Design Stage Research Articles

Rancang Bangun Media Pembelajaran Interaktif pada Mata Pelajaran Desain Grafis

. Design and Development of Interactive Learning Media in Graphic Design Subjects is a research that aims to develop effective and practical interactive learning media on basic graphic design topics. This research uses the ADDIE development model, which consists of five development stages: analysis, design, development, implementation, and evaluation.At the analysis stage, this research understands the problems found in the use of learning media in graphic design subjects, such as the limited use of print media and the need for more interactive and interesting media. At the design stage, this research develops a learning media design that involves multimedia elements such as text, images, graphics, sound, video, animation and comprehensive simulations. At the development stage, this research develops multimedia-based interactive learning media, which can provide certain forms of interaction that allow users to interact actively with the program. The research results show that the Basic Graphic Design interactive learning media developed is valid from the instructional and display aspects, and is practical and suitable for use for basic graphic design learning. Thus, this research contributes to the development of interactive learning media that is effective and practical in improving the quality of learning in graphic design subjects.

Pengembangan Modul Pembelajaran Mata Pelajaran Pengecatan Bodi Pada SMK Program Keahlian Teknik Bodi Otomotif

This research is a development research (research and development) with the development of learning media in the form of Automotive Body Engineering modules in Class XI Body Painting Subjects at SMK Kristen 5 Klaten using the Four-D method by Thiagarajan and Semmel which has been modified. The stages used in the module development process are the defining stage (define), the design stage (design), the development stage (develop) and the dissemination stage (disseminate). Collecting feasibility data using questionnaires and observations. This study involved material experts, media experts, subject teachers and students to obtain module feasibility assessments and responses. The data analysis technique used was quantitative descriptive analysis.The results showed that: 1) produce an Automotive Body Engineering learning module; 2) the Automotive Body Engineering learning module at SMK Kristen 5 Klaten is feasible to use based on the results of material expert validation with a percentage of 76.08% and the results of validation by media experts with a percentage of 73.80% with a decent category; The results of the assessment of the feasibility level of the Automotive Body Engineering learning module at SMK Kristen 5 Klaten by the subject teacher with a percentage of 88.23% with a decent category; 4) The results of the assessment response from class XI students were 94.14% with a very feasible category.

Assessing Approaches to Strengthen Monitoring and Evaluation in Development Projects: Evidence from Donor-Funded Projects in Machakos County, Kenya

Monitoring and Evaluation improves the quality of programme or project management since it provides information on how results namely outcomes, outputs and impact are achieved and assesses the effectiveness, relevance, coherence, efficiency, impact and sustainability of specific development interventions. The objectives of the study were to examine the influence of participatory monitoring and evaluation among development project teams in Machakos County and to assess the influence of M & E as a learning tool on implementation of development projects in Machakos County, Kenya. The study was guided by the Theory of Change which describes how particular interventions or sets of interventions lead to specific changes. The target population of this study was 102 programme staff implementing donor-funded projects. A census was done and therefore the target group formed the sample for the study. Primary data sources used were key informant interviews and a survey questionnaire. Quantitative data was analyzed in SPSS Version 28 and qualitative data was thematically analyzed. According to the survey results, 58.2% agreed that the involvement of all relevant project stakeholders during the preliminary stages of project design strengthens M&E. The survey results showed that 49.45% of the respondents agreed that project planning reflected the various community needs and supported decision-making processes during project implementation. A majority (58.23%) agreed that feedback from various stakeholders was often incorporated and used to strengthen the delivery of various project activities informant interviews. Majority of the survey respondents (72%) indicated that learning is integral to ensuring M&E is effective and project teams can learn immensely from M & E. A majority (71%) agreed that project teams feared participating in M&E activities due to fear that it could be used against them. The findings show that the involvement of stakeholders in project design and implementation directly influenced successful project M & E. The study recommended involving relevant parties and stakeholders in a project since this influences its implementation and M & E among donor-funded development projects. Project managers need to put in place incentives for project teams to learn not just for reporting to funding agencies but for the benefit of internal learning among project teams.

Effects on the design of aeronautical fuel cell systems by inclusion of reliability requirements

AbstractThe change towards carbon neutrality in air traffic involves a huge reduction of greenhouse gas emissions. This goal is beyond reach by the step wise improvement of conventional technologies. Hence, at present a solution which gains much of attraction are electric motors and electric aircraft systems in combination with fuel cells which can be run by green hydrogen. For a holistic comparison of various concepts the consideration of reliability aspects is required even at an early stage of design. In the scope of this work methods from reliability and safety engineering will be introduced and set in context of aeronautical fuel cell systems. On that basis the consequences arising by the requirement of redundancy are investigated on a system level approach. For this purpose, a model of an aeronautical fuel cell system will be set up in order to simulate a generic flight envelope at stationary points. The fuel cell system is chosen to be central-monolithic and its components are sized for the propulsion of a regional aircraft. With the aid of the system simulation, various failure scenarios are investigated from which mitigation strategies can be derived. Finally, the baseline design will be improved in terms of redundancy in order to last in a generic failure scenario. A comparison between the baseline and improved design shows that the additional redundancy comes with the cost of 4.6% weight increase and a 2.5% drop in cruise efficiency.

Impact of Employee Performance in Context of Sustainable Growth in Education Sector: A Prospective of Mentorship’s Effect

This research introduces an innovative educational resource for Physics education, focusing on the captivating story of J. J. Thomson's. Comics, with their visually immersive nature, effectively merge text and visuals to accommodate diverse learning styles. They engage students through narratives and vivid visuals, enhancing the educational experience. Utilizing Thiagarajan’s 4D approach (define, design, develop, disseminate), the study collects historical sources in the definition stage and meticulously plans visual narratives in the design stage. Visual literacy is highlighted, enabling students to critically analyze visual information. In the development stage, comics are refined, expert-evaluated, and tested on users. These comics are then disseminated via the Webtoon platform. The results highlight comics' potential as a valuable teaching tool, captivating students with engaging narratives and rich visuals, making Physics education more enjoyable. Moreover, comics demonstrate their broader relevance in Physics instruction, contributing to the ongoing discourse on innovative and visually engaging teaching methods.

Utility of real-world evidence in biosimilar development

ABSTRACT Biosimilar development refers to the process of creating a biologic drug that is similar to an existing approved biologic drug, also known as a reference drug. Due to the complex nature of biologics drugs and the inherent variability in their manufacturing process biosimilars are not identical but highly similar to the reference drug in terms of quality, safety, and efficacy. Efficacy and safety trials for biosimilars involve large numbers of patients to confirm comparable clinical performance of the biosimilar and the reference product in appropriately sensitive clinical indications and for appropriate sensitive endpoints. The objective of a biosimilar clinical data is to address slight differences observed at previous steps and to confirm comparable clinical performance of the biosimilar and the reference product. In recent years with advances in big data computing, there has been increasing interest to incorporate the totality of information from different data sources (e.g. Real World data and published literature) in design and conduct of clinical trial to support regulatory objectives. The biosimilar development is an ideal framework for utilization of Real-World Evidence in design of trials as potentially large amount of data are available for the reference dug. Hence there may be an opportunity to use RWD in establishing, improving or validating equivalence margins (EQM) for biosimilar designs, specifically in the case there is no historical published data in the intended sensitive population. In this article, we propose a variation of matching method that seems promising to identify the matched set from a real-world data for which the effect size of targeted endpoint would be comparable to historical data. We believe this is a reasonable approach because in design stage, we can view covariates and secondary endpoints as data feature that can be used in a matching method. This approach was illustrated through a case study which indicated the estimate of the primary endpoint is within 1% of published results and thus RWD may be used to justify or estimate the equivalence margin. To ensure consistent results we recommend using this approach in different indications and endpoint scenarios. Thus utilization of RWD/RWE can provide an important opportunity to increase access to biologic therapies, reducing cost by repurposing existing data.

Engineering Information Format Utilisation Across Building Design Stages: An Exploration of BIM Applicability in China

Building Information Modelling (BIM) has been extensively advocated in the construction industry for its potential to improve design efficiency and quality. However, its application continues to encounter considerable resistance from designers because BIM is less efficient than conventional 2D and 3D data formats in some design tasks. Consequently, a flexible approach that integrates BIM into existing workflows, instead of fully replacing traditional data formats, is believed to better enhance BIM application. Given this concern, this study conducts a questionnaire survey among Chinese designers to investigate the engineering information formats used in practice and to assess the potential and applicability of this flexible approach. Analysis of the survey responses using relevance analysis, logistic regression, and multiple correspondence analysis reveals that BIM is more frequently used for coordinating multi-disciplinary data in the later stages of project development than in early design phases. Conversely, conventional 2D and 3D formats are preferred for creating and comparing design alternatives during the concept and developed design stages. A practical application for BIM emerges in the technical design stage of prefabricated construction projects. These results suggest a promising approach for BIM application: allowing the use of conventional data format in the concept and developed design stages, integrating these designs into a shared BIM model in the technical design stage, and maintaining them in the BIM model thereafter. Besides offering an in-depth analysis of engineering information format utilization, this study offers practical strategies for contractors, policymakers, and BIM developers to extend BIM application and promotion.

Synergizing BIM and RIBA in architectural practice – technology workflow efficiencies, challenges, and insights

ABSTRACT Productivity improvements are constrained by insufficient consideration of technology adoption within professions. This study clarifies the limited knowledge between BIM and RIBA architectural workflow synergies and proposes a framework to improve identified inefficiencies. Consequently, a qualitative approach consisting of 10 interviews with architects was conducted to understand their personal experiences and opportunities for improvement. The findings revealed that multidisciplinary design cooperation and risk reduction are major possibilities for workflow improvements in the design stage, while site communication and error detection increase the need for an architect’s presence onsite during the construction stage. Additionally, this study identifies interoperability, barriers to change, and design inflexibility as professional drawbacks of using BIM. These findings provide hierarchical data to form an architect’s BIM matrix, which aims to maximise opportunities and reduce challenges in BIM implementation. This study highlights the importance of considering both technical and human factors in BIM adoption and uses management theories to explain how architects can better utilise technology to enhance their practice.

Pole placement tuning of proportional integral derivative feedback controller for knee extension model

Functional electrical stimulation (FES) has shown potential in rehabilitative exercises for patients recovering from spinal cord injuries. In recent developments, conventional open-loop FES control techniques have evolved into closed-loop systems that employ feedback controllers for automation. However, closed-loop FES systems often face challenges due to muscle non-linear effects, such as fatigue, time delays, stiffness, and spasticity. Therefore, an accurate non-linear knee model is required during the design stage, and precise tuning of the feedback controller parameters is vital. A proportional– integral–derivative (PID) controller is commonly used as a feedback controller due to its simplicity and ease of implementation. However, most PID tuning methods are complex and time consuming. This paper investigates the viability of employing the pole placement technique for tuning a PID controller that regulates the non-linear knee extension model. The pole placement method aims to improve the control and adaptability of the PID controller in closed-loop FES systems, specifically by facilitating knee extension exercises. MATLAB Simulink was used to assess the effectiveness of this tuning approach. Results showed that the PID controller performed satisfactorily without non-linearities, but performance varied with the inclusion of specific non-linearities. The pole placement tuning method facilitated preliminary assessments of PID controller performance, preceding highly advanced optimization.

User interface design of context-input-process-product evaluation application based on weighted product

This study aimed to show the user interface design form of the <br /> context-input-process-product (CIPP) evaluation application based on weighted product as a measuring tool for the effectiveness level of blended learning in health colleges. This research approach was development research. The development model used was Borg and Gall. It focused on the design stage, initial trials, and revisions. The initial test of the user interface design involved 32 respondents. The tool for conducting it was in the form of a questionnaire, which contains 16 questions. The research was at the health colleges in Buleleng Regency. The data analysis technique of the initial test results was quantitative descriptive. It compared the percentage level of user interface design quality from the weighted product-based CIPP evaluation application with a quality standard which referred to a five scale. The results of this study indicated that the quality of the user interface design was relatively good. The research result’s impact on educational evaluation was new knowledge for pedagogic evaluators in maximizing the development of digital-based evaluation tools by integrating the decision support system method (weighted product) with the educational evaluation model (CIPP model).

Phase 1b/2a of narmafotinib (AMP945) in combination with gemcitabine and nab-paclitaxel in first-line patients with advanced pancreatic cancer (ACCENT trial): Interim analysis.

e16337 Background: Narmafotinib (AMP945) is a highly potent and selective, orally bioavailable inhibitor of Focal Adhesion Kinase (FAK). FAK is a non-receptor tyrosine kinase over-expressed in pancreatic cancer, where it contributes to cell survival, proliferation, migration and chemoresistance and thus plays a key role in tumor growth, FAK also contributes to multiple mechanisms underlying fibrosis and immunosuppression in the tumor microenvironment. Narmafotinib has successfully completed a Phase 1 study in healthy volunteers where the drug was safe and well tolerated with pharmacokinetics consistent with once-a-day dosing. A Phase 1b/2a trial of narmafotinib, in combination with gemcitabine and Abraxane, in advanced pancreatic cancer patients – the ACCENT trial – is currently underway in Australia and South Korea. Methods: The ACCENT trial (NCT05355298) is a Phase 1b/2a, open label study of the pharmacokinetics, safety and tolerability, and efficacy of narmafotinibin combination with gemcitabine and Abraxane (nab-paclitaxel) standard of care as first-line therapy in patients with advanced pancreatic cancer. The trial is a single-arm open label study conducted in two stages. In Part A, patients were enrolled in a 3+3 design to determine the narmafotinib recommended Phase 2 dose (RP2D), with narmafotinibdose-escalation (100, 200 and 400 mg). Safety and tolerability were assessed according to incidence and severity of adverse events. Narmafotinibplasma PK samples were collected on Days -8, -7, 1, 3, 8, and 10 of Run-In/Cycle 1. Imaging was conducted every 2 months. Part B of the trial is a Simon’s two stage design, with the primary objectives of assessing safety, tolerability, and efficacy of the combination using RECIST v1.1. Results: Preliminary analysis across all doses (14 patients) showed narmafotinib to be generally safe and well-tolerated and showed promising signs of efficacy. All patients who completed their first 28-day cycle of treatment elected to stay on narmafotinib and 9/14 patients have remained on trial for 5 months or more. There have been 6 confirmed PRs (4 in 400 mg cohort; 2 in 200 mg cohort) as best response. A single DLT was reported: uncontrolled grade 3 nausea (400 mg cohort). Fatigue, grade 3 or below related to narmafotinib occurred in more than one participant. The PK for narmafotinib is dose-proportional across the dose range tested, and the chemotherapy regimen used in this study did not impact narmafotinib PK. Safety, tolerability and efficacy data continues to be collected and will be presented. Conclusions: Based on this promising Phase 1b data, 400 mg of narmafotinib has been selected for the RP2D and Part B of the trial is now underway and recruiting patients in Australia and South Korea. The trial will enrol up to 50 patients as part of the Phase 2 expansion cohort. Clinical trial information: NCT05355298 .

Neoadjuvant treatment with camrelizumab in combination with doxorubicin and ifosfamide: A phase II clinical study of high-risk soft tissue sarcoma.

e23548 Background: Surgery remains the cornerstone in the management of non-metastatic soft tissue sarcomas. However, high rate of recurrence and metastasis are not uncommon in patients(pts) with high-risk soft tissue sarcoma. Although doxorubicin plus ifosfamide resulted in better tumor shrinkage which facilitate surgical resection, approaches of reducing recurrence and metastasis are still needed. Chemotherapy combined with PD-1 antibodies showed promising activity in several tumors. To date, there is no study to evaluate the efficacy and safety of camrelizumab combined with chemotherapy for high-risk Soft Tissue Sarcoma. Methods: This is a phase II, open-label single-arm study (NCT04606108), aimed to include pts aged 14-65 with histopathologically confirmed high risk soft tissue sarcoma and ECOG 0-1, at least one measurable lesion. One course of treatment every three weeks (camrelizumab 200 mg on day 1, doxorubicin 37.5 mg/m2 or liposomal doxorubicin 25 mg/m2 on days 1-2, and ifosfamide 3 g/m2 on days 1-3). After completing the 2nd course of chemotherapy, the drug will be stopped for 14 days, and surgery or the next stage of treatment will be carried out according to the efficacy of the treatment. Six courses of preoperative chemotherapy will be administered 2 weeks ± 5 days after surgery based on the effectiveness, followed by radiotherapy (50 Gy in 25 fractions or 60 Gy in 30 fractions.) within 3 months after surgery. The primary objective is the Objective response rate (ORR). Using the Simon minimax 2 stage design, planned sample size is 62 pts with 80% power and alpha of 5% to detect an increase in ORR from 27% to 42%. Interim analysis requiring at least 9 confirmed responses in the first 30 pts to proceed to full accrual. Results: 35 pts completed neoadjuvant therapy and surgery, 30 pts received postoperative adjuvant therapy and 1 patient achieved partial response (PR). Median age was 36.4 years (14-61), 62.8% were females, and 57.1% were ECOG-PS 0. Surgery was performed in 35 pts including 16/35 Synovial Sarcoma (SS), 5/35 Liposarcoma (LPS), 2/35 Myxofibrosarcoma (MFS), 2/35 Undifferentiated pleomorphic sarcoma (UPS), 1/35 Leiomyosarcoma (LMS), 5/35 Malignant mesenchymal tumors and 4/35 other pathologic subtype. The 2-year PFS rate was 84.9%, the 2-year OS rate was 96.77%, and the 2-year RFS rate was 72.6%. The most common grade 3-4 adverse events included leukopenia (37.7%), Neutrophil count decreased (37.7%), Platelet count decreased (20.0%), Blennisthmia (3.1%), and Aspartate aminotransferase increased (0.8%). Conclusions: Camrelizumab combined with doxorubicin, liposomal doxorubicin, and ifosfamide in the perioperative treatment of soft tissue sarcoma pts were safe and tolerable. Survival follow-up is still ongoing to analyze the effect of perioperative immunotherapy combined with chemotherapy on long-term outcomes of pts with soft tissue sarcoma. Clinical trial information: NCT04606108 .

Phase 2 study of novel HER2-targeting, TLR7/8 immune-stimulating antibody conjugate (ISAC) BDC-1001 (trastuzumab imbotolimod) +/- pertuzumab (P) in patients (pts) with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab deruxtecan (T-DXd).

TPS1121 Background: Therapies to manage pts with HER2+ MBC have significantly improved, but better agents are still needed. BDC-1001 (trastuzumab imbotolimod) is being studied for MBC and other HER2+ cancers. The ISAC BDC-1001 consists of a trastuzumab biosimilar conjugated to a cell membrane impermeable TLR7/8 agonist via a non-cleavable linker and is given IV every 2 wks. Designed to trigger the innate immune system, BDC-1001 causes a durable tumor-targeted adaptive immune response. Early studies show that HER2-targeted ISACs elicit potent and durable immune-mediated antitumor efficacy, and tumor regression, in a TLR- and Fc receptor-dependent manner (1). Preclinical studies with a murine surrogate of BDC-1001 (trastuzumab-T785 ISAC) show better efficacy with trastuzumab-T785 compared to trastuzumab + P. In the BDC-1001 dose-escalation trial (BBI-20201001), 6 PRs and 12 SDs ≥ 24 weeks in 8 tumor types were observed, particularly in 20mg/kg q2w dose cohorts. The most frequent drug-related AE was low grade (grade 1/2) infusion-related reactions (29%) (2). We showed the combination of a surrogate ISAC (trastuzumab-T785) + P significantly enhances efficacy in multiple HER2-expressing tumors, including those with lower HER2 expression (1). The addition of P lowered the quantity of ISAC required for anti-tumor activity in the JIMT-1 HER2 IHC2+ model. The combination of P with the ISAC significantly increased the tumor cytokine and chemokine concentration compared to monotherapy or antibody-alone, indicating enhanced tumor myeloid activation suggesting this combination may enhance the clinical activity of trastuzumab-based ISACs. Methods: The Phase 2 multicenter, open-label, randomized study (BBI-20231001) is enrolling up to 66 patients with HER2-positive (ASCO/CAP 2018) MBC previously treated with 2 or more anti-HER2 therapies including T-DXd. Patients must be > 18 years, have measurable disease, and have ECOG performance status of 0 or 1. Patients will be randomized 1:1 to receive BDC-1001 20mg/kg every 2 weeks with or without P (840mg initial dose, followed by 420mg IV q 3w). Each arm has a Simon 2 stage design. The primary objective is anti-tumor activity of BDC-1001 alone and in combination with P. Secondary objectives will evaluate safety, PK, and immunogenicity of BDC-1001 alone and in combination with P. Exploratory objectives will include PD biomarkers in tumor tissue and in peripheral blood to elucidate the MOA and biomarkers associated with BDC-1001 activity with or without P. This study began accrual in Nov 2023. 1. Ackerman S, et al. Nature Cancer. 2021. 2. Li B, et al. ASCO 2023, Abstract 2538. Clinical trial information: NCT05954143 .

Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).

TPS4614 Background: First-line treatment for patients with metastatic clear cell renal cell carcinoma (mccRCC) often includes an anti-PD1 inhibitor in combination with either an anti-CTLA inhibitor (IO/IO) or a VEGF receptor tyrosine kinase inhibitor (TKI) (IO/TKI). Although some patients treated with nivolumab/ipilimumab (Nivo/Ipi) (IO/IO) experience durable responses leading to treatment free intervals, over two-thirds experience disease progression. Resistance to Nivo (anti-PD1) monotherapy has been associated with increased presence of a subpopulation of Tregs in the tumor microenvironment. Botensilimab (Bot) is an IO agent that leverages novel FcyR-associated mechanisms of action to enhance T cell priming, deplete intratumoral Tregs and enhance myeloid activation. Combination botensilimab/balstilimab (Bot/Bal) (anti-CTLA/anti-PD1) has shown impressive anti-tumor activity in diseases where Nivo/Ipi has shown little to no efficacy. Methods: ARCITECT is a phase II, multicenter investigator initiated trial evaluating the efficacy and safety of Bot/Bal relative to Nivo/Ipi. Patients with mccRCC (favorable, intermediate, or poor risk), no prior systemic therapy (including adjuvant or neoadjuvant), and at least one measurable lesion as defined by RECIST 1.1 are eligible for enrollment. 120 patients will be randomized in a 2:1 fashion to Arm A (Bot/Bal induction followed by Bal maintenance) or Arm B (Nivo/Ipi induction followed by Nivo maintenance) each for a maximum of 2 years. Stratification factors include IMDC risk groups and sarcomatoid histology. The primary endpoint is overall response rate (ORR) per RECIST 1.1. We hypothesize that Bot/Bal will lead to a superior ORR (55%) relative to Nivo/Ipi (40%). This trial has > 90% power to detect the alternative hypothesis while maintaining a one-sided significance level of not more than 0.10 using the exact binomial. The study will be monitored for early stopping in favor of the null hypothesis based on a Simon’s two stage design. In the first stage, 69 patients will be enrolled (Arm A:46 and Arm B:23). If at the end of the first stage, Arm A has either at least 18/42 (42.8%) of eligible patients responding or an ORR at least numerically equivalent to that for eligible patients in Arm B, then the trial will progress to the second stage. The primary endpoint will be met if there are 38/80 responders (ORR > 47.5%) in Arm A. Key secondary endpoints include landmark progression-free survival, treatment-free survival and rates of immune-related adverse events. Correlative studies will explore immune and molecular predictors of response and resistance to IO/IO in tumor and blood. Clinical trial information: NCT05928806 .

Product Development Targeting Users from Whom It Is Difficult to Obtain Qualitative Data in the Initial Stage of Product Design

Product Development Targeting Users from Whom It Is Difficult to Obtain Qualitative Data in the Initial Stage of Product Design

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training

ObjectiveIn this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodeling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice. MethodsCombining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise. ResultsMuscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of ‘exercise-training’ responsive genes shared for each tissue between genotypes. ConclusionsOur investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.

Towards understanding and improving medication safety for patients with mental illness in primary care: A multimethod study.

Medication safety incidents have been identified as an important target to improve patient safety in mental healthcare. Despite this, the causes of preventable medication safety incidents affecting patients with mental illness have historically been poorly understood, with research now addressing this knowledge gap through a healthcare professional lens. However, patients and carers can also provide complimentary insight into safety issues, and as key stakeholders in healthcare, it is vital to consider their needs when designing effective interventions. A two-stage approach was adopted by (i) conducting three focus groups (FG) comprising 13 patients with mental illness and their carers to develop a holistic picture of medication safety in primary care with extraction of themes guided by the P-MEDS framework; (ii) conducting two separate nominal group consensus workshops with seven patients with mental illness/carers and seven healthcare professionals to identify priority areas for targeted interventions. Seven themes were identified in the FGs: communication; trust, involvement and respect; continuity and support; access; the healthcare professional; the patient and carer;and the organisation. Priority areas identified for intervention by key stakeholders included improving communication within and between clinical services, enhancing patient support with holistic continuity of care, maximising shared decision-making and empowerment, ensuring timely access to medicines and services, strengthening healthcare professional knowledge regarding mental illnesses and associated medications,and increasing patient dignity and respect. This study has developed a holistic picture of contributors to medication safety incidents affecting patients with mental illness in primary care. This theory was then used by key stakeholders to inform and generate priority recommendations for targeted interventions. These findings can be used to inform future intervention research, as they consider the needs of those who access or work within primary care services. An advisory group consisting of three expert patients with lived experience of mental illness was consulted on the design of both stages of this study. Patients with mental illness and/or their carers were recruited and participated in both stages of this study. Patients/carers aided with data analysis and interpretation during the patient/carer nominal group consensus workshop.

The Power of Molecular Dynamics Simulations and Their Applications to Discover Cysteine Protease Inhibitors.

A large family of enzymes with the function of hydrolyzing peptide bonds, called peptidases or cysteine proteases (CPs), are divided into three categories according to the peptide chain involved. CPs catalyze the hydrolysis of amide, ester, thiol ester, and thioester peptide bonds. They can be divided into several groups, such as papain-like (CA), viral chymotrypsin-like CPs (CB), papain-like endopeptidases of RNA viruses (CC), legumain-type caspases (CD), and showing active residues of His, Glu/Asp, Gln, Cys (CE). The catalytic mechanism of CPs is the essential cysteine residue present in the active site. These mechanisms are often studied through computational methods that provide new information about the catalytic mechanism and identify inhibitors. The role of computational methods during drug design and development stages is increasing. Methods in Computer-Aided Drug Design (CADD) accelerate the discovery process, increase the chances of selecting more promising molecules for experimental studies, and can identify critical mechanisms involved in the pathophysiology and molecular pathways of action. Molecular dynamics (MD) simulations are essential in any drug discovery program due to their high capacity for simulating a physiological environment capable of unveiling significant inhibition mechanisms of new compounds against target proteins, especially CPs. Here, a brief approach will be shown on MD simulations and how the studies were applied to identify inhibitors or critical information against cysteine protease from several microorganisms, such as Trypanosoma cruzi (cruzain), Trypanosoma brucei (rhodesain), Plasmodium spp. (falcipain), and SARS-CoV-2 (Mpro). We hope the readers will gain new insights and use our study as a guide for potential compound identifications using MD simulations.

Development and validation of a supportive programme for family caregivers of children suffering from cystic fibrosis: protocol for a sequential exploratory mixed-methods study

IntroductionFamilies with children who have cystic fibrosis (CF) face a multitude of challenges. They require complex and time-consuming daily care, various forms of knowledge and intricate care responsibilities. One of...

Assessment of a Simplified Methodology for Preliminary Blast-Resistant Design of Insulated Precast Concrete Wall Panels

Abstract A Blast loading history can be represented by the peak pressure value and the impulse. Combinations of pressure and impulse of various blast loading scenarios can be collected to draw a pressure-impulse (P-I) curve that corresponds to a level of damage of a blast-resistant structural component. The P-I curve is typically used for a preliminary design or assessment of blast resistance structural components. Generating a P I curve for a given structural component and level of protection requires repeatedly ru nning a single degree of freedom system (SDOF) model, which can be tedious for early design stages. Hence, a simplified approach (i.e., the normalization approach) was utilized to promptly generate the P- I curve for insulated precast concrete wall panels, which relies on shifting a control P I curve using normalization factors. The generated P-I curves using the normalization approach are validated with the traditional SDOF approach curves; 95% of the examined insulted panel configurations have an error between +/-7%. As a result of the reached low error percentages, a spreadsheet- design tool was developed using this approach. The tool can further enable rapid evaluation of the performance of insulated precast concrete panels under blast loading during the preliminary design phase.