Specific Tools Research Articles

Structurally Specific Z-DNA Proteolysis Targeting Chimera Enables Targeted Degradation of Adenosine Deaminase Acting on RNA 1.

Given the prevalent advancements in DNA- and RNA-based PROTACs, there remains a significant need for the exploration and expansion of more specific DNA-based tools, thus broadening the scope and repertoire of DNA-based PROTACs. Unlike conventional A- or B-form DNA, Z-form DNA is a configuration that exclusively manifests itself under specific stress conditions and with specific target sequences, which can be recognized by specific reader proteins, such as ADAR1 or ZBP1, to exert downstream biological functions. The core of our innovation lies in the strategic engagement of Z-form DNA with ADAR1 and its degradation is achieved by leveraging a VHL ligand conjugated to Z-form DNA to recruit the E3 ligase. This ingenious construct engendered a series of Z-PROTACs, which we utilized to selectively degrade the Z-DNA-binding protein ADAR1, a molecule that is frequently overexpressed in cancer cells. This meticulously orchestrated approach triggers a cascade of PANoptotic events, notably encompassing apoptosis and necroptosis, by mitigating the blocking effect of ADAR1 on ZBP1, particularly in cancer cells compared with normal cells. Moreover, the Z-PROTAC design exhibits a pronounced predilection for ADAR1, as opposed to other Z-DNA readers, such as ZBP1. As such, Z-PROTAC likely elicits a positive immunological response, subsequently leading to a synergistic augmentation of cancer cell death. In summary, the Z-DNA-based PROTAC (Z-PROTAC) approach introduces a modality generated by the conformational change from B- to Z-form DNA, which harnesses the structural specificity intrinsic to potentiate a selective degradation strategy. This methodology is an inspiring conduit for the advancement of PROTAC-based therapeutic modalities, underscoring its potential for selectivity within the therapeutic landscape of PROTACs to target undruggable proteins.

Is there a role for routine intraoperative cholangiogram in diagnosing CBD stones in patients with normal liver function tests? A prospective study

Abstract Objectives Cholecystectomy with or without intraoperative cholangiogram (IOC) is an accepted treatment for cholelithiasis. Up to 11.6 % of cholecystectomies have incidental common bile duct (CBD) stones on IOC and 25.3 % of undiagnosed CBD stones will develop life-threatening complications. These will require additional intervention after primary cholecystectomy, further straining the healthcare system. We seek to examine the role of IOC in patients with normal LFTs by evaluating its predictive values, intending to treat undiagnosed CBD stones and therefore ameliorate these issues. Methods All patients who underwent cholecystectomies with normal LFTs from October 2019 to December 2020 were prospectively enrolled. IOC was done, ERCPs were performed for filling defects and documented as “true positive” if ERCP was congruent with the IOC. “False positives” were recorded if ERCP was negative. “True negative” was assigned to normal IOC and LFT after 2 weeks of follow-up. Those with abnormal LFTs were subjected to ERCP and documented as “false negative”. Sensitivity, specificity, and predictive values were calculated. Results A total of 180 patients were analysed. IOC showed a specificity of 85.5 % and a NPV of 88.1 % with an AUC of 73.7 %. The positive predictive value and sensitivity were 56.5 and 61.9 % respectively. Conclusions Routine IOC is a specific diagnostic tool with good negative predictive value. It is useful to exclude the presence of CBD stones when LFT is normal. It does not significantly prolong the length of hospitalization or duration of the cholecystectomy hence reducing the incidence of undetected retained stones and preventing its complications effectively.

Health-related quality of life in patients with hematologic malignancies treated with chimeric antigen receptor T-cell therapy: review and current progress.

Chimeric antigen receptor (CAR) T-cell therapy has transformed the care of patients with relapsed/refractory B-cell derived hematologic malignancies. To date, six CAR T-cell therapies, targeting either CD19 or B-cell maturation antigen, have received regulatory approval. Along with the promising survival benefit, CAR T-cell therapy is associated with potentially lifethreatening adverse events (AE), including cytokine release syndrome and immune effector cellassociated neurotoxicity syndrome. While clinical trials evaluating CAR T-cell therapy consistently report the incidence of these AE, most trials do not collect health-related quality of life (HRQoL) data. As such, the impact of CAR T-cell therapy process and related AE on the physical and psychological well-being of patients remains uncertain. HRQoL and other patientreported outcome (PRO) assessments in patients with relapsed or refractory hematologic malignancies are of utmost importance, as individuals may have unmet needs and a high demand for tolerable therapy if a cure is not obtained. In addition, it is important to standardize methods of data collection to better assess the impact of CAR T-cell therapy on quality of life, optimize patient care and costs, and enable comparison between different studies. We conducted a literature search up to June 2023 to identify the HRQoL tools used in clinical trials and in realworld studies investigating CAR T-cell therapy in patients with lymphomas or leukemias. In the present comprehensive review, we summarize the most commonly used CAR T-cell specific and non-specific HRQoL tools and discuss how the use of HRQoL and other PRO tools may be optimized.

Mobile Applications to Support Multiple Sclerosis Communities: The Post-COVID-19 Scenario.

Introduction: The increase in the use of mobile apps since the COVID-19 pandemic, even among people with multiple sclerosis (PwMS) and health care providers (HCPs), has enabled access to reliable information, symptoms monitoring and management, and social connections. The pandemic has undoubtedly contributed to the acceleration of the "digital revolution." But how far has it progressed for the MS communities? Methods: Italian Google Play and App Store were queried, selecting MS-specific apps in English or Italian language and usable by a wide public. Results: Fifty-four (n = 54) MS-specific apps were identified; most were PwMS-oriented (83%), free of charge (94%), and in English language (76%). The 45 PwMS-oriented apps focused on increasing MS knowledge (71%), tracking symptoms (33%), and promoting networking with peers or HCPs (38%). The 13 HCPs-oriented tools addressed education and updates on MS (62%), disease assessment and management (54%), and research (15%). Google Search tool was also queried to find non-MS-specific apps to fulfill some unmet domains (as sleep, pain, sexual or mental health). Twenty-four additional apps were listed to provide a valuable contribution. Conclusion: The "digital revolution" led to increasingly customized tools for PwMS, especially as m-health or social-networking apps. However, apps to support other specific MS-relevant domains, appealing HCPs-oriented apps, and specific mobile tools for MS caregivers are still lacking. The absence of data assessing the usability and quality of MS apps in ecologically contexts leads to not reliable conclusions about potential benefits. A strong dialogue between MS communities and the digital industry is encouraged to fill this gap.

Developing a disease-specific patient reported outcome measure to enhance understanding of the lived experiences of ANCA associated vasculitis: A protocol paper.

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a chronic, relapsing-remitting condition associated with increased morbidity. Previous research has shown patients with AAV report high levels of fatigue, pain, depression and anxiety. Over recent years successful work has been carried out to improve clinical outcomes, resulting in reduced mortality and end stage kidney disease (ESKD). Despite this, little work has been done to better understand the role of the patient within this condition. The prevalence of AAV is increasing and to date, there is a shortage of specific tools that assess and measure key features relating to patient reported outcomes (PROs). This protocol details how we can better understand the lived experiences of those with AAV through the development of a disease specific, patient reported outcome measure (PROM), to be used in clinic practice. This will allow us to recognise and validate PROs and the impact the disease and its treatment has on patients' health related quality of life (HRQoL). In addition, we aim to identify potential differences in PRO's between demographics, organ involvement and treatment subgroups in AAV as well as outcomes relating to the patient experience. Patients from a single centre in the UK will be recruited to take part in the exploratory qualitative study which will include focus groups and semi-structured interviews. The inclusion criteria comprise anyone with a diagnosis of AAV and willing to participate, including those who have active or relapsing disease, those are economically active, unemployed, retired and patients receiving renal replacement therapy. The aim of the project is to identify key issues patients experience in relation to their disease and its management and how these can be better assessed in a new PROM developed for use in the clinic setting. This will enable better delivery of individualised care and inform shared decision making, while also serving as a platform for future research looking at PROs in other glomerulonephritides.

Identifying and assisting sedentary patients: a practical guide

A sedentary lifestyle is a significant cardiovascular risk factor and increases premature mortality. Engaging in routine physical activity (PA) provides a wide range of health benefits. Accordingly, physical inactivity must be identified and sedentary patients supported systematically to achieve recommended levels of PA. The level of PA can be assessed by taking patients' history and using specific tools. Support begins by assessing PA contraindications and patients' level of motivation to change their lifestyle. Patients are then encouraged to adopt a more active lifestyle through tailored advice, and if necessary, referred to specialists with expertise in exercise medicine. This article details the key aspects of accompanying sedentary patients, to help healthcare professionals integrate them into their practice.

Genetics of inborn errors of immunity: Diagnostic strategies and new approaches to CNV detection.

Genetic diagnosis of inborn errors of immunity (IEI) is complex due to the large number of genes involved and their molecular features. Missense variants have been reported as the most common cause of IEI. However, the frequency of copy number variants (CNVs) may be underestimated since their detection requires specific quantitative techniques. At this point, the use of Next Generation Sequencing (NGS) is acquiring relevance. In this article, we present our experience in the genetic diagnosis of IEI based on three diagnostic algorithms that allowed the detection of single nucleotide variants (SNVs) and CNVs. Following this approximation, 703 index cases were evaluated between 2014 and 2021. Sanger sequencing, MLPA, CGH array, breakpoint spanning PCR or a customized NGS-based multigene-targeted panel were performed. A genetic diagnosis was reached in 142 of the 703 index cases (20%), 19 of them presented deletions as causal variants. Deletions were also detected in 5 affected relatives and 16 healthy carriers during the family studies. Additionally, we compile, characterize and present all the CNVs detected by our diagnostic algorithms, representing the largest cohort of deletions related to IEI to date. Furthermore, three bioinformatic tools (LACONv, XHMM, VarSeq™) based on NGS data were evaluated. VarSeq™ was the most sensitive and specific bioinformatic tool; detecting 21/23 (91%) deletions located in captured regions. Based on our results, we propose a strategy to guide the molecular diagnosis that can be followed by expert and non-expert centres in the field of IEI.

A Novel AI Approach for the Systematic Creation of Empathy Maps

The utilization of Empathy Maps in User Experience and Design Thinking is becoming commonplace. They can be seen as a valuable tool to help developers better understand the user’s requirements. During the interaction design, it is essential to have a thorough knowledge of what the user wants, which might be difficult to gather or portray to others. In this sense, Empathy Maps visually represent the user’s information, attitude, and behavior. Nevertheless, creating Empathy Maps can become tedious, as this usually requires the involvement of a group of people with expert knowledge, deeply analyzing the information elicited from the user. This is the reason why most Empathy Maps are created manually. A first literature analysis reports that there are still no specific tools to generate Empathy Maps automatically, although there are technologies to take on this challenge. In this paper, we present a tool for automatically generating an initial version of an Empathy Map that can help speed up the capture of explicit knowledge, and then it can be further worked on by the development team. The tool creates the Empathy Map from an audio interview, featuring audio transcription technology and natural language processing. More specifically, this paper includes the architecture, a proof of concept, and user testing, reporting numerical evidence and promising results to corroborate the proposal’s feasibility, reaching an overall accuracy of 86% at classification.

EPAC inhibitor suppresses angiogenesis and tumor growth of triple-negative breast cancer

AimsExchange protein directly activated by cAMP 1 (EPAC1), a major isoform of guanine nucleotide exchange factors, is highly expressed in vascular endothelia cells and regulates angiogenesis in the retina. High intratumor microvascular densities (MVD) resulting from angiogenesis is responsible for breast cancer development. Downregulation of EPAC1 in tumor cell reduces triple-negative breast cancer (TNBC)-induced angiogenesis. However, whether Epac1 expressed in vascular endothelial cells contributes to angiogenesis and tumor development of TNBC remains elusive. Main methodsWe employed NY0123, a previously identified potent EPAC inhibitor, to explore the anti-angiogenic biological role of EPAC1 in vitro and in vivo through vascular endothelial cells, rat aortic ring, Matrigel plug, and chick embryo chorioallantoic membrane (CAM) and yolk sac membrane (YSM) assays, as well as the in vivo xenograft tumor models of TNBC in both chick embryo and mice. Key findingsInhibiting EPAC1 in vascular endothelial cells by NY0123 significantly suppresses angiogenesis and tumor growth of TNBC. In addition, NY0123 possesses a better inhibitory efficacy than ESI-09, a reported specific EPAC inhibitor tool compound. Importantly, inhibiting EPAC1 in vascular endothelia cells regulates the typical angiogenic signaling network, which is associated with not only vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor-2 (VEGFR2) signaling, but also PI3K/AKT, MEK/ERK and Notch pathway. ConclusionsOur findings support that EPAC1 may serve as an effective anti-angiogenic therapeutic target of TNBC, and EPAC inhibitor NY0123 has the therapeutic potential to be developed for the treatment of TNBC.

Przemoc, przymus i eskalacja we współczesnej rywalizacji strategicznej

Celem badań było wyjaśnienie i scharakteryzowanie znaczenia przemocy, przymusu i eskalacji we współczesnej rywalizacji strategicznej. Główny problem badawczy wyartykułowano pytaniem: w czym wyraża się i charakteryzuje się przemoc, przymus i eskalacja we współczesnej rywalizacji strategicznej? W procesie badawczym wykorzystano analizę i krytykę literatury, obserwację nieuczestniczącą oraz studium przypadków. W rezultacie przeprowadzonych badan ustalono, że w rywalizacji strategicznej zawsze jest obecna przemoc i przymus. Są one swoistymi narzędziami oddziaływania międzynarodowego do osiągania określonych celów politycznych. Przymus jest użyciem siły w sposób ograniczony, demonstracją siły, lub użyciem sił zbrojnych i prowadzenie starcia zbrojnego. Przymus zawiera w sobie odstraszanie i wymuszanie. Eskalacja to wzrost intensywności lub zakresu sporu albo konfliktu pomiędzy dwiema stronami, który przekracza próg uznawany za istotny przez jednego lub więcej jego uczestników. Eskalacja jest zjawiskiem interaktywnym, zachodzącym pomiędzy dwoma (lub więcej) stronami konfliktu, które dążą do uzyskania jednostronnej przewagi. Eskalacji zapobiega się poprzez odstraszanie strategiczne lub posiadanie dominacji eskalacyjnej.

Developing Integrated STEM Teacher Identity Using Guided Curation of K-12 Engineering Activities

Abstract This qualitative study examines how guided curation develops practicing teachers’ task perception as a dimension of integrated STEM teacher identity. Task perception is defined as teachers’ beliefs about their roles and responsibilities as integrated STEM educators. Analysis of teachers’ (n = 22) guided curation assignments from a graduate STEM education course revealed how teachers perceived their roles and responsibilities as integrated STEM educators and potential challenges to integrating STEM. These beliefs included the importance of centering the engineering design process, encouraging collaborative problem solving, providing productive mistake-making opportunities, and connecting mathematics and engineering. Teacher educators’ adaptation of a freely available STEM lesson specification tool scaffolded the collection and analysis of curriculum resources. This adaptation was instrumental in developing task perception. Implications for building elementary teachers’ capacity to implement and sustain innovative integrated STEM instruction are offered.

EHealth tools use and mental health: a cross-sectional network analysis in a representative sample

eHealth tools usage is vital for health care systems and increased significantly after the COVID-19 pandemic, which aggravated mental health issues. This cross-sectional study explored whether sociodemographic characteristics and mental health indices (stress and symptoms of anxiety and depression) were linked to the behavioral intention to use eHealth tools and eHealth tools usage in a representative sample from Poland using a network approach. Measurements were conducted in March 2023 among 1000 participants with a mean age of 42.98 (18–87) years, with 51.50% women. The measures included the behavioral intention to use eHealth tools (BI) based on the UTUAT2; eHealth tool use frequency (use behavior) including ePrescription, eSick leave, eReferral, electronic medical documentation (EMD), Internet Patient Account (IKP), telephone consultation, video consultation, mobile health applications, and private and public health care use; and the PSS-4, GAD-2, and PHQ-2. Furthermore, sociodemographic factors (sex, age, children, relationship status, education, and employment) were included in the research model. Network analysis revealed that mental health indices were weakly related to eHealth tools use. Higher stress was positively linked with mobile health application use but negatively linked to video consultation use. Use of various eHealth tools was intercorrelated. Sociodemographic factors were differentially related to the use of the eight specific eHealth tools. Although mental health indices did not have strong associations in the eHealth tools use network, attention should be given to anxiety levels as the factor with the high expected influence.

Effectiveness and Costs of Molecular Screening and Treatment for Bacterial Vaginosis to Prevent Preterm Birth: The AuTop Randomized Clinical Trial

ABSTRACT One of the risk factors for preterm birth (PTB) is bacterial vaginosis (BV), a common, often asymptomatic, vaginal dysbiosis. The earlier BV is diagnosed based on gestational age, the higher the risk of PTB. The effectiveness of a screen-and-treat strategy for BV during pregnancy remains a source of debate. One meta-analyses, including 5 studies and 2346 patients, showed a benefit to screen and treat using clindamycin. Another, with 21 studies and 7847 patients, did not recommend BV screening but observed reductions in preterm delivery by 50% and miscarriages by 80%. In another systematic review, with 48 studies, there was varying accuracy across conventional screening tests for BV and suggested no or inconclusive efficacy in the treatment of asymptomatic BV in the general obstetric population and in those with a history of preterm delivery. Based on these studies, French and international organizations recommend against screening for BV with conventional diagnosis tools in low-risk populations. However, molecular diagnostic tools have been shown to be more accurate in identifying vaginal microbiota than conventional tools, such as clinical diagnosis based on Amsel or Nugent criteria. Molecular tools have been shown to provide an objective, reproducible, quantitative diagnosis of BV, identifying emergent pathogen species, such as Atopobium vaginae (now known as Fannyhessea vaginae). To date, no randomized studies have been conducted to assess the impact of molecular tools on a screen-and-treat intervention to BV. The aim of this study was to assess whether a screen-and-treat intervention using a molecular diagnostic tool is cost-effective in reducing the rate of PTB. The AuTop Trial was a prospective, open-label superiority trial conducted in 19 French maternity hospitals from March 9, 2015, to December 18, 2017. Included were adult women in early pregnancy (<20 weeks of gestation), with no history of PTB or late abortion and no major risk factors for prematurity. Excluded were patients who had extrauterine pregnancy or nonprogressive pregnancy, or were treated with antibiotics a week before inclusion in the study. Women were randomly assigned 1:1 to undergo molecular screening and treatment (intervention group) or receive usual care (control group). The intervention group was asked to self-collect vaginal swabs and return them within 15 days of collection for each month until 28 weeks of gestation. If BV was detected, treatment with azithromycin (1 g repeated after 48 hours) or amoxicillin (2 g/d for 7 days) was provided within 48 hours. A molecular biology-based rapid diagnostic tool designed for point-of-care testing was developed using real-time polymerase chain reaction assays to quantify DNA levels of A. vaginae. The tool's specificity, sensitivity, positive predictive value, and negative predicative value of the tool were 99%, 95%, 95%, and 99%, respectively, compared with other diagnostic techniques. The control group received usual care with no systematic screening of BV. A total of 6671 women were randomly assigned 1:1 to the intervention group (n = 3333) or control group (n = 3338). At inclusion, a total of 3438 were nulliparous pregnancies, with 1671 in the intervention group and 1767 in the control group. In the intention-to-treat analysis, no reduction in the rate of PTB was observed between the intervention and control group (3.8% vs 4.6%, respectively; risk ratio, 0.83; 95% confidence interval [CI], 0.66–1.05; P = 0.12). The average cost of intervention per woman was €203.60 (US $218.00). No significant differences were observed in the total cost in the intervention group versus control group (€3344.30 [US $3580.50] vs €3272.90 [US $3504.10]). In addition, no evidence of superiority was observed for the intervention strategy compared with usual care. However, in the nulliparous subgroup, the number of PTBs was significantly lower in the intervention group (3.6%; 95% CI, 2.9–4.6) than the control group (5.9%, 95% CI, 4.8–7.2), and the cost was nonsignificant. In conclusion, the molecular diagnostic tool for screening and treating BV did not significantly reduce the risk of PTBs. Although no significant benefit was found in the overall population, the screen-and-treat strategy using a molecular tool was more effective than usual care in reducing PTBs among nulliparous pregnant women.

XFuzz: Machine Learning Guided Cross-Contract Fuzzing

Smart contract transactions are increasingly interleaved by cross-contract calls. While many tools have been developed to identify a common set of vulnerabilities, the cross-contract vulnerability is overlooked by existing tools. Cross-contract vulnerabilities are exploitable bugs that manifest in the presence of more than two interacting contracts. Existing methods are however limited to analyze a maximum of two contracts at the same time. Detecting cross-contract vulnerabilities is highly non-trivial. With multiple interacting contracts, the search space is much larger than that of a single contract. To address this problem, we present <small>xFuzz</small>, a machine learning guided smart contract fuzzing framework. The machine learning models are trained with novel features (e.g., word vectors and instructions) and are used to filter likely benign program paths. Comparing with existing static tools, machine learning model is proven to be more robust, avoiding directly adopting manually-defined rules in specific tools. We compare <small>xFuzz</small> with three state-of-the-art tools on 7,391 contracts. <small>xFuzz</small> detects 18 exploitable cross-contract vulnerabilities, of which 15 vulnerabilities are exposed for the first time. Furthermore, our approach is shown to be efficient in detecting non-cross-contract vulnerabilities as well&#x2014;using less than 20&#x0025; time as that of other fuzzing tools, <small>xFuzz</small> detects twice as many vulnerabilities.

A GIS-Based Approach for Shallow Landslides Risk Assessment in the Giampilieri and Briga Catchments Areas (Sicily, Italy)

Shallow landslides pose a widely growing hazard and risk, globally and particularly in Mediterranean areas. The implementation of adequate adaptation and mitigation measures necessarily requires the development of practical and affordable methodologies and technologies for assessing the shallow landslides hazard and its territorial impact. The assessment of shallow landslide hazard maps involves two different and sequential steps: the susceptibility and the runout analysis, respectively, aimed at the identification of the initiation and the propagation areas. This paper describes the application in the Giampilieri and Briga Villages area (Sicily, Italy) of a shallow landslide risk process at a basin scale with an innovative approach in the runout assessment segment. The runout analysis was conducted using specific GIS tools employing an empirical–geometric approach at a basin scale. The exposure and vulnerability values of the elements at risk were assigned using a qualitative and semi-quantitative approach, respectively. The results highlight the effectiveness of the procedure in producing consistent runout hazard and risk assessments in the valley areas where the more important and vulnerable exposed elements are located. This study contributes to addressing the public administration demand for valuable and user-friendly tools to manage and drive regional planning.

ЭТИКА И МОРАЛЬ В СОВРЕМЕННОМ БИЗНЕСЕ: ЭТИЧЕСКИЕ ОСНОВЫ ПРИНЯТИЯ УПРАВЛЕНЧЕСКИХ РЕШЕНИЙ

In the last of the series of three articles on ethics in business, the author notes that there are various models and tools that help managers make professional decisions and which tend to focus on the functional needs of the manager, but do not take into account the moral and ethical aspect. Based on suggestions from other thinkers studying this topic and his own professional experience, the author formulates a model of decision-making in situations of ethical uncertainty. The author offers specific tools that help, first of all, to determine the presence of an ethical dilemma in the problem facing a manager and then steps that will allow him to make an ethically verified decision. However, the author does not stop there and notes that often managers, understanding which decision is ethical, nevertheless act differently, succumbing to moral weakness. The author analyzes the reasons for this behavior and gives advice on how to overcome it at the team level and at the personal level of a particular person. This model and the issues of its application are novel in this branch of thought and provide new tools in the hands of business leaders. In conclusion, the author concludes that in our time, when fears of replacing humans with artificial intelligence have become especially high, decisions regarding the moral component of the activities of companies will certainly remain one of the few prerogatives of a human person.

Irritability in Youths: A Critical Integrative Review.

Irritability, defined as proneness to anger that may impair an individual's functioning, is common in youths. There has been a recent upsurge in relevant research. The authors combine systematic and narrative review approaches to integrate the latest clinical and translational findings and provide suggestions for addressing research gaps. Clinicians and researchers should assess irritability routinely, and specific assessment tools are now available. Informant effects are prominent, are stable, and vary by age and gender. The prevalence of irritability is particularly high among individuals with attention deficit hyperactivity disorder, autism spectrum disorder, and mood and anxiety disorders. Irritability is associated with impairment and suicidality risk independent of co-occurring diagnoses. Developmental trajectories of irritability (which may begin early in life) have been identified and are differentially associated with clinical outcomes. Youth irritability is associated with increased risk of anxiety, depression, behavioral problems, and suicidality later in life. Irritability is moderately heritable, and genetic associations differ based on age and comorbid illnesses. Parent management training is effective for treating psychological problems related to irritability, but its efficacy in treating irritability should be tested rigorously, as should novel mechanism-informed interventions (e.g., those targeting exposure to frustration). Associations between irritability and suicidality and the impact of cultural context are important, underresearched topics. Analyses of large, diverse longitudinal samples that extend into adulthood are needed. Data from both animal and human research indicate that aberrant responses to frustration and threat are central to the pathophysiology of irritability, revealing important translational opportunities.

Feasibility Analysis of Subject Specific Pedagogy Physics Learning Module Based on Project Based Learning Integrated with Merdeka Curriculum on Alternative Energy Material

This study aims to analyse the feasibility of Subject Specific Pedagogy Physics tools based on Project Based Learning (PjBL) integrated with Merdeka Curriculum on alternative energy material for grade X high school students. This research uses the Research and Development (RnD) method with the 5D model (Define, Design, Develop, Disseminate, and Evaluate) which is limited to the devalope stage. The Define stage includes needs analysis and identification of competencies that must be achieved by students. The Design stage includes designing learning module in the form of modules and student worksheets. The Develop stage includes the development and validation of learning modules by experts in the aspects of material, learning, language and limited testing. The results showed that the PjBL-based Physics Subject Specific Pedagogy device integrated with the Merdeka Curriculum on alternative energy material for grade X high school students had high feasibility based on expert review in terms of material, learning, and language aspects. In addition, students also gave positive responses to the developed learning module. Therefore, the learning module is suitable for use in the Physics learning process in high school.

Determinants of Implementing an Information and Communication Technology Tool for Social Interaction Among Older People: Qualitative Content Analysis of Social Services Personnel Perspectives.

Older people are particularly vulnerable to social isolation and loneliness, which can lead to ill-health, both mentally and physically. Information and communication technology (ICT) can supplement health and social care and improve health among the vulnerable, older adult population. When ICT is used specifically for communication with others, it is associated with reduced loneliness in older populations. Research is sparse on how the implementation of ICT, used specifically for communication among older people in social services, can be performed. It is recommended to consider the determinants of implementation, that is, barriers to and facilitators of implementation. Determinants related to older people using ICT tools are reported in several studies. To the best of our knowledge, studies investigating the determinants related to the social services perspective are lacking. This study aims to explore the determinants of implementing the Fik@ room, a new, co-designed, and research-based ICT tool for social interaction among older people, from a social services personnel perspective. This study used an exploratory, qualitative design. An ICT tool called the Fik@ room was tested in an intervention study conducted in 2021 in 2 medium-sized municipalities in Sweden. Informants in this study were municipal social services personnel with experience of implementing this specific ICT tool in social services. We conducted a participatory workshop consisting of 2 parts, with 9 informants divided into 2 groups. We analyzed the data using qualitative content analysis with an inductive approach. The results included 7 categories of determinants for implementing the ICT tool. Being able to introduce the ICT tool in an appropriate manner concerns the personnel's options for introducing and supporting the ICT tool, including their competencies in using digital equipment. Organizational structure concerns a structure for communication within the organization. Leadership concerns engagement and enthusiasm as driving forces for implementation. The digital maturity of the social services personnel concerns the personnel's skills and attitudes toward using digital equipment. Resources concern time and money. IT support concerns accessibility, and legal liability concerns possibilities to fulfill legal responsibilities. The results show that implementation involves an entire organization at varying degrees. Regardless of how much each level within the organization comes into direct contact with the ICT tool, all levels need to be involved to create the necessary conditions for successful implementation. The prerequisites for the implementation of an ICT tool will probably change depending on the digital maturity of future generations. As this study only included 9 informants, the results should be handled with care. The study was performed during the COVID-19 pandemic, which has probably affected the results.

Droplet digital PCR as alternative to microbiological culture for Mycobacterium tuberculosis complex detection in bovine lymph node tissue samples.

Bovine tuberculosis (bTB) caused by Mycobacterium tuberculosis complex (MTC) remains a significant concern for public health. Direct real-time PCR and droplet digital PCR (ddPCR) are proposed as alternative tools to enhance diagnostic precision and efficiency. This study aims to assess the diagnostic performance of a ddPCR assay targeting IS6110 for the detection of MTC DNA in both microbiological culture and fresh lymph node (LN) tissue samples obtained from cattle, in comparison with the established reference standard, the microbiological culture followed by real-time PCR. The fresh LNs (N=100) were collected each from a different cattle carcass at the slaughterhouse. The limit of detection of ddPCR-IS6110 was set to 101 copies per 20 μl reaction. DdPCR-IS6110 detected 44 out of 49 reference-standard positive samples and yielded negative results in 47 out of 51 reference-standard negative samples, resulting in adjusted sensitivity (Se) and specificity (Sp) of 90.76% [95% confidence interval (CI): 82.58 - 98.96%)], and 100% (95% CI: 100%) respectively. The estimated adjusted false negative rate (FNR) was 9.23% (95% CI: 1.04 - 17.42%) and the false positive rate (FPR) was 0% (95% CI: 0%). When directly applied from fresh bovine LN tissues, ddPCR-IS6110 identified 47 out of 49 reference-standard positive samples as ddPCR-IS6110-positive and 42 out of 51 reference-standard negative samples as ddPCR-IS6110-negative, resulting in adjusted Se and Sp values of 94.80% [95% (CI): 88.52 - 100%] and 100% (95% CI: 100%), respectively. The adjusted FNR was 5.20% (95% CI: 0 - 11.50%) and the FPR was 0% (95% CI: 0%). Noteworthy, ddPCR-IS6110 disclosed as positive 9 samples negative to reference-standard. DdPCR-IS6110 proved to be a rapid, highly sensitive, and specific diagnostic tool as an alternative to reference-standard method.