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Abstract Background A minority of European countries have participated in international comparisons with high level data on lung cancer. However, the nature and extent of data collection across the continent is simply unknown, and without accurate data collection it is not possible to compare practice and set benchmarks to which lung cancer services can aspire. Methods Using an established network of lung cancer specialists in 37 European countries, a survey was distributed in December 2014. The results relate to current practice in each country at the time, early 2015. The results were compiled and then verified with co-authors over the following months. Results Thirty-five completed surveys were received which describe a range of current practice for lung cancer data collection. Thirty countries have data collection at the national level, but this is not so in Albania, Bosnia-Herzegovina, Italy, Spain and Switzerland. Data collection varied from paper records with no survival analysis, to well-established electronic databases with links to census data and survival analyses. Conclusion Using a network of committed clinicians, we have gathered validated comparative data reporting an observed difference in data collection mechanisms across Europe. We have identified the need to develop a well-designed dataset, whilst acknowledging what is feasible within each country, and aspiring to collect high quality data for clinical research.

The development of consumerism led to an increase in toy production. Such consumer products may contain non-intentionally added toxic substances that can emit from the product and may be inhaled by the consumer. Little data is available on the inhalation exposure of humans to volatile organic compounds (VOCs) from consumer products, so a reliable exposure assessment is needed. Only the emission chamber technique developed for building material emissions can provide solid estimations as it allows the products to be studied under real room conditions. This paper proposes a strategy to interpret emission experiment results from consumer products and assess the corresponding potential risk. It focuses on 14 common VOCs. The identification of the polymer type of 41 plastic articles was first performed by pyrolysis coupled online to gas chromatography with mass spectrometric detection (pyr-GC/MS). Their VOC profile was also determined by Dynamic Headspace-GC/MS (DHS-GC/MS). Softer polymers caused higher and broader emission profiles. Four specific toy samples were selected to be studied in a 203 l emission chamber and their emissions were compared to a reference material. A rapid decrease in the emissions was observed for each product and VOC. Based on these emission curves over time, the corresponding indoor air concentration could be calculated for the target VOCs for short-term or long-term exposures. The indoor air levels obtained were at least 35 times lower than the levels according to conventional indoor air guidelines. Guideline values were only exceeded using very conservative exposure scenarios.

The design and the silicon characterization of two mostly digital, low-voltage, energy- and area-efficient Relaxation Digital-to-Analog Converters (ReDACs) in 180nm featuring digital self-calibration and parasitics-induced error suppression are presented and compared in this paper. The first design is a single-ended ReDAC (SE-ReDAC) and operates at 880kS/s with a 10-bit resolution, while the second is based on a differential ReDAC (Diff-ReDAC) architecture and operates at 100kS/s with a 13-bit resolution. The SE-ReDAC testchip in 180nm occupies just 5,030 $\mu $ m2 and operates with a supply voltage ranging from 0.6V to 1V. Experimental results at 0.65V reveal a 72.18dB-SFDR, a 65.59dB-THD and a 56.09dB SINAD, resulting in 9.02ENOB, with a power dissipation of just $3.3\mu $ W, achieving a competitive energy-efficiency (area-normalized energy efficiency) figure of merit FOM ( $\mathrm {FOM_{A}}$ ) of 166dB (175dB). On the other hand, the 180-nm Diff-ReDAC testchip occupies 7,800 $\mu $ m2 and operates in a supply voltage range from 0.45V to 1V, while achieving a 77.81dB-SFDR, a 77.52dB-THD and a 65.82dB-SINAD (10.64ENOB) at 0.6V supply with a power consumption of just 880nW, leading to a very competitive FOM (FOMA) of 172dB (178dB).

The study advocates for a qualitative research design to address knowledge gaps regarding Collective Energy Initiatives (CEIs), utilising evidence-based research and a maximum variation principle. Focused on EU countries, the study employs desk research and surveys to identify stages of CEI development and explore impactful practices. It examines initiatives aligned with EU Directives and broader energy transition efforts, categorising them by complexity. Through surveys, the study identifies drivers and barriers to coalition phenomena, aiming to enhance understanding of energy policies’ impact. This approach responds to the need for comprehensive investigations into energy initiatives’ impediments and facilitators, aligning with recent calls for research in this area.

Objective One key target of treating patients with systemic lupus erythematosus (SLE) is to prevent organ damage. This analysis quantified the association between time spent in four specific SLE low disease activity (LDA) states and organ damage rate.Methods This retrospective real-world data analysis (GSK Study 207168), undertaken to help contextualise the BLISS-BELIEVE clinical trial, included adults with SLE enrolled for≥1 year in the Hopkins Lupus Cohort and treated with standard therapy in a specialist care centre between 1987 and 2019. LDA states (Lupus Low Disease Activity State (LLDAS), disease control, clinical and complete remissions) were defined using SLE Disease Activity Index (SLEDAI)/Physician Global Assessment scores, prednisone-equivalent dose and medication use criteria combinations. Time spent in each LDA state was expressed as a percentage of total follow-up (0%; >0–0–

Aims To establish the usability and tolerability, as well as accuracy of measurements of a handheld KardiaMobile ECG device in an inpatient older adult dementia ward. Methods Between February 2023 and April 2023, KardiaMobile ECGs and 12-lead ECGs were taken for patients admitted within a dementia ward in Liverpool. The standard 12-lead ECGs were analysed as per current practice, by Broomwell Health Watch. The KardiaMobile ECGs were read manually, by two independent raters, for heart rate and QTc. The user-rated tolerability was measured out of 5, 5 being the most tolerable, and was measured for both KardiaMobile and 12-lead ECGs, allowing comparison. The QTc and heart rate were calculated for both methods, and then compared. QTc was calculated using Bazett's formula. Results 13 inpatients had a 12-lead ECG, and a KardiaMobile ECG performed. Both were tolerated by all patients, except one who tolerated neither, leaving 12 ECGs for comparison. KardiaMobile ECGs were quicker to obtain, more well tolerated, and easy to use. However, manual calculation of QTc, versus expert and computer analysis for 12-lead ECGs, led to some variability between QTc measurements. Inter-rater reliability between raters for the KardiaMobile QTc was poor, however, when both were combined, correlation with 12-lead ECG QTc was moderate. KardiaMobile ECGs were harder to obtain in those with tremors, and the lack of computerised readings made interpretation more difficult. 12-lead ECGs also offer reassurance in the form of a fully interpreted, more detailed ECG. Conclusion KardiaMobile devices are faster to use and as/more tolerable in a dementia ward setting than 12-lead ECGs. The ECG trace is fed back instantly to the mobile device, however, automatic interpretation is limited and QTc calculation relies on the operator. Visual inspection of QTc can be difficult, and unreliable. However, the combination of two different raters led to more reliable results. The device has potential for use in this setting, however, an increase in automatic interpretation, or interpretation by a third party such as with Broomwell Health Watch, would increase its usability.

Multivariate time series (MTS) are captured in a great variety of real-world applications. However, analysing and modeling the data for classification and forecasting purposes can become very challenging if values are missing in the data set. The need for imputation methods, to fill the gaps in MTS, is well known. Thus, a great variaty of algorithms for solving this task has been proposed in the literature. However, the research community is constantly working on the development of advanced algorithms, that fulfill the special requirements of multidimensional temporal data, since most of the existing imputation methods treat MTS as ordinary structured data and fail to model the temporal relationships within and between sequences of observations. The main emphasis of MTS imputation research is currently put on deep learning (DL) models, especially those making use of generative adversarial networks (GANs). In our survey, we present our categorization of imputation algorithms, especially of GAN-models. We included eighteen different GAN-models designed for the MTS imputation task, which we introduce in detail. We provide a comparison of the models including their performance regarding MTS imputation, based on our findings in the literature. The following points can be considered the most important findings from our survey: The research on GAN-based imputation models for MTS has gained momentum in the last years across different domains, therewhile showing the effectiveness of these methods. The latest trend in the research area is the incorporation of attention mechanisms into the algorithms. Nevertheless, there are open research challenges, e.g. the transferability of models across data sets from different domains.

Abstract Plants, animals and humans metabolically produce volatile isoprene (C5H8). Humans continuously exhale isoprene and exhaled concentrations differ under various physio-metabolic and pathophysiological conditions. Yet unknown metabolic origin hinders isoprene to reach clinical practice as a biomarker. Screening 2000 individuals from consecutive mass-spectrometric studies, we herein identify five healthy German adults without exhaled isoprene. Whole exome sequencing in these adults reveals only one shared homozygous (European prevalence:

This study thoroughly compares multiple single bidirectional and multiport converters (MPCs), highlighting the significant role of MPCs in multi-input and multi-output (MIMO) systems. MPCs offer a more efficient and cost-effective solution than multiple single converters, especially in applications involving photovoltaic (PV), electric vehicles (EVs) with storage systems, and power grids. This research emphasizes the importance of multi-input converters (MICs) in integrating diverse voltage sources. It notes the rising popularity of multi-output DC-DC converters in portable electronics, owing to their reduced component count, lower costs, and compact design. This paper emphasizes comparisons based on diverse aspects and applications, shedding light on recent developments in basic bidirectional converters. Additionally, it delves into the advancements in MPC topologies, focusing on efficiency, reliability, and modularity improvements. These advancements are crucial for harnessing cost reduction, simplicity, and compactness. Furthermore, this paper introduces an innovative multiport DC-DC converter tailored for integrating and managing renewable sources. This new converter design enhances PV system and battery storage performance by reducing power conversion steps, using fewer components, and improving voltage-boosting capabilities. Its unique bidirectional buck-boost structure allows for versatile connections between sources and loads with varying voltage and power requirements. The performance of this novel converter is evaluated through MATLAB/Simulink simulations under different scenarios. Experimental studies further validate its effectiveness, marking a significant contribution to power conversion and management in integrating renewable sources such as DC microgrids.

En los últimos años, la figura del arrepentido ha recibido un mayor interés, que también se refleja en su inclusión –de manera explícita o implícita– en diferentes ordenamientos jurídicos. Junto con ello aumentaron las discusiones alrededor de esta nueva herramienta de investigación de delitos y una de las preguntas más recurrentes versa sobre si y cómo se puede justificar la implementación de la delación premiada en nuestros ordenamientos jurídicos. En especial, me interesan dos cosas. Por un lado, intentaré ordenar y agrupar o sistematizar las diferentes posturas de aceptación o rechazo de la figura y por el otro lado buscaré formas para evaluar la aceptabilidad de sus argumentos. Espero que estas observaciones tentativas tengan utilidad para un problema recurrente en el análisis de los procedimientos y la prueba: el riesgo de aceptar o no ciertos errores y su vinculación con los estándares de prueba.

Abstract Dysregulation of the intrinsic BCL-2 pathway-mediated apoptosis cascade is a common feature of hematological malignancies including acute B-lymphoblastic leukemia (B-ALL). The KMT2A-rearranged high-risk cytogenetic subtype is characterized by high expression of antiapoptotic protein BCL-2, likely due to the direct activating binding of KMT2A fusion proteins to the BCL2 gene. The BCL-2 inhibitor venetoclax (VEN) has proven great clinical value in other blood cancers, however, data on B-ALL is sparse and past studies have not so far described the effects of VEN on gene and protein expression profiles. Using cell lines and patient-derived in vivo xenograft models, we show BCL-2 pathway-mediated apoptosis induction and decelerated tumor cell counts in KMT2A-rearranged B-ALL but not in other cytogenetic subtypes. VEN treatment of cell line- and patient-derived xenografts reduced blast frequencies in blood, bone marrow, and spleen, and tumor cell doubling times were increased. Growth rates are further correlated with VEN concentrations in blood. In vitro incubation with VEN resulted in BCL-2 dephosphorylation and targeted panel RNA sequencing revealed reduced gene expression of antiapoptotic pathway members BCL2, MCL1, and BCL2L1 (BCL-XL). Reinforced translocation of BAX proteins towards mitochondria induced caspase activation and cell death commitment. Prolonged VEN application led to upregulation of antiapoptotic proteins BCL-2, MCL-1, and BCL-XL. Interestingly, the extrinsic apoptosis pathway was strongly modulated in SEM cells in response to VEN. Gene expression of members of the tumor necrosis factor signaling cascade was increased, resulting in canonical NF-kB signaling. This possibly suggests a previously undescribed mechanism of BCL-2-independent and NF-kB-mediated upregulation of MCL-1 and BCL-XL. In summary, we herein prove that VEN is a potent option to suppress tumor cells in KMT2A-rearranged B-ALL in vitro and in vivo. Possible evasion mechanisms, however, must be considered in subsequent studies.

We focus on transition teams and social interactions and innovation in three energy cases. In PXL University of Applied Sciences, the transition team is built using the quadruple helix framework. Arestart has been made from here to put a new M(aintenance) E(nergy) P(erformance) C(ontract) on the market for (campus) buildings. The transition team is a catalyst to include sustainability within the mission and vision. PXL is the first Flemish higher education institution to acquire the SDG Pioneer label awarded by the UN. Stedin Netbeheer, (distribution system operators) though strictly regulated, has set itself the goal of accelerating the energy transition where possible. The transition team focuses on ensuring that the technical blue-collar employees obtain more decisiveness and greater autonomy necessary to “do different” and “organize differently”. In the grassroot experiment in Haarlem the transition team improves environmental and climate indicators (reduction of CO2, NOX and particulate matter, creation of more vacant spaces, ….), together with behavioral changes. It is indicated how the transition team worked and progressed towards “coalitions for change” and how “change processes” have started. These paradigm shifts to new “energy systems” in combination with new business models and societal transition are needed to achieve a post carbon society.

Abstract Aim District Nurses apply specialized nursing knowledge and assessment skills to provide care in New Zealand communities. This study aimed to identify whether District Nurse's (both Registered and supervised Enrolled Nurse's) had knowledge of, and used the 15‐Minute Interview tool, including Ecomaps/Genograms, and if not, what they saw as enablers or barriers to doing so. Design Participatory action research was used, following the phases of look, think and act. Methods Two pre‐intervention focus groups occurred, two education sessions which introduced the 15‐Minute Interview and four postintervention interviews which explored the use of the tools and their potential use in the future. Results District Nurses demonstrated working with families, and the selection of when and where to apply the 15‐Minute Interview.

This paper proposes an improved topology of the three-phase series resonant DC-DC Boost converter with variable frequency control. The DC output voltage can be properly regulated at a constant value from no-load condition to full-load condition by adjusting the switching frequency. This is feasible with the three series resonant circuits coupled to the three-phase inverter. The leakage and mutual inductances of the step-up transformer are used implicitly in the series resonant circuits. Therefore, the proposed converter, when matched to the traditional three-phase inter-leaved LLC converters, requires fewer transformers, passive components, and switching devices. Furthermore, it offers better efficiency and size reduction. The proposed SRC converter also relies on the transformer’s magnetizing inductance to ensure zero voltage switching (ZVS) for all the switches within the considered range of the operating frequency. The deployed variable frequency controller shows a good level of stability at the considered loading conditions. The output voltage-to-input voltage ratio is steadily regulated at 6:1, irrespective of the load variation, by varying the switching frequency. The experimental validation of the theoretical findings proceeded on a low power scaled-down laboratory prototype. From the achieved results, the performance of the proposed converter (in terms of its effectiveness) was validated.

The paper presents the emerging topics of the international debate for safe mobility in urban areas with an innovative interpretation. This is the bibliometric mapping of the most recurrent concepts (keywords) of almost 80 scientific publications. The paper framework moves from the issue of the “sustainability” of cities to the “safe” and “innovative” city through a mobility lens. In Europe by 2030 cities have to become climate-neutral and some main urban strategy to achieve this result is focused on transport and mobility sectors. The interpretation of the bibliometric mapping results leads to highlighting the shortcomings of some topics within the scientific debate. The Qualiquantitaive Data Analysis was applied to set the interdependency among research fields and better understand the interrelation among the different topics. The key concepts of ‘time’ and ‘innovation’ don’t emerge clearly as an object of research and they will be included in future reflections about the transformative capacity of the city through sustainability and in the development of city strategies.

Digital-based differential amplifiers (DDA) are particularly suitable to low voltage digital integrated circuit technologies. This paper presents an exhaustive analysis of digital-based analog amplifiers to take advantage of today’s high-performance digital technologies, and of computer aided design (CAD), which is commonly employed to design integrated circuits. The operating principle and the main mathematical relations of digital-based differential amplifiers are discussed along with an exhaustive explanation of its operating regions and of the corresponding power consumption. These aspects, which are not discussed in the literature, are very important for the circuit designers. Finally, a detailed description of the design procedure of the UMC 180nm standard CMOS technology is provided.

While numerous studies on the impacts of COVID-19 on university learning and teaching are now emerging, there has been less critical attention focused on the impact of the shift to online engagement on student-staff partnership (SSP) practices. This article analyses the experiences and perceptions of students and staff from an Australian university as they shifted their partnership practices online during the pandemic. It provides valuable insights into the specific positive and negative impacts of online SSP for students and staff, foregrounding both groups’ perceptions of the accessibility and communication aspects of online SSP. The study’s findings lead to the recommendation of a blended approach and will be of use as SSP programs recalibrate for a post-COVID context.

Objective To characterise disease control and remission in patients with SLE receiving belimumab for up to 12 months in the real world.Methods This post hoc analysis (GSK Study 213502) used data from the US evaluation Of use of Belimumab in clinical practice SEttings (OBSErve) study (GSK Study 117295), an observational cohort study of adults with SLE initiating and continuing belimumab for ≥6 months. Data were collected every 6 months by physician chart review; details of disease activity using the Safety of Estrogens in Lupus Erythematosus National Assessment–SLE Disease Activity Index (SELENA-SLEDAI) score were collected if routinely used by physicians. Disease control definitions evaluated were SELENA-SLEDAI score of ≤2 at 12 months, SELENA-SLEDAI score of ≤2 and glucocorticoid (prednisone equivalent) dose of ≤5 mg/day at 12 months, SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day at both 6 and 12 months. Disease remission definition was SELENA-SLEDAI score=0 at 12 months. Glucocorticoid dose during follow-up was quantified.Results US OBSErve enrolled 501 patients, 90 of whom had eligible SELENA-SLEDAI scores for inclusion in this analysis. Mean (SD) SELENA-SLEDAI scores were 13.1 (3.0) at baseline and 4.9 (3.4) at 12 months. Disease control at 12 months was achieved by 31.1% of patients when defined as a SELENA-SLEDAI score of ≤2 (95% CI 21.8 to 41.7); this decreased to 25.6% when requiring a SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day (95% CI 16.9 to 35.8) and 17.8% when requiring a SELENA-SLEDAI score of ≤2 and glucocorticoid dose of ≤5 mg/day at both 6 and 12 months (95% CI 10.5 to 27.3). No patient achieved remission at 12 months. Glucocorticoids decreased from a baseline median of 20.0 mg/day (IQR 15.0–30.0) to 5.0 mg/day (IQR 0–10.0) at 12 months.Conclusion Improved disease control and reduced glucocorticoid use was achieved for a proportion of patients following up to 12 months of belimumab treatment in a US real-world setting.

This study aims to describe the local guidelines for the supplemental feeding of infants of Swedish women’s clinics with maternity wards. Purposeful sampling was used during a four-week data collection time in 2019. Guidelines from 41 of the 43 Swedish women’s clinics with maternity wards were analysed using qualitative and quantitative content analysis. The information provided, and length of the guidelines varied widely in 38 guidelines. Feeding methods were included in 28 guidelines, but 10 provided no information about feeding methods. The most common feeding methods were cup feeding and feeding probes. Suggestions for supplemental feeding included infant formula (32), breast milk (27) and no suggestions (6). The methods to support breastfeeding were skin-to-skin contact (25), breastfeeding freely (22), a caring plan (18), extra supervision (3), optimising the caring environment (2), supplying a breast pump (1) and breastfeeding observation (1). Twenty-two guidelines included information about how long formula should be given and that the feeding should be phased out gradually. We conclude that a national guideline for the supplemental feeding of infants is needed to ensure equal best practice care for infant safety and the support of parents to increase the breastfeeding rate. More national guidelines are needed in general because it is easier to update only one set of guidelines.

The success of an urban redevelopment project is often determined by the preliminary study of the site and by the knowledge thereby acquired to guide the regeneration strategies. Local administrations of small and medium-sized municipalities are unable to play a strong role in governing regeneration since Urban Plans do not include strategic analyses of the regionswide focussing on abandoned or unused areas. A clearly-oriented framework of knowledge can make it possible to regulate urban renewal more effectively and ensure a greater likelihood of successful redevelopments. The paper presents a fast method that highlights the objective limits of brownfield sites in order to better support decisions related to the Urban Plan forecasts. The method is based on four main indicators: Accessibility, Density, Functional Mix and Compactness that link a site to the context. The quali-quantitative evaluation of the indicators and their sub-components allows the establishment of the weaknesses and the strengths of the site within the urban fabric in which it is located. The method is tested by applying it to three case studies in the area of Franciacorta in the Province of Brescia.

Abstract Background Casein kinase II (CK2) is involved in multiple tumor-relevant signaling pathways affecting proliferation and apoptosis. CK2 is frequently upregulated in acute B-lymphoblastic leukemia (B-ALL) and can be targeted by the ATP-competitive CK2 inhibitor CX-4945. While reduced proliferation of tumor entities including B-ALL after CX-4945 incubation has been shown in vitro and in vivo, the detailed way of action is unknown. Here, we investigated the influence on the PI3K/AKT and apoptosis cascades in vivo and in vitro for further clarification. Methods A B-ALL xenograft model in NSG mice was used to perform in vivo longitudinal bioluminescence imaging during six day CX-4945 treatment. CX-4945 serum levels were determined at various time points. Flow cytometry of bone marrow and spleen cells was performed to analyze CX-4945-induced effects on tumor cell proliferation and distribution in B-ALL engrafted mice. ALL cells were enriched and characterized by targeted RNA sequencing. In vitro, B-ALL cell lines SEM, RS4;11 and NALM-6 were incubated with CX-4945 and gene expression of apoptosis regulators BCL6 and BACH2 was determined. Results In B-ALL-engrafted mice, overall tumor cell proliferation and distribution was not significantly influenced by CK2 inhibition. CX-4945 was detectable in serum during therapy and serum levels declined rapidly after cessation of CX-4945. While overall proliferation was not affected, early bone marrow and spleen blast frequencies seemed reduced after CK2 inhibition. Gene expression analyses revealed reduced expression of anti-apoptotic oncogene BCL6 in bone marrow blasts of CX-4945-treated animals. Further, BCL6 protein expression decreased in B-ALL cell lines exposed to CX-4945 in vitro. Surprisingly, levels of BCL6 opponent and tumor suppressor BACH2 also declined after prolonged incubation. Simultaneously, increased phosphorylation of direct CK2 target and tumor initiator AKT was detected at respective time points, even in initially pAKT-negative cell line NALM-6. Conclusions The CK2 inhibitor CX-4945 has limited clinical effects in an in vivo B-ALL xenograft model when applied as a single drug over a six day period. However, gene expression in B-ALL cells was altered and suggested effects on apoptosis via downregulation of BCL6. Unexpectedly, the BCL6 opponent BACH2 was also reduced. Interactions and regulation loops have to be further evaluated.

Abstract Background The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways. Methods Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice. Results CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous. Conclusions We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL.

A key part of the student experience in the higher education context is employability. There is an expectation that universities will contribute to their students’ employability and indeed they are measured on this contribution and are allocated funding based on it. Despite the importance of employability in higher education, it remains a complex and contested concept, often conflated with employment – graduates in jobs and the roles they occupy – and seen as a quantifiable outcome of the student experience. Where employability is understood as an individual’s knowledge, capabilities, and personal attributes that make them more likely to gain employment and be successful in their professional lives, it is often framed by the discourse of skills. There are some employability models, however, that champion a more holistic view of employability and highlight the role that experiences play in individual employability development. This paper reports on the development of an institutional employability framework and reflective process in an Australian research-intensive university. The paper discusses the experiential learning theories that underpin the reflective process that supports students to understand and articulate employability learning, for framing narratives around the potential to contribute to an organisation for employment, and for the transfer of this potential to professional contexts. The framework and reflective process represent employability as a learning process through which students make meaning from their experiences and learning opportunities. This involves understanding the value of their experiences, how to articulate that value, and how to transfer it to workplace performance

Recombinant human factor H (hFH) has potential for treating diseases linked to aberrant complement regulation including C3 glomerulopathy (C3G) and dry age-related macular degeneration. Murine FH (mFH), produced in the same host, is useful for pre-clinical investigations in mouse models of disease. An abundance of FH in plasma suggests high doses, and hence microbial production, will be needed. Previously, Pichia pastoris produced useful but modest quantities of hFH. Herein, a similar strategy yielded miniscule quantities of mFH. Since FH has 40 disulfide bonds, we created a P. pastoris strain containing a methanol-inducible codon-modified gene for protein-disulfide isomerase (PDI) and transformed this with codon-modified DNA encoding mFH under the same promoter. What had been barely detectable yields of mFH became multiple 10s of mg/L. Our PDI-overexpressing strain also boosted hFH overproduction, by about tenfold. These enhancements exceeded PDI-related production gains reported for other proteins, all of which contain fewer disulfide-stabilized domains. We optimized fermentation conditions, purified recombinant mFH, enzymatically trimmed down its (non-human) N-glycans, characterised its functions in vitro and administered it to mice. In FH-knockout mice, our de-glycosylated recombinant mFH had a shorter half-life and induced more anti-mFH antibodies than mouse serum-derived, natively glycosylated, mFH. Even sequential daily injections of recombinant mFH failed to restore wild-type levels of FH and C3 in mouse plasma beyond 24 hours after the first injection. Nevertheless, mFH functionality appeared to persist in the glomerular basement membrane because C3-fragment deposition here, a hallmark of C3G, remained significantly reduced throughout and beyond the ten-day dosing regimen.

Multi-level inverters (MLIs) have been widely used in recent years due to their various advantages in industrial and grid-connected applications. Traditional MLI topologies are being hampered by the rapid surge of renewable energy systems (RES) as a result of performance difficulties such as poor power reliability, an economically unviable structure, and a lack of efficiency. These difficulties are due to the traditional MLI topologies’ inability to keep up with the increasing demand for RES. Because of concerns about performance and limitations posed by classic MLI topologies, researchers have found themselves driven to the idea of building innovative hybrid MLI topologies. This study provides a comprehensive analysis of multilevel inverter systems that are wired into the main power supply. Grid-connected inverter types and their configurations are discussed in depth in this review. Diverse multi-level inverter topologies, as well as the different approaches, are divided into various categories and discussed in depth. Additionally, a number of control reference frames for inverters were brought forward for discussion. Furthermore, different inverter control strategies were investigated, followed by a tabular summary of recent developments in the inverter-related literature for the convenience of the readers. Moreover, the recently proposed grid-connected multi-level inverter systems were discussed including their findings and innovations. In conclusion, a brief description of the study’s scope was offered and research directions for future studies were provided.

Background: Isoprene (C5H8) is a clinically important breath metabolite. Although, hundreds of studies have reported differential expressions in isoprene exhalation as breath biomarker for diverse diseases, the substance couldn't enter to clinical practice as diagnostic marker. Moreover, many experimental/basic observations upon breath isoprene remained unrelated to the corresponding pathophysiological effects on its putative metabolic origin (i.e. mevalonate pathway). Here, we investigated the fundamental reason that hindered the rational interpretation and translation of this marker from basic to clinical science. Methods: Via high-resolution mass-spectrometry based breathomics in 1026 human subjects, we discovered adults with significant deficiency (order of magnitude lower than the normal) and complete absence of breath isoprene. We prospectively applied real-time breathomics, quantitative gene expression analysis of the mevalonate pathway enzymes, lipid-profiling and hemodynamic monitoring on those isoprene deficient subjects and controls. Additionally, the subject with absence of isoprene was followed up throughout different phases of her womanhood. Results: In contrast to convention, we witnessed that adults can live healthy without exhaling isoprene or with significant deficiency. This rare phenotype represents a recessive inheritance. Despite physio-metabolic changes during menstrual cycle (that is known to profoundly affect isoprene exhalation) and profoundly increased plasma cholesterol during pregnancy and after childbirth, isoprene remained absent. All genes of mevalonate pathway enzymes were normally expressed in all participants, without any down-regulation or compensatory up-regulation. Conclusions: Absence/deficiency of isoprene despite normal lipid profiles and no mevalonate pathway malfunction disqualifies the long-believed metabolic origin of isoprene from cholesterol biosynthesis. Thus, clinical translation of breath isoprene expressions should not be generally attributed to corresponding pathophysiological effects onto mevalonate/cholesterol pathway. Our finding has refined and optimized the clinical interpretation of isoprene as biomarker in volatile metabolomics and breathomics. Future studies will address the correct metabolic origin of isoprene to imply this important marker to routine practice.

En la primera mitad del 2019, la editorial Ad-Hoc publicó un libro pequeño pero contundente con el título Régimen penal y procesal del arrepentido y la delación premiada. Incorporación de la Ley 27304 al Código Procesal Penal Federal —Ley 27482— de la pluma de Maximiliano Hairabedián. Tal como indica el subtítulo, el trabajo está dedicado a la nueva ley del arrepentido, la Ley 27304, que cobró validez en el 2016 y cuyos rasgos fundamentales fueron incorporados al Código Procesal Federal, mediante la Ley 27482, en el 2018...

En su libro, Razones públicas, Rosler analiza seis conceptos bá- sicos de la república y del republicanismo clásico, la libertad, la virtud, el debate, la ley, la patria y, como antagonismo al republicanismo, el cesarismo. Propone investigar no solo qué se entendía por esos conceptos en el republicanismo clásico, sino también qué rol cumplirían en nuestras sociedades contemporáneas. En el presente trabajo se pretende indagar un poco más en esa supuesta utilidad de las virtudes para las sociedades contemporáneas, y eso a partir de los siguientes interrogantes: ¿se pueden trasladar las exigencias de virtuosidad del republicanismo clásico a nuestros tiempos? Y ¿qué significarían tales exigencias ahora? Estas preguntas se pueden agrupar en dos ejes: primero habría que establecer cuáles virtudes se necesitarían en una república contemporánea y en segundo lugar habría que analizar en qué momento o instancia de la vida republicana cobran relevancia.

Silmitasertib (CX-4945) is currently being investigated in clinical trials against various types of cancer. The U.S. Food and Drug Administration (FDA) has already granted orphan drug designation to the compound for the treatment of advanced cholangiocarcinoma, medulloblastoma, and biliary tract cancer. Silmitasertib inhibits the serine/threonine protein kinase CK2, which exerts a proliferation-promoting and anti-apoptotic effect on cancer cells. In view of current and future applications, the measurement of silmitasertib levels in plasma is expected to play an important role in the evaluation of therapeutic and toxic concentrations in cancer patients. In the present work, we therefore present an LC–MS/MS method for the quantification of silmitasertib in human plasma. Using a simple liquid–liquid extraction with ethyl acetate and a mixture of n-hexane and ethyl acetate, this method can be performed in any laboratory with mass spectrometry. The validation was carried out according to the FDA guideline.

In acute lymphoblastic leukemia (ALL), conventional cell lines do not recapitulate the clonal diversity and microenvironment. Orthotopic patient-derived xenograft models (PDX) overcome these limitations and mimic the clinical situation, but molecular stability and engraftment patterns have not yet been thoroughly assessed. We herein describe and characterize the PDX generation in NSG mice. In vivo tumor cell proliferation, engraftment and location were monitored by flow cytometry and bioluminescence imaging. Leukemic cells were retransplanted for up to four passages, and comparative analyses of engraftment pattern, cellular morphology and genomic hotspot mutations were conducted. Ninety-four percent of all samples were successfully engrafted, and the xenograft velocity was dependent on the molecular subtype, outcome of the patient and transplantation passage. While BCR::ABL1 blasts were located in the spleen, KMT2A-positive cases had higher frequencies in the bone marrow. Molecular changes appeared in most model systems, with low allele frequency variants lost during primary engraftment. After the initial xenografting, however, the PDX models demonstrated high molecular stability. This protocol for reliable ALL engraftment demonstrates variability in the location and molecular signatures during serial transplantation. Thorough characterization of experimentally used PDX systems is indispensable for the correct analysis and valid data interpretation of preclinical PDX studies.

In several energy applications, DC/DC converters are one of the most important components [...]

Abstract Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter personality and cognition. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP E2 was performed on sections of frontal and temporal cortex with hippocampus from 80 patients with FTLD, stratified by pathology into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those with no known mutation, and on 10 healthy controls. Semi-quantitative analysis assessed hnRNP staining in frontal and temporal cortex, and in dentate gyrus (DG) of hippocampus, in the different pathology and genetic groups. We find that hnRNP E2 immunostaining detects the TDP-43 positive dystrophic neurites (DN) within frontal and temporal cortex, and the neuronal cytoplasmic inclusions (NCI) seen in DG granule cells, characteristic of patients with Semantic Dementia (SD) and type C TDP-43 pathology, but did not detect TDP-43 or tau inclusions in any of the other pathological or genetic variants of FTLD. Double immunofluorescence for hnRNP E2 and TDP-43 showed most TDP-43 immunopositive DN to contain hnRNP E2. Present findings indicate an association between TDP-43 and hnRNP E2 which might underlie the pathogenetic mechanism of this form of FTLD.

Abstract Frontotemporal Lobar Degeneration (FTLD) encompasses certain related neurodegenerative disorders which alter behaviour, personality and language. Heterogeneous ribonuclear proteins (hnRNPs) maintain RNA metabolism and changes in their function may underpin the pathogenesis of FTLD. Immunostaining for hnRNP A1, A2/B1 and A3 was performed on sections of temporal cortex with hippocampus from 61 patients with FTLD, stratified by pathological hallmarks into FTLD-tau and FTLD-TDP type A, B and C subtypes, and by genetics into patients with C9orf72 expansions, MAPT or GRN mutations, or those without known mutation. Four patients with Motor Neurone Disease (MND) with C9orf72 expansions and 10 healthy controls were also studied. Semi-quantitative analysis assessed hnRNP staining intensity in dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx) in the different pathological and genetic groups. Immunostaining for hnRNP A1, A2/B1 and A3 revealed no consistent changes in pattern or amount of physiological staining across any of the pathological or genetic groups. No immunostaining of any inclusions resembling TDP-43 immunoreactive neuronal cytoplasmic inclusions or dystrophic neurites, was seen in either Tcx or DG of the hippocampus in any of the FTLD cases investigated for hnRNP A1, A2/B1 and A3. However, immunostaining for hnRNP A3 showed that inclusion bodies, resembling those TDP-43 negative, p62-immunopositive structures containing dipeptide repeat proteins (DPR) were variably observed in hippocampus and cerebellum. The proportion of cases showing hnRNP A3-immunoreactive DPR, and the number of hnRNP A3-positive inclusions within cases, was significantly greater in DG than in cells of CA4 region and cerebellum, but the latter was significantly less in all three regions compared to that detected by p62 immunostaining.

Este comentario se centra en dos enfoques del análisis económico-conductista del derecho, el enfoque de la toma de decisiones y el enfoque intuicionista, así como en los problemas que surgen al emplear el análisis económico-conductista del derecho para la evaluación de leyes penales existentes o el diseño de políticas criminales futuras. Mientras el artículo central resalta los problemas empíricos a los que el análisis econó- mico-conductista del derecho se ve confrontado en la aplicación a ordenamientos jurídicos penales, voy a argumentar que también existen desafíos normativos a tener en cuenta. Éstos giran alrededor de la pregunta de si los legisladores y responsables para la política criminal están restringidos por ciertos límites al interferir en el proceso de toma de decisión de potenciales delincuentes. Respecto del enfoque intuicionista surge la pregunta de si la moral social detectada a través del enfoque intuicionista ha de ser tenida en cuenta más allá de sus efectos disuasorios.

The Internet of Things (IoT) has found application in many components of implantable medical devices, wearable smart devices, monitoring systems, etc. The IoT devices are conventionally battery powered, even though, in several low power applications, they can also be powered using energy harvesting technology. Independently of the power sources (if batteries or environment), efficient and robust power converters must be designed to provide the small and distributed energy required by such IoT devices. This review paper will first provide an overview about the power consumption in IoT devices; second, it will discuss the most recent research and advance in the field of fully-integrated or embedded DC/DC converters, starting from high-performance integrated charge pumps or embedded inductive boost converters for specific harvesting sources (temperature, solar, and so on), to novel DC/DC converters for multiple energy sources.

Over the last decade, energy demand from the power grid has increased significantly due to the increasing number of users and the emergence of high-power industries. This has led to a significant increase in global emissions with conventional energy generation. Therefore, the penetration of renewable energy resources into the power grid has increased significantly. Photovoltaic systems have become the most popular resources as their protentional is enormous, thus, the worldwide installed PV capacity has increased to more than 635 gigawatts (GW), covering approximately 2% of the global electricity demand. Power electronics are an essential part of photovoltaic generation; the drive for efficient power electronic converters is gaining more and more momentum. Presently, multilevel inverters (MLI) have become more attractive to researchers compared to two-level inverters due to their abilities to provide lower electromagnetic interference, higher efficiency, and larger DC link voltages. This paper reviews multilevel inverters based on their classifications, development, and challenges with practical recommendations in utilizing them in renewable energy systems. Moreover, PV systems with various maximum power point tracking (MPPT) methods have been extensively considered in this paper as well. The importance and the development of a modified multilevel inverter are also highlighted in this review. In general, this paper focuses on utilizing multilevel inverters for PV systems to motivate and guide society to focus on inventing an efficient and economical multilevel inverter that has the combined capabilities of these converters reported in the literature.

Diet failures are often attributed to an increase in cravings for attractive foods. However, accumulating evidence shows that food cravings actually decrease during energy-restricting weight-loss interventions. The current study aimed at elucidating possible mechanisms that may explain how and under which circumstances food cravings in- or decrease during dieting. Specifically, decreases in food cravings during weight-loss diets may be due to effects of energy restriction (homeostatic changes) and to effects of avoiding specific foods (hedonic changes). Thus, we used a selective, hedonic deprivation (i.e., restricting intake of a specific food in the absence of an energy deficit) that precludes homeostatic changes due to energy restriction. Furthermore, interindividual differences in food craving experiences might affect why some individuals are more prone to experience cravings during dieting than others. Thus, we investigated whether a selective deprivation of chocolate would in- or decrease craving and implicit preference for chocolate as a function of trait-level differences in chocolate craving. Participants with high and low trait chocolate craving (HC, LC) refrained from consuming chocolate for 2 weeks but otherwise maintained their usual food intake. Both groups underwent laboratory assessments before and after deprivation, each including explicit (i.e., state chocolate craving) and implicit measures (i.e., Single Category Implicit Association Test, SC-IAT; Affect Misattribution Procedure, AMP). Results showed that hedonic deprivation increased state chocolate craving in HCs only. HCs also showed more positive implicit attitudes toward chocolate than LCs on the SC-IAT and the AMP irrespective of deprivation. Results help to disambiguate previous studies on the effects of dieting on food cravings. Specifically, while previous studies showed that energy-restricting diets appear to decrease food cravings, the current study showed that a selective, hedonic deprivation in the absence of an energy deficit increases food cravings. However, this effect can only be observed for individuals with high trait craving levels. Thus, if attractive foods are strictly avoided through a selective deprivation, HCs are at risk to experience craving bouts in the absence of an energy deficit. As implicit preference was unaffected by chocolate deprivation, strong implicit preference for chocolate likely characterize a stable mechanism that drives consumption in HCs.

In recent years and throughout the European Union, “active ageing” has become a prominent conception of how to “age well”. In analyzing the governmentality of old age inherent to the “active ageing” paradigm, this paper tries to avoid the short-cut from program to praxis commonly being taken in governmentality studies. It reports on the findings of an empirical research project that asks for the specific images of “old age” and “retirement” becoming prominent in the context of last decade’s push for “activation” in German politics. The analysis combines the reconstruction of so-called “story lines” emerging in public discourse with the evaluation of qualitative interviews with “young” elderly people, conceptualizing older people’s narrations as being an integral part of the discourse itself. Moving from simple, ad-hoc illustrations of theoretical claims concerning a “neoliberal” government of old age to a systematic empirical reconstruction of what may be called the dispositif of “active ageing”, the paper claims to make an innovative contribution to an “empirical theory” of governmentality.

Introduction In 2003, the Institute of Medicine recommended that interprofessional education be incorporated into the training programs of health care professionals. However, many logistical challenges hinder formal interprofessional learning in health care profession programs. Methods This resource is a 3-hour interprofessional small-group session designed for health professions student teams to engage in a standardized patient encounter, each team member contributing a profession-specific perspective to create a collaborative care plan across five discharge decisions. The activity includes a simulated standardized patient encounter and debrief session wherein students discuss the role of bias and communication and create a collaborative care plan. Results Following the activity, participants were surveyed about the value of the educational experience. Over 12 months, 106 students (81 medicine, nine nursing, 16 pharmacy) participated in the interprofessional activity. Eighty-four students responded to the postevent survey (79% response rate). Students were confident that the experience helped them integrate profession-specific knowledge, create a shared care plan, and understand how interprofessional collaboration contributes to quality care. The debriefing session and interprofessional interaction were an integral component of the experience. Discussion This resource is a feasible interprofessional small-group activity that has been implemented without excessive faculty time or institutional resources. It is adaptable to institutional needs, local resources, level of trainee, and professions. The session provides interprofessional students the opportunity to engage with one another and with the patient in a collaborative decision-making activity focused around a critical transition of care.

Reducing voltage supply is one of the most effective way to reduce the power consumption, but, on the other hand it is a challenging choice for the analog designers. In this paper, different topologies, well-suited for low voltage and ultra-low voltage supply, are depicted, investigated, designed in the same standard 180 nm technology and compared, highlighting the benefits and the possible applications.

The complement regulator CD46 is a costimulatory molecule for human T cells that induces a regulatory Tr1 phenotype, characterized by large amounts of IL-10 secretion. Secretion of IL-10 upon CD46 costimulation is largely impaired in T cells from patients with multiple sclerosis (MS). Vitamin D can exert a direct effect on T cells, and may be beneficial in several pathologies, including MS. In this pilot study, we examined whether active vitamin D (1,25(OH)(2)D(3) or calcitriol) could modulate the CD46 pathway and restore IL-10 production by CD46-costimulated CD4+ T cells from patients with MS. In healthy T cells, calcitriol profoundly affects the phenotype of CD46-costimulated CD4+ T cells, by increasing the expression of CD28, CD25, CTLA-4 and Foxp3 while it concomitantly decreased CD46 expression. Similar trends were observed in MS CD4+ T cells except for CD25 for which a striking opposite effect was observed: while CD25 was normally induced on MS T cells by CD46 costimulation, addition of calcitriol consistently inhibited its induction. Despite the aberrant effect on CD25 expression, calcitriol increased the IL-10:IFNγ ratio, characteristic of the CD46-induced Tr1 phenotype, in both T cells from healthy donors and patients with MS. Hence, we show that calcitriol affects the CD46 pathway, and that it promotes anti-inflammatory responses mediated by CD46. Moreover, it might be beneficial for T cell responses in MS.

With the functional demonstration of a role in erythrocyte invasion by Plasmodium falciparum parasites, implications in the aetiology of common conditions that prevail in individuals of African origin, and a wealth of pharmacological knowledge, the stimulatory G protein (Gs) signal transduction pathway presents an exciting target for anti-malarial drug intervention. Having previously demonstrated a role for the G-alpha-s gene, GNAS, in severe malaria disease, we sought to identify other important components of the Gs pathway. Using meta-analysis across case-control and family trio (affected child and parental controls) studies of severe malaria from The Gambia and Malawi, we sought evidence of association in six Gs pathway candidate genes: adenosine receptor 2A (ADORA2A) and 2B (ADORA2B), beta-adrenergic receptor kinase 1 (ADRBK1), adenylyl cyclase 9 (ADCY9), G protein beta subunit 3 (GNB3), and regulator of G protein signalling 2 (RGS2). Our study amassed a total of 2278 cases and 2364 controls. Allele-based models of association were investigated in all genes, and genotype and haplotype-based models were investigated where significant allelic associations were identified. Although no significant associations were observed in the other genes, several were identified in ADORA2A. The most significant association was observed at the rs9624472 locus, where the G allele (approximately 20% frequency) appeared to confer enhanced risk to severe malaria [OR = 1.22 (1.09-1.37); P = 0.001]. Further investigation of the ADORA2A gene region is required to validate the associations identified here, and to identify and functionally characterize the responsible causal variant(s). Our results provide further evidence supporting a role of the Gs signal transduction pathway in the regulation of severe malaria, and request further exploration of this pathway in future studies.

Interferon Regulatory Factor 1 (IRF-1) is a member of the IRF family of transcription factors, which have key and diverse roles in the gene-regulatory networks of the immune system. IRF-1 has been described as a critical mediator of IFN-gamma signalling and as the major player in driving TH1 type responses. It is therefore likely to be crucial in both innate and adaptive responses against intracellular pathogens such as Plasmodium falciparum. Polymorphisms at the human IRF1 locus have been previously found to be associated with the ability to control P. falciparum infection in populations naturally exposed to malaria. In order to test whether genetic variation at the IRF1 locus also affects the risk of developing severe malaria, we performed a family-based test of association for 18 Single Nucleotide Polymorphisms (SNPs) across the gene in three African populations, using genotype data from 961 trios consisting of one affected child and his/her two parents (555 from The Gambia, 204 from Kenya and 202 from Malawi). No significant association with severe malaria or severe malaria subphenotypes (cerebral malaria and severe malaria anaemia) was observed for any of the SNPs/haplotypes tested in any of the study populations. Our results offer no evidence that the molecular pathways regulated by the transcription factor IRF-1 are involved in the immune-based pathogenesis of severe malaria.

BACKGROUND:Localising regulatory variants that control gene expression is a challenge for genome research. Several studies have recently identified non-coding polymorphisms associated with inter-individual differences in gene expression. These approaches rely on the identification of signals of association against a background of variation due to other genetic and environmental factors. A complementary approach is to use an Allele-Specific Expression (ASE) assay, which is more robust to the effects of environmental variation and trans-acting genetic factors. METHODOLOGY/PRINCIPAL FINDINGS:Here we apply an ASE method which utilises heterozygosity within an individual to compare expression of the two alleles of a gene in a single cell. We used individuals from three HapMap population groups and analysed the allelic expression of genes with cis-regulatory regions previously identified using total gene expression studies. We were able to replicate the results in five of the six genes tested, and refined the cis- associated regions to a small number of variants. We also showed that by using multi-populations it is possible to refine the associated cis-effect DNA regions. CONCLUSIONS/SIGNIFICANCE:We discuss the efficacy and drawbacks of both total gene expression and ASE approaches in the discovery of cis-acting variants. We show that the ASE approach has significant advantages as it is a cleaner representation of cis-acting effects. We also discuss the implication of using different populations to map cis-acting regions and the importance of finding regulatory variants which contribute to human phenotypic variation.