Translational Gap Research Articles

Neuronutraceuticals Combating Neuroinflammaging: Molecular Insights and Translational Challenges-A Systematic Review.

Neuropathologies, such as neuroinflammaging, have arisen as a serious concern for preserving the quality of life due to the global increase in neurodegenerative illnesses. Nowadays, neuronutraceuticals have gained remarkable attention. It is necessary to investigate the bioavailability, off-target effects, and mechanism of action of neuronutraceuticals. To comprehend the comprehensive impact on brain health, well-designed randomized controlled trials testing combinations of neuronutraceuticals are also necessary. Although there is a translational gap between basic and clinical research, the present knowledge of the molecular perspectives of neuroinflammaging and neuronutraceuticals may be able to slow down brain aging and to enhance cognitive performance. The present review also highlights the key emergent issues, such as regulatory and scientific concerns of neuronutraceuticals, including bioavailability, formulation, blood–brain permeability, safety, and efficacy.

Fluorescent hiPSC-derived MYH6-mScarlet cardiomyocytes for real-time tracking, imaging, and cardiotoxicity assays

Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) hold great potential in the cardiovascular field for human disease modeling, drug development, and regenerative medicine. However, multiple hurdles still exist for the effective utilization of hiPSC-CMs as a human-based experimental platform that can be an alternative to the current animal models. To further expand their potential as a research tool and bridge the translational gap, we have generated a cardiac-specific hiPSC reporter line that differentiates into fluorescent CMs using CRISPR-Cas9 genome editing technology. The CMs illuminated with the mScarlet fluorescence enable their non-invasive continuous tracking and functional cellular phenotyping, offering a real-time 2D/3D imaging platform. Utilizing the reporter CMs, we developed an imaging-based cardiotoxicity screening system that can monitor distinct drug-induced structural toxicity and CM viability in real time. The reporter fluorescence enabled visualization of sarcomeric disarray and displayed a drug dose–dependent decrease in its fluorescence. The study also has demonstrated the reporter CMs as a biomaterial cytocompatibility analysis tool that can monitor dynamic cell behavior and maturity of hiPSC-CMs cultured in various biomaterial scaffolds. This versatile cardiac imaging tool that enables real time tracking and high-resolution imaging of CMs has significant potential in disease modeling, drug screening, and toxicology testing.Graphical abstract

A Hierarchical Framework for Assessing Transmission Causality of Respiratory Viruses.

Systematic reviews of 591 primary studies of the modes of transmission for SARS-CoV-2 show significant methodological shortcomings and heterogeneity in the design, conduct, testing, and reporting of SARS-CoV-2 transmission. While this is partly understandable at the outset of a pandemic, evidence rules of proof for assessing the transmission of this virus are needed for present and future pandemics of viral respiratory pathogens. We review the history of causality assessment related to microbial etiologies with a focus on respiratory viruses and suggest a hierarchy of evidence to integrate clinical, epidemiologic, molecular, and laboratory perspectives on transmission. The hierarchy, if applied to future studies, should narrow the uncertainty over the twin concepts of causality and transmission of human respiratory viruses. We attempt to address the translational gap between the current research evidence and the assessment of causality in the transmission of respiratory viruses with a focus on SARS-CoV-2. Experimentation, consistency, and independent replication of research alongside our proposed framework provide a chain of evidence that can reduce the uncertainty over the transmission of respiratory viruses and increase the level of confidence in specific modes of transmission, informing the measures that should be undertaken to prevent transmission.

Real-World Implementation of Precision Psychiatry: A Systematic Review of Barriers and Facilitators.

Background: Despite significant research progress surrounding precision medicine in psychiatry, there has been little tangible impact upon real-world clinical care. Objective: To identify barriers and facilitators affecting the real-world implementation of precision psychiatry. Method: A PRISMA-compliant systematic literature search of primary research studies, conducted in the Web of Science, Cochrane Central Register of Controlled Trials, PsycINFO and OpenGrey databases. We included a qualitative data synthesis structured according to the ‘Consolidated Framework for Implementation Research’ (CFIR) key constructs. Results: Of 93,886 records screened, 28 studies were suitable for inclusion. The included studies reported 38 barriers and facilitators attributed to the CFIR constructs. Commonly reported barriers included: potential psychological harm to the service user (n = 11), cost and time investments (n = 9), potential economic and occupational harm to the service user (n = 8), poor accuracy and utility of the model (n = 8), and poor perceived competence in precision medicine amongst staff (n = 7). The most highly reported facilitator was the availability of adequate competence and skills training for staff (n = 7). Conclusions: Psychiatry faces widespread challenges in the implementation of precision medicine methods. Innovative solutions are required at the level of the individual and the wider system to fulfil the translational gap and impact real-world care.

Multiphysics pharmacokinetic model for targeted nanoparticles.

Nanoparticles (NP) are being increasingly explored as vehicles for targeted drug delivery because they can overcome free therapeutic limitations by drug encapsulation, thereby increasing solubility and transport across cell membranes. However, a translational gap exists from animal to human studies resulting in only several NP having FDA approval. Because of this, researchers have begun to turn toward physiologically based pharmacokinetic (PBPK) models to guide in vivo NP experimentation. However, typical PBPK models use an empirically derived framework that cannot be universally applied to varying NP constructs and experimental settings. The purpose of this study was to develop a physics-based multiscale PBPK compartmental model for determining continuous NP biodistribution. We successfully developed two versions of a physics-based compartmental model, models A and B, and validated the models with experimental data. The more physiologically relevant model (model B) had an output that more closely resembled experimental data as determined by normalized root mean squared deviation (NRMSD) analysis. A branched model was developed to enable the model to account for varying NP sizes. With the help of the branched model, we were able to show that branching in vasculature causes enhanced uptake of NP in the organ tissue. The models were solved using two of the most popular computational platforms, MATLAB and Julia. Our experimentation with the two suggests the highly optimized ODE solver package DifferentialEquations.jl in Julia outperforms MATLAB when solving a stiff system of ordinary differential equations (ODEs). We experimented with solving our PBPK model with a neural network using Julia's Flux.jl package. We were able to demonstrate that a neural network can learn to solve a system of ODEs when the system can be made non-stiff via quasi-steady-state approximation (QSSA). Our model incorporates modules that account for varying NP surface chemistries, multiscale vascular hydrodynamic effects, and effects of the immune system to create a more comprehensive and modular model for predicting NP biodistribution in a variety of NP constructs.

Iterative Development of a Software to Facilitate Independent Home Use of BCI Technologies for Children with Quadriplegic Cerebral Palsy.

Brain-computer interfaces (BCIs) are emerging as a new solution for children with severe disabilities to interact with the world. However, BCI technologies have yet to reach end-users in their daily lives due to significant translational gaps. To address these gaps, we applied user-centered design principles to establish a home BCI program for children with quadriplegic cerebral palsy. This work describes the technical development of the software we designed to facilitate BCI use at home. Children and their families were involved at each design stage to evaluate and provide feedback. Since deployment, seven families have successfully used the system independently at home and continue to use BCI at home to further enable participation and independence for their children. Clinical relevance- The design and successful implementation of user-centered software for home use will both inform on the feasibility of BCI as a long-term access solution for children with neurological disabilities as well as decrease barriers of accessibility and availability of BCI technologies for end-users.

Translational Gap between Guidelines and Clinical Medicine: The Viewpoint of Italian General Practitioners in the Management of IBS.

Irritable bowel syndrome (IBS) guidelines are generally developed by experts, with the possibility of a translational gap in clinical medicine. The aim of our study was to assess an Italian group of general practitioners (GPs) for their awareness and use of criteria for the diagnosis and management of IBS. For this purpose, a survey was carried out involving 235 GPs, divided into two groups according to their years of activity: 65 “junior general practitioners” (JGPs) (≤10 years) and 170 “senior general practitioners” (SGPs) (>10 years). JGPs were more familiar with the Rome IV Criteria and Bristol Scale than SGPs. Abdominal pain, bowel movement frequency and bloating were the symptoms most frequently used to make a diagnosis. The most probable causes of IBS were reported to be abnormal gastrointestinal motility and psychological triggers. SGPs reported more frequently than JGPs that challenging management and patient’s request were motivations for a gastroenterological consultation. The practice of clinical medicine is still far from the guidelines provided by the specialists. Abdominal pain related to defecation and changes in bowel frequency are considered to be the more important symptoms for IBS diagnosis, but most GPs, both JGPs and SGPs, like to consider abdominal bloating as another useful symptom. Involving both gastroenterologists and GPs in developing shared guidelines would be highly desirable in order to improve IBS management strategies in everyday clinical practice.

Towards Biohybrid Lung Development: Establishment of a Porcine In Vitro Model.

Lung transplantation (LTx) is the only curative therapy option for patients with end-stage lung diseases, though only available for chosen patients. To provide an alternative treatment option to LTx, we aim for the development of an implantable biohybrid lung (BHL) based on hollow fiber membrane (HFM) technology used in extracorporeal membrane oxygenators. Crucial for long-lasting BHL durability is complete hemocompatibility of all blood contacting surfaces, which can be achieved by their endothelialization. In continuation to successful in vitro investigations using human endothelial cells (ECs), indicating general feasibility, the appropriate porcine in vivo model needs to be prepared and established to fill the translational data gap prior to patient’s application. Therefore, isolation of porcine ECs from carotid arteries (pCECs) was established. Following, pCECs were used for HFM endothelialization and examined under static and dynamic conditions using cell medium or heparinized blood, to assess their proliferation capacity, flow resistance and activation state, especially under clinically relevant conditions. Additionally, comparative hemocompatibility tests between native and endothelialized HFMs were performed. Overall, pure pCECs formed a viable and confluent monolayer, which resisted applied flow conditions, in particular due to physiological extracellular matrix synthesis. Additionally, pCECs remained the non-inflammatory and anti-thrombogenic status, significantly improving the hemocompatibility of endothelialized HFMs. Finally, as relevant for reliable porcine to human translation, pCECs behaved in the same way as human ECs. Concluding, generated in vitro data justify further steps towards pre-clinical BHL examination, in particular BHL application to porcine lung injury models, reflecting the clinical scenario with end-stage lung-diseased patients.

Understanding Cancer Genetic Risk Assessment Intentions in a Tailored Risk Communication Intervention Randomized Controlled Trial

Background: Pathogenic variants in cancer predisposition genes increase second, hereditary cancer risk among women with breast and/or ovarian cancer, and primary cancers in their relatives. National guidelines recommend cancer genetic risk assessment (CGRA) (genetic counseling and/or genetic testing) for women at increased hereditary breast and ovarian cancer (HBOC) risk. Yet, less than half of high risk women, including rural dwellers and racial minorities have accessed CGRA. Purpose: The Genetic Risk Assessment for Cancer Education and Empowerment Project (GRACE), a superiority trial, addressed this translational gap, testing the efficacy of a targeted print brochure (TP) vs tailored counseling and navigation (TCN) vs usual care (UC) on CGRA intentions. TCN targeted behavioral variables theorized to mediate CGRA intentions. We believe GRACE is the first study of its kind promoting guideline-based CGRA to women at increased HBOC risk. Methods: CGRA-eligible women were recruited from three state cancer registries (N=641), completed a baseline survey, and randomized to TCN, TP or UC. TP and TCN received the mailed educational brochure. TCN also engaged in a telephone-based decision coaching and navigation session using motivational interviewing and tailored materials based on the Extended Parallel Process Model and Health Action Process Approach. Participants completed a follow-up survey at one month. Results: TCN improved CGRA intentions compared to TP (0.64, p<0.001, CI 0.32, 0.97) and UC (0.69, p<0.001, CI 0.37, 1.02). Theoretical targets, perceived risk (0.77, p=0.02, CI 0.11, 1.44) and self-efficacy (0.67, p=0.04, CI 0.05, 1.28) mediated CGRA intentions in TCN. Stratification showed increases in CGRA intentions for TCN vs TP among non-Hispanic Whites, Hispanics, urban dwellers, and women with low health literacy and no family history of breast and/or ovarian cancer (FBOC). In TCN, perceived self-efficacy improved in women with no FBOC. Conclusions: Improvements in CGRA intentions and theorized mediators support use of tailored risk communication interventions in Hispanics and women with low health literacy and no FBOC. Further tailoring may improve CGRA intentions in Blacks, other minorities, rural dwellers, and women with high health literacy and FBOC.

Nano- and Crystal Engineering Approaches in the Development of Therapeutic Agents for Neoplastic Diseases

Cancer is a leading cause of death worldwide. It is a global quandary that requires the administration of many different active pharmaceutical ingredients (APIs) with different characteristics. As is the case with many APIs, cancer treatments exhibit poor aqueous solubility which can lead to low drug absorption, increased doses, and subsequently poor bioavailability and the occurrence of more adverse events. Several strategies have been envisaged to overcome this drawback, specifically for the treatment of neoplastic diseases. These include crystal engineering, in which new crystal structures are formed to improve drug physicochemical properties, and/or nanoengineering in which the reduction in particle size of the pristine crystal results in much improved physicochemical properties. Co-crystals, which are supramolecular complexes that comprise of an API and a co-crystal former (CCF) held together by non-covalent interactions in crystal lattice, have been developed to improve the performance of some anti-cancer drugs. Similarly, nanosizing through the formation of nanocrystals and, in some cases, the use of both crystal and nanoengineering to obtain nano co-crystals (NCC) have been used to increase the solubility as well as overall performance of many anticancer drugs. The formulation process of both micron and sub-micron crystalline formulations for the treatment of cancers makes use of relatively simple techniques and minimal amounts of excipients aside from stabilizers and co-formers. The flexibility of these crystalline formulations with regards to routes of administration and ability to target neoplastic tissue makes them ideal strategies for effectiveness of cancer treatments. In this review, we describe the use of crystalline formulations for the treatment of various neoplastic diseases. In addition, this review attempts to highlight the gaps in the current translation of these potential treatments into authorized medicines for use in clinical practice.

Promising Strategies for the Development of Advanced In Vitro Models with High Predictive Power in Ischaemic Stroke Research

Although stroke is one of the world’s leading causes of death and disability, and more than a thousand candidate neuroprotective drugs have been proposed based on extensive in vitro and animal-based research, an effective neuroprotective/restorative therapy for ischaemic stroke patients is still missing. In particular, the high attrition rate of neuroprotective compounds in clinical studies should make us question the ability of in vitro models currently used for ischaemic stroke research to recapitulate human ischaemic responses with sufficient fidelity. The ischaemic stroke field would greatly benefit from the implementation of more complex in vitro models with improved physiological relevance, next to traditional in vitro and in vivo models in preclinical studies, to more accurately predict clinical outcomes. In this review, we discuss current in vitro models used in ischaemic stroke research and describe the main factors determining the predictive value of in vitro models for modelling human ischaemic stroke. In light of this, human-based 3D models consisting of multiple cell types, either with or without the use of microfluidics technology, may better recapitulate human ischaemic responses and possess the potential to bridge the translational gap between animal-based in vitro and in vivo models, and human patients in clinical trials.

Dogs as a Natural Animal Model of Epilepsy.

Epilepsy is a common neurological disease in both humans and domestic dogs, making dogs an ideal translational model of epilepsy. In both species, epilepsy is a complex brain disease characterized by an enduring predisposition to generate spontaneous recurrent epileptic seizures. Furthermore, as in humans, status epilepticus is one of the more common neurological emergencies in dogs with epilepsy. In both species, epilepsy is not a single disease but a group of disorders characterized by a broad array of clinical signs, age of onset, and underlying causes. Brain imaging suggests that the limbic system, including the hippocampus and cingulate gyrus, is often affected in canine epilepsy, which could explain the high incidence of comorbid behavioral problems such as anxiety and cognitive alterations. Resistance to antiseizure medications is a significant problem in both canine and human epilepsy, so dogs can be used to study mechanisms of drug resistance and develop novel therapeutic strategies to benefit both species. Importantly, dogs are large enough to accommodate intracranial EEG and responsive neurostimulation devices designed for humans. Studies in epileptic dogs with such devices have reported ictal and interictal events that are remarkably similar to those occurring in human epilepsy. Continuous (24/7) EEG recordings in a select group of epileptic dogs for >1 year have provided a rich dataset of unprecedented length for studying seizure periodicities and developing new methods for seizure forecasting. The data presented in this review substantiate that canine epilepsy is an excellent translational model for several facets of epilepsy research. Furthermore, several techniques of inducing seizures in laboratory dogs are discussed as related to therapeutic advances. Importantly, the development of vagus nerve stimulation as a novel therapy for drug-resistant epilepsy in people was based on a series of studies in dogs with induced seizures. Dogs with naturally occurring or induced seizures provide excellent large-animal models to bridge the translational gap between rodents and humans in the development of novel therapies. Furthermore, because the dog is not only a preclinical species for human medicine but also a potential patient and pet, research on this species serves both veterinary and human medicine.

An integrative literature review of menstruation patterns in people with congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) encompasses a range of inherited autosomal recessive enzyme conditions that impact steroid hormone production. This lifelong condition has associated health risks for some individuals, including adrenal crisis, and menstruation and fertility issues. Health literacy materials focused on the physical and pharmacological aspects of managing menstruation (i.e., treatment to initiate or maintain menses for those with CAH) are scarce. This article addresses this gap by exploring menses patterns in people with CAH. An integrative literature review searched articles published between 2005 and 2020, and 30 articles met inclusion criteria. Study findings indicated that while menarche seems to occur at an average age for people with CAH, menstruation is commonly disrupted and irregular. Several studies reported individuals achieving regular menses and pregnancy, while others noted individuals consistently showing poor control, irregular menses, and infertility despite ongoing treatment. A few studies reported such individuals as “non-adherent” or worse “non-compliant” with their medication regimens when health outcomes were lower than expected. We emphasize that such fault finding by health service providers around adherence acts as a barrier to communication with people with CAH. We argue that a sustained and coordinated person-centred approach focusing on communication and education across situational, developmental, and organizational transitions, can promote health literacy, foregrounding individuals’ health and bodily autonomy across their life span. Future research needs to address gaps in knowledge translation that supports menstrual education for individuals with CAH. Studies should also address how medication management is assessed and adherence negotiated with individuals with CAH.

Abstract CT216: A phase 0 master protocol utilizing a novel intratumoral microdosing approach for simultaneously evaluating multiple drugs and drug combinations in patients with solid tumors

Abstract Purpose/Objectives: Tumor responses to cancer treatments are highly context-specific and often involve complex interactions between the anti-cancer therapy, genetically diverse tumor cells, and a heterogeneous tumor microenvironment (TME). All preclinical models fall short in capturing this complexity. CIVO (Comparative In Vivo Oncology) is an intratumoral microdose injection research tool intended to bridge the translational gap between preclinical and clinical studies by enabling in situ assessment of up to 8 oncology drugs or drug combinations simultaneously within a patient’s tumor. The CIVO Phase 0 model was established under FDA’s exploratory IND guidelines for microdosing. A Master Protocol was then developed, enabling ongoing evaluation of multiple investigational drugs and combinations without a need for stand-alone new protocols. Each investigational drug or combination is specified as a substudy of the Master Protocol, thus reducing administrative burden to clinical site staff and creating an infrastructure to ensure quality data and oversight of patient safety. This is a multi-center, open-label Phase 0 Master Protocol designed to study the localized pharmacodynamics (PD) of anti-cancer therapies within the TME when administered intratumorally in microdose quantities via the CIVO device. The safety of intratumoral microdose administration via the CIVO device will also be evaluated. Materials/Methods: Approximately 12 subjects are expected to be enrolled per substudy. All substudies will evaluate subjects ≥18 years with a diagnosis of solid tumors with scheduled surgical intervention. Eligible subjects have at least one lesion (primary or recurrent tumor or effaced metastatic lymph node) ≥2 cm in the shortest diameter that is surface accessible for CIVO injection. Each substudy will define the tumor type and specific eligibility criteria for enrollment. The study visits consist of screening, CIVO injection, surgical intervention, and two follow-up visits. All patients will be injected by the CIVO device containing microdose quantities of drugs specified in respective substudies. The CIVO device can be configured with 3, 5, or 8 needles and the device configuration will be assigned on a per-patient basis, dependent upon lesion size. Following surgical resection, the injected portion of the tumor will undergo central PD biomarker analysis. At the time of submission, the study is open for enrollment with 1 substudy enrolling Head and Neck Squamous Cell Carcinoma (HNSCC) patients and 1 substudy enrolling HNSCC or soft tissue sarcoma patients. The Master Protocol was established to efficiently add substudies and accommodate evaluation of a wider repertoire of new agents in order to continually inform and de-risk drug development via the CIVO platform. Clinical trial information: NCT04541108. Citation Format: Karthik Rajasekaran, Jason G. Newman, Robert G. Maki, Thomas J. Ow, Vikas Mehta, Kenneth R. Gundle, Daniel R. Clayburgh, Ryan J. Li, Mercedes Porosnicu, Cherie-Ann O. Nathan, Alice Tang, Beryl A. Hatton, Kimberly H. Sottero, Gloria Kung, Marc O. Grenley, Kirsten Anderson, Richard A. Klinghoffer. A phase 0 master protocol utilizing a novel intratumoral microdosing approach for simultaneously evaluating multiple drugs and drug combinations in patients with solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT216.

Perspectives From Advancing National Institutes of Health Research to Inform and Improve the Health of Women: A Conference Summary.

The health of women remains understudied. In response to a request from Congress, the Office of Research on Women's Health of the National Institutes of Health (NIH) evaluated research on the health of women currently underway related to 1) rising rates of maternal morbidity and mortality, 2) rising rates of chronic debilitating conditions in women, and 3) stagnant cervical cancer survival rates. Input on the three priority areas was obtained from experts in women's health, members of the public, and federal stakeholders. The NIH research portfolios on these three topics were reviewed. On October 20, 2021, a conference on advancing NIH research on women's health was held to present, discuss, and delineate gaps and opportunities in the current portfolio. Across the life course, significant gaps in evidence regarding conditions, disorders, and diseases that occur in women were illustrated. Fundamental basic and translational knowledge gaps in many female-specific conditions and diseases with sex-specific presentations, symptoms, or responses to treatments have hampered the generation of robust scientific data needed to provide high-quality, evidence-based care to women. Key opportunities identified to improve the health of women include enhanced implementation of existing best practices and interventions to reduce disparities. Undertaking intentional clinical research on the health of women will produce significant returns on investment and has the potential to greatly improve human health.

Jazz Diasporas: Race, Music, and Migration in Post-World War II ParisJazz Diaspora: Music and Globalisation

Jazz Diasporas: Race, Music, and Migration in Post-World War II ParisJazz Diaspora: Music and Globalisation

The Human Genome Project as a Singular Episode in the History of Genomics

In this paper, we progressively de-center the Human Genome Project (HGP) in the history of genomics and human genomics. We show that the HGP, understood as an international effort to make the human reference genome sequence publicly available, constitutes a specific model of genomics: prominent and influential but nevertheless distinct from others that preceded, existed alongside, and succeeded it. Our analysis of a comprehensive corpus of publications describing human DNA sequences submitted to public databases from 1985 to 2005 reveals a plethora of authoring institutions, with only a few contributing to the HGP. Examining these publications in a co-authorship network enables us to propose two different sequencing approaches—horizontal and vertical sequencing—whose changing dynamics shaped the history of human genomics. We argue that investigating the extent to which different institutions combined these approaches or prioritized one of them captures the history of genomics better than using the categories of large-scale sequence production and sequence use, as much scholarly literature concerning the HGP has done. Sequence production and use became fully distinct only within the HGP model, and especially during the last stages of this endeavor. By exploring a collaboration between Celera Genomics, a large-scale sequencing institution, and two medical genetics laboratories, we show the potential of our co-authorship network and its analysis for historical research. Our study connects the historiographies of medical genetics and human genomics and indicates that the so-called translational gap from sequence data to clinical outcomes may reflect the assumption that genomics was substantially different from prior and parallel genetics research. This essay is part of a special issue entitled The Sequences and the Sequencers: A New Approach to Investigating the Emergence of Yeast, Human, and Pig Genomics, edited by Miguel García-Sancho and James Lowe.

Knowledge gaps in diabetes research: an evidence mapping of the literature.

Mapping the available evidence can be used to inform current diabetes research, identify relevant gaps, and prioritize future research. In this regard, we mapped diabetes research performed in Iran. We searched the Scopus and PubMed databases from 01/01/2015 till 01/01/2020 using keywords such as diabetes and Iran. The included articles were classified according to their document types, level of evidence, and subject areas. The majority of the included articles (53%) were related to diabetes types, followed by complications (28%). Most of the documents were original articles (82%), and reviews were 18% of the publications. Systematic reviews constitute only 6% of the total documents. Observational studies were the most common types of study designs (26%), followed by clinical trials (20%). Moreover, topics on control and management of diabetes were the most prevalent subject areas (58%), and fewer studies were on preventive strategies (6%). In diabetes management studies, less attention has been paid to evaluate psychological (10%), educational (9%), and physical activity-related (7%) interventions. There was a shortage of secondary studies related to physical activity, psychology, diagnostic, and screening-related studies. To fill diabetes research gaps, more investment in cost-effectiveness interventions, such as preventive strategies and behavioral self-management programs, need. Moreover, we need to pay more attention on applied sciences and real world evidence to bridge translational gaps from bench to bedside. In this regard, further data synthesis can be helpful in evaluating the effectiveness of the available studies and avoiding unnecessary investigations.

Towards a Generic Description Schema for Clinical Decision Support Systems.

Many clinical decision support systems (CDSS) have shown good performance in the research context, but only a few have been brought into routine care. Analysis of success or failure factors in the design of CDSS may support translation from development to routine care by guiding CDSS design and development along these factors. In this work, we propose a schema to describe CDSS designs in a consistent way. We focus on design criteria with the aim to investigate the observed translation gap in CDSS. Existing description models on different aspects relevant for CDSS are combined to a comprehensive schema that allows description and comparison of CDSS without limitation to the domain or architecture.

Effects of heart failure and diabetes on invasive biomarkers of skeletal muscle wasting

Abstract Funding Acknowledgements Type of funding sources: None. Background Muscle wasting is common in patients with diabetes mellitus (DM) and chronic heart failure (HF), which exacerbates cachexia and poor quality of life. However, a gap in clinical translation remains as the mechanisms underlying muscle wasting in DM and HF remain poorly validated, with most evidence assumed from experimental small-animal models. Purpose Validate if markers of muscle wasting (e.g., autophagy, proteolysis, myogenesis) were correlated to muscle phenotype and clinical indices in humans with DM and HF. Method Male patients with DM (n=4), HF (n=4; NYHA=2), DMHF (n=7; NYHA=2) were included. DM was classified as a HbA1c level ≥48mmol/mol and HF classified as a left ventricular ejection fraction (LVEF) ≤40%, with patients on optimised medication. Muscle biopsies of pectoralis major were excised during routine pacemaker surgery and frozen at -80°C for both histological and gene expression analysis. Muscle samples were sectioned, stained, and imaged for fibre cross-sectional area and fibre type. RT-PCR gene expression was conducted for markers of muscle regeneration (myod, myogenin), protein degradation (myostatin and autophagy-related LC3B, ATG7, CTSL), and anabolic signalling (IGF-1). Statistical analysis included ANOVAs and correlation analysis to identify relationships between variables. Values of p<0.05 were accepted as significant. Results Groups (DM, HF, DMHF) were not different (P>0.05) in relation to age (79±9, 72±8, 72±10 years) or BMI (24.5±3.6, 28.5±4.2, 29.5±6.0) respectively. Fibre size or fibre type were not different (P>0.05) between groups. In line with this, gene expression for markers of myogenesis and anabolism as well as myostatin were not different (P>0.05) between groups, but a trend in downregulation of the proteolytic autophagy-related genes (LC3B, ATG7, CTSL) in DMHF vs DM or HF was found on average by 21, 36, and 30% respectively. Autophagy-related genes LC3B, ATG7, CTSL were positively correlated (P<0.05) to type IIa fibre numerical density (R=0.82, 0.86, 0.89) and LVEF (R=0.85, 0.92, 0.83), respectively. Conclusion Our findings indicate that gene expression of autophagy could represent a robust marker of muscle wasting and cardiac dysfunction in humans with DM and HF. Muscle biopsies from patients with DM and HF identified the proteolytic system of autophagy, important for cellular homeostasis, may be inhibited and this was correlated to fibre phenotype and LVEF. However, the process of muscle wasting in DM and HF within the clinical setting may not necessarily reflect those reported in animal models given various other markers were not changed.