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IntroductionStimulant use is an important health issue. In the US in 2018, 2.8% of males and 1.5% of females older than 18 had used cocaine in the preceding 12 months.ObjectiveTo intervene in a specific targeted group of Stimulant Use Disorder (SUD) patients according to CBT and relapse prevention theories, and to determine the program’s feasibility and attendance.MethodStimulant Use Disorder patients in addiction care were evaluated for addictive, psychological and psychiatric dimensions at baseline and conclusion in a 9-session CBT group program with several themes: define SUD, enhance motivation, involve close companions, cope with craving, decline a proposal, solve problems, invite expert patients, invest time and money, and review content.ResultsIn total, 41 patients attended at least one session. They were mainly poly dependent, primarily cocaine users. Sixty percent of the population also suffered from another psychiatric comorbidity. Median attendance for participants was 7/9 sessions.ConclusionA specific targeted CBT group for stimulant dependent highly comorbid patients is feasible. These findings suggest that peers should be included in addiction care services.

The tissue microenvironment in the mouse pancreas has been shown to promote very different polarizations of resident macrophages with islet-resident macrophages displaying an inflammatory “M1” profile and macrophages in the exocrine tissue mostly displaying an alternatively activated “M2” profile. The impact of this polarization on tissue homeostasis and diabetes development is unclear. In this study, the ability of pancreas-resident macrophages to phagocyte bacterial and endogenous debris was investigated. Mouse endocrine and exocrine tissues were separated, and tissue-resident macrophages were isolated by magnetic immunolabeling. Isolated macrophages were subjected to flow cytometry for polarization markers and qPCR for phagocytosis-related genes. Functional in vitro investigations included phagocytosis and efferocytosis assays using pH-sensitive fluorescent bacterial particles and dead fluorescent neutrophils, respectively. Intravital confocal imaging of in situ phagocytosis and efferocytosis in the pancreas was used to confirm findings in vivo. Gene expression analysis revealed no significant overall difference in expression of most phagocytosis-related genes in islet-resident vs. exocrine-resident macrophages included in the analysis. In this study, pancreas-resident macrophages were shown to differ in their ability to phagocyte bacterial and endogenous debris depending on their microenvironment. This difference in abilities may be one of the factors polarizing islet-resident macrophages to an inflammatory state since phagocytosis has been found to imprint macrophage heterogeneity. It remains unclear if this difference has any implications in the development of islet dysfunction or autoimmunity.

5-MeO-DMT is a psychoactive substance found in high concentrations in the bufotoxin of the Colorado River Toad (Bufo alvarius). Emerging evidence suggests that vaporized 5-MeO-DMT may occasion mystical experiences of comparable intensity to those occasioned by more widely studied psychedelics such as psilocybin, but no empirical study has tested this hypothesis. Data was obtained from 20 individuals (Mage = 38.9, ± 10.7; male = 55%, Caucasian = 85%) who were administered 5-MeO-DMT as part of a psychospiritual retreat program in Mexico. All participants received 50 mg of inhaled vaporized toad bufotoxin which contains 5-MeO-DMT and completed the Mystical Experience Questionnaire (MEQ30) approximately 4–6 h after their session. Administration of 5-MeO-DMT occasioned strong mystical experiences (MEQ30 Overall Mintensity = 4.17, ± 0.64, range 0–5) and the majority (n = 15, 75%) had “a complete mystical experience” (≥60% on all MEQ30 subscales). Compared to a prior laboratory-based psilocybin study, there were no differences in the intensity of mystical effects between 5-MeO-DMT and a high dose (30 mg/70 kg) of psilocybin, but the intensity of mystical effects was significantly higher in the 5-MeO-DMT sample compared to moderate/high dose (20 mg/70 kg) of psilocybin (MEQ30 Total Score: p = 0.02, d = 0.81). Administration of vaporized 5-MeO-DMT reliably occasioned complete mystical experiences in 75% of individuals and was similar in intensity to high dose psilocybin administered in a laboratory setting. The short duration of action may be advantageous for clinical interventions and for studying mystical-type experiences.

Although medication use during pregnancy is common, most available products lack sufficient safety information. As prospective data collection and perinatal pharmacoepidemiologic research on medication safety in pregnancy did not exist in Belgium yet, the BELpREG data registration system was developed. BELpREG enables comprehensive “real-world” data collection on perinatal medication use and mother-infant outcomes via online questionnaires that are completed by pregnant women every 4 weeks during pregnancy and in the first 8 weeks after childbirth. This paper describes the development and current design of the BELpREG system, including the list of BELpREG variables. To compile this list of variables, relevant documents were explored, followed by consultation of an interdisciplinary expert panel. The included variables were structured in seven categories: 1) Sociodemographic characteristics; 2) Information on the current pregnancy and health status; 3) Maternal-obstetric history; 4) Use of medicines, folic acid/pregnancy vitamins and other health products; 5) Substance use; 6) Pregnancy outcomes; and 7) Neonatal outcomes. An electronic informed consent and linkage to medication databases, with images of drug packages and underlying structured data fields, are built into the system. Data collection has officially started in November 2022. Based on its rigorous design, BELpREG holds the potential to be a successful and sustainable research tool, enabling perinatal pharmacoepidemiologic research in Belgium and beyond.

Research has demonstrated high rates of mental health problems in university students, and even higher rates in students belonging to historically marginalised populations. However, research on disparities in student mental health has almost exclusively focused on internalising problems (like symptoms of depression and anxiety), overlooking other ways in which individuals experience and express negative emotion. To address this limitation, the present study employed the Brief Problem Monitor to examine three types of mental health problems—internalising, externalising, and attentional problems—across six sociodemographic characteristics: gender (male vs. female), sexual orientation (heterosexual vs. non-heterosexual), ethnicity (Dutch without vs. with migration background), internationality (domestic vs. international), disability (no disabilities vs. disabilities), and parental education (continuing- vs. first-generation). These sociodemographic variables were included in regression models simultaneously, thereby controlling for the effects of the others. Across a sample of 2,256 students, internalising problems were significantly higher in students who were female, non-heterosexual, international, and in those with disabilities. Higher externalising problems were found in female students, students with disabilities, those with a migration background, and first-generation students. Finally, attentional problems were higher in non-heterosexual students and students with disabilities. These findings support the premise that different groups of students experience different types of mental health concerns, emphasising the importance of measuring mental health multidimensionally. As an example, had the present study only examined internalising problems, we would not have found mental health disparities for students with a migration background and first-generation students, which has clear implications for outreach and resources offered to them.

IntroductionMultidrug-resistant Enterobacteriaceae are among the most urgent global public health threats associated with various life-threatening infections. In the absence of a rapid method to identify antimicrobial susceptibility, empirical use of broad-spectrum antimicrobials such as carbapenem monotherapy has led to the spread of resistant organisms. Rapid determination of antimicrobial resistance is urgently needed to overcome this issue.MethodsBy capturing dynamic single-cell morphological features, including growth-independent, antibiotic-induced changes, of cells from 19 strains of Klebsiella pneumoniae, we evaluated data processing strategies based on time and concentration differentials to develop models for classifying its susceptibility to a commonly used carbapenem, meropenem, and predicting their minimum inhibitory concentrations (MIC).Results and discussionWe report morphometric antimicrobial susceptibility testing (MorphoAST), a growth independent, computer vision-based machine learning workflow, for rapid determination of antimicrobial susceptibility by single-cell morphological analysis within sub-doubling time of K. pneumoniae. We demonstrated the technological feasibility of predicting MIC/antimicrobial susceptibility in a fraction of the bacterial doubling time (

The French National Animal Health Surveillance Platform (NAHSP) was created in 2011. This network of animal health stakeholders was set up to improve surveillance efficiency for all health risks that threaten animal health, as well as zoonoses affecting human health. The NAHSP steering committee decides on the strategies and program of activities. It is composed of 11 institutions from both public and private sectors (policy-makers, scientific institutions, and representatives of farmers, veterinarians, hunters, and laboratories). A coordination team guarantees the implementation of the program and facilitates the activities of different working groups (WGs). Each WG is composed of technical experts with scientific, legal, and field knowledge from the sectors of animal health (livestock, companion animals, and wildlife), human health, and environmental health. Some WGs focus on a specific disease or health indicator, such as African swine fever or cattle mortality, while others cover cross-cutting topics, such as epidemic intelligence (EI), or specialize in aiding epidemiological investigations, such as the Q fever WG. The NAHSP stands out for its innovative approach because it is based on the concepts of consensus-building among participants, fostering collaboration, and embracing interdisciplinarity. Each proposal designed to improve surveillance is jointly developed by all the stakeholders involved, thereby ensuring its sustainability and acceptability among stakeholders. This process also has added value for decision-makers. As a pioneer platform, the NAHSP inspired the creation of two additional national surveillance platforms in 2018, one for plant health and the other for food chain safety. Both are organized in the same way as the NAHSP, which created a framework to place the emphasis on a One Health approach. For instance, four WGs are common to the three national surveillance platforms. This article aims to present this innovative approach to improve surveillance efficiency that could be of interest to other European countries or that could be rolled out at the European level.

A sealed container for the geological disposal of spent nuclear fuel and vitrified high-level waste is the only component of a deep geological repository that provides complete containment of radionuclides. As such, attention is focused on its lifetime. The lifetime of the container is influenced by material degradation processes during disposal and is typically of the order of several millennia and, for some container materials, up to one million years. Designing, manufacturing, and predicting the performance of containers over such long periods requires an in-depth understanding of their material properties, fabrication processes, and degradation mechanisms. Scientific and technological progress can improve both the performance of containers and the robustness of lifetime predictions. Optimization of these aspects is of primary importance for many national radioactive waste disposal programs. In this article, the state of the art of complex coupled degradation processes, as well as the optimization potential of novel container materials, is presented. Furthermore, the existing tools allowing the prediction of long-term barrier integrity are discussed.

Perception of quality of life for cats and dogs of low-income Spanish and English-speaking veterinary clients attending problem focused or routine veterinary visits is an important area of focus for community based veterinary service providers. Using a qualitative approach, 50 New York City based American Society for the Prevention of Cruelty to Animals (ASPCA) veterinary clients completed semi-structured interviews as well as a survey about their perception of life with their pets. Veterinary clients shared both human-animal bond (HAB) related and quality of life (QoL) related factors in their daily experience of life with their pets. Results indicated that this demographic perceives QoL similarly to previous QoL research that either does not report sample demographics or reports sample demographics with more affluence. Moreover, 60% of qualitative excerpts included both HAB and QoL themes and 40% were discretely HAB or QoL. An analog single item 10-point scale measuring veterinary client perception of their pets QoL did not differentiate between sample demographics at a statistically significant level. Finally, pet QoL literature has not traditionally reflected diverse demographic identities of veterinary clients or widely included reliable and valid measures of the human-animal bond (HAB). These results support the importance of measuring the HAB when researching pet QoL and provide evidence that lower-income Spanish and English-speaking veterinary clients are similarly bonded and attentive to their pets as other demographics.

BackgroundMelanoma patients’ prognosis is based on the primary tumor characteristics and the tumor status of the regional lymph nodes. The advent of lymphoscintigraphy with SLN biopsy (SLNB) has shown that melanoma can drain to multiple nodal basins but the significance of multiple basins (vs. one basin) with tumor-positive sentinel lymph node(s) (+SLN) of similar tumor burden has not been shown. We examined the impact of the number of nodal basins with +SLN (+basin) in melanoma patients and its significance for patients’ prognosis and survival.Study designWe identified 1,915 patients with +SLN from two randomized surgical clinical trials: Multicenter Selective Lymphadenectomy Trials I and II. Patient groups were divided based on number of +SLNs and number of +basins. Disease-free survival (DFS), distant disease-free survival (DDFS) and melanoma-specific survival (MSS) were compared with the Kaplan-Meier method and log-rank tests. Univariable and multivariable analyses were performed using Cox proportional hazard regressions.ResultsAmong the 1,915 patients, 1,501 had only one +SLN (78%) in one basin and 414 (22%) had multiple +SLNs: 340 located in one basin and 74 in multiple basins. Among patients with multiple +SLNs, those with multiple +basins have a worse DFS, DDFS and MSS than those with a single basin (p ≤ 0.0001 for all comparisons). MSS was significantly different based on AJCC stages: AJCC IIIA and IIIB (p ≤ 0.001 and 0.0287, respectively).ConclusionOur results suggest that the number of tumor-positive basins may be important for staging and in understanding the biology of lymph node metastases.

This pan-Canadian study investigates the effects of musical practice on the well-being, mental health, and social support of Canadian musicians during the COVID-19 pandemic. Using a survey questionnaire, data was collected from 1,618 participants aged 14 and above during the first wave of the pandemic up to the first half of 2022. The survey included standardized questionnaires to self-assess well-being (WHO-5), mental health (MHC-SF), and social support (SPS-10 measures social support). Results show that increased musical practice frequency correlates with improved well-being and mental health, particularly among amateurs. Professional musicians and those at a post-secondary level exhibit lower well-being scores, likely due to pandemic-related challenges. Factors such as age, gender, sports engagement, and participation in social clubs or volunteer work significantly influenced outcomes. While sports engagement was associated with higher scores on well-being, mental health and social support, no significant differences were found among participants engaged in artistic hobbies. As for involvement in social clubs or volunteer work, benefits were reported on two of the three outcomes. Overall, the findings suggest that regular amateur musical practice, especially in group settings, alongside engagement in sports and social activities, may have promoted well-being, mental health, and social support among musicians during the challenging period of the COVID-19 pandemic.

We benchmark Quantum Annealing (QA) vs. Simulated Annealing (SA) with a focus on the impact of the embedding of problems onto the different topologies of the D-Wave quantum annealers. The series of problems we study are especially designed instances of the maximum cardinality matching problem that are easy to solve classically but difficult for SA and, as found experimentally, not easy for QA either. In addition to using several D-Wave processors, we simulate the QA process by numerically solving the time-dependent Schrödinger equation. We find that the embedded problems can be significantly more difficult than the unembedded problems, and some parameters, such as the chain strength, can be very impactful for finding the optimal solution. Thus, finding a good embedding and optimal parameter values can improve the results considerably. Interestingly, we find that although SA succeeds for the unembedded problems, the SA results obtained for the embedded version scale quite poorly in comparison with what we can achieve on the D-Wave quantum annealers.

IntroductionIn the evolving healthcare landscape, precision medicine's rise necessitates adaptable doctoral training. The European Union has recognized this and promotes the development of international, training-focused programmes called Innovative Training Networks (ITNs). In this article, we introduce TranSYS, an ITN focused on educating the next generation of precision medicine researchers. In an ambition to go beyond describing the consortium goals, our article explores two key aspects of ITNs: the training and collaboration.MethodsUsing self-report questionnaires, we evaluate the scientific, professional, and personal growth of ESRs over the duration of the ITN and investigate whether this can be linked to network activities.ResultsOur quantitative analysis approach reveals substantial improvements in scientific, professional, and social skills among young researchers facilitated by the engagement in this interdisciplinary network. We provide case studies underlining the advantages of collaborative environments, featuring innovative scientific exchange within TranSYS.DiscussionWhile challenging, ITNs foster positive growth in young researchers, yet exhibit weaknesses such as balancing stakeholder interests and partner commitment. We believe this study may benefit a variety of stakeholders, from prospective ITN creators to industry partners, to design better sustainable training networks going forward.

Death initiates a cascade of physiological and biochemical alterations in organs and tissues, resulting in microscopic changes that challenge the histopathological evaluation. Moreover, the brain is particularly susceptible to artifacts owing to its unique composition and its location within the cranial vault. The aim of this study was to compile and illustrate the microscopic changes in the central nervous system (CNS) of rats subjected to delayed postmortem fixation. It also scrutinizes the influence of exsanguination and cooling methods on the initiation and progression of these alterations. Twenty-four Wistar Han outbred rats (RccHan™: WIST) were sacrificed and stored either at room temperature (18–22°C) or under refrigeration (2–4°C). Necropsies were conducted at different time points postmortem (i.e., 0.5 h, 1 h, 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, 7 days and 14 days). Brain sections underwent simultaneous digital evaluation by 14 pathologists until a consensus was reached on terminology, key findings, and intensity levels. Microscopic observations varied among cell types. Glial cells were similarly affected throughout the CNS and showed pericellular halo, chromatin condensation and nuclear shrinkage. Neurons showed two types of postmortem changes as most of them showed progressive shrinkage, cytoplasmic dissolution and karyorrhexis whereas others acquired a dark-neuron-like appearance. Neuronal changes showed marked differences among neuroanatomical locations. Additional postmortem changes encompassed: granulation and microcavitation in neuropil and white matter; retraction spaces; detachment of ependyma, choroid plexus, and leptomeninges. Severity of findings after 48 h at room temperature was higher than after seven days under refrigeration and similar to or slightly lower than after 14 days under refrigeration. No clear differences were observed related to the sex or weight of the animals or their exsanguination status. This work elucidates the onset and progression of autolytic changes in the brains of Wistar Han rats, offering insights to accurately identify and enhance the histopathological evaluation.

Strong Teens and Resilient Minds (STORM) is a multimodal, school-based approach for depression and suicide prevention in adolescents that is currently implemented in a region in the Netherlands. The STORM approach will be implemented in new regions in the coming years. This study used the implementation mapping protocol to report on the development of the STORM implementation plan. First, a needs assessment was conducted through semi-structured interviews with stakeholders and brainstorming sessions with regional programme leaders in the two regions that started implementing STORM in 2023. This led to the identification of six main barriers to implementation: high level of demands for schools, insufficient understanding of the programme content, insufficient network collaboration, no perceived relative advantage of STORM by stakeholders, lack of attention to sustainability, and high work pressure. Second, performance and change objectives were formulated based on these barriers. For example, a performance objective for potential providers was that they felt supported by STORM. Third, implementation strategies were selected from theory and translated into practical applications through brainstorming sessions with programme leaders. The following strategies were included in the implementation plan: collaborate with similar initiatives within the region, free up time for STORM tasks, tailor strategies, identify and prepare STORM champions, and promote network weaving. Last, a plan to evaluate the implementation of STORM and the application of the STORM implementation plan was formulated. Planned evaluation research will provide more insight into the usefulness and impact of the STORM implementation plan.

IntroductionPU.1-mutated agammaglobulinemia (PU.MA) represents a recently described autosomal-dominant form of agammaglobulinemia caused by mutation of the SPI1 gene. This gene codes for PU.1 pioneer transcription factor important for the maturation of monocytes, B lymphocytes, and conventional dendritic cells. Only six cases with PU.MA, presenting with chronic sinopulmonary and systemic enteroviral infections, have been previously described. Accumulating literature evidence suggests a possible relationship between SPI1 mutation, microglial phagocytic dysfunction, and the development of Alzheimer’s disease (AD).Case descriptionWe present a Caucasian female patient born from a non-consanguineous marriage, who was diagnosed with agammaglobulinemia at the age of 15 years when the immunoglobulin replacement therapy was started. During the following seventeen years, she was treated for recurrent respiratory and intestinal infections. At the age of 33 years, the diagnosis of celiac-like disease was established. Five years later progressive cognitive deterioration, unstable gait, speech disturbances, and behavioral changes developed. Comprehensive microbiological investigations were negative, excluding possible infective etiology. Brain MRI, 18FDG-PET-CT, and neuropsychological testing were suggestive for a diagnosis of a frontal variant of AD. Clinical exome sequencing revealed the presence of a novel frameshift heterozygous variant c.441dup in exon 4 of the SPI1 gene. Despite intensive therapy, the patient passed away a few months after the onset of the first neurological symptoms.ConclusionWe describe the first case of PU.MA patient presenting with a rapidly progressive neurocognitive deterioration. The possible role of microglial dysfunction in patients with SPI1 mutation could explain their susceptibility to neurodegenerative diseases thus highlighting the importance of genetic testing in patients with inborn errors of immunity. Since PU.MA represents a newly described form of agammaglobulinemia, our case expands the spectrum of manifestations associated with SPI1 mutation.

IntroductionThe use of various telecommunication tools has grown significantly. However, many of these tools (e.g., computer-based teleconferencing) are problematic in relaying non-verbal human communication. Telepresence robots (TPRs) are seen as telecommunication tools that can support non-verbal communication.MethodsIn this paper, we examine the usability of TPRs, and communication distance related behavioral realism in communication situations between physically present persons and a TPR-mediated person. Twenty-four participants, who played out 36 communication situations with TPRs, were observed and interviewed.ResultsThe results indicate that TPR-mediated people, especially women, choose shorter than normal communication distances. The type of the robot did not influence the choice of communication distance. The participants perceived the use of TPRs positively as a feasible telecommunication method.DiscussionWhen introducing TPRs, situations with greater intrapersonal distances require more practice compared to scenarios where a physically present person communicates with a telepresent individual in the audience. In the latter situation, the robot-mediated person could be perceived as “behaviorally realistic” much faster than in vice versa communication situations.

Overseas Filipino Workers (OFWs) are considered bagong bayani, or modern-day heroes, as their remittances have a positive long-term impact on the Philippines economy. The Philippines ranked 10th worldwide in terms of net emigration from 2010 to 2020. The deployment of OFWs declined during the pandemic, and this was estimated to have adverse effects on remittances. As a migrant-sending country, the Philippine government had to deal with the mass of unemployed OFWs stranded in their host countries and organize large-scale repatriation of OFWs. This scoping review aims to assess the existing literature, identify research gaps, and propose future research directions concerning the socio-economic impact of the COVID-19 pandemic on OFWs and their left-behind families. The results indicate that the impact of the pandemic on OFWs was not uniform. It is evident that OFWs in precarious situations beforehand have become even more vulnerable. The loss of their source of income in the host country and the restrictions on international mobility during the pandemic had significant detrimental effects on their wellbeing and their families left behind, regardless of their income level or type of job. Upon returning to their home country, they often experienced anxiety, depression, discrimination, and difficulty in finding a job. Overall, this scoping review highlights the urgent need for greater recognition and protection of OFWs in times of crisis. It is crucial to address the systemic issues that contribute to their vulnerability and to ensure that they receive adequate support and protection in host countries and the Philippines.

IntroductionPersonality is a central factor associated with relationship discord, conflicts, and separation, as well as with dyadic adjustment and relationship stability. The Alternative Model for Personality Disorders (AMPD) of the DSM-5 offers a hybrid model for understanding personality based on personality dysfunction (Criterion A) and pathological domains and facets (Criterion B). So far, few studies have integrated this model into the understanding of relationship quality. Therefore, the aim of this study was to examine the contribution of Criterion B to relationship satisfaction in individuals involved in an intimate relationship. We also explored the joint contribution of Criteria A and B, as well as their interaction effects, to relationship satisfaction.MethodsParticipants were drawn from two clinical samples: patients with personality disorders (PD; N = 101) and clients consulting in private practice clinics (PPC; N = 350). They completed self-report questionnaires assessing relationship satisfaction and AMPD Criteria A (only for PPC sample) and B.ResultsHierarchical regressions showed that, for the PD sample, the Detachment and Negative Affectivity domains, especially the pathological facets of Intimacy Avoidance and Separation Insecurity, explained 22.5% of relationship satisfaction’s variance. For PPC clients, Detachment, Negative Affectivity, and Antagonism domains, and especially the pathological facets of Intimacy Avoidance, Anxiousness, and Grandiosity, contribute significantly to relationship satisfaction, explaining 14.8% of its variance. Criterion A elements did not evince incremental value to the regression models in the PPC sample, and no Criteria A and B interaction effects were found. Clinical implications as well as limitations of the study are discussed.

Introduction: Multi-view data offer advantages over single-view data for characterizing individuals, which is crucial in precision medicine toward personalized prevention, diagnosis, or treatment follow-up.Methods: Here, we develop a network-guided multi-view clustering framework named netMUG to identify actionable subgroups of individuals. This pipeline first adopts sparse multiple canonical correlation analysis to select multi-view features possibly informed by extraneous data, which are then used to construct individual-specific networks (ISNs). Finally, the individual subtypes are automatically derived by hierarchical clustering on these network representations.Results: We applied netMUG to a dataset containing genomic data and facial images to obtain BMI-informed multi-view strata and showed how it could be used for a refined obesity characterization. Benchmark analysis of netMUG on synthetic data with known strata of individuals indicated its superior performance compared with both baseline and benchmark methods for multi-view clustering. The clustering derived from netMUG achieved an adjusted Rand index of 1 with respect to the synthesized true labels. In addition, the real-data analysis revealed subgroups strongly linked to BMI and genetic and facial determinants of these subgroups.Discussion: netMUG provides a powerful strategy, exploiting individual-specific networks to identify meaningful and actionable strata. Moreover, the implementation is easy to generalize to accommodate heterogeneous data sources or highlight data structures.

Triple-negative breast cancer (TNBC) remains difficult to treat, especially due to ineffective immune responses. Current treatments mainly aim at a cytotoxic effect, whereas (stem) cell therapies are being investigated for their immune stimulatory capacities to initiate the anti-tumor immunity. Here, a thoroughly characterized, homogenous and non-tumorigenic mixture of equine mesenchymal stem cells (eMSCs) harvested from horse peripheral blood as innovative xenogeneic immunomodulators were tested in a 4T1-based intraductal mouse model for TNBC. The eMSCs significantly reduced 4T1 progression upon systemic injection, with induction of inflammatory mediators and T-cell influx in primary tumors, already after a single dose. These xenogeneic anti-cancer effects were not restricted to MSCs as systemic treatment with alternative equine epithelial stem cells (eEpSCs) mimicked the reported disease reduction. Mechanistically, effective eMSC treatment did not rely on the spleen as systemic entrapment site, whereas CD4+ and CD8α+ T-cell infiltration and activation were critical. These results show that eMSCs and potentially also other equine stem cell types can be a valuable TNBC treatment strategy for further (pre)clinical evaluation.

Molecular profiling technologies, such as RNA sequencing, offer new opportunities to better discover and understand the molecular networks involved in complex biological processes. Clinically important variations of diseases, or responses to treatment, are often reflected, or even caused, by the dysregulation of molecular interaction networks specific to particular network regions. In this work, we propose the R package PLEX.I, that allows quantifying and testing variation in the direct neighborhood of a given node between networks corresponding to different conditions or states. We illustrate PLEX.I in two applications in which we discover variation that is associated with different responses to tamoxifen treatment and to sex-specific responses to bacterial stimuli. In the first case, PLEX.I analysis identifies two known pathways i) that have already been implicated in the same context as the tamoxifen mechanism of action, and ii) that would have not have been identified using classical differential gene expression analysis.

BackgroundThe concept of “positive health” emerged from the need for a holistic and more dynamic perspective on health, emphasising the ability of individuals to adapt and self-manage. The positive health conversation tool helps understand how people score on six positive health dimensions. However, skills within these dimensions to maintain or improve health have not yet been described. This is important for enabling individuals to put health advice into practise. Therefore, this paper aims to define and suggest skills for maintaining and improving positive health.SubsectionsSuggestions for definitions of skills within the positive health dimensions are described using the functional, interactive, and critical health literacy framework. Additionally, executive functions and life skills were incorporated. Moreover, the environment's role in these individual skills was noted, mentioning organisational health literacy that emphasises organisations' responsibility to provide comprehensible health information to all individuals. We propose that health promotion interventions can incorporate the proposed skills in practical exercises while aligning intervention materials and implementation tools with end-users and implementers.Discussion and conclusionThe suggested skills for maintaining and improving positive health are a first step towards a more comprehensive understanding and open to discussion. These skills may also be applied to other practical conversation tools for maintaining or improving health. Increasing positive health through the defined skills may be especially relevant to those with a lower socioeconomic position who also have limited health literacy and thereby may contribute to reducing health inequalities. Taken together, strengthening the defined skills may hopefully contribute to allowing people to flourish in life.

Detection dogs were trained to detect SARS-CoV-2 infection based on armpit sweat odor. Sweat samples were collected using cotton pads under the armpits of negative and positive human patients, confirmed by qPCR, for periods of 15–30 min. Multiple hospitals and organizations throughout Belgium participated in this study. The sweat samples were stored at −20°C prior to being used for training purposes. Six dogs were trained under controlled atmosphere conditions for 2–3 months. After training, a 7-day validation period was conducted to assess the dogs’ performances. The detection dogs exhibited an overall sensitivity of 81%, specificity of 98%, and an accuracy of 95%. After validation, training continued for 3 months, during which the dogs’ performances remained the same. Gas chromatography/mass spectrometry (GC/MS) analysis revealed a unique sweat scent associated with SARS-CoV-2 positive sweat samples. This scent consisted of a wide variety of volatiles, including breakdown compounds of antiviral fatty acids, skin proteins and neurotransmitters/hormones. An acceptability survey conducted in Belgium demonstrated an overall high acceptability and enthusiasm toward the use of detection dogs for SARS-CoV-2 detection. Compared to qPCR and previous canine studies, the detection dogs have good performances in detecting SARS-CoV-2 infection in humans, using frozen sweat samples from the armpits. As a result, they can be used as an accurate pre-screening tool in various field settings alongside the PCR test.

PurposeThis study aimed to determine the relationship between demographic diversity and veterinary professionals regarding their psychological distress and suicidal experiences. This study also aimed to determine what demographic factors were associated with psychological distress and suicidal experiences for veterinary professionals.MethodsThis study used a cross-sectional web-based questionnaire to assess the prevalence of diversity, psychological distress, and suicidality in individuals over 18 working in the veterinary field within the United States. The study received 2,482 responses resulting in 2,208 responses that were included in the analysis. Descriptive statistics were performed to identify the categories with the highest rates of psychological distress, suicidal thoughts, and suicidal behaviors. Binomial logistic regressions were conducted to identify the strongest statistical predictors of psychological distress (Kessler-6-K6), suicidal thinking and suicide behaviors.ResultsOf the 2,208 respondents included in the analysis, 888 (41%) were experiencing serious psychological distress and 381 (17.3%) had considered suicide in the past 12 months. Results of the binomial regressions indicate gender, social class, age, and disability status were the strongest predictors of psychological distress. When controlling for psychological distress, the strongest predictors of suicidal thinking were sexual orientation, marital status, and professional role.ImplicationsLimited research has been done to explore the relationship between demographic diversity of veterinary professionals and psychological distress, suicidal thoughts, and suicidal behaviors specifically. These results shed light on multiple demographic factors that promote and attenuate mental health, as well as the importance of asking respondents their demographic identities in veterinary medicine research. This research attempts to identify these mental health factors without collapsing categories with small sample sizes, which does cause a limitation in statistical power, yet also demonstrates how to increase inclusivity in research.

IntroductionGlobal HIV infections due to HIV-1 recombinants are increasing and impede prevention and treatment efforts. Key populations suffer most new HIV infections, but their role in the spread of HIV-1 recombinants is unknown. We conducted a global analysis of the associations between key populations and HIV-1 recombinants.MethodsWe searched PubMed, EMBASE, CINAHL, and Global Health for HIV-1 subtyping studies published from 1/1/1990 to 31/12/2015. Unpublished data was collected through a global survey. We included studies with HIV-1 subtyping data of key populations collected during 1990-2015. Key populations assessed were heterosexual people (HET), men who have sex with men (MSM), people who inject drugs (PWID), vertical transmissions (VERT), commercial sex workers (CSW), and transfusion-associated infections (BLOOD). Logistic regression was used to determine associations of key populations with HIV-1 recombinants. Subgroup analyses were performed for circulating recombinant forms (CRFs), unique recombinant forms (URFs), regions, and time periods.ResultsEight hundred and eighty five datasets including 77,284 participants from 83 countries were included. Globally, PWID were associated with the greatest odds of recombinants and CRFs (OR 2.6 [95% CI 2.46–2.74] and 2.99 [2.83–3.16]), compared to HET. CSW were associated with increased odds of recombinants and URFs (1.59 [1.44–1.75] and 3.61 [3.15–4.13]). VERT and BLOOD were associated with decreased odds of recombinants (0.58 [0.54–0.63] and 0.43 [0.33–0.56]). MSM were associated with increased odds of recombinants in 2010–2015 (1.43 [1.35–1.51]). Subgroup analyses supported our main findings.DiscussionAs PWID, CSW, and MSM are associated with HIV-1 recombinants, increased preventative measures and HIV-1 molecular surveillance are crucial within these key populations.Systematic review registrationPROSPERO [CRD42017067164].

Probiotics have demonstrated oral health benefits by influencing the microbiome and the host. Although promising, their current use is potentially constrained by several restrictions. One such limiting factor lies in the prevailing preparation of a probiotic product. To commercialize the probiotic, a shelf stable product is achieved by temporarily inactivating the live probiotic through drying or freeze drying. Even though a lyophilized probiotic can be kept dormant for an extended period of time, their viability can be severely compromised, making their designation as probiotics questionable. Additionally, does the application of an inactive probiotic directly into the oral cavity make sense? While the dormancy may allow for survival on its way towards the gut, does it affect their capacity for oral colonisation? To evaluate this, 21 probiotic product for oral health were analysed for the number of viable (probiotic), culturable (CFU) and dead (postbiotic) cells, to verify whether the commercial products indeed contain what they proclaim. After isolating and uniformly lyophilizing three common probiotic species in a simple yet effective lyoprotective medium, the adhesion to saliva covered hydroxyapatite discs of lyophilized probiotics was compared to fresh or reactivated lyophilized probiotics. Unfortunately, many of the examined products failed to contain the claimed amounts of viable cells, but also the strains used were inadequately characterized and lacked clinical evidence for that unknown strain, questioning their label of a ‘probiotic’. Additionally, lyophilized probiotics demonstrated low adhesive capacity compared to their counterparts, prompting the question of why fresh or reactivated probiotics are not currently used.

BackgroundDespite numerous attempts to improve interprofessional collaboration and integration (IPCI) in primary care, patients, care providers, researchers, and governments are still looking for tools and guidance to do this more efficiently. To address these issues, we decided to develop a generic toolkit, based on sociocracy and psychological safety principles, to guide care providers in their collaboration within and outside their practice. Finally, we reasoned that, in order to obtain integrated primary care, different strategies should be combined.MethodsDevelopment of the toolkit consisted of a multiyear co-development process. Data originating from 65 care providers, through 13 in-depth interviews and five focus groups were analysed and subsequently evaluated in eight co-design workshop sessions, organised with a total of 40 academics, lecturers, care providers and members of the Flemish patient association. Findings from the qualitative interviews and co-design workshops were gradually, and inductively adapted and transformed into the content for the IPCI toolkit.ResultsTen themes were identified: (i) awareness of the importance of interprofessional collaboration, (ii) the need for a self-assessment tool to measure team performance, (iii) preparing a team to use the toolkit, (iv) enhancing psychological safety, (v) developing and determining consultation techniques, (vi) shared decision making, (vii) developing workgroups to tackle specific (neighbourhood) problems, (viii) how to work patient-centred, (ix) how to integrate a new team member, and (x) getting ready to implement the IPCI toolkit. From these themes, we developed a generic toolkit, consisting of eight modules.ConclusionIn this paper, we describe the multiyear co-development process of a generic toolkit for the improvement of interprofessional collaboration. Inspired by a mix of interventions from in and outside healthcare, a modular open toolkit was produced that includes aspects of Sociocracy, concepts as psychological safety, a self-assessment tool and other modules concerned with meetings, decision-making, integrating new team members and population health. Upon implementation, evaluation and further development and improvement, this compounded intervention should have a beneficial effect on the complex problem of interprofessional collaboration in primary care.

Longitudinal analysis of multivariate individual-specific microbiome profiles over time or across conditions remains dauntin. Most statistical tools and methods that are available to study microbiomes are based on cross-sectional data. Over the past few years, several attempts have been made to model the dynamics of bacterial species over time or across conditions. However, the field needs novel views on handling microbial interactions in temporal analyses. This study proposes a novel data analysis framework, MNDA, that combines representation learning and individual-specific microbial co-occurrence networks to uncover taxon neighborhood dynamics. As a use case, we consider a cohort of newborns with microbiomes available at 6 and 9 months after birth, and extraneous data available on the mode of delivery and diet changes between the considered time points. Our results show that prediction models for these extraneous outcomes based on an MNDA measure of local neighborhood dynamics for each taxon outperform traditional prediction models solely based on individual-specific microbial abundances. Furthermore, our results show that unsupervised similarity analysis of newborns in the study, again using the notion of a taxon's dynamic neighborhood derived from time-matched individual-specific microbial networks, can reveal different subpopulations of individuals, compared to standard microbiome-based clustering, with potential relevance to clinical practice. This study highlights the complementarity of microbial interactions and abundances in downstream analyses and opens new avenues to personalized prediction or stratified medicine with temporal microbiome data.

Human brain organoid technology has the potential to generate unprecedented insight into normal and aberrant brain development. It opens up a developmental time window in which the effects of gene or environmental perturbations can be experimentally tested. However, detection sensitivity and correct interpretation of phenotypes are hampered by notable batch-to-batch variability and low reproducibility of cell and regional identities. Here, we describe a detailed, simplified protocol for the robust and reproducible generation of brain organoids with cortical identity from feeder-independent induced pluripotent stem cells (iPSCs). This self-patterning approach minimizes media supplements and handling steps, resulting in cortical brain organoids that can be maintained over prolonged periods and that contain radial glial and intermediate progenitors, deep and upper layer neurons, and astrocytes.

IntroductionTelepresence robots (TPRs) are the subject of an emerging field of application and research that has recently received attention from various disciplines. Most of the relevant research has been done in computer science, while the interest from psychology and education has been relatively modest. Proximity plays an important role in personal interactions. Although human spatial behavior has been widely studied in social psychology, little attention has been paid to the spatial behavior of humans and TPRs.MethodsThe purpose of this paper is to present the results of a pilot study that investigated a certain aspect of spatial behavior – physical proximity or interpersonal distance – based on four social zones of interpersonal distance that characterize Western culture: intimate, personal, social, and public. The study conducted an experiment involving participants both in person and via TPRs, using the Double 3 TPRs in various simulated situations.ResultsAccording to the findings, when interacting with a TPR, most participants maintained a communication distance of 60 to 160 cm, which is the borderline between personal and social distance, quite similar to normal human-to-human social communication. Status and previous relationship did not play any role in the choice of communication distance, but there were significant gender differences. On average, male participants chose a shorter distance to interact with TPRs compared to female participants. Persons with previous computer gaming experience chose a significantly shorter communication distance compared to persons with no such experience. A little more than half of the participants found the method of communication through TPRs to be pleasant.DiscussionTPR mediated persons might be perceived as “real” when communicating with physically present persons, with similar norms applied as in human-to-human social interactions. Especially in the context of classroom communication, people keep communication distances comparable to far personal or close social distances. These findings suggest that implementation of TPRs in education does not put additional requirements for physical space in classroom.

IntroductionThe impact of multi-domain preventive interventions on older adults, in particular on those with higher risk to develop Alzheimer's disease (AD), could be beneficial, as it may delay cognitive decline. However, the precise mechanism of such positive impact is not fully understood and may involve brain reserve and adaptability of brain functional connectivity (FC).MethodsTo determine the effect of multidomain interventions (involving physical activity, cognitive training, nutritional counseling alone or in combination with omega-3 fatty acid supplementation and vs. a placebo) on the brain, longitudinal FC changes were assessed after 36 months of intervention on 100 older adults (above 70 year-old) with subjective cognitive complaints.ResultsNo global change in FC was detected after uni or multidomain preventive interventions. However, an effect of omega-3 fatty acid supplementation dependent on cognitive decline status was underlined for frontoparietal, salience, visual and sensorimotor networks FC. These findings were independent of the cortical thickness and vascular burden.DiscussionThese results emphasize the importance of patient stratification, based on risk factors, for preventive interventions.

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the loss of upper and lower motor neurons, leading to progressive weakness of voluntary muscles, with death following from neuromuscular respiratory failure, typically within 3 to 5 years. There is a strong genetic contribution to ALS risk. In 10% or more, a family history of ALS or frontotemporal dementia is obtained, and the Mendelian genes responsible for ALS in such families have now been identified in about 50% of cases. Only about 14% of apparently sporadic ALS is explained by known genetic variation, suggesting that other forms of genetic variation are important. Telomeres maintain DNA integrity during cellular replication, differ between sexes, and shorten naturally with age. Sex and age are risk factors for ALS and we therefore investigated telomere length in ALS.MethodsSamples were from Project MinE, an international ALS whole genome sequencing consortium that includes phenotype data. For validation we used donated brain samples from motor cortex from people with ALS and controls. Ancestry and relatedness were evaluated by principal components analysis and relationship matrices of DNA microarray data. Whole genome sequence data were from Illumina HiSeq platforms and aligned using the Isaac pipeline. TelSeq was used to quantify telomere length using whole genome sequence data. We tested the association of telomere length with ALS and ALS survival using Cox regression.ResultsThere were 6,580 whole genome sequences, reducing to 6,195 samples (4,315 from people with ALS and 1,880 controls) after quality control, and 159 brain samples (106 ALS, 53 controls). Accounting for age and sex, there was a 20% (95% CI 14%, 25%) increase of telomere length in people with ALS compared to controls (p = 1.1 × 10−12), validated in the brain samples (p = 0.03). Those with shorter telomeres had a 10% increase in median survival (p = 5.0×10−7). Although there was no difference in telomere length between sporadic ALS and familial ALS (p=0.64), telomere length in 334 people with ALS due to expanded C9orf72 repeats was shorter than in those without expanded C9orf72 repeats (p = 5.0×10−4).DiscussionAlthough telomeres shorten with age, longer telomeres are a risk factor for ALS and worsen prognosis. Longer telomeres are associated with ALS.

Background and objectiveBlood-based biomarkers represent a promising approach to help identify early Alzheimer’s disease (AD). Previous research has applied traditional machine learning (ML) to analyze plasma omics data and search for potential biomarkers, but the most modern ML methods based on deep learning has however been scarcely explored. In the current study, we aim to harness the power of state-of-the-art deep learning neural networks (NNs) to identify plasma proteins that predict amyloid, tau, and neurodegeneration (AT[N]) pathologies in AD.MethodsWe measured 3,635 proteins using SOMAscan in 881 participants from the European Medical Information Framework for AD Multimodal Biomarker Discovery study (EMIF-AD MBD). Participants underwent measurements of brain amyloid β (Aβ) burden, phosphorylated tau (p-tau) burden, and total tau (t-tau) burden to determine their AT(N) statuses. We ranked proteins by their association with Aβ, p-tau, t-tau, and AT(N), and fed the top 100 proteins along with age and apolipoprotein E (APOE) status into NN classifiers as input features to predict these four outcomes relevant to AD. We compared NN performance of using proteins, age, and APOE genotype with performance of using age and APOE status alone to identify protein panels that optimally improved the prediction over these main risk factors. Proteins that improved the prediction for each outcome were aggregated and nominated for pathway enrichment and protein–protein interaction enrichment analysis.ResultsAge and APOE alone predicted Aβ, p-tau, t-tau, and AT(N) burden with area under the curve (AUC) scores of 0.748, 0.662, 0.710, and 0.795. The addition of proteins significantly improved AUCs to 0.782, 0.674, 0.734, and 0.831, respectively. The identified proteins were enriched in five clusters of AD-associated pathways including human immunodeficiency virus 1 infection, p53 signaling pathway, and phosphoinositide-3-kinase–protein kinase B/Akt signaling pathway.ConclusionCombined with age and APOE genotype, the proteins identified have the potential to serve as blood-based biomarkers for AD and await validation in future studies. While the NNs did not achieve better scores than the support vector machine model used in our previous study, their performances were likely limited by small sample size.

An important fraction of the currently stored volume of long-lived intermediate-level radioactive waste in Belgium contains large amounts of NaNO3 homogeneously dispersed in a hard bituminous matrix. Geological disposal of this waste form in a water-saturated sedimentary formation such as Boom Clay will result in the leaching of high concentrations of NaNO3, which could cause a geochemical perturbation of the surrounding clay, possibly affecting some of the favorable characteristics of the host formation. In addition, hyper-alkaline conditions are expected for thousands of years, imposed by the cementitious materials used as backfill material. Microbial nitrate reduction is a well-known process and can result in the accumulation of nitrite or nitrogenous gases. This could lead to the oxidation of redox-active Boom Clay components, which could (locally) decrease the reducing capacity of the clay formation. Here, we compared nitrate reduction processes between two microbial communities at different pH related to a geological repository environment and in the presence of a nitrate-containing waste simulate during 1 year in batch experiments. We showed that the microbial community from in Boom Clay borehole water was able to carry out nitrate reduction in the presence of acetate at pH 10.5, although the maximum rate of 1.3 ± 0.2 mM NO3−/day was much lower compared to that observed at pH 9 (2.9 mM NO3−/day). However, microbial activity at pH 10.5 was likely limited by a phosphate shortage. This study further confirmed that the Harpur Hill sediment harbors a microbial community adapted to high pH conditions. It reduced twice as much nitrate at pH 10.5 compared to pH 9 and the maximum nitrate reduction rate was higher at pH 10.5 compared to that at pH 9, i.e., 3.4 ± 0.8 mM NO3−/day versus 2.2 ± 0.4 mM NO3−/day. Both communities were able to form biofilms on non-radioactive Eurobitum. However, for both microbial communities, pH 12.5 seems to be a limiting condition for microbial activity as no nitrate reduction nor biofilm was observed. Nevertheless, pH alone is not sufficient to eliminate microbial presence, but it can induce a significant shift in the microbial community composition and reduce its nitrate reducing activity. Furthermore, at the interface between the cementitious disposal gallery and the clay host rock, the pH will not be sufficiently high to inhibit microbial nitrate reduction.

Within the framework of the current COVID-19 pandemic, there is a race against time to find therapies for the outbreak to be controlled. Since vaccines are still tedious to develop and partially available for low-income countries, passive immunity based on egg-yolk antibodies (IgY) is presented as a suitable approach to preclude potential death of infected patients, based on its high specificity/avidity/production yield, cost-effective manufacture, and ease of administration. In the present study, IgY antibodies against a recombinant RBD protein of SARS-CoV-2 were produced in specific-pathogen-free chickens and purified from eggs using a biocompatible method. In vitro immunoreactivity was tested, finding high recognition and neutralization values. Safety was also demonstrated prior to efficacy evaluation, in which body weight, kinematics, and histopathological assessments of hamsters challenged with SARS-CoV-2 were performed, showing a protective effect administering IgY intranasally both as a prophylactic treatment or a post-infection treatment. The results of this study showed that intranasally delivered IgY has the potential to both aid in prevention and in overcoming COVID-19 infection, which should be very useful to control the advance of the current pandemic and the associated mortality.

At the beginning of the pandemic, many music ensembles had to stop their activities due to the confinement. While some found creative ways to start making music again with the help of technologies, the transition from “real” rehearsals to “online” rehearsals was challenging, especially among older amateur musicians. The aim of this case study was to examine the effects of this transition on three community band conductors and three older amateur musicians. Specific objectives were to explore (1) intergenerational relationships to support online group music-making; (2) digital literacy and access in later life; and (3) online music-making in a COVID-19 context. Semi-structured interviews were conducted and theoretical thematic analysis was undertaken (Braun and Clarke, 2006). Results were analyzed from the conductors’ and older musicians’ perspectives, and common trends were combined to facilitate interpretation. The first theme showed that being part of an intergenerational ensemble contributed positively to the learning experience online. The second theme demonstrated that because both conductors and musicians were new to the online rehearsals, it contributed to attenuate the age-related digital divide that may have been observed in other studies. Regarding access in later-life, older musicians reported benefits associated with rehearsing online, specifically in terms of distance/commute, time, energy, and cost. However, for those who did not already have internet and electronic devices, the cost of acquiring all the necessary equipment to make music online could have been too high. Finally, the third theme revealed that musicians appreciated the opportunity to make music online and indicated that it was definitely better than having nothing, especially for its social aspects. In conclusion, while participants noted several challenges associated with online music-making (e.g., zoom fatigue and technological issues), they were also appreciative of the opportunity to continue making music at a time when in-person rehearsals were not possible. Pedagogical implications are discussed, specifically the importance of the support network, of meeting people where they are, of learning to adapt, and of collaborative teaching.

We present and analyze large-scale simulation results of a hybrid quantum-classical variational method to calculate the ground state energy of the anti-ferromagnetic Heisenberg model. Using a massively parallel universal quantum computer simulator, we observe that a low-depth-circuit ansatz advantageously exploits the efficiently preparable Néel initial state, avoids potential barren plateaus, and works for both one- and two-dimensional lattices. The analysis reflects the decisive ingredients required for a simulation by comparing different ansätze, initial parameters, and gradient-based versus gradient-free optimizers. Extrapolation to the thermodynamic limit accurately yields the analytical value for the ground state energy, given by the Bethe ansatz. We predict that a fully functional quantum computer with 100 qubits can calculate the ground state energy with a relatively small error.

Introduction: Quantitative information on disposition of maternal medicines in human milk remains a major knowledge gap. This case report presents the clinical and pharmacokinetic data of a single mother-infant pair exposed to bosentan and sildenafil for the treatment of pulmonary arterial hypertension (PAH) during lactation.Case presentation: A 43-year old mother was treated with sildenafil (20 mg, 3x/day) and bosentan (125 mg, 2x/day) for PAH. Her 21-months old infant received breastfeeding in combination with adequate complementary foods. Milk samples were collected over 24 h, at day 637 and 651 after delivery. The observed average steady-state concentrations of sildenafil (2.84 μg/L) and bosentan (49.0 μg/L) in human milk were low. The Daily Infant Dosage ingested by the nursing infant through human milk was 0.02 μg/kg/day for sildenafil and 0.29 μg/kg/day for bosentan at day 637, and 0.03 μg/kg/day and 0.60 μg/kg/day at day 651. The Relative Infant Dose calculated for an exclusively breastfed infant with an estimated milk intake of 150 ml/kg/day, was 0.06% for sildenafil and 0.24% for bosentan. General health outcome of the infant, reported by the mother, was uneventful until the sampling days.Conclusion: Low medicine concentrations were found in human milk expressed 21 months after delivery after maternal intake of 20 mg sildenafil three times daily and 125 mg bosentan twice daily. General health of the nursing infant until sampling was reported as optimal by the mother.

Transcription pause-release is an important, highly regulated step in the control of gene expression. Modulated by various factors, it enables signal integration and fine-tuning of transcriptional responses. Mutations in regulators of pause-release have been identified in a range of neurodevelopmental disorders that have several common features affecting multiple organ systems. This review summarizes current knowledge on this novel subclass of disorders, including an overview of clinical features, mechanistic details, and insight into the relevant neurodevelopmental processes.

Alternariol (AOH), alternariol monomethyl-ether (AME), and tenuazonic acid (TeA) are major mycotoxins produced by fungi of the genus Alternaria and are common contaminants of food products such as fruits, vegetables, cereals and grains. Alternaria mycotoxins are known to cause relevant economic losses and to have a negative impact on human and animal health. EFSA stated in its scientific opinion that data on the toxicity of Alternaria mycotoxins in humans and livestock are generally lacking, precluding proper hazard characterization. This study aimed to fill some knowledge gaps by studying the in vitro cytotoxicity toward human intestinal epithelial cells (Caco-2) and hepatocytes (HepG2). Cytotoxic properties were assessed by flow cytometric analyses of remaining viable cells (i.e., propidium iodide negative) after mycotoxin exposure for 24–48 h versus solvent control. Treatment of cells with single doses of AOH, AME, and TeA resulted in a dose-dependent loss of cell viability for both cell lines. Half maximal effective concentrations (EC50) of the different mycotoxins were comparable for the two cell lines. On HepG2 cells, EC50 values varying between 8 and 16, 4 and 5, and 40 and 95 μg/mL were calculated for AOH, AME, and TeA, respectively. On Caco-2 cells, EC50 values of 19 μg/mL and varying between 6 and 23, and 60 and 90 μg/mL were calculated for AOH, AME, and TeA, respectively. A general relative cytotoxicity ranking of about 1 = 1 >>> 3 was obtained for AOH, AME, and TeA, respectively. Treatment of both cell lines with combined binary and ternary mixtures of AOH, AME, and TeA in a 1:1:3 ratio, also showed a dose-dependent decrease in cell viability. For both cell lines, the binary combination of especially AME and TeA (1:3 ratio) but also of AOH and AME (1:1 ratio) significantly increased the cytotoxicity compared to the single compound toxicity, although mainly at the highest concentrations tested. The ternary combinations of AOH, AME, and TeA induced only a slight increase in cytotoxicity compared to the single mycotoxins, again at the highest concentrations tested.

Environmental uranium pollution due to industries producing naturally occurring radioactive material or nuclear accidents and releases is a global concern. Uranium is hazardous for ecosystems as well as for humans when accumulated through the food chain, through contaminated groundwater and potable water sources, or through inhalation. In particular, uranium pollution pressures microbial communities, which are essential for healthy ecosystems. In turn, microorganisms can influence the mobility and toxicity of uranium through processes like biosorption, bioreduction, biomineralization, and bioaccumulation. These processes were characterized by studying the interaction of different bacteria with uranium. However, most studies unraveling the underlying molecular mechanisms originate from the last decade. Molecular mechanisms help to understand how bacteria interact with radionuclides in the environment. Furthermore, knowledge on these underlying mechanisms could be exploited to improve bioremediation technologies. Here, we review the current knowledge on bacterial uranium resistance and how this could be used for bioremediation applications.

ObjectiveThe resistance created by the PEEP-valve of a T-piece resuscitator is bias gas flow dependent and might affect breathing in preterm infants. In this study we investigated the effect of a higher bias gas flow on the imposed inspiratory and expiratory T-piece resistance and expiratory breaking manoeuvres (EBM) in preterm infants during spontaneous breathing on CPAP at birth.MethodsIn a retrospective pre-post implementation study of preterm infants

Alzheimer’s disease (AD) is the most frequent neurodegenerative disease with an increasing prevalence in industrialized, aging populations. AD susceptibility has an established genetic basis which has been the focus of a large number of genome-wide association studies (GWAS) published over the last decade. Most of these GWAS used dichotomized clinical diagnostic status, i.e., case vs. control classification, as outcome phenotypes, without the use of biomarkers. An alternative and potentially more powerful study design is afforded by using quantitative AD-related phenotypes as GWAS outcome traits, an analysis paradigm that we followed in this work. Specifically, we utilized genotype and phenotype data from n = 931 individuals collected under the auspices of the European Medical Information Framework for Alzheimer’s Disease Multimodal Biomarker Discovery (EMIF-AD MBD) study to perform a total of 19 separate GWAS analyses. As outcomes we used five magnetic resonance imaging (MRI) traits and seven cognitive performance traits. For the latter, longitudinal data from at least two timepoints were available in addition to cross-sectional assessments at baseline. Our GWAS analyses revealed several genome-wide significant associations for the neuropsychological performance measures, in particular those assayed longitudinally. Among the most noteworthy signals were associations in or near EHBP1 (EH domain binding protein 1; on chromosome 2p15) and CEP112 (centrosomal protein 112; 17q24.1) with delayed recall as well as SMOC2 (SPARC related modular calcium binding 2; 6p27) with immediate recall in a memory performance test. On the X chromosome, which is often excluded in other GWAS, we identified a genome-wide significant signal near IL1RAPL1 (interleukin 1 receptor accessory protein like 1; Xp21.3). While polygenic score (PGS) analyses showed the expected strong associations with SNPs highlighted in relevant previous GWAS on hippocampal volume and cognitive function, they did not show noteworthy associations with recent AD risk GWAS findings. In summary, our study highlights the power of using quantitative endophenotypes as outcome traits in AD-related GWAS analyses and nominates several new loci not previously implicated in cognitive decline.

Exposure to metals is ubiquitous and emission sources include gasoline, diesel, smoke from wildfires, contaminated soil, water and food, medical implants, waste recycling facilities, subway exposures, and occupational environments. PM2.5 exposure is associated with impaired cognitive performance, neurobehavioral alterations, incidence of dementia, and Alzheimer's disease (AD) risk. Heavy-duty diesel vehicles are major emitters of metal-rich PM2.5 and nanoparticles in Metropolitan Mexico City (MMC). Cognitive impairment was investigated in 336 clinically healthy, middle-class, Mexican volunteers, age 29.2 ± 13.3 years with 13.7 ± 2.4 years of education using the Montreal Cognitive Assessment (MoCA). MoCA scores varied with age and residency in three Mexican cities with cognition deficits impacting ~74% of the young middle-class population (MoCA ≤ 25). MMC residents ≥31 years (x¯46.2 ± 11.8 y) had MoCA x¯20.4 ± 3.4 vs. low pollution controls 25.2 ± 2.4 (p < 0.0001). Formal education years positively impacted MoCA total scores across all participants (p < 0.0001). Residency in PM2.5 polluted cities impacts multi-domain cognitive performance. Identifying and making every effort to lower key pollutants impacting neural risk trajectories and monitoring cognitive longitudinal performance are urgent. PM2.5 emission control should be prioritized, metal emissions targeted, and neuroprevention interventions implemented early.

Background: Preterm infants are commonly supported with 5–8 cmH2O CPAP. However, animal studies demonstrate that high initial CPAP levels (12–15 cmH2O) which are then reduced (termed physiological based (PB)-CPAP), improve lung aeration without adversely affecting cardiovascular function. We investigated the feasibility of PB-CPAP and the effect in preterm infants at birth.Methods: Preterm infants (24–30 weeks gestation) were randomized to PB-CPAP or 5–8 cmH2O CPAP for the first 10 min after birth. PB-CPAP consisted of 15 cmH2O CPAP that was decreased when infants were stabilized (heart rate ≥100 bpm, SpO2 ≥85%, FiO2 ≤ 0.4, spontaneous breathing) to 8 cmH2O with steps of ~2/3 cmH2O/min. Primary outcomes were feasibility and SpO2 in the first 5 min after birth. Secondary outcomes included physiological and breathing parameters and short-term neonatal outcomes. Planned enrollment was 42 infants.Results: The trial was stopped after enrolling 31 infants due to a low inclusion rate and recent changes in the local resuscitation guideline that conflict with the study protocol. Measurements were available for analysis in 28 infants (PB-CPAP n = 8, 5–8 cmH2O n = 20). Protocol deviations in the PB-CPAP group included one infant receiving 3 inflations with 15 cmH2O PEEP and two infants in which CPAP levels were decreased faster than described in the study protocol. In the 5–8 cmH2O CPAP group, three infants received 4, 10, and 12 cmH2O CPAP. During evaluations, caregivers indicated that the current PB-CPAP protocol was difficult to execute. The SpO2 in the first 5 min after birth was not different [61 (49–70) vs. 64 (47–74), p = 0.973]. However, infants receiving PB-CPAP achieved higher heart rates [121 (111–130) vs. 97 (82–119) bpm, p = 0.016] and duration of mask ventilation was shorter [0:42 (0:34–2:22) vs. 2:58 (1:36–6:03) min, p = 0.020]. Infants in the PB-CPAP group required 6:36 (5:49-11:03) min to stabilize, compared to 9:57 (6:58–15:06) min in the 5–8 cmH2O CPAP group (p = 0.256). There were no differences in short-term outcomes.Conclusion: Stabilization of preterm infants with PB-CPAP is feasible but tailoring CPAP appeared challenging. PB-CPAP did not lead to higher SpO2 but increased heart rate and shortened the duration of mask ventilation, which may reflect faster lung aeration.

Nutrition plays an important role in the development and progress of several health conditions, but the exact mechanism is often still unclear. Blood metabolites are likely candidates to be mediating these relationships, as their levels are strongly dependent on the frequency of consumption of several foods/drinks. Understanding the causal effect of food on metabolites is thus of extreme importance. To establish these effects, we utilized two-sample Mendelian randomization using the genetic variants associated with dietary traits as instrumental variables. The estimates of single-nucleotide polymorphisms’ effects on exposures were obtained from a recent genome-wide association study (GWAS) of 25 individual and 15 principal-component dietary traits, whereas the ones for outcomes were obtained from a GWAS of 123 blood metabolites measured by nuclear magnetic resonance spectroscopy. We identified 413 potentially causal links between food and metabolites, replicating previous findings, such as the association between increased oily fish consumption and higher DHA, and highlighting several novel associations. Most of the associations were related to very-low-density, intermediate-density (IDL), and low-density lipoproteins (LDL). For example, we found that constituents of IDL particles and large LDL particles were raised by coffee and alcohol while lowered by an overall healthier diet and fruit consumption. Our findings provide a strong base of evidence for planning future RCTs aimed at understanding the role of diet in determining blood metabolite levels.

Cereal grains and products provide calories globally. The health benefits of cereals attributed to their diverse phenolic constituents have not been systematically explored. Post-harvest processing, such as drying, storing, and milling cereals, can alter the phenolic concentration and influence the antioxidant activity. Furthermore, cooking has been shown to degrade thermo-labile compounds. This review covers several methods for retaining and enhancing the phenolic content of cereals to develop functional foods. These include using bioprocesses such as germination, enzymatic, and fermentation treatments designed to enhance the phenolics in cereals. In addition, physical processes like extrusion, nixtamalization, and parboiling are discussed to improve the bioavailability of phenolics. Recent technologies utilizing ultrasound, micro- or nano-capsule polymers, and infrared utilizing processes are also evaluated for their effectiveness in improving the phenolics content and bio-accessibility. We also present contemporary products made from pigmented cereals that contain phenolics.

Given that bovine herpesvirus 1 (BoHV-1) -the causative agent of Infectious Bovine Rhinotracheitis (IBR)- is still endemic in most European countries, BoHV-1 free herds are subject to a considerable risk of (re)introduction of the virus. The aim of this literature review was to describe published, quantified risk factors that are relevant for the introduction of BoHV-1. The risk factors described in this study can be used as input for modeling eradication scenarios and for communication on biosecurity measures to stakeholders. A literature search was conducted in November 2020 in two major online search databases, PubMed and Web of Science. The search criteria “risk factor” combined with different synonyms for BoHV-1 were explored, which resulted in 564 hits. Only studies performed in Europe, written in Dutch, English, French, German or Spanish with an English summary and that quantified risk factors for introduction of BoHV-1 into cattle herds were included. Studies had to quantify the risk factors with crude odds ratios (OR), an estimate of the chance of a particular event occurring in an exposed group to a non-exposed group. After checking for duplicates and excluding articles that did not meet the inclusion criteria, 12 publications remained for this review. Risk factors were classified into seven groups, i.e., herd characteristics, management, animal characteristics, purchase, direct animal contact, neighborhood and indirect transmission routes. Most relevant factors for introduction of BoHV-1 into cattle herds include herd size, purchase of cattle, cattle density, age of cattle, distance to neighboring cattle herds and professional visitors. Together with other direct and indirect animal contacts, these factors are important when elimination of BoHV-1 is considered. A closed farming system and protective clothing for professional visitors can eliminate the major routes of introduction of BoHV-1 in cattle herds. To the best of our knowledge, this is the first systematic review solely focussing on measures that can be taken to control introduction of BoHV-1 into cattle herds. Besides testing, focus on managing these (biosecurity) factors will decrease the risk of introducing the virus.

Little is known about placental drug transfer and fetal pharmacokinetics despite increasing drug use in pregnant women. While physiologically based pharmacokinetic (PBPK) models can help in some cases to shed light on this knowledge gap, adequate parameterization of placental drug transfer remains challenging. A novel in silico model with seven compartments representing the ex vivo cotyledon perfusion assay was developed and used to describe placental transfer and fetal pharmacokinetics of acetaminophen. Unknown parameters were optimized using observed data. Thereafter, values of relevant model parameters were copied to a maternal-fetal PBPK model and acetaminophen pharmacokinetics were predicted at delivery after oral administration of 1,000 mg. Predictions in the umbilical vein were evaluated with data from two clinical studies. Simulations from the in silico cotyledon perfusion model indicated that acetaminophen accumulates in the trophoblasts; simulated steady state concentrations in the trophoblasts were 4.31-fold higher than those in the perfusate. The whole-body PBPK model predicted umbilical vein concentrations with a mean prediction error of 24.7%. Of the 62 concentration values reported in the clinical studies, 50 values (81%) were predicted within a 2-fold error range. In conclusion, this study presents a novel in silico cotyledon perfusion model that is structurally congruent with the placenta implemented in our maternal-fetal PBPK model. This allows transferring parameters from the former model into our PBPK model for mechanistically exploring whole-body pharmacokinetics and concentration-effect relationships in the placental tissue. Further studies should investigate acetaminophen accumulation and metabolism in the placenta as the former might potentially affect placental prostaglandin synthesis and subsequent fetal exposure.