Search

The Golgi apparatus, a crucial organelle involved in protein processing, including glycosylation, exhibits complex sub-structures, i.e., cis-, medial, and trans-cisternae. This study investigated the distribution of glycosyltransferases within the Golgi apparatus of mammalian cells via 3D super-resolution imaging. Focusing on human glycosyltransferases involved in N-glycan modification, we found that even enzymes presumed to coexist in the same Golgi compartment exhibit nuanced variations in localization. By artificially making their N-terminal regions [composed of a cytoplasmic, transmembrane, and stem segment (CTS)] identical, it was possible to enhance the degree of their colocalization, suggesting the decisive role of this region in determining the sub-Golgi localization of enzymes. Ultimately, this study reveals the molecular codes within CTS regions as key determinants of glycosyltransferase localization, providing insights into precise control over the positioning of glycosyltransferases, and consequently, the interactions between glycosyltransferases and substrate glycoproteins as cargoes in the secretory pathway. This study advances our understanding of Golgi organization and opens avenues for programming the glycosylation of proteins for clinical applications. Key words: Golgi apparatus, glycosyltransferase, 3D super-resolution imaging, N-glycosylation

Background and objective: Focal therapy (FT) is increasingly recognized as a promising approach for managing localized prostate cancer (PCa), notably reducing treatment-related morbidities. However, post-treatment anatomical changes present significant challenges for surveillance using current imaging techniques. This study aimed to evaluate the inter-reader agreement and efficacy of the Prostate Imaging after Focal Ablation (PI-FAB) scoring system in detecting clinically significant prostate cancer (csPCa) on post-FT multiparametric magnetic resonance imaging (mpMRI). Methods: A retrospective cohort study was conducted involving patients who underwent primary FT for localized csPCa between 2013 and 2023, followed by post-FT mpMRI and a prostate biopsy. Two expert genitourinary radiologists retrospectively evaluated post-FT mpMRI using PI-FAB. The key measures included inter-reader agreement of PI-FAB scores, assessed by quadratic weighted Cohen’s kappa (κ), and the system’s efficacy in predicting in-field recurrence of csPCa, with a PI-FAB score cutoff of 3. Additional diagnostic metrics including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy were also evaluated. Key findings and limitations: Scans from 38 patients were analyzed, revealing a moderate level of agreement in PI-FAB scoring (κ = 0.56). Both radiologists achieved sensitivity of 93% in detecting csPCa, although specificity, PPVs, NPVs, and accuracy varied. Conclusions and clinical implications: The PI-FAB scoring system exhibited high sensitivity with moderate inter-reader agreement in detecting in-field recurrence of csPCa. Despite promising results, its low specificity and PPV necessitate further refinement. These findings underscore the need for larger studies to validate the clinical utility of PI-FAB, potentially aiding in standardizing post-treatment surveillance. Patient summary: Focal therapy has emerged as a promising approach for managing localized prostate cancer, but limitations in current imaging techniques present significant challenges for post-treatment surveillance. The Prostate Imaging after Focal Ablation (PI-FAB) scoring system showed high sensitivity for detecting in-field recurrence of clinically significant prostate cancer. However, its low specificity and positive predictive value necessitate further refinement. Larger, more comprehensive studies are needed to fully validate its clinical utility.

A presença do invasor mexilhão dourado em águas brasileiras acarreta em impactos ecológicos ou econômicos. Uma alternativa de controle populacional é promissora: a imersão de uma espécie geneticamente modificada com o objetivo de, em contato com o molusco selvagem, produzir gerações inférteis. Uma proposta de modelo matemático que contemple tal competição torna-se importante, uma vez que pode fornecer informações para nortear futuros experimentos. Contudo, o modelo de competição necessita de uma dinâmica de crescimento bem estabelecida. Este trabalho apresenta dois modelos para a dinâmica do mexilhão selvagem, estudados de forma analítica. O estudo expõe as soluções de equilíbrio, sua estabilidade local nos pontos estacionários e uma análise de sensibilidade do números de reprodução basal (R_0's). Com isso, define-se o modelo mais adequado para receber as parcelas que modelem a competição. São realizadas simulações numéricas a fim de aferir possíveis desfechos da competição, utilizando o método de Runge-Kutta de quarta ordem. O estudo é capaz de apresentar dois pontos conclusivos importantes: que através da competição planejada a erradicação pode ser atingida e que há necessidade de vantagens competitivas para que a estratégia funcione. Este estudo ressalta a necessidade de vantagens competitivas para o mexilhão modificado. Das possíveis vantagens, o trabalho indica a eficiência reprodutiva e a taxa de mortalidade do mexilhão modificado como as mais promissoras. À vista de um tópico tão importante, este trabalho é necessário para que essa estratégia de controle populacional seja estudada e testada para auxiliar no desenvolvimento da espécie modificada de forma a respeitar a ecologia.

Abstract Background It is well established in the literature that active learning instruction in introductory STEM courses results in many desired student outcomes. Yet, regular use of high-quality active learning is not the norm in many STEM departments. Using results of a national survey, we identified 16 departments where multiple instructors reported using high levels of active learning in their introductory chemistry, mathematics, or physics courses. We conducted interviews with 27 instructors in these 16 departments to better understand the characteristics of such departments. Results Using grounded theory methodology, we developed a model that highlights relevant characteristics of departments with high use of active learning instruction in their introductory courses. According to this model, there are four main, interconnected characteristics of such departments: motivated people, knowledge about active learning, opportunities, and cultures and structures that support active learning. These departments have one or more people who are motivated to promote the use of active learning. These motivated people have knowledge about active learning as well as access to opportunities to promote the use of active learning. Finally, these departments have cultures and structures that support the use of active learning. In these departments, there is a positive feedback loop that works iteratively over time, where motivated people shape cultures/structures and these cultures/structures in turn increase the number and level of commitment of the motivated people. A second positive feedback loop was found between the positive outcome of using active learning instruction and the strengthening of cultures/structures supportive of active learning. Conclusions According to the model, there are two main take-away messages for those interested in promoting the use of active learning. The first is that all four components of the model are important. A weak or missing component may limit the desired outcome. The second is that desired outcomes are obtained and strengthened over time through two positive feedback loops. Thus, there is a temporal aspect to change. In all of the departments that were part of our study, the changes took at minimum several years to enact. While our model was developed using only high-use of active learning departments and future work is needed to develop the model into a full change theory, our results do suggest that change efforts may be made more effective by increasing the robustness of the four components and the connections between them.

The primary aim of this study was to establish the feasibility of implementing a larger RCT designed to evaluate the effect of financial incentives on HCV treatment initiation among persons receiving opioid agonist therapy and/or who have injected drugs in the prior six months. ETHOS Engage is an observational cohort of participants recruited from drug treatment and needle and syringe programs in Australia. Among 11 drug and alcohol clinics, participants who were HCV RNA-positive were randomized (1:1) to receive standard of care or a AUD $60 gift card at treatment initiation. Regarding feasibility, 100% (57/57) of eligible participants enrolled to take part. Twenty-eight participants were randomised to the financial incentive arm (AUD $60 gift card) plus standard of care and 29 participants to the standard of care arm. In this pilot RCT (n = 57), median age was 42 years (IQR 37–49), 63% were male (n = 36), 35% Indigenous (n = 20) and 36% (n = 21) reported injecting drugs daily in the past month. Twelve weeks post-study enrolment, 11 (39%) participants in the financial incentive arm and 17 (59%) participants in the standard of care arm initiated HCV treatment. Findings indicate high feasibility among people who inject drugs to be randomised to receive financial incentives to initiate HCV treatment.

Network analysis has become a well-recognized methodology in physics education research (PER), with study topics including student performance and persistence, faculty change, and the structure of conceptual networks. The social network analysis side of this work has focused on quantitative analysis of whole-network cases, such as the structure of networks in single classrooms. Egocentric or personal network approaches are largely unexplored, and qualitative methods are underdeveloped. In this paper, we outline theoretical and practical differences between two major network paradigms—whole-network and egocentric—and introduce theoretical frameworks and methodological considerations for egocentric studies. We also describe qualitative and mixed-methods approaches that are currently missing from the PER literature. We identify areas where these additional network methods may be of particular interest to physics education researchers and end by discussing example cases and implications for new PER studies.

Not available.

The study assessed the peptidomic profile of in-bag dry-aged (2 °C, RH 75 %, 0.5 m.s−1, n = 30) and wet-aged (-1.5 °C, n = 30) lamb with high and low levels of lipid oxidation. A total of 1056 low molecular weight peptides (< 10 kDa) were identified in aged lamb samples, using LC-MS/MS and label free quantification (data are available via ProteomeXchange with identifier PXD047738). Partial Least Squares – Discriminant analysis highlighted that all discriminating peptides in dry-aged lamb were from titin, whereas discriminating peptides in the wet-aged samples were predominantly from nebulin, myotilin, collagen type IV, LIM domain binding 3, and heat shock protein family B. Comparison of peptides from aged lamb meat with high- and low-levels of lipid oxidation showed that most discriminatory peptides within an ageing method are derived from oxidatively modified peptides from creatine kinase. These peptides could thus potentially be used as signature biomolecules to discriminate ageing techniques and indicate lipid oxidation levels.

Abstract Numerous policy and international frameworks consider that “destructive fishing” hampers efforts to reach sustainability goals. Though ubiquitous, “destructive fishing” is undefined and therefore currently immeasurable. Here we propose a definition developed through expert consultation: “Destructive fishing is any fishing practice that causes irrecoverable habitat degradation, or which causes significant adverse environmental impacts, results in long‐term declines in target or nontarget species beyond biologically safe limits and has negative livelihood impacts.” We show strong stakeholder support for a definition, consensus on many biological and ecological dimensions, and no clustering of respondents from different sectors. Our consensus definition is a significant step toward defining sustainable fisheries goals and will help interpret and implement global political commitments which utilize the term “destructive fishing.” Our definition and results will help reinforce the Food and Agricultural Organization's Code of Conduct and meaningfully support member countries to prohibit destructive fishing practices.

Variants in ATP-binding cassette transporter type A4 (ABCA4) have been linked to several forms of inherited retinal diseases (IRDs) besides the classically defined Stargardt disease (STGD), known collectively as ABCA4 retinopathies. ABCA4 is a sizable locus harboring 50 exons; thus, its analysis has revealed over 2,400 variants described, of which more than 2,000 are causal. Due to the clinical and genetic heterogeneity, diagnosing ABCA4 retinopathies is challenging. To date, no ABCA4-related retinopathy has been detected in Lebanon. Using next-generation sequencing, we analyzed our IRDs' cohort retrospectively (61 families) and identified five with ABCA4-related retinopathies, making it a relatively abundant cause of IRDs (about 8 %). Three families were diagnosed with rod-cone dystrophy (RCD), two with STGD, and one with cone-rod dystrophy (CRD). In conclusion, our study showed the presence of ABCA4 variants with a high degree of heterogeneity in Lebanon.

ABSTRACTAntigen-based rapid diagnostic tests (Ag-RDTs) were widely deployed to enhance SARS-CoV-2 testing capacity during the COVID-19 pandemic. Consistent with national guidance for low prevalence settings, positive Ag-RDTs were confirmed using nucleic acid amplification tests (NAATs) to avoid false positive results. However, increasing demands for positive Ag-RDT confirmation competed with other testing priorities in clinical laboratories. This work hypothesized that real-time RT-PCR without nucleic acid extraction (NAE) would be sufficiently sensitive to support positive Ag-RDT confirmation. Ag-RDT and NAAT results from community-based asymptomatic testing sites prior to the omicron variant wave were compared to calculate the weekly false positive rate (FPR) and false detection rate (FDR). Real-time RT-PCR was compared with and without NAE using 752 specimens previously tested positive for SARS-CoV-2 using commercial NAATs and 344 specimens from Ag-RDT-positive individuals. The impact of SARS-CoV-2 prevalence on laboratory resources required to sustain Ag-RDT confirmation was modeled for the RT-PCR with and without NAE. Overall, FPR was low [0.07% (222/330,763)] in asymptomatic testing sites, but FDR was high [30.7% (222/724)]. When RT-PCR was compared with and without NAE, 100% concordance was obtained with NAAT-positive specimens, including those from Ag-RDT-positive individuals. NAE-free RT-PCR significantly reduced time to results, human resources, and overall costs. A 30.7% FDR reaffirms the need for NAAT-based confirmation of positive Ag-RDT results during low SARS-CoV-2 prevalence. NAE-free RT-PCR was shown to be a simple and cost-sparing NAAT-based solution for positive Ag-RDT confirmation, and its implementation supported data-driven broader Ag-RDT deployment into communities, workplaces, and households.IMPORTANCERapid antigen testing for SARS-CoV-2 was widely deployed during the COVID-19 pandemic. In settings of low prevalence, national guidance recommends that positive antigen test results be confirmed with molecular testing. Given the high testing burden on clinical laboratories during the COVID-19 pandemic, the high volume of positive antigen tests submitted for confirmatory testing posed challenges for laboratory workflow. This study demonstrated that a simple PCR method without prior nucleic acid purification is an accurate and cost-effective solution for positive rapid antigen test confirmation. Implementing this method allowed molecular confirmatory testing for positive antigen tests to be sustained as antigen testing was expanded into large populations such as workplaces, schools, and households.

Tropical cyclone (TC) genesis prediction is a major scientific challenge to the TC operation and research community. This report surveys the current status of TC genesis forecasts by a number of major operational centers covering the key ocean basins across both hemispheres. Since IWTC-9, we see an emergence of probabilistic TC genesis forecast products by operational centers, typically supported by the statistical processing of a combination of ensemble prediction and satellite analysis, covering time periods of couple of days to weeks ahead. The prevalence of multi-center grand ensemble approach highlights the uncertainties involved and the forecast challenges in quantitative genesis prediction. While operational practice might differ across agencies, verification efforts generally report a steady or slightly improving skill level in terms of reliability, which likely results from the continual improvement in global numerical weather prediction capability.

The major crises of the contemporary world make it all the more important for the teaching of history to all students, but at the same time require a renewal of its aims and rationale. After outlining the societal challenges we face at the start of the 21st century, and those that lie ahead for the generations to come, this contribution considers and supports five functions of school history that could serve to address them: the discovery of the strangeness and difference of the past; the explanation of what is observed on the basis of plural documentation; the protection of traces and memories, particularly the most fragile and hidden; the inclusion of all human groups in the narratives and reflections, by crossing their points of view; and the idea of defatalizing history by examining the experiences and room for action of men and women of the past in their present, its uncertainties and possibilities.

Abstract This ethnic sensitivity analysis used data from the phase III POLARIX study (NCT03274492) to assess polatuzumab vedotin pharmacokinetics (PKs) in Asian versus non‐Asian patients with previously untreated diffuse large B‐cell lymphoma and examined the appropriateness of extrapolating global study findings to Asian patients. PK and population PK (PopPK) analyses assessed polatuzumab vedotin analyte exposures by ethnicity (Asian [n = 84] vs. non‐Asian [n = 345] patients) and region (patients enrolled from Asia [n = 80] vs. outside Asia [n = 349]). In patients from Asia versus outside Asia, observed mean antibody‐conjugated monomethyl auristatin E (acMMAE) concentrations were comparable (1.2% lower at cycle [C]1 postdose, 4.4% higher at C4 predose; and 6.8% lower at C4 postdose in patients from Asia). Observed mean unconjugated MMAE was lower in patients from Asia by 6.5% (C1 postdose), 20.0% (C4 predose), and 15.3% (C4 postdose). In the PopPK analysis, C6 area under the curve and peak plasma concentrations were also comparable for acMMAE (6.3% and 3.0% lower in Asian vs. non‐Asian patients, respectively) and lower for unconjugated MMAE by 19.1% and 16.7%, respectively. By region, C6 mean acMMAE concentrations were similar, and C6 mean unconjugated MMAE concentrations were lower, in patients enrolled from Asia versus outside Asia, by 3.9%–7.0% and 17.3%–19.7%, respectively. In conclusion, polatuzumab vedotin PKs were similar between Asian and non‐Asian patients by ethnicity and region, suggesting PKs are not sensitive to Asian ethnicity and dose adjustments are not required in Asian patients to maintain efficacy and safety.

Background: Distinct molecular subtypes of muscle-invasive bladder cancer (MIBC) have been identified via gene expression profiling. Objective: We investigated the feasibility of a simple immunohistochemistry (IHC)-based Lund subtyping method and the association of MIBC subtypes with oncological outcomes for patients after bladder-preserving radiation-based therapy. Design, setting, and participants: Transurethral resected tumor tissues from 104 patients treated with radiation-based therapy were sampled on tissue microarray blocks. Outcome measurements and statistical analysis: The expression of KRT5, GATA3, and p16 proteins was scored via digital image analysis. Hierarchical clustering was used to classify tumors as the basal subtype or one of two luminal subtypes: genomically unstable (GU) or urothelial-like (URO). Subtypes were evaluated for association with complete response (CR), recurrence-free survival (RFS), and overall survival (OS). Results and limitations: The median OS was 43 mo (95% confidence interval 19–77) and median follow-up was 55 mo (interquartile range 39–75). Age and clinical stage had a significant impact on OS (p

Despite knowing physics and astronomy doctoral programs are laden with identity-based inequities, they continue to push minoritized students to the margins. This qualitative social network analysis of 100 women and/or lesbian, gay, bisexual, transgender, queer, and more (LGBT+) physics and astronomy Ph.D.’s explores how minoritized physics and astronomy students utilize social networks to navigate departmental exclusion. Our findings indicate that many of the participants’ identities were often unacknowledged or negatively addressed within their graduate education, with only four participants reporting a positive or favorable experience during this period of their career. Direct support from peers, faculty, and identity-based affinity groups was necessary for participants to navigate their educations. This study demonstrated that generic best practices often cannot fully support the diverse range of persons who come to physics and that identity-neutral values in physics further isolate students by insinuating that their own minoritized experiences are not valid.

In this article, we summarize recent theoretical and experimental studies of the impedance and beam-induced heating of titanium-coated ceramic vacuum chambers used in the NSLS-II injection kickers. The impedance was calculated using the field matching theory assuming planar approximation and compared with the impedancewake2d code. For the coating thickness of a few microns, we demonstrated that the beam-induced power is dissipated in the titanium coating and that the longitudinally averaged two-dimensional power density is approximated by an analytical expression, thus allowing the use of a simplified model of the power density as input for the ansys code to simulate the temperature distribution with realistic nonuniform thickness of the Ti coating. For a few values of the NSLS-II beam current, we measured the beam-induced heating of two ceramic chambers using thermal sensors installed along the chamber and compared the measurement results with the simulations.

This paper asserts that honor-based peoples have and maintain a distinct cultural identity that is valid for at least eighty-five percent of the world population. It is necessarily considered relative to dignity-based societies which make up the other fifteen percent. Practically all dignity-based cultures originated during the Enlightenment; modern honor-based groups will oftentimes through diffusion manifest some dignity-based traits or observe fewer of the traditional honor-based features. This paper will survey both traditional and modern forms of the honor-based culture.

Multiple randomized controlled trials have extensively examined the therapeutic effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors, ushering in a transformative approach to treating individuals with type 2 diabetes mellitus (DM). Notably, emerging reports have drawn attention to the potential positive impacts of SGLT2 inhibitors in nondiabetic patients. In an effort to delve into this phenomenon, a comprehensive systematic literature review spanning PubMed (NLM), Medline (Ovid), and Cochrane Library, covering publications from 2000 to 2024 was undertaken. This systematic review encompassed twenty-six randomized control trials (RCTs) involving 35,317 participants. The findings unveiled a multifaceted role for SGLT2 inhibitors, showcasing their ability to enhance metabolic control and yield cardioprotective effects through a reduction in cardiovascular death (CVD) and hospitalization related to heart failure (HF). Additionally, a renalprotective effect was observed, evidenced by a slowdown in chronic kidney disease (CKD) progression and a decrease in albuminuria. Importantly, these benefits were coupled with an acceptable safety profile. The literature also points to various biological plausibility and underlying mechanistic pathways, offering insights into the association between SGLT2 inhibitors and these positive outcomes in nondiabetic individuals. Current research trends indicate a continual exploration of additional role for SGLT2 inhibitors in. Nevertheless, further research is imperative to fully elucidate the mechanisms and long-term outcomes associated with the nondiabetic use of SGLT2 inhibitors.

Abstract Africa is highly vulnerable to climate change but emits a small portion of global greenhouse gases. Additionally, decarbonization might lead to a ‘climate penalty’ whereby reductions in cooling aerosols offset temperature benefits from CO2 reductions for several decades. However, climate change impacts conditions other than temperatures, including precipitation. Using the NASA Goddard Institute for Space Studies climate model, we find that although African emissions cuts have weak impacts on projected African temperatures, they significantly impact rainfall. Whereas business-as-usual increasing emissions lead to substantial drying over tropical Northern Hemisphere Africa during local summer, that drying is essentially eliminated under a sustainable development pathway. The reduction in cooling aerosols is responsible for ~33–90% of the avoided drying in our model, with the remainder largely attributable to reduced absorbing aerosols. African policy choices may therefore greatly reduce regional African summer drying, giving parts of Africa substantial leverage over their own climate and air quality future.

Solid tumors account for approximately 90% of all adult human cancers. As such, the development of novel cellular therapies has become of increasing importance to target solid tumor malignancies, such as prostate, lung, breast, bladder, colon, and liver cancers. One such cellular therapy relies on the use of chimeric antigen receptor T cells (CAR-T cells). CAR-T cells are engineered to target specific antigens on tumor cells. To date, there are six FDA-approved CAR-T cell therapies that have been utilized for hematologic B cell malignancies. Immune cell trafficking and immunosuppressive factors within the tumor microenvironment increase the relative difficulty in developing a robust CAR-T cell therapy against solid tumors. Therefore, it is critical to develop novel methodologies for high-throughput phenotypic and functional assays using 3D tumor spheroid models to assess CAR-T cell products against solid tumors. In this manuscript, we discuss the use of CAR-T cells targeted towards PSMA, an antigen that is found on prostate cancer tumor cells, the second most common cause of cancer deaths among men worldwide. We demonstrate the use of high-throughput, plate-based image cytometry to characterize CAR-T cell-mediated cytotoxic potency against 3D prostate tumor spheroids. We were able to kinetically evaluate the efficacy and therapeutic value of PSMA CAR-T cells by analyzing the cytotoxicity against prostate tumor spheroids. In addition, the CAR-T cells were fluorescently labeled to visually identify the location of the T cells as cytotoxicity occurs, which may provide more meaningful information for assessing the functionality of the CAR-T cells. The proposed image cytometry method can overcome limitations placed on traditional methodologies to effectively assess cell-mediated 3D tumor spheroid cytotoxicity and efficiently generate time- and dose-dependent results.

We investigated the impact of mesenchymal stem cell (MSC) therapy on treating bilateral human hip osteonecrosis, analyzing 908 cases. This study assesses factors such as tissue source and cell count, comparing core decompression with various cell therapies. This research emphasizes bone repair according to pre-treatment conditions and the specificities of cell therapy in osteonecrosis repair, indicating a potential for improved bone repair strategies in hips without femoral head collapse. This study utilized a single-center retrospective analysis to investigate the efficacy of cellular approaches in the bone repair of osteonecrosis. It examined the impact on bone repair of tissue source (autologous bone marrow concentrate, allogeneic expanded, autologous expanded), cell quantity (from none in core decompression alone to millions in cell therapy), and osteonecrosis stage and volume. Excluding hips with femoral head collapse, it focused on patients who had bilateral hip osteonecrosis, both pre-operative and post-operative MRIs, and a follow-up of over five years. The analysis divided these patients into seven groups based on match control treatment variations in bilateral hip osteonecrosis, primarily investigating the outcomes between core decompression, washing effect, and different tissue sources of MSCs. Younger patients (

Multiple myeloma (MM) is a hematological malignancy characterized by an abnormal clonal proliferation of malignant plasma cells. Despite the introduction of novel agents that have significantly improved clinical outcome, most patients relapse and develop drug resistance. MM is characterized by genomic instability and a high level of replicative stress. In response to replicative and DNA damage stress, MM cells activate various DNA damage signaling pathways. In this study, we reported that high CHK1 and WEE1 expression is associated with poor outcome in independent cohorts of MM patients treated with high dose melphalan chemotherapy or anti-CD38 immunotherapy. Combined targeting of Chk1 and Wee1 demonstrates synergistic toxicities on MM cells and was associated with higher DNA double-strand break induction, as evidenced by an increased percentage of γH2AX positive cells subsequently leading to apoptosis. The therapeutic interest of Chk1/Wee1 inhibitors’ combination was validated on primary MM cells of patients. The toxicity was specific of MM cells since normal bone marrow cells were not significantly affected. Using deconvolution approach, MM patients with high CHK1 expression exhibited a significant lower percentage of NK cells whereas patients with high WEE1 expression displayed a significant higher percentage of regulatory T cells in the bone marrow. These data emphasize that MM cell adaptation to replicative stress through Wee1 and Chk1 upregulation may decrease the activation of the cell-intrinsic innate immune response. Our study suggests that association of Chk1 and Wee1 inhibitors may represent a promising therapeutic approach in high-risk MM patients characterized by high CHK1 and WEE1 expression.

ABSTRACT Objective: To verify the COVID-19 clinical characteristics, associated comorbidities, and outcomes in adolescents. Data source: This is a systematic review study based on articles published between 2020 and 2022 in the United States National Library of Medicine - PubMed (MedLine), Virtual Health Library – VHL (LILACS), Science Direct, Web of Science, and Scopus (Elsevier) databases. The study was registered in the International Prospective Register of Systematic Reviews, under No. CRD42022309108. Data synthesis: A total of 1188 studies were identified. After applying the selection criteria, 13 articles were included. Prevalence was 25%; mild cases were predominant; and fever, cough, headache, anosmia, nasal congestion, and ageusia were frequent. Fever and cough were proportionally higher in hospitalized cases: 81 and 68%, respectively. Dyspnea (odds ratio [OR] 6.3; confidence interval 95%[CI] 2.8–14.3), fever (OR 3.8; 95%CI 2.0–7.4), and cough (OR 3.4; 95%CI 2.0–6.0) were associated with severe cases. Up to 28% required intensive care and 38% required mechanical ventilation. Pre-existing comorbidities increased the risk of hospitalization and death. Severe cases were associated with the risk of death (relative risk [RR] 4.6; 95%CI 2.8–7.5). The black, mixed, and indigenous races/skin colors represented risk groups, as well as residents of poorer regions. Conclusions: The review provided a better understanding of the disease profile and may favor the development of public policies, in addition to contributing to the current literature in the field of adolescent health.

Natural hydrogen exploration is picking up around the world while the geogenic hydrogen system is still a Frontier science. Natural hydrogen seepage can occur in the form of a sub-circular surface feature named by some authors “fairy circles.” Numerous hydrogen seep-alike surface features are visible from the sky in Australia but can be difficult to distinguish from the many salt lakes. In this study, we combined literature review, remote sensing, field and lab measurements (soil gas sampling, X-Ray diffraction, salinity) to uncover a potential hydrogen system and its differences with the salt lakes in the Grass Patch area in Western Australia. The local geology shows a good potential to generate hydrogen. Study of the surface geology and Digital Elevation Model showed that salt lakes are static old features influenced by the soil composition and long-term climatic trend whereas potential hydrogen seeps have recently appeared. This study soil-gas sampling method includes a monitoring procedure compatible with time series measurements via a portable gas analyser, getting rid of artificially produced hydrogen. Low hydrogen values (

Abstract Introduction The transition from medical student to surgical resident is not a simple one. The aim of this study was to report the experience of a university hospital in the organization of the induction course for future surgical residents and the contribution of a video support in the learning of the suture. Material and method We were able to study two consecutive years of students (October 2020 and 2021). Concerning the practical and technical workshops (learning suture) we carried out a comparative study between two groups of students. A group that had video support for learning suture (video group) and a group without video (control group). The evaluation of the suture was performed in a blinded manner by two supervising surgeons. The other practical workshop was drain fixation; the students did not have a video for this workshop. A comparative study was also performed for the drain fixation workshop between the two groups (video group and control group). A program of theoretical courses was also set up. This program is established according to the different future functions of the residents by integrating medico-legal notions and teamwork. Satisfaction questionnaires were given to the students and the answers were given two months after taking up their duties in the hospital (6 questions with Likert scale and 4 free questions). Results The cohort consisted of 58 students (29 each in 2020 and 29 in 2021). Comparative analyses of the evaluation of the suture workshops showed better performance in the video group compared with the group without video. The comparison of these two groups did not show significant differences in the drain fixation workshop. The theoretical teaching was broken down according to the students' future tasks and each speaker was a specialist in his or her field of expertise. The results of the questionnaires showed a desire on the part of the students to increase the time spent on practical workshops and theoretical forensic teaching. Conclusion We were able to show through these two years of a program that we were able to offer a surgical resident preparation course. In addition, we have highlighted the contribution of a video support in the learning curve of the suture.

This paper attempts to illustrate a process of analysis that will hopefully open a path to more complete and useful definitions of sign and symbol. It applies a form-content analysis to the metaphysical properties of these two concepts. The objective is to locate criteria necessary and sufficient to derive formal definitions for these terms. Wittgenstein’s concept of “forms of representation” is analyzed and applied to the topic. Criteria are outlined that determine the appropriateness of the sign and symbol to be applied as labels. Criteria of definition are then developed using gesture, metaphor, and several other example types to illustrate the use of the criteria in distinguishing between sign and symbol. The structural organization of these two concepts proved to be especially complex and led to what some readers may find somewhat obscure. It is not our intention to be purposefully obscure.

Erratum to "The launch of the first-ever Integrated Assessment of Air Pollution and Climate Change for Sustainable Development in Africa" published in Clean Air Journal, 32(2), 2022, https://doi.org/10.17159/caj/2022/32/2.15320 The original article can be found here: https://cleanairjournal.org.za/article/view/15320

Introduction Patients with kidney failure receiving chronic haemodialysis have elevated risk of arrhythmias potentially increasing the likelihood of sudden cardiac death, stroke and hospitalisation. The DIALIZE study (NCT03303521) demonstrated that sodium zirconium cyclosilicate (SZC) was an efficacious and well-tolerated treatment for predialysis hyperkalaemia in patients undergoing haemodialysis. The DIALIZE-Outcomes study evaluates the effect of SZC on sudden cardiac death and arrhythmia-related cardiovascular outcomes in patients receiving chronic haemodialysis with recurrent hyperkalaemia.Methods and analysis International, multicentre, randomised, double-blind, placebo-controlled study conducted at 357 study sites across 25 countries. Adults (≥18 years) receiving chronic haemodialysis three times per week with recurrent predialysis serum potassium (K+) ≥5.5 mmol/L post long interdialytic interval (LIDI) are eligible. Patients (~2800) will be randomised 1:1 to SZC or placebo, starting at 5 g orally once daily on non-dialysis days and titrated weekly in 5 g increments (maximum 15 g) to target predialysis serum K+ 4.0–5.0 mmol/L post LIDI. The primary objective is to evaluate efficacy of SZC versus placebo in reducing occurrence of the primary composite endpoint of sudden cardiac death, stroke or arrhythmia-related hospitalisation, intervention or emergency department visit. Secondary endpoints include efficacy of SZC versus placebo in maintaining normokalaemia (serum K+ 4.0–5.5 mmol/L post LIDI) at the 12-month visit, preventing severe hyperkalaemia (serum K+ ≥6.5 mmol/L post LIDI) at the 12-month visit and reducing the incidence of individual cardiovascular outcomes. Safety of SZC will be evaluated. The study is event driven, with participants remaining in the study until 770 primary endpoint events have occurred. Average time in the study is expected to be ~25 months.Ethics and dissemination Approval was obtained from the relevant institutional review board/independent ethics committee from each participating site (approving bodies in supplementary information). The results will be submitted to a peer-reviewed journal.Trial registration numbers EudraCT 2020-005561-14 and clinicaltrials.gov identifier NCT04847232.

Instructors’ interactions can foster knowledge sharing around teaching and the use of research-based instructional strategies (RBIS). Coordinated teaching presents an impetus for instructors’ interactions and creates opportunities for instructional improvement but also potentially limits an instructor’s autonomy. In this study, we sought to characterize the extent of coordination present in introductory undergraduate courses and to understand how departments and instructors implement and experience course coordination. We examined survey data from 3,641 chemistry, mathematics, and physics instructors at three institution types and conducted follow-up interviews with a subset of 24 survey respondents to determine what types of coordination existed, what factors led to coordination, how coordination constrained instruction, and how instructors maintained autonomy within coordinated contexts. We classified three approaches to coordination at both the overall course and course component levels: independent (i.e., not coordinated), collaborative (decision-making by instructor and others), controlled (decision-making by others, not instructor). Two course components, content coverage and textbooks, were highly coordinated. These curricular components were often decided through formal or informal committees, but these decisions were seldom revisited. This limited the ability for instructors to participate in the decision-making process, the level of interactions between instructors, and the pedagogical growth that could have occurred through these conversations. Decision-making around the other two course components, instructional methods and exams, was more likely to be independently determined by the instructors, who valued this autonomy. Participants in the study identified various ways in which collaborative coordination of courses can promote but also inhibit pedagogical growth. Our findings indicate that the benefits of collaborative course coordination can be realized when departments develop coordinated approaches that value each instructor’s autonomy, incorporate shared and ongoing decision-making, and facilitate collaborative interactions and knowledge sharing among instructors.

Abstract Background Global commitment to achieving hepatitis C virus (HCV) elimination has enhanced efforts in improving access to direct-acting antiviral (DAA) treatments for people who inject drugs (PWID). Scale-up of efforts to engage hard-to-reach groups of PWID in HCV testing and treatment is crucial to success. Automatic needle/syringe dispensing machines (ADMs) have been used internationally to distribute sterile injecting equipment. ADMs are a unique harm reduction service, affording maximum anonymity to service users. This paper explores the feasibility and acceptability of extending the HCV cascade of care to sites where ADMs are located. Methods The ADM users into Treatment (ADMiT) study was undertaken in a metropolitan region in Sydney, Australia. This mixed methods study involved analysis of closed-circuit television footage, ethnographic methods (fieldwork observation and in-depth interviews) and structured surveys. Researchers and peers conducted fieldwork and data collection over 10 weeks at one ADM site, including offering access to HCV testing and treatment. Results Findings from 10 weeks of fieldwork observations, 70 survey participants and 15 interviews highlighted that there is scope for engaging with this population at the time they use the ADM, and enhanced linkage to HCV testing and treatment may be warranted. Most survey participants reported prior HCV testing, 61% in the last 12 months and 38% had received HCV treatment. However, fieldwork revealed that most people observed using the ADM were not willing to engage with the researchers. Field work data and interviews suggested that extending the HCV cascade of care to ADMs may encroach on what is a private space for many PWID, utilized specifically to avoid engagement. Discussion Enhanced linkage to HCV testing and treatment for people who use ADMs may be warranted. However, data suggested that extending the HCV cascade of care to ADMs may encroach on what is a private space for many PWID, utilized specifically to avoid engagement. The current study raises important public health questions about the need to ensure interventions reflect the needs of affected communities, including their right to remain anonymous.

Abstract Background Active learning used in science, technology, engineering, and mathematics (STEM) courses has been shown to improve student outcomes. Nevertheless, traditional lecture-orientated approaches endure in these courses. The implementation of teaching practices is a result of many interrelated factors including disciplinary norms, classroom context, and beliefs about learning. Although factors influencing uptake of active learning are known, no study to date has had the statistical power to empirically test the relative association of these factors with active learning when considered collectively. Prior studies have been limited to a single or small number of evaluated factors; in addition, such studies did not capture the nested nature of institutional contexts. We present the results of a multi-institution, large-scale (N = 2382 instructors; N = 1405 departments; N = 749 institutions) survey-based study in the United States to evaluate 17 malleable factors (i.e., influenceable and changeable) that are associated with the amount of time an instructor spends lecturing, a proxy for implementation of active learning strategies, in introductory postsecondary chemistry, mathematics, and physics courses. Results Regression analyses, using multilevel modeling to account for the nested nature of the data, indicate several evaluated contextual factors, personal factors, and teacher thinking factors were significantly associated with percent of class time lecturing when controlling for other factors used in this study. Quantitative results corroborate prior research in indicating that large class sizes are associated with increased percent time lecturing. Other contextual factors (e.g., classroom setup for small group work) and personal contexts (e.g., participation in scholarship of teaching and learning activities) are associated with a decrease in percent time lecturing. Conclusions Given the malleable nature of the factors, we offer tangible implications for instructors and administrators to influence the adoption of more active learning strategies in introductory STEM courses.

Introduction: Rituximab monotherapy represents the main therapeutic option for cryoglobulinemic vasculitis (CV) with severe organ involvement. However, initial worsening of the CV, known as rituximab-associated CV flare (=CV flare), has been described and are associated with high mortality rates. The aim of the present study is to evaluate the outcomes of plasmapheresis initiated before or during rituximab treatment, as prevention of CV flare. Methods: We conducted a retrospecttive study in our tertiary referral center from 2001 to 2020. We have included all patients with CV receiving rituximab and divided them in two groups whether they had flare prevention by plasmapheresis or not. We evaluated rituximab-related CV flare incidence in both groups. CV flare was defined as the onset of a new organ involvement or worsening of the initial manifestations within 4 weeks following rituximab. Results: Among the 71 patients included, 44 received rituximab without plasmapheresis (control = CT cohort) and 27 received plasmapheresis before or during rituximab treatment (preventive plasmapheresis = PP cohort). PP was given to patients thought to have a high risk of CV flare, with significantly more severe diseases than patients in the CT cohort. Despite this, no CV flare was observed in the PP group. In the other hand, 5 flares occurred in the CT cohort. Conclusion: Our results show that plasmapheresis is efficient and well tolerated to prevent rituximab-associated CV flare. We believe that our data support the use of plasmapheresis in this indication, especially in patients with high risk of CV flare.

Abstract Background Portal vein thrombosis (PVT) is a common complication following splenectomy. It affects between 5 and 55% of patients undergoing surgery with no clearly defined pre-operative risk factors. The aim of this study was to determine the pre-operative risk factors of PVT. Patients and method Single centre, retrospective study of data compiled for every consecutive patient who underwent splenectomy at Toulouse University Hospital between January 2009 and January 2019. Patients with pre- and post-surgical CT scans have been included. Results 149 out of 261 patients were enrolled in the study (59% were males, mean age 52 years). The indications for splenectomy were splenic trauma (30.9%), malignant haemopathy (26.8%) and immune thrombocytopenia (8.0%). Twenty-nine cases of PVT (19.5%) were diagnosed based on a post-operative CT scan performed on post-operative day (POD) 5. Univariate analysis identifies three main risk factors associated with post-operative PVT: estimated splenic weight exceeding 500 g with an OR of 8.72 95% CI (3.3–22.9), splenic vein diameter over 10 mm with an OR of 4.92 95% CI (2.1–11.8) and lymphoma with an OR of 7.39 (2.7–20.1). The role of splenic vein diameter with an OR of 3.03 95% CI (1.1–8.6), and splenic weight with an OR of 5.22 (1.8–15.2), as independent risk factors is confirmed by multivariate analysis. A screening test based on a POD 5 CT scan with one or two of these items present could indicate sensitivity of 86.2% and specificity of 86.7%. Conclusion This study suggests that pre-operative CT scan findings could predict post-operative PVT. A CT scan should be performed on POD 5 if a risk factor has been identified prior to surgery.

Preview: /Review: Michael Webb, The Whole at Once: A Conversation on Meaning (Austin,TX: Fire Hill Press, 2020), 244 pages./ This is a book about a phenomenological challenge: to reach the depths of meaning. It relies principally on becoming aware of the self and of the core essence of wholes, be they collections of objects or sentences or ideas. But meaning is the end point constituting, according to the author, a drive more powerful even than the will to live (WO, 137). It lies beyond any given perspective. The work is presented as a dialogue between student and master; its 244 pages actually make for a quick and relatively easy read, not burdening the reader with jargon. It intends to be a popular presentation but without skimping on issues of relevance to philosophy.

David Graeber wrote about debt, jobs and the negative effects of globalization. He was an American anthropologist, anarchist activist, and was an author known for his books Debt: The First 5000 Years, The Utopia of Rules and Bullshit Jobs: A Theory. A professor of anthropology at the London School of Economics, he passed away 2 September 2020, at age 59.

This work shows the construction of a simple, functional and real-time application to estimate the population dynamics of the Golden Mussel, an invasive species that has been causing great ecological and economic damage, particularly to the electricity sector by obstructing water collection routes of hydroelectric plant equipment. The tool Golden Mussel App, developed with Shiny package of the R©, programming language, aims to enable professionals engaged in harm reduction in the energy generation sector to follow the temporal evolution of populations, even without advanced knowledge about the mathematical modeling of the problem. In this way, the application configures itself as an auxiliary tool in the planning of actions to control the Golden Mussel

BACKGROUND:. Surrogate decision-making is a stressful process for many family members of critically ill patients. The COVID-19 pandemic may have amplified the risk for anxiety, depression, and posttraumatic stress disorder (PTSD) symptoms in ICU surrogates. OBJECTIVES:. This study piloted an online group-based behavioral intervention with family members of deceased COVID-19 patients. Participant engagement, perceptions, and responses related to the intervention were assessed. DESIGN:. A single-arm pilot study was conducted with bereaved families. Quantitative analysis of measures of anxiety, depression, and PTSD symptoms was conducted with mixed models. Qualitative data were analyzed to identify themes in surrogates’ experiences with the intervention. SETTING:. Participants were recruited from ICUs at a tertiary academic medical center. Participants completed the intervention, measures, and interviews online. SUBJECTS:. Participants were family members of patients who died from COVID-19. INTERVENTIONS:. The intervention involved six online group-based behavioral activation sessions. Sessions covered topics pertinent to grieving and engagement in personally meaningful activities. MEASUREMENTS AND MAIN RESULTS:. Semi-structured interviews explored participants’ experiences with the intervention. Surrogates also completed measures of anxiety, depression, and PTSD symptoms before and after the intervention. Nineteen of 26 participants (73.1%) completed the study. Thematic analysis suggested that surrogates found the group helpful for overcoming perceived isolation, receiving validation, and developing coping skills. Significant pre-to-post reductions were observed in symptoms of Hospital and Anxiety Disorder Scale (HADS) anxiety (pre-mean = 9.27, sd = 5.30 vs post-mean = 6.80, sd = 4.16; p = 0.0271), HADS depression (pre-mean =6 .65, sd = 4.58 vs post- mean = 4.89, sd = 3.40; p = 0.0436), and Impact of Events Scale-Revised PTSD (pre-mean = 36.86, sd = 16.97 vs post-mean = 24.14, sd = 13.49; p = 0.0008). LIMITATIONS:. This was a preliminary study based on qualitative and self-report measures. Future studies should include a control group. CONCLUSIONS:. Online group-based behavioral activation therapy appears to be a potentially useful intervention for family members of ICU patients who died from COVID-19.

Multiple myeloma (MM) is a hematologic cancer characterized by accumulation of malignant plasma cells in the bone marrow. To date, no definitive cure exists for MM and resistance to current treatments is one of the major challenges of this disease. The DNA helicase BLM, whose depletion or mutation causes the cancer-prone Bloom’s syndrome (BS), is a central factor of DNA damage repair by homologous recombination (HR) and genomic stability maintenance. Using independent cohorts of MM patients, we identified that high expression of BLM is associated with a poor outcome with a significant enrichment in replication stress signature. We provide evidence that chemical inhibition of BLM by the small molecule ML216 in HMCLs (human myeloma cell lines) leads to cell cycle arrest and increases apoptosis, likely by accumulation of DNA damage. BLM inhibition synergizes with the alkylating agent melphalan to efficiently inhibit growth and promote cell death in HMCLs. Moreover, ML216 treatment re-sensitizes melphalan-resistant cell lines to this conventional therapeutic agent. Altogether, these data suggest that inhibition of BLM in combination with DNA damaging agents could be of therapeutic interest in the treatment of MM, especially in those patients with high BLM expression and/or resistance to melphalan.

The COVID-19 pandemic has led health schools to cancel many on-site training and exams. Teachers were looking for the best option to carry out online OSCEs, and Zoom was the obvious choice since many schools have used it to pursue education purposes. Methods: We conducted a feasibility study during the 2020–2021 college year divided into six pilot phases and the large-scale eOSCEs on Zoom on June 30th, 2021. We developed a specific application allowing us to mass create Zoom meetings and built an entire organization, including a technical support system (an SOS room and catching-up rooms) and teachers’ training sessions. We assessed satisfaction via an online survey. Results: On June 30th, 531/794 fifth-year medical students (67%) participated in a large-scale mock exam distributed in 135 Zoom meeting rooms with the mobilization of 298 teachers who either participated in the Zoom meetings as standardized patients (N =135, 45%) or examiners (N =135, 45%) or as supervisors in the catching-up rooms (N =16, 6%) or the SOS room (N =12, 4%). In addition, 32/270 teachers (12%) experienced difficulties connecting to their Zoom meetings and sought the help of an SOS room member. Furthermore, 40/531 students (7%) were either late to their station or had technical difficulties and declared those issues online and were welcomed in one of the catching-up rooms to perform their eOSCE stations. Additionally, 518/531 students (98%) completed the entire circuit of three stations, and 225/531 students (42%) answered the online survey. Among them, 194/225 (86%) found eOSCES helpful for training and expressed their satisfaction with this experience. Conclusion: Organizing large-scale eOSCEs on Zoom is feasible with the appropriate tools. In addition, eOCSEs should be considered complementary to on-site OSCEs and to train medical students in telemedicine.

Introduction This study aims to measure how transmission of SARS-CoV-2 occurs in communities and to identify conditions that lend to increased transmission focusing on congregate situations. We will measure SARS-CoV-2 in exhaled breath of asymptomatic and symptomatic persons using face mask sampling—a non-invasive method for SARS-CoV-2 detection in exhaled air. We aim to detect transmission clusters and identify risk factors for SARS-CoV-2 transmission in presymptomatic, asymptomatic and symptomatic individuals.Methods and analysis In this observational prospective study with daily follow-up, index cases and their respective contacts are identified at each participating institution. Contact definitions are based on Centers for Disease Control and Prevention and local health department guidelines. Participants will wear masks with polyvinyl alcohol test strips adhered to the inside for 2 hours daily. The strips are applied to all masks used over at least 7 days. In addition, self-administered nasal swabs and (optional) finger prick blood samples are performed by participants. Samples are tested by standard PCR protocols and by novel antigen tests.Ethics and dissemination This study was approved by the Colorado Multiple Institutional Review Board and the WHO Ethics Review Committee. From the data generated, we will analyse transmission clusters and risk factors for transmission of SARS-CoV-2 in congregate settings. The kinetics of asymptomatic transmission and the evaluation of non-invasive tools for detection of transmissibility are of crucial importance for the development of more targeted control interventions—and ultimately to assist with keeping congregate settings open that are essential for our social fabric.Trial registration number ClinicalTrials.gov (#NCT05145803).