduction (p < 0.01) without significant toxicity compared with no adjuvant control. In summary, we developed a highly efficient lentiviral transduction method in high-density CD34+ cell culture with poloxamer 407 and prostaglandin E2, allowing overall ∼10-fold improvement in transduction efficiency and consistently achieving more than 90% transduction and an average vector copy number of ∼10. Our optimized transduction method should improve gene therapy approaches using lentiviral vectors targeting HSCs. Keywords: lentiviral vector, hematopoietic stem cells, transduction efficiency

Background: American Indian populations have experienced marked disparities in respiratory disease burden. Extracellular vesicle-encapsulated microRNAs (EV-miRNAs) are a novel class of biomarkers that may improve recognition of lung damage in indigenous populations., Research Question: Are plasma EV-miRNAs viable biomarkers of respiratory health in American Indian populations?, Study Design and Methods: The Strong Heart Study (SHS) is a prospective cohort study that enrolled American Indians aged 45 to 74 years. EV-miRNA expression was measured in plasma (1993-1995). Respiratory health outcomes, including pre-bronchodilator FEV 1 , FVC, and respiratory symptom burden, were ascertained in the same study visit. Club cell secretory protein (CC-16), an antiinflammatory pneumoprotein implicated in COPD pathogenesis, was measured in serum. Linear and logistic regression were used for statistical analyses. Biological pathway analyses were used to elucidate gene targets of significant EV-miRNAs., Results: Among 853 American Indian adults, three EV-miRNAs were associated with FEV 1 , four EV-miRNAs were associated with FVC, and one EV-miRNA was associated with FEV 1 /FVC (P < .05). Increased miR-1294 expression was associated with higher odds of airflow limitation (OR, 1.29; 95% CI, 1.07-1.55), whereas increased expression of miR-1294 (OR, 1.32; 95% CI, 1.07-1.63) and miR-532-5p (OR, 1.57; 95% CI, 1.02-2.40) was associated with higher odds of restriction. Increased miR-451a expression was associated with lower odds of exertional dyspnea (OR, 0.71; 95% CI, 0.59-0.85). Twenty-two EV-miRNAs were associated with serum CC-16 levels (q < 0.05), suggesting that EV-miRNAs may play a role in the pathway linking CC-16 to COPD pathogenesis. A pathway analysis showed key EV-miRNAs targeted biological pathways that modulate inflammation, immunity, and structural integrity in the lungs., Interpretation: Circulating EV-miRNAs are novel mechanistic biomarkers of respiratory health and may facilitate the early detection and treatment of lung damage in American Indian populations that have been disproportionately affected by chronic lung diseases., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Snake venoms are known to be major sources of peptides with different pharmacological properties. In this study, we comprehensively explored the venom peptidomes of three specimens of Lachesismuta, the largest venomous snake in South America, using mass spectrometry techniques. The analysis revealed 19 main chromatographic peaks common to all specimens. A total of 151 peptides were identified, including 69 from a metalloproteinase, 58 from the BPP-CNP precursor, and 24 from a l-amino acid oxidase. To our knowledge, 126 of these peptides were reported for the first time in this work, including a new SVMP-derived peptide fragment, Lm-10a. Our findings highlight the dynamic nature of toxin maturation in snake venoms, driven by proteolytic processing, post-translational modifications, and cryptide formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Humor is universal but also culturally nuanced. This review (including 31 empirical articles in English) systematically examines cultural differences in humor perception and use. Most notably, North Americans tend to perceive humor more positively, rate themselves as more humorous, and use humor more than East Asians. Moreover, this review highlights complex cultural differences in the use of four humor styles (affiliative, self-enhancing, aggressive, and self-defeating). Finally, I discuss limitations of the cross-cultural literature on humor and propose future research directions. Theoretically, more studies should move beyond comparing East Asian and North American cultures, examine the consequences of cultural differences in humor, and track changes in humor perception and use over time. Methodologically, more studies should employ experiments to strengthen causality, recruit larger and more representative samples, and preregister theory-driven hypotheses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Ultrasound shear wave elastography (SWE) is a tool that can be utilized to assess biomechanical properties of tendons. Anisotropy, an ultrasound imaging artifact has been commonly cited as a potential source of error in the accuracy and reproducibility of SWE. The aim of the study was to assess reproducibility in performing SWE of patella tendons and differences in SWE and anisotropy between normal patella tendons and patellar tendinopathy., Methods: After obtaining the Institutional Review Board approval and written informed consent, we prospectively measured the shear wave velocity (SWV) of patella tendons with and without tendinopathy in 25 volunteers. SWVs were measured in three anatomic planes: longitudinal, perpendicular transverse, and tilted transverse with the probe tilted 15-30° from the perpendicular transverse plane by three operators with varied levels of experience. Anisotropy coefficient (A) was calculated by formula of A = (SWV Longitudinal  - SWV Transverse ) / SWV Transverse ., Results: Differences in SWV and anisotropy coefficient between normal tendons and tendons with tendinopathy were significant (p < 0.05). The intra- and inter-observer reproducibility in performing SWE were moderate to good (intraclass correlation coefficient: 0.81-0.95). The mean difference of 95% Bland-Altman limits of agreement for measuring tendon SWV ranged -0.08 to 0.41 (upper 0.08 to 1.14, lower -1.22 to -0.22) between senior and junior operators., Conclusion: The results of this study suggest that SWE and anisotropy coefficient are feasible tools to differentiate patellar tendinopathy from normal patella tendons. The reproducibility of performing SWE of patella tendons is moderate to good., Competing Interests: Declaration of competing interest Jing Gao, MD received cosigned equipment from Siemens Healthineers to support this study., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Prediction of individual patient benefit from lenalidomide (Len) maintenance after autologous stem cell transplant (ASCT) remains challenging. Here, we investigated extended molecular profiling for outcome prediction in patients in the National Cancer Research Institute Myeloma XI (MyXI) trial. Patients in the MyXI trial randomized to Len maintenance or observation after ASCT were genetically profiled for t(4;14), t(14;16), t(14;20), del(1p), gain(1q), and del(17p) and co-occurrence of risk markers was computed. Progression-free survival (PFS), subsequent progression (PFS2), and overall survival (OS) were calculated from maintenance randomization, and groups were compared using Cox proportional hazards regression. Of 556 patients, 17% with double-hit multiple myeloma (MM) (≥2 risk markers), 32% with single-hit (1 risk marker), and 51% without risk markers were analyzed. Single-hit MM derived the highest PFS benefit from Len maintenance, specifically, isolated del(1p), del(17p), and t(4;14), with ∼40-fold, 10-fold, and sevenfold reduced risk of progression or death (PFS), respectively, compared with observation. This benefit translated into improved PFS2 and OS for this group of patients compared with observation; median PFS was 10.9 vs 57.3 months for observation vs Len maintenance. Patients with isolated gain(1q) derived no benefit, and double-hit MM limited benefit (regardless or risk lesions involved) from Len maintenance. Extended genetic profiling identifies patients deriving exceptional benefit from Len maintenance and should be considered for newly diagnosed patients to support management discussions along their treatment pathway. This trial was registered at www.isrctn.com/ISRCTN49407852 as # ISRCTN49407852., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Alzheimer's disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end of their life dementia free. However, evidence obtained from the observational studies does not take into account how risk factors are correlated with one another, and whether they causally contribute to increased AD risk. In this study, we determine whether the relationship between previously speculated AD risk factors and AD susceptibility is consistent with causality using large-scale genetic data. We focus on educational attainment (EA), intelligence and household income which have been previously shown to be causally associated with AD. Using GWAS-by-subtraction and Multivariable Mendelian Randomization we show that of these, only the cognitive component of EA (intelligence) is independently causally associated with AD. This work has ramifications for the modifiability of lifestyle risk factors for AD., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Global genetic correlation analysis has provided valuable insight into the shared genetic basis between psychiatric and substance use disorders. However, little is known about which regions disproportionately contribute to the global correlation., Methods: We used Local Analysis of [co]Variant Annotation to calculate bivariate local genetic correlations across 2495 approximately equal-sized, semi-independent genomic regions for 20 psychiatric and substance use phenotypes. We performed a transcriptome-wide association study using expression weights from the prefrontal cortex to identify risk genes for each phenotype, followed by probabilistic fine-mapping to prioritize credible causal genes within each bivariate locus., Results: We detected 80 significant (p < 2.08 × 10 -6 ) bivariate local genetic correlations across 61 loci. The expression effect directions for risk genes within each bivariate locus were largely consistent with the local correlation coefficients, suggesting that genetically regulated gene expression may be used in the functional interpretation of local genetic correlations. Probabilistic fine-mapping identified several genes that may drive pleiotropic mechanisms for genetically correlated phenotypes. For example, we confirmed a local genetic correlation between schizophrenia and smoking behavior at 15q25 and prioritized PSMA4 as the most credible gene candidate underlying both phenotypes., Conclusions: Our study reveals previously unreported local bivariate genetic correlations between psychiatric and substance use phenotypes, which we fine-mapped to identify shared credible causal genes underlying genetically correlated phenotypes., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Objective: To explore the cortical morphological associations of the psychoses of epilepsy., Methods: Psychosis of epilepsy (POE) has two main subtypes - postictal psychosis and interictal psychosis. We used automated surface-based analysis of magnetic resonance images to compare cortical thickness, area, and volume across the whole brain between: (i) all patients with POE (n = 23) relative to epilepsy-without psychosis controls (EC; n = 23), (ii) patients with interictal psychosis (n = 10) or postictal psychosis (n = 13) relative to EC, and (iii) patients with postictal psychosis (n = 13) relative to patients with interictal psychosis (n = 10)., Results: POE is characterised by cortical thickening relative to EC, occurring primarily in nodes of the cognitive control network; (rostral anterior cingulate, caudal anterior cingulate, middle frontal gyrus), and the default mode network (posterior cingulate, medial paracentral gyrus, and precuneus). Patients with interictal psychosis displayed cortical thickening in the left hemisphere in occipital and temporal regions relative to EC (lateral occipital cortex, lingual, fusiform, and inferior temporal gyri), which was evident to a lesser extent in postictal psychosis patients. There were no significant differences in cortical thickness, area, or volume between the postictal psychosis and EC groups, or between the postictal psychosis and interictal psychosis groups. However, prior to correction for multiple comparisons, both the interictal psychosis and postictal psychosis groups displayed cortical thickening relative to EC in highly similar regions to those identified in the POE group overall., Significance: The results show cortical thickening in POE overall, primarily in nodes of the cognitive control and default mode networks, compared to patients with epilepsy without psychosis. Additional thickening in temporal and occipital neocortex implicated in the dorsal and ventral visual pathways may differentiate interictal psychosis from postictal psychosis. A novel mechanism for cortical thickening in POE is proposed whereby normal synaptic pruning processes are interrupted by seizure onset., Competing Interests: Conflicts of interest None of the authors have any conflict of interest to disclose., (Copyright © 2022 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Wastewater-based epidemiology (WBE) approach for COVID-19 surveillance is largely based on the assumption of SARS-CoV-2 RNA shedding into sewers by infected individuals. Recent studies found that SARS-CoV-2 RNA concentration in wastewater (C RNA ) could not be accounted by the fecal shedding alone. This study aimed to determine potential major shedding sources based on literature data of C RNA , along with the COVID-19 prevalence in the catchment area through a systematic literature review. Theoretical C RNA under a certain prevalence was estimated using Monte Carlo simulations, with eight scenarios accommodating feces alone, and both feces and sputum as shedding sources. With feces alone, none of the WBE data was in the confidence interval of theoretical C RNA estimated with the mean feces shedding magnitude and probability, and 63% of C RNA in WBE reports were higher than the maximum theoretical concentration. With both sputum and feces, 91% of the WBE data were below the simulated maximum C RNA in wastewater. The inclusion of sputum as a major shedding source led to more comparable theoretical C RNA to the literature WBE data. Sputum discharging behavior of patients also resulted in great fluctuations of C RNA under a certain prevalence. Thus, sputum is a potential critical shedding source for COVID-19 WBE surveillance., (Copyright © 2022. Published by Elsevier B.V.)

On the 26th of November 2021, the World Health Organization (WHO) designated the newly detected B.1.1.529 lineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) the Omicron Variant of Concern (VOC). The genome of the Omicron VOC contains more than 50 mutations, many of which have been associated with increased transmissibility, differing disease severity, and potential to evade immune responses developed for previous VOCs such as Alpha and Delta. In the days since the designation of B.1.1.529 as a VOC, infections with the lineage have been reported in countries around the globe and many countries have implemented travel restrictions and increased border controls in response. We putatively detected the Omicron variant in an aircraft wastewater sample from a flight arriving to Darwin, Australia from Johannesburg, South Africa on the 25th of November 2021 via positive results on the CDC N1, CDC N2, and del(69-70) RT-qPCR assays per guidance from the WHO. The Australian Northern Territory Health Department detected one passenger onboard the flight who was infected with SARS-CoV-2, which was determined to be the Omicron VOC by sequencing of a nasopharyngeal swab sample. Subsequent sequencing of the aircraft wastewater sample using the ARTIC V3 protocol with Nanopore and ATOPlex confirmed the presence of the Omicron variant with a consensus genome that clustered with the B.1.1.529 BA.1 sub-lineage. Our detection and confirmation of a single onboard Omicron infection via aircraft wastewater further bolsters the important role that aircraft wastewater can play as an independent and unintrusive surveillance point for infectious diseases, particularly coronavirus disease 2019., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Wastewater surveillance for pathogens using reverse transcription-polymerase chain reaction (RT-PCR) is an effective and resource-efficient tool for gathering community-level public health information, including the incidence of coronavirus disease-19 (COVID-19). Surveillance of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) in wastewater can potentially provide an early warning signal of COVID-19 infections in a community. The capacity of the world's environmental microbiology and virology laboratories for SARS-CoV-2 RNA characterization in wastewater is increasing rapidly. However, there are no standardized protocols or harmonized quality assurance and quality control (QA/QC) procedures for SARS-CoV-2 wastewater surveillance. This paper is a technical review of factors that can cause false-positive and false-negative errors in the surveillance of SARS-CoV-2 RNA in wastewater, culminating in recommended strategies that can be implemented to identify and mitigate some of these errors. Recommendations include stringent QA/QC measures, representative sampling approaches, effective virus concentration and efficient RNA extraction, PCR inhibition assessment, inclusion of sample processing controls, and considerations for RT-PCR assay selection and data interpretation. Clear data interpretation guidelines (e.g., determination of positive and negative samples) are critical, particularly when the incidence of SARS-CoV-2 in wastewater is low. Corrective and confirmatory actions must be in place for inconclusive results or results diverging from current trends (e.g., initial onset or reemergence of COVID-19 in a community). It is also prudent to perform interlaboratory comparisons to ensure results' reliability and interpretability for prospective and retrospective analyses. The strategies that are recommended in this review aim to improve SARS-CoV-2 characterization and detection for wastewater surveillance applications. A silver lining of the COVID-19 pandemic is that the efficacy of wastewater surveillance continues to be demonstrated during this global crisis. In the future, wastewater should also play an important role in the surveillance of a range of other communicable diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.)

The COVID-19 global pandemic and subsequent implementation of measures to reduce contact within the community have affected fisheries worldwide, yet few studies have reported the impacts on recreational fisheries. This study investigates boat-based recreational fishing in Western Australia from March to August 2020, where COVID-19 measures relevant to recreational fishers included various travel restrictions, and social and physical distancing measures. Information from surveys of licensed recreational fishers and fisheries compliance officers, and camera footage from key boat ramps is presented. A lower proportion of Perth metropolitan fishers went fishing compared with regional fishers. Metropolitan fishers also reported fewer days fished and lower participation in demersal and shore-based line fishing than regional fishers. In contrast, compliance officers observed more fishing activity in both metropolitan and regional locations. Fishing plans were mostly affected by travel restrictions with more metropolitan fishers affected compared with regional fishers. Daily recreational vessel retrievals at key boat ramps varied between locations, with metropolitan fishers initially unable to travel to regional centres. There was no decline in vessel retrievals at metropolitan boat ramps during the most rigid restrictions and northern regional boat ramps experienced substantial increases in recreational vessel activity once travel restrictions eased. Studies of this kind highlight the value of utilising established recreational fishing monitoring programmes to provide a responsive and scientific basis for policymakers to address societal behavioural changes associated with atypical events such as COVID-19., (Crown Copyright © 2021 Published by Elsevier Ltd. All rights reserved.)

Background: Sex differences in the incidence and outcomes of several cancers are well established. Multiple myeloma (MM) is a malignant plasma cell dyscrasia accounting for 2% of all new cancer cases in the UK. There is a clear sex disparity in MM incidence, with 57% of cases in males and 43% in females. The mechanisms behind this are not well understood and the impact of sex on patient outcomes has not been thoroughly explored., Patients and Methods: We investigated the association of sex with baseline disease characteristics and outcome in 3894 patients recruited to the phase III UK NCRI Myeloma XI trial, in which treatment exposure to lenalidomide predominated., Results: Females were significantly more likely to have the molecular lesions t(14;16) and del(17p) and were more likely to meet the cytogenetic classification of high-risk (HiR) or ultra-high-risk disease (UHiR). There was no difference in progression-free survival (PFS) or overall survival (OS) between the sexes in the overall population., Conclusion: Our data suggest that the genetic lesions involved in the initiation and progression of MM may be different between the sexes. Although females were more likely to have the poor prognosis lesions t(14;16) and del(17p), and were more likely to be assessed as having HiR or UHiR disease, this was not associated with reduced PFS or OS. In female patients the trial treatment may have been able to overcome some of the adverse effects of high-risk cytogenetic lesions. MicroAbstract Multiple myeloma (MM) is more common in males compared to females but the reasons behind this are not well understood and the impact of sex on patient outcomes is unclear. This study demonstrates fundamental differences in genetic lesions underlying the biology of MM between males and females. However, we found that progression-free survival and overall survival were the same in both sexes., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Markup of generalized interictal epileptiform discharges (IEDs) on EEG is an important step in the diagnosis and characterization of epilepsy. However, manual EEG markup is a time-consuming, subjective, and the specialized task where the human reviewer needs to visually inspect a large amount of data to facilitate accurate clinical decisions. In this study, we aimed to develop a framework for automated detection of generalized paroxysmal fast activity (GPFA), a generalized IED seen in scalp EEG recordings of patients with the severe epilepsy of Lennox-Gastaut syndrome (LGS)., Methods: We studied 13 children with LGS who had GPFA events in their interictal EEG recordings. Time-frequency information derived from manually marked IEDs across multiple EEG channels was used to automatically detect similar events in each patient's interictal EEG. We validated true positives and false positives of the proposed spike detection approach using both standalone scalp EEG and simultaneous EEG-functional MRI (EEG-fMRI) recordings., Results: GPFA events displayed a consistent low-high frequency arrangement in the time-frequency domain. This 'bimodal' spectral feature was most prominent over frontal EEG channels. Our automatic detection approach using this feature identified EEG events with similar time-frequency properties to the manually marked GPFAs. Brain maps of EEG-fMRI signal change during these automatically detected IEDs were comparable to the EEG-fMRI brain maps derived from manual IED markup., Conclusion: GPFA events have a characteristic bimodal time-frequency feature that can be automatically detected from scalp EEG recordings in patients with LGS. The validity of this time-frequency feature is demonstrated by EEG-fMRI analysis of automatically detected events, which recapitulates the brain maps we have previously shown to underlie generalized IEDs in LGS., Significance: This study provides a novel methodology that enables a fast, automated, and objective inspection of generalized IEDs in LGS. The proposed framework may be extendable to a wider range of epilepsy syndromes in which monitoring the burden of epileptic activity can aid clinical decision-making and faster assessment of treatment response and estimation of future seizure risk., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

This review (178 published articles) is the first to systematically examine the psychological (affective, cognitive, behavioral), economic, and social effects of air pollution beyond its physiological and environmental effects. Affectively, air pollution decreases happiness and life satisfaction, and increases annoyance, anxiety, mental disorders, self-harm, and suicide. Cognitively, it impairs cognitive functioning and decision making. Behaviorally, air pollution triggers avoidance behavior, defensive expenditure, and migration as coping strategies. Economically, it hurts work productivity and stock markets. Socially, it exacerbates criminal activities and worsens perception of the government. Importantly, both actual and perceived air pollution levels matter. Limitations of past research and future directions are discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: There have been recent increases in use of new psychoactive substances (NPS) associated with acute health harms including hospital presentations due to toxicity and increasing numbers of deaths. In response, the UK Government enacted generic legislation on 26th May 2016 (the Psychoactive Substances Act) making it an offence to produce, possess with intent to supply, supply, import or export, or possess within a custodial setting a psychoactive substance. We studied the impact of this Act on monthly frequency of enquiries made by health professionals to the UK National Poisons Information Service (NPIS) about NPS. We also studied five commonly used 'conventional' drugs of misuse that had been controlled prior to January 2009., Method: Anonymised clinical enquiries to the NPIS and accesses to the poisons information database TOXBASE were reviewed retrospectively from January 2009 to December 2018 to ascertain the trends in reported toxicity for NPS, cocaine, heroin, cannabis, amphetamines and MDMA. Data were analysed using interrupted time series analysis with the date of the PSA used as an independent predictor., Results: Over the period of study there were 3,866 NPIS telephone enquiries and 79,271 TOXBASE user accesses made by UK health professionals concerning NPS. There were increases in monthly TOXBASE accesses (t = 7.408, P < 0.0001) and telephone enquiries (t = 4.74, P < 0.001) over the pre-specified period January 2009 to May 2016. Comparing the period after the PSA with that before, there were significant reductions in TOXBASE accesses (t = -3.327, P < 0.001) and telephone enquiries (t = -6.97, P < 0.001), although reductions started before May 2016. There were no significant changes for the five conventional drugs. There were significant reductions in telephone enquiries (t = -3.418, P < 0.001) and non-significant reductions in TOXBASE accesses (t = -1.713, P = 0.089) for NPS between June 2016 and December 2018. Increases in telephone enquiries for cocaine and reductions TOXBASE accesses for MDMA were also observed over that period., Conclusions: There have been significant recent reductions in NPIS enquiry activity relating to NPS; although these began before enactment of the PSA in May 2016., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The quest for effective treatments of oxidative stress has concentrated over the years on new nanomaterials with improved antioxidant and antiradical activity, thereby attracting broad research interest. In that regard, research efforts in our lab were launched to pursue such hybrid materials involving a) synthesis of silica gel matrices, b) evaluation of the suitability of atoxic matrices as potential carriers for the controlled release of V(IV)(VOSO 4 ), V(V)(NaVO 3 ) compounds and a newly synthesized heterometallic lithium-vanadium(IV,V) tetranuclear compound containing vanadium-bound hydroxycarboxylic 1,3-diamine-2-propanol-N,N,N',N'-tetraacetic acid (DPOT), and c) investigation of structural and textural properties of silica nanoparticles (NPs) by different and complementary characterization techniques, inquiring into the nature of the encapsulated vanadium species and their interaction with the siloxane matrix, collectively targeting novel antioxidant and antiradical nanomaterials biotechnology. The physicochemical characterization of the vanadium-loaded SiO 2 NPs led to the formulation of optimized material configuration linked to the delivery of the encapsulated antioxidant-antiradical load. Entrapment and drug release studies showed a) the competence of hybrid nanoparticles with respect to encapsulation efficiency of the vanadium compound (concentration dependence), b) congruence with the physicochemical features determined, and c) a well-defined release profile of NP load. Antioxidant properties and the free radical scavenging capacity of the new hybrid materials (containing VOSO 4 , NaVO 3 , and V-DPOT) were demonstrated through a) 2-diphenyl-1-picrylhydrazyl (DPPH) free radical, and b) intracellular-extracellular reactive oxygen species (ROS) assays, through UV-Visible spectroscopy techniques, collectively showing that the hybrid silica NPs (empty-loaded) could serve as an efficient platform for nanodrug formulations counteracting oxidative stress., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)