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As a rule, an experiment carried out at school or in undergraduate study courses is rather simple and not very informative. However, when the experiments are to be performed using modern methods, they are often abstract and difficult to understand. Here, we describe a quick and simple experiment, namely the enzymatic characterization of ptyalin (human salivary amylase) using a starch degradation assay. With the experimental setup presented here, enzyme parameters, such as pH optimum, temperature optimum, chloride dependence, and sensitivity to certain chemicals can be easily determined. This experiment can serve as a good model for enzyme characterization in general, as modern methods usually follow the same principle: determination of the activity of the enzyme under different conditions. As different alleles occur in humans, a random selection of test subjects will be quite different with regard to ptyalin activities. Therefore, when the students measure their own ptyalin activity, significant differences will emerge, and this will give them an idea of the genetic diversity in human populations. The evaluation has shown that the pupils have gained a solid understanding of the topic through this experiment.

Despite well-documented benefits for students--particularly students belonging to minorized groups--all tenets of Culturally Relevant Pedagogy (CRP) are rarely fully enacted in practice. This study examines the interrelationship between the race-related beliefs of Servant Leader Interns (SLIs) who facilitated class sessions during a summer, Children's Defense Fund (CDF) Freedom School program and their subsequent instructional practices. We also documented the relationship between these beliefs, practices, and students' self-reported exeriences. In particular, we drew on the interest convergence and understanding of racism tenets of Critical Race Theory (CRT) to inform our grounded theory analysis using constant comparative methods to integrate data collected through SLI interviews, virtual classroom observations, and student surveys. We observed high alignment between SLI's race-related beliefs and their instructional practices. However, despite some slightly more positive experiences among students taught by SLIs with more evolved race-related beliefs, ultimately many of the same programmatic structures that helped SLIs deepen their understanding of racism (and its connection to their lives) ensured that all students benefited from the enactment of CRP-aligned curriculum, assignments, and family involvement activities.

Abstract Background The SOPHYA-cohort-study investigated whether the objectively characterized and perceived residential neighborhood of Swiss youth predict accelerometer-measured physical activity and activity in specific domains (participation in a sports club and cycling) five years later. Methods At baseline in 2014, 1230 children and adolescents aged 6 to 16 years participated and wore accelerometers for 7 days. Of these children, 447 participated again in the follow-up study in 2019 and provided longitudinal accelerometer measurements. Sociodemographic factors and perceptions of the local neighbourhood were assessed by questionnaire. Specific objective environmental data (e.g. built environment or social environment) was modelled to the children’s address at baseline. Multivariate linear and logistic regression models were applied to identify short- and long-term characteristics that are associated with accelerometer-based physical activity, cycling and participation in organised sport. Results If the neighborhood-score as perceived by the parents in 2014 was in the middle or lowest tertile, children were significantly less active cross-sectionally in 2014 (-41.1 (-78.0;-4.2) and -52.4 (-88.6;-16.2) counts per minute, cpm), and five years later (-52.4 (-88.6;-16.2) and 48.1 (-86.6;-9.7) cpm). In addition, they were also less likely to accumulate active minutes above the median at both measuring points compared to peers of the same age and sex. Using objective environmental data modeled around the children’s residential address, similar associations were found: In the tertile with the lowest proportion of green space children achieved less cpm in 2014, while a high main street density and a low socioeconomic environment, respectively, hindered physical activity tracking above the median longitudinally. Also for cycling and participation in a sport club, the associations with the perceived and objective environment were more pronounced in the longitudinal analyses. Conclusion The results suggest that growing up in a physical activity friendly neighborhood increases the likelihood of remaining active during adolescence and early adulthood. Interventions should be implemented to ensure that children growing up in an unfavorable neighborhood do not fall behind at an early stage.

Abstract Aims Hospitalizations are common in patients with heart failure and are associated with high mortality, readmission and economic burden. Detecting early signs of worsening heart failure may enable earlier intervention and reduce hospitalizations. The HeartLogic algorithm is designed to predict worsening heart failure using diagnostic data from multiple device sensors. The main objective of this analysis was to evaluate the sensitivity of the HeartLogic alert calculation in predicting worsening heart failure events (HFEs). We also evaluated the false positive alert rate (FPR) and compared the incidence of HFEs occurring in a HeartLogic alert state to those occurring out of an alert state. Methods The HINODE study enrolled 144 patients (81 ICD and 63 CRT‐D) with device sensor data transmitted via a remote monitoring system. HeartLogic alerts were then retrospectively simulated using relevant sensor data. Clinicians and patients were blinded to calculated alerts. Reported adverse events with HF symptoms were adjudicated and classified by an independent HFE committee. Sensitivity was defined as the ratio of the number of detected usable HFEs (true positives) to the total number of usable HFEs. A false positive alert was defined as an alert with no usable HFE between the alert onset date and the alert recovery date plus 30 days. The patient follow‐up period was categorized as in alert state or out of alert state. The event rate ratio was the HFE rate calculated in alert to out of alert. Results The patient cohort was 79% male and had an average age of 68 ± 12 years. This analysis yielded 244 years of follow‐up data with 73 HFEs from 37 patients. A total of 311 HeartLogic alerts at the nominal threshold (16) occurred across 106 patients providing an alert rate of 1.27 alerts per patient‐year. The HFE rate was 8.4 times greater while in alert compared with out of alert (1.09 vs. 0.13 events per patient‐year; P

Critical consciousness (CC) is the ability to understand, critique, and act against oppressive social structures and systemic forces. To assist educators in understanding and enacting strategies that foster CC, the authors identified examples of CC in third through fifth grade virtual classes of a 2020 "Children's Defense Fund's" Freedom School. Using focused qualitative coding of videos and transcripts representing the teaching of four Servant Leader Interns (SLIs), five main strategies for developing critical consciousness were identified: (1) sharing power in the classroom; (2) making questions to critique society; (3) critiquing society; (4) taking social justice action; and (5) using text with critical content. This paper presents these strategies based on their prevalence in the Freedom School transcripts and argues that CC can manifest in young children and should be developed in virtual elementary settings, thus empowering students to understand, critique, and act against oppressive social forces.

In this study, the authors engaged with 54 peer financial mentors from seven institutions of higher education across the US through a qualitative inquiry using a Maslowian lens. PFMs, a type of college student worker, are typically hired by program managers or supervisors of financial wellness programs housed within financial offices, student affairs units, or other departments within institutions of higher education. Three core themes emerged from the data related to motivations of PFMs for seeking employment at their institution: (a) mentors wanted pre-professional work experiences aligned with a career in finance, (b) they wanted an on-campus position that provided future safety through pre-professional experience good for a résumé, and (c) they sought an altruistic job where they could help their peers with financial knowledge and skills.

In this article, the authors posit that generative artificial intelligence offers universities an opportunity to make long-needed structural changes in teaching and learning. Given the complexities of generative AI, faculty need time and resources to learn to use it effectively and to adapt classes in ways that help students approach AI ethically and critically. There must be creative thinking in developing AI-powered learning assistants, adaptive learning systems, faculty assistants, and other tools to improve learning and to aid time-pressed instructors. Recommendations are offered for the implementation of generative AI so universities can focus on inclusiveness, transparency, privacy, and safety with unwavering commitment to centering human interaction and improving teaching and learning quality.

Abstract Objective To assess the effectiveness of an exercise intervention, in addition to standard care, in preventing or delaying insulin prescription in women with gestational diabetes mellitus (GDM). Design Randomised controlled trial. Setting University hospital. Population Pregnant women at 25–35 weeks of gestation diagnosed with GDM. Methods Women in the intervention group participated in weekly, supervised, 30–45 min exercise sessions and were encouraged to accumulate more than 5000 steps per day, tracked by a pedometer, in addition to receiving usual care. The control group received standard care only. Main outcome measure Insulin prescription. Results From February 2008 through April 2013, 109 women were randomized into the intervention group (n = 57) or the usual care group (n = 52). Two women in the intervention group were excluded from the analysis (one was randomised in error and one was lost to follow-up). Six women never attended the exercise sessions, and two attended fewer than two sessions. However, two-third of women were considered as compliant to the intervention (attended more than 50% of sessions and/or averaged more than 5000 steps/day). The incidence of insulin prescription did not differ between the groups: 31 women (56%) in the intervention group versus 24 women (46%) in the control group (RR 1.22, 95% CI 0.84 to 1.78). The median time from randomization to insulin prescription was also similar between groups (14 days in the intervention group and 13 days in the control group). Conclusion This study did not demonstrate that an exercise program reduces or delays insulin prescription in women with GDM. Low adherence to the intervention, a small sample size, and the short duration of the program may explain the lack of observed benefit. Registered At clinicaltrials.gov, NCT03174340, 02/06/2017

Abstract Background Patients with immune-mediated rheumatic diseases (IMRDs) have been prioritized for COVID-19 vaccination to mitigate the infection severity risks. Patients with rheumatoid arthritis (RA) are at a high risk of severe COVID-19 outcomes, especially those under immunosuppression or with associated comorbidities. However, few studies have assessed the safety of the COVID-19 vaccine in patients with RA. Objective To evaluate the safety of vaccines against SARS-CoV-2 in patients with RA. Methods This data are from the study “Safety and Efficacy on COVID-19 Vaccine in Rheumatic Diseases,” a Brazilian multicentric prospective phase IV study to evaluate COVID-19 vaccine in IMRDs in Brazil. Adverse events (AEs) in patients with RA of all centers were assessed after two doses of ChAdOx1 (Oxford/AstraZeneca) or CoronaVac (Sinovac/Butantan). Stratification of postvaccination AEs was performed using a diary, filled out daily and returned at the end of 28 days for each dose. Results A total of 188 patients with RA were include, 90% female. CoronaVac was used in 109 patients and ChAdOx1 in 79. Only mild AEs were observed, mainly after the first dose. The most common AEs after the first dose were pain at the injection (46,7%), headache (39,4%), arthralgia (39,4%), myalgia (30,5%) and fatigue (26,6%), and ChAdOx1 had a higher frequency of pain at the injection (66% vs 32 %, p

Abstract Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0–36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients.

Abstract Background Systemic sclerosis (SSc) is a rare chronic autoimmune disease with heterogeneous manifestations. In the last decade, several clinical trials have been conducted to evaluate new treatment options for SSc. The purpose of this work is to update the recommendations of the Brazilian Society of Rheumatology in light of the new evidence available for the pharmacological management of SSc. Methods A systematic review including randomized clinical trials (RCTs) for predefined questions that were elaborated according to the Patient/Population, Intervention, Comparison, and Outcomes (PICO) strategy was conducted. The rating of the available evidence was performed according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. To become a recommendation, at least 75% agreement of the voting panel was needed. Results Six recommendations were elaborated regarding the pharmacological treatment of Raynaud’s phenomenon, the treatment (healing) and prevention of digital ulcers, skin involvement, interstitial lung disease (ILD) and gastrointestinal involvement in SSc patients based on results available from RCTs. New drugs, such as rituximab, were included as therapeutic options for skin involvement, and rituximab, tocilizumab and nintedanib were included as therapeutic options for ILD. Recommendations for the pharmacological treatment of scleroderma renal crisis and musculoskeletal involvement were elaborated based on the expert opinion of the voting panel, as no placebo-controlled RCTs were found. Conclusion These guidelines updated and incorporated new treatment options for the management of SSc based on evidence from the literature and expert opinion regarding SSc, providing support for decision-making in clinical practice.

Abstract Carcinogenesis and tumor proliferation are characterized by a complex interaction of cancer cells with the tumor microenvironment. In particular, a tumor-promoting effect can be assumed for the stroma and its fibroblasts. An influence of the immune system on non small cell lung cancer (NSCLC) is now also suspected. In our study, we examined 309 sections of squamous cell carcinoma (SCC), a subtype of NSCLC. We determined the cell densities and areas of the different tissues in SCC using the software QuPath. Spearman rank correlation showed a significant positive correlation between the different tumor cell densities and stromal cell densities, and between tumor cell densities and immune cell densities. Overall survival curves by the Kaplan–Meier method revealed a prominent negative curve in cases of low immune cell density. Based on our results, we can assume a positive influence of the tumor microenvironment, especially the stromal cells, on tumor proliferation in SCC. We have also revealed that low density of immune cells is prognostically unfavorable.

This viewpoint is written by authors with industrial, clinical, and academic backgrounds within medical and social sciences. The purpose is to share our experiences with digital health innovation from a sociotechnical perspective. The audience for the viewpoint is innovators, researchers, service designers, and project managers with little or some experience with theory-informed programs, complex interventions, and implementation or reorganization of sociotechnical ecosystems in health care. In digital health innovation projects, barriers related to traditions and cultures among researchers, clinicians, and industry may arise. Moreover, the final digital solutions may not always fit into existing digital ecosystems and may thus require a reorganization of how health care is provided at horizontal and vertical levels. The collaborating researchers have experience working in the field of digital health innovation for more than a decade, and we have developed and used 4 frameworks and models that are particularly relevant for theory-based complex interventions and can be used to inform inclusive co-design of digital health solutions with a sociotechnical perspective. These are (1) the 4E, a matrix to include, engage, empower, and emancipate marginalized people; (2) the GO-TO model, which can be used as a design navigator; (3) the Epital Care Model, to inform infrastructure; and (4) the Readiness and Enablement Index for Health Technology instrument, to stratify service users. From January 2021 to September 2024, we had the opportunity to apply these into practice in 4 living labs located in Denmark, Norway, the Netherlands, and Canada as a part of a European Union–funded project on “Smart Inclusive Living Environments.” The goal was to cocreate a digital solution and reorganize health care services to reduce social isolation, increase health literacy, and enhance well-being for older adults living with frailty or impairments. Based on our experiences with the Smart Inclusive Living Environments project, we have formed a proposal for how design guidelines for sociotechnical innovation projects can be structured, backed up with reflections based on our experiences. With that, design guidelines should include three areas: (1) a common vocabulary including theories, frameworks, and models; (2) templates and protocols for methods, including detailed guidelines and templates for the planned development of the technologies; and (3) methods to implement and provide education and training of service users and informal and formal caregivers. In the design process, we emphasize the importance of involving relevant stakeholders in the implementation of the created design guidelines to obtain preparedness in the organizations, as well as including putative service users to ensure the likelihood of adoption. Moreover, it is important to align expectations, have a common understanding of the applied frameworks and methods, and have access to the necessary resources to reach successful results.

Introdução: O mieloma múltiplo (MM) é uma neoplasia maligna de plasmócitos da medula óssea que possui uma grande carga de sintomas, comprometendo a qualidade de vida (QV) e a capacidade funcional dos pacientes. O seu tratamento envolve o uso de fármacos potencialmente causadores de NIPQ, como talidomida, lenalidomida e bortezomibe. A NPIQ é relatada entre 10 e 55% dos pacientes em uso de talidomida e entre 31 e 64% daqueles em uso de bortezomibe. Nesse sentido, objetivou-se avaliar a NPIQ em pacientes em tratamento para MM em um hospital terciário em Passo Fundo (RS). Metodologia: Estudo transversal, descritivo e quantitativo no qual aplicou-se, mediante autorização de Comitê de Ética em Pesquisa (n° 6.544.927), o instrumento Indication for Common Toxicity Criteria – Grading of Peripheral Neuropathy Questionnaire (ICPNQ), que contém três subescalas hipotéticas que avaliou sintomas sensoriais, autonômicos e motores em 23 pacientes que estavam em uso de drogas neurotóxicas no momento da pesquisa. Resultados e discussão: O ICPNQ é usado para avaliação da NPIQ em pacientes com MM. Mediante as respostas dos pacientes é possível uma indicação em relação ao grau CTCAE (Critérios de Terminologia Comum para Eventos Adversos) da NPIQ, de modo que em nosso estudo obteve-se os seguintes resultados: grau 0, assintomático, apenas um (4,3%) paciente; grau I, presença de sintomas sensoriais como dormência, formigamento e alterações proprioceptivas, 5 pacientes (21,7%); grau II, sintomas autonômicos e/ou perda de força, e/ou problemas vivenciados em atividades instrumentais acompanhadas de sintomas sensoriais e/ou dor, 13 pacientes (56,5%); e grau III, problemas nas atividades de autocuidado acompanhadas de sintomas sensoriais e/ou dor e/ou perda de força, 4 pacientes (17,4%). Quanto aos protocolos de tratamento utilizados, 39,1% estavam em uso de talidomida; 39% de bortezomibe; 13% associação de talidomida com bortezomibe e 8,7% em uso de lenalidomida. A neuropatia é um efeito adverso comum da quimioterapia, sendo observado, em nosso estudo, em mais de 95% dos entrevistados. Do mesmo modo, um estudo realizado na Holanda com 56 pacientes portadores de MM, evidenciou que 65% deles relataram graus 2 ou 3 de neuropatia, de acordo com o ICPNQ. Os fármacos empregados no tratamento do MM tem aumentado a sobrevida dos pacientes, porém os efeitos adversos vivenciados impactam negativamente na QV. Tendo em vista que não existem agentes terapêuticos preventivos da NPIQ, os seus instrumentos de mensuração são fundamentais na prática clínica, pois auxiliam os médicos na tomada de decisão frente a manutenção ou redução de doses, visando manter o controle da doença e melhorar os sintomas experimentados pelos pacientes. Deve-se salientar que além da quimioterapia, existem outras potenciais causas de neuropatia, porém, exames mais objetivos como eletroneuromiografia nem sempre estão disponíveis. Conclusão: Com aumento da expectativa de vida, as neoplasias estão entre uma das principais causas de morbimortalidade na população e os pacientes enfrentam os efeitos da quimioterapia na QV. Diante disso, o uso de instrumentos de avaliação da NIPQ, ajudam a compreender o quanto a neuropatia interfere no tratamento oncológico, além de auxiliar os profissionais sobre as medidas cabíveis para assegurar a manutenção do bem estar do paciente durante o tratamento.

Introdução: Mieloma Múltiplo (MM) é uma neoplasia maligna relacionada à proliferação descontrolada de plasmócitos na medula óssea. Possui diferentes classificações e prognósticos e seus sintomas dependem do sítio acometido. A síndrome da doença inclui hipercalcemia, insuficiência renal, anemia e doença óssea. É um diagnóstico desafiador e de grande impacto na qualidade de vida. Logo, o presente estudo busca compreender as características sociodemográficas e clínicas dos pacientes com diagnóstico de MM em um hospital de grande porte do RS. Metodologia: Estudo transversal, descritivo e quantitativo, aprovado pelo Comitê de Ética em Pesquisa (n° 6.544.927). Foram avaliados 31 pacientes em acompanhamento no ambulatório de Hematologia do Hospital São Vicente de Paulo (HSVP). Analisou-se os dados demográficos, comorbidades e efeitos adversos do tratamento, os quais foram coletados por meio de questionário de autoria própria e os exames laboratoriais do prontuário eletrônico (TASY). Resultados: A média de idade e de tempo desde o diagnóstico foram de 60,6 e 5,45 anos. Predominou o sexo masculino (64,5%), raça branca (71%), religião católica (77,4%), estado civil casado (64,5%) e ensino fundamental incompleto (48,5%). 22,6% dos pacientes relataram uma comorbidade e 51,6% duas ou mais. A de maior prevalência foi hipertensão arterial sistêmica (58,1%), seguida de doença cardiovascular (29%), fratura óssea (25,8%), anemia (19,4%), hipotireoidismo (16,1%), doença pulmonar (12,9%), doença renal crônica (9,7%). Nos efeitos adversos do tratamento, predominou a perda de apetite (61,3%), seguida de perda de peso (58,1%), náuseas/vômitos (58,1%), dificuldade de visão (58,1%), cansaço (54,8%), constipação (51,6%), redução de sensibilidade (48,4%). Discussão: O MM representa 1% de todos os tipos de câncer e 10% das neoplasias hematológicas. De acordo com o Ministério da Saúde, houve 3.064 óbitos por essa doença no BR em 2016. Concordando com a literatura, a maioria dos pacientes eram do sexo masculino com idade entre 60 e 65 anos. A literatura traz a raça negra como fator de risco, mas em nossos dados a raça branca prevaleceu - o que possui relação com a colonização predominantemente europeia no RS. Em um estudo feito no estado do MS, a cor branca também foi predominante, sendo um estado onde 47% da população se declarava branca. Há fatores relacionados ao risco aumentado dessa neoplasia, como exposição à radiação ionizante e a agentes químicos contendo hidrocarbonetos aromáticos, agentes poluentes e agrotóxicos. A maioria dos entrevistados era casada e com ensino fundamental incompleto. Do total, 22 pacientes não eram tabagistas. Sobre as comorbidades, predominou a hipertensão arterial sistêmica, um dado que não surpreende devido à alta prevalência dessa doença na sociedade. A maioria dos pacientes não reportou câncer prévio e poucos eram portadores de doença renal crônica. Conclusão: Compreender o perfil dos pacientes com MM pode contribuir diretamente para o maior conhecimento da doença por parte dos profissionais de saúde, possibilitando diagnóstico precoce e melhor manejo da doença. Ressalta-se que com os dados coletados não é possível correlacionar, com indubitável significância, a incidência de MM em um determinado grupo demográfico. Além disso, a alta prevalência de efeitos adversos reflete a dificuldade de manter a qualidade de vida diante dos tratamentos disponíveis.

BACKGROUND: Maintaining physical activity throughout life is crucial for overall health and wellbeing. Yet the age-related decline in average physical activity, a natural phenomenon also observed in animals, poses a challenge. This study aimed to investigate whether participation in organised sports supported by the Swiss Youth+Sports (Y+S) programme is associated with sustaining or enhancing physical activity among children and adolescents during 5 years of follow-up. METHODS: The longitudinal study was nested in the population-based SOPHYA (Swiss children’s Objectively measured PHYsical Activity) cohort. Participants aged 6–16 years at SOPHYA1 (2014) with complete accelerometer data from baseline and follow-up assessment (SOPHYA2, 2019) were included. The primary exposure was participation in organised sport during the follow-up period, calculated by linkage with the Y+S database as the number of days with at least one activity in Y+S-offered programmes for ages 5 to 20 years. The primary outcome was the categorisation of participants into physical activity “improvers” or “worseners”. Improvers in the respective physical activity categories – total activity counts per minute (CPM), minutes in moderate-to-vigorous activity (MVPA), minutes in light activity (LPA) and minutes in sedentary behaviour (SB) – increased or maintained their active physical activity during the 5 follow-up years. Information on confounders and effect modifiers (sex, age, body mass index (BMI), language region, household income, education) was obtained by self-report at baseline. Logistic regressions examined the relationship between organised sport participation and the probability of being a physical activity improver in each physical activity intensity category separately. Covariates for the final models were selected through a stepwise procedure based on the Bayesian information criterion from a maximal model containing all covariates as well as all two-way interactions with organised sport and between them. All models were a priori adjusted for technical variables (season of measurement; wear time; duration of follow-up). RESULTS: The analysis included 432 participants. There was a strong CPM, MVPA and LPA decline from 2014 to 2019, but an increase in SB. Nevertheless, the prevalence of improvers was 22.5% for CPM, 9.5% for MVPA, 26.9% for LPA and 9.7% for SB. Engagement in organised sport between 2014 and 2019 was positively associated with CPM, MVPA and SB, but not with LPA improver status. For 30 additional days of participation in organised sport over the five years of the study, the odds of being an improver vs being a worsener increased by 4.0% for CPM (95% CI: 0.13–7.69), 6.2% for MVPA (95% CI: 0.82–11.54) and 6.0% for SB (95% CI:−1.49–13.97). CONCLUSION: The results provide supporting evidence that organised sport in the context of the Swiss Y+S programme may empower the young to maintain an active lifestyle and even offset the age-related decline in physical activity.

We evaluated response to VEN/HMA in 46 patients with acute myeloid leukemia (AML) characterized by extramedullary disease (EMD). Median age was 65 (range, 19-81) years. Patients had a median of two EMD sites (range, 1-5) and 35 (76%) patients had concurrent bone marrow involvement. Twenty (43%) patients had highrisk genetic features according to the European Leukemia Net 2022 classification. Twenty-nine (63%) were relapsed or refractory after intensive chemotherapy (CTX) including 13 (28%) with prior allogeneic hematopoietic cell transplantation (allo-HCT). Patients received a median of 2 cycles of VEN/HMA (range, 1-31). Twenty (43%) patients achieved complete remission (CR) or CR with incomplete hematological recovery (CRi) after VEN/HMA and five (11%) achieved a partial remission (PR). Six patients were subsequently consolidated with allo-HCT (CR/CRi, n=4; PR, n=2). Median follow-up was 49.1 months (95%-CI, 26.1 months - not reached) and median overall survival (OS) 6.4 months (95%-CI, 5.1-11 months). One-year and 2-years OS rates were 29.3% (95%-CI, 18.6-46.2%) and 12.3% (95%-CI, 5.5-27.6%), respectively. Age with a cut-off of 60 years had no impact on OS (P=0.90). Relapse occurred in 12 of 20 (60%) patients who achieved CR/CRi after VEN/HMA treatment. Of those, all except one succumbed to their disease. Six (30%) patients were in CR/CRi at last follow-up and 2 (10%) died in CR. In our cohort of patients with AML with EMD with high-risk features, treatment with VEN/HMA resulted in an encouraging ORR of 54% with a CR/CRi rate of 43.5%. However, VEN/HMA alone may not be effective in maintaining disease control.

Abstract Yeast metabolism can be engineered to produce xenobiotic compounds, such as cannabinoids, the principal isoprenoids of the plant Cannabis sativa, through heterologous metabolic pathways. However, yeast cell factories continue to have low cannabinoid production. This study employed an integrated omics approach to investigate the physiological effects of cannabidiol on S. cerevisiae CENPK2-1C yeast cultures. We treated the experimental group with 0.5 mM CBD and monitored CENPK2-1C cultures. We observed a latent-stationary phase post-diauxic shift in the experimental group and harvested samples in the inflection point of this growth phase for transcriptomic and metabolomic analysis. We compared the transcriptomes of the CBD-treated yeast and the positive control, identifying eight significantly overexpressed genes with a log fold change of at least 1.5 and a significant adjusted p-value. Three notable genes were PDR5 (an ABC-steroid and cation transporter), CIS1, and YGR035C. These genes are all regulated by pleiotropic drug resistance linked promoters. Knockout and rescue of PDR5 showed that it is a causal factor in the post-diauxic shift phenotype. Metabolomic analysis revealed 48 significant spectra associated with CBD-fed cell pellets, 20 of which were identifiable as non-CBD compounds, including fatty acids, glycerophospholipids, and phosphate-salvage indicators. Our results suggest that mitochondrial regulation and lipidomic remodeling play a role in yeast’s response to CBD, which are employed in tandem with pleiotropic drug resistance (PDR). We conclude that bioengineers should account for off-target product C-flux, energy use from ABC-transport, and post-stationary phase cell growth when developing cannabinoid-biosynthetic yeast strains.

Abstract Selective attention is a crucial ability of the auditory system. Computationally, following an auditory object can be illustrated as tracking its acoustic properties, e.g., pitch, timbre, or location in space. The difficulty is related to the fact that in a complex auditory scene, the information about the tracked object is not available in a clean form. The more cluttered the sound mixture, the more time and frequency regions where the object of interest is masked by other sound sources. How does the auditory system recognize and follow acoustic objects based on this fragmentary information? Numerous studies highlight the crucial role of top-down processing in this task. Having in mind both auditory modeling and signal processing applications, we investigated how computational methods with and without top-down processing deal with increasing sparsity of the auditory features in the task of estimating instantaneous voice states, defined as a combination of three parameters: fundamental frequency F0 and formant frequencies F1 and F2. We found that the benefit from top-down processing grows with increasing sparseness of the auditory data.

Abstract Thromboembolic events are complications in cancer patients and hypercoagulability has been linked to the tissue factor (TF) pathway, making this an attractive target. Here, we investigated the effects of chemotherapeutics and CDK inhibitors (CDKI) abemaciclib/palbociclib (CDK4/6), THZ-1 (CDK7/12/13), and dinaciclib (CDK1/2/5/9) alone and in combination regimens on TF abundance and coagulation. The human colorectal cancer (CRC) cell line HROC173 was treated with 5-FU or gemcitabine to stimulate TF expression. TF+ cells were sorted, recultured, and re-analyzed. The effect of treatment alone or in combination was assessed by functional assays. Low-dose chemotherapy induced a hypercoagulable state and significantly upregulated TF, even after reculture without treatment. Cells exhibited characteristics of epithelial-mesenchymal transition, including high expression of vimentin and mucin. Dinaciclib and THZ-1 also upregulated TF, while abemaciclib and palbociclib downregulated it. Similar results were observed in coagulation assays. The same anticoagulant activity of abemaciclib was seen after incubation with peripheral immune cells from healthy donors and CRC patients. Abemaciclib reversed 5-FU-induced TF upregulation and prolonged clotting times in second-line treatment. Effects were independent of cytotoxicity, senescence, and p27kip1 induction. TF-antibody blocking experiments confirmed the importance of TF in plasma coagulation, with Factor XII playing a minor role. Short-term abemaciclib counteracts 5-FU-induced hypercoagulation and eventually even prevents thromboembolic events.

Abstract Background Water, sanitation, and hygiene (WASH) access is critical to public health and human dignity. People who inject drugs (PWID) experience stigma and structural violence that may limit WASH access. Few studies have assessed WASH access, insecurity, and inequities among PWID. We describe WASH access, social and geographic inequalities, and factors associated with WASH insecurity among PWID in the Tijuana-San Diego metropolitan area. Methods In this cross-sectional binational study, we interviewed PWID (age 18+) in 2020–2021 about WASH access and insecurity. City of residence (Tijuana/San Diego) and housing status were considered as independent variables to describe key WASH access outcomes and to assess as factors associated with WASH insecurity outcomes. Measures of association between outcomes and independent variables were assessed using log modified-Poisson regression models adjusting for covariates. Results Of 586 PWID (202 Tijuana; 384 San Diego), 89% reported basic access to drinking water, 38% had basic hand hygiene, 28% basic sanitation, and 46% access to bathing, and 38% reported recent open defecation. Participants residing in Tijuana reported significantly higher insecurity in accessing basic drinking water (aRR: 1.68, 95%CI: 1.02–2.76), basic hygiene (aRR: 1.45, 95%CI: 1.28–1.64), and bathing (aRR: 1.21, 95%CI: 1.06–1.39) than those living in San Diego. Participants experiencing unsheltered homelessness experienced significantly higher insecurity in accessing basic drinking water (aRR: 2.03, 95%CI: 1.07–3.86), basic sanitation (aRR: 1.68, 95%CI: 1.48, 1.92), bathing (aRR: 1.84, 95%CI: 1.52–2.22), and improved water sources for cleaning wounds (aRR: 3.12, 95%CI: 1.55–6.29) and for preparing drugs (aRR: 2.58, 95%CI: 1.36–4.89) than participants living in permanent housing. Conclusion WASH access among PWID in the Tijuana-San Diego metropolitan area was low by international standards and lower than the national averages in both countries. Homelessness was significantly associated with WASH insecurity in this population. Concentrated efforts are needed to guarantee continuously available WASH services for PWID—especially those who are unsheltered.

Abstract Fast neutron beams (E $$_n > $$ n > 1 MeV) are of relevance for many scientific and industrial applications. This paper explores fast neutron production using a TANDEM accelerator at the Legnaro National Laboratories, via an energetic ion beam (90 MeV $$^{14}N$$ 14 N ) onto a lithium target. The high energy models for nuclear collision of FLUKA foresee large neutron yields for reactions of this kind. The experiment aimed at validating the expected neutron yields from FLUKA simulations, using two separate and independent set-ups: one based on the multi-foil activation technique, and the other on the time of flight technique, by using liquid scintillator detectors. The results of the experiment show clear agreement of the measured spectra with the FLUKA simulations, both in the shape and the magnitude of the neutron flux at the measured positions. The neutron spectrum is centered around the 8 MeV range with mild tails, and a maximum neutron energy spanning up to 50 MeV. These advantageous results provide a starting point in the development of fast neutron beams based on high energy ion beams from medium-sized accelerator facilities.

The heterozygous mutation c.155G > T in GNB2 clinically leads to sinus bradycardia and sinus node dysfunction. Here, patient-specific skin fibroblasts of the mutation carrier were used for Sendai virus reprogramming into human induced-pluripotent stem cells (hiPSC). For generating the isogenic control cell line, a CRISPR/Cas9-mediated HDR-repair of the hiPSCs was carried out. Both generated cell lines (GNB2 SV5528, GNB2 K26) maintained a normal karyotype, cell morphology, pluripotency in immunofluoresence and RT-qPCR analysis. Both hiPSC-lines showed differentiation potential into all three germ layers. Differentiated cardiomyocytes of this isogenic set may pave the way for investigating pharmacological rescue strategies for sinus node dysfunction.