The impact of consuming technologically processed functional foods enriched/fortified with (poly)phenols on cardiometabolic risk factors: a systematic review of randomized controlled trials.

Cardiovascular diseases are a major global cause of death and healthcare costs, emphasizing the need for effective prevention and management of cardiometabolic risk factors. One promising approach is the consumption of technologically processed functional foods enriched/fortified with (poly)phenols. The current systematic review aimed to evaluate the human clinical trials evidence on the effect of intake of these foods on reducing the most common cardiometabolic risk factors. 12 randomized controlled studies were included in the systematic review, with varying food intake amounts (27-360 g/day) and (poly)phenol doses (32.5-850 mg/day). These interventions included consumption of functional bakery goods, cereal bars, pasta, chocolate, and yogurt, with supplementation periods spanning from 2 to 52 wk. Several foods, such as green tea extract-fortified rye bread and olive fruit (poly)phenol-fortified yogurt, significantly lowered blood pressure. Flavonoid-enriched chocolate, hydroxytyrosol-fortified bread, and other products influenced glucose metabolism. Additionally, various functional foods were associated with improved blood lipid levels. While these results indicate the health advantages of consuming technologically processed functional foods enriched/fortified with (poly)phenols, caution is warranted due to the scarcity and limitations of existing studies. Further research is needed to confirm and expand upon these results in the prevention and management of cardiometabolic risk factors.

Challenges and opportunities of translating animal research into human trials in Ethiopia.

BACKGROUND AND OBJECTIVES: Although the goal of translational research is to bring biomedical knowledge from the laboratory to clinical trial and therapeutic products for improving health, this goal has not been well achieved as often as desired because of many barriers documented in different countries. Therefore, the aim of this study was to investigate the challenges and opportunities of translating animal research into human trials in Ethiopia. METHODS: A descriptive qualitative study, using in-depth interviews, was conducted in which preclinical and clinical trial researchers who have been involved in animal research or clinical trials as principal investigator were involved. Data were analyzed using inductive thematic process. RESULTS: Six themes were emerged for challenges: lack of financial and human capacity, inadequate infrastructure, operational obstacles and poor research governance, lack of collaboration, lack of reproducibility of results and prolonged ethical and regulatory approval processes. Furthermore, three themes were synthesized for opportunities: growing infrastructure and resources, improved human capacity and better administrative processes and initiatives for collaboration. CONCLUSION AND RECOMMENDATIONS: The study found that the identified characteristics/features are of high importance either to hurdle or enable the practice of translating animal research into human trials. The study suggests that there should be adequate infrastructure and finance, human capacity building, good research governance, improved ethical and regulatory approval process, multidisciplinary collaboration, and incentives and recognition for researchers to overcome the identified challenges and allow translating of animal research into human trials to proceed more efficiently.

Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation.

The use of nanotechnology has the potential to revolutionize the detection and treatment of cancer. Developments in protein engineering and materials science have led to the emergence of new nanoscale targeting techniques, which offer renewed hope for cancer patients. While several nanocarriers for medicinal purposes have been approved for human trials, only a few have been authorized for clinical use in targeting cancer cells. In this review, we analyze some of the authorized formulations and discuss the challenges of translating findings from the lab to the clinic. This study highlights the various nanocarriers and compounds that can be used for selective tumor targeting and the inherent difficulties in cancer therapy. Nanotechnology provides a promising platform for improving cancer detection and treatment in the future, but further research is needed to overcome the current limitations in clinical translation.

Transcriptomic response and immunological responses to chimpanzee adenovirus- and MVA viral-vectored vaccines for RSV in healthy adults.

Cohorts of healthy younger adults (18-50yrs) and healthy older adults (60-75yrs) were immunized intramuscularly or intranasally with an adenovirus-vectored RSV vaccine (PanAd3-RSV) as a prime dose and boosted with PanAd3-RSV or a poxvirus-vectored vaccine (MVA-RSV) encoding the same insert. Whole blood gene expression was measured at baseline, 3- and 7-days post vaccination. Intramuscular prime vaccination with PanAd3-RSV induced differential expression of 643 genes (DEGs, FDR < 0.05). Intranasal prime vaccination with PanAd3-RSV did not induce any differentially expressed genes (DEGs) in blood samples at 3 days post vaccination. Intranasally primed participants showed greater numbers of DEGS on boosting than intramuscularly primed participants. The most highly enriched biological processes related to DEGs after both prime and boost vaccination were type-1 interferon related pathways, lymphocytic and humoral immune responses.

Initial heritable genome editing: mapping a responsible pathway from basic research to the clinic.

Following the Second Summit on Human Gene Editing in Hong Kong in 2018, where the birth of two girls with germline genome editing was revealed, the need for a responsible pathway to the clinical application of human germline genome editing has been repeatedly emphasised. This paper aims to contribute to the ongoing discussion on research ethics issues in germline genome editing by exploring key issues related to the initial applications of CRISPR in reproductive medicine. Following an overview of the current discussion on bringing germline genome editing into clinical practice, we outline the specific challenges associated with such interventions and the features that distinguish them from conventional clinical testing of new medical treatments. We then review proposed ethical requirements for initial heritable genome editing, such as the absence of reasonable alternatives, the existence of sufficient and reliable preclinical data, appropriate informed consent, requirements related to safety, and long-term follow-up.

Modulation of the hypothalamic-pituitary-adrenal (HPA) axis by plants and phytonutrients: a systematic review of human trials.

INTRODUCTION: The hypothalamic-pituitary-adrenal (HPA) axis plays a central role in the stress response. Plants, herbs, spices, and plant-based nutrients may influence HPA-axis activity. OBJECTIVE: To evaluate randomised controlled, human trials assessing the effects of single plants or phytonutrients on HPA-axis related hormones. METHODS: A systematic review of PubMed, Cochrane library, and the Cumulative Index to Nursing and Allied Health Literature was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria comprised of human, randomised controlled studies with a control intervention examining the effects of a single herb, spice, plant, or extract on pre- and post-changes in blood, saliva, urine, or hair concentrations of cortisol, cortisone, corticotrophin-releasing hormone, or adrenocorticotropic hormone. Databases were searched from inception until October 2020. RESULTS: Fifty-two studies were identified examining the effects of ashwagandha, Korean ginseng, St John's Wort, cannabidiol, Rhodiola rosea, curcumin, cherry juice, asparagus, Jiaogulan, Black cohosh, Siberian ginseng, Bacopa monnieri, blueberries, green tea, Caralluma fimbriata, cashew apple juice, melon, American ginseng, Ginkgo biloba, grape juice, grapefruit juice, rosella, hops, mangosteen, holy basil, and pomegranate juice. Due to significant variability in study designs, the effect of phytonutrients on HPA-axis activity in humans was unclear. The most consistent finding was a morning, cortisol-lowering effect from ashwagandha supplementation. CONCLUSION: For most phytonutrients, the effects of supplementation on HPA-axis activity in humans is unclear. Before more definitive conclusions about the effects of phytonutrients on the HPA-axis can be made, further research is required.

Vaccines for COVID-19: The current state of play.

There is a strong consensus globally that a COVID-19 vaccine is likely the most effective approach to sustainably controlling the COVID-19 pandemic. An unprecedented research effort and global coordination has resulted in a rapid development of vaccine candidates and initiation of trials. Here, we review vaccine types, and progress with 10 vaccine candidates against SARS-CoV-2 - the virus that causes COVID-19 - currently undergoing early phase human trials. We also consider the many challenges of developing and deploying a new vaccine on a global scale, and recommend caution with respect to our expectations of the timeline that may be ahead.

Current and future experimental approaches in the study of grape and wine polyphenols interacting gut microbiota.

Interactions between polyphenols and gut microbiota are indeed a major issue of current interest in food science research. Knowledge in this subject is progressing as the experimental procedures and analysis techniques do. The aim of this article is to critically review the more leading-edge approaches that have been applied so far in the study of the interactions between grape/wine polyphenols and gut microbiota. This is the case of in vitro dynamic gastrointestinal simulation models that try to mitigate the limitations of simple static models (batch culture fermentations). More complex approaches include the experimentation with animals (mice, rats, pigs, lambs and chicks) and nutritional intervention studies in humans. Main advantages and limitations as well as the most relevant findings achieved by each approach in the study of how grape/wine polyphenols can modulate the composition and/or functionality of gut microbiota, are detailed. Also, common findings obtained by the three approaches (in vitro, animal models and human nutritional interventions) such as the fact that the Firmicutes/Bacteroidetes ratio tends to decrease after the feed/intake/consumption of grape/wine polyphenols are highlighted. Additionally, a nematode (Caenorhabditis elegans) model, previously used for investigating the mechanisms of processes such as aging, neurodegeneration, oxidative stress and inflammation, is presented as an emerging approach for the study of polyphenols interacting gut microbiota. © 2020 Society of Chemical Industry.

The Effects of Green Tea Amino Acid L-Theanine Consumption on the Ability to Manage Stress and Anxiety Levels: a Systematic Review.

The green tea amino acid, L-theanine (L-THE) is associated with several health benefits, including improvements in mood, cognition and a reduction of stress and anxiety-like symptoms. This systematic review evaluated the effect of pure L-THE intake, in the form of orally administered nutritional supplements, on stress responses and anxiety levels in human randomised controlled trials. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist, 9 peer-reviewed journal articles were identified where L-THE as a supplement was compared to a control. Our findings suggest that supplementation of 200-400 mg/day of L-THE may assist in the reduction of stress and anxiety in people exposed to stressful conditions. Despite this finding, longer-term and larger cohort clinical studies, including those where L-THE is incorporated into the diet regularly, are needed to clinically justify the use of L-THE as a therapeutic agent to reduce stress and anxiety in people exposed to stressful conditions.

A few ethical issues in translational research for gene and cell therapy.

BACKGROUND: Although translational research for drug development can provide patients with valuable therapeutic resources it is not without risk, especially in the early-phase trials that present the highest degree of uncertainty. With the extraordinary evolution of biomedical technologies, a growing number of innovative products based on human cells and gene therapy are being tested and used as drugs. Their use on humans poses several challenges. METHODS: In this work, we discuss some ethical issues related to gene and cell therapies translational research. We focus on early-phase studies analysing the regulatory approach of Europe and the United States. We report the current recommendations and guidelines of international scientific societies and European and American regulatory authorities. RESULTS: The peculiarity of human cell- or tissue-based products and gene therapy has required the development of specific regulatory tools that must be continually updated in line with the progress of the research. The ethics of translational research for these products also requires further considerations, particularly with respect to the specificity of the associated risk profiles. CONCLUSIONS: An integrated ethical approach that aims for transparency and regulation of development processes, the support of independent judgment in clinical trials and the elimination of unregulated and uncontrolled grey areas of action are necessary to move gene and cell therapy forward.

Synthetic Biology and the Translational Imperative.

Advances at the interface between the biological sciences and engineering are giving rise to emerging research fields such as synthetic biology. Harnessing the potential of synthetic biology requires timely and adequate translation into clinical practice. However, the translational research enterprise is currently facing fundamental obstacles that slow down the transition of scientific discoveries from the laboratory to the patient bedside. These obstacles including scarce financial resources and deficiency of organizational and logistic settings are widely discussed as primary impediments to translational research. In addition, a number of socio-ethical considerations inherent in translational research need to be addressed. As the translational capacity of synthetic biology is tightly linked to its social acceptance and ethical approval, ethical limitations may-together with financial and organizational problems-be co-determinants of suboptimal translation. Therefore, an early assessment of such limitations will contribute to proactively favor successful translation and prevent the promising potential of synthetic biology from remaining under-expressed. Through the discussion of two case-specific inventions in synthetic biology and their associated ethical implications, we illustrate the socio-ethical challenges ahead in the process of implementing synthetic biology into clinical practice. Since reducing the translational lag is essential for delivering the benefits of basic biomedical research to society at large and promoting global health, we advocate a moral obligation to accelerating translational research: the "translational imperative."

How plausible is the use of dietary n-3 PUFA in the adjuvant therapy of cancer?

Considerable debate exists regarding the potential antineoplastic effect of dietary long-chain n-3 PUFA contained in fatty fishes. Since the majority of published data has proven that their intake does not induce toxic or carcinogenic effects in humans, their possible preventive use against cancer has been suggested. On the other hand, it is unlikely that they could be effective in cancer patients as a single therapy. Nevertheless, a considerable effort has been put forth in recent years to evaluate the hypothesis that n-3 PUFA might improve the antineoplastic efficiency of currently used anticancer agents. The rationale for this therapeutic combinatory strategy is trying to increase cancer sensitivity to conventional therapies. This could allow the use of lower drug/radiation doses and, thereby, a reduction in the detrimental health effects associated with these treatments. We will here critically examine the studies that have investigated this possibility, by focusing particularly on the biological and molecular mechanisms underlying the antineoplastic effect of these combined treatments. A possible use of n-3 PUFA in combination with the innovative single-targeted anti-cancer therapies, that often are not completely devoid of dangerous side-effects, is also suggested.

Rethinking risk assessment for emerging technology first-in-human trials.

Recent progress in synthetic biology (SynBio) has enabled the development of novel therapeutic opportunities for the treatment of human disease. In the near future, first-in-human trials (FIH) will be indicated. FIH trials mark a key milestone in the translation of medical SynBio applications into clinical practice. Fostered by uncertainty of possible adverse events for trial participants, a variety of ethical concerns emerge with regards to SynBio FIH trials, including 'risk' minimization. These concerns are associated with any FIH trial, however, due to the novelty of the approach, they become more pronounced for medical applications of emerging technologies (emTech) like SynBio. To minimize potential harm for trial participants, scholars, guidelines, regulations and policy makers alike suggest using 'risk assessment' as evaluation tool for such trials. Conversely, in the context of emTech FIH trials, we believe it to be at least questionable to contextualize uncertainty of potential adverse events as 'risk' and apply traditional risk assessment methods. Hence, this issue needs to be discussed to enable alterations of the evaluation process before the translational phase of SynBio applications begins. In this paper, we will take the opportunity to start the debate and highlight how a misunderstanding of the concept of risk, and the possibilities and limitations of risk assessment, respectively, might impair decision-making by the relevant regulatory authorities and research ethics committees, and discuss possible solutions to tackle the issue.

Stakeholder views on participant selection for first-in-human trials in cancer nanomedicine.

BACKGROUND: Participant selection for first-in-human (fih) trials involves complex decisions. The trial design makes it unlikely that participants will receive clinically relevant therapeutic benefit, but they are likely to experience risks of various magnitudes and types. The aim of the present paper was to describe and discuss the views of investigators and ethics committee members about the choice of trial participants for fih trials in cancer nanomedicine. METHODS: We drew insights from an exploratory qualitative study involving thematic analysis of 46 in-depth interviews with key stakeholders in Europe and North America involved in fih nanomedicine trials. The present work draws on subset of 21 interviews with investigators and ethics committee members who have either conducted or reviewed a fih cancer nanomedicine trial or are planning one. RESULTS: Investigators and ethics committee members are aware of the ethics standards for recruiting patients with end-stage cancer into fih trials, but they nonetheless question the practice and provide reasons against it. CONCLUSIONS: Although it is a standard and ethically accepted practice to enrol patients with end-stage cancer and no treatment options into fih trials of investigational chemotherapeutic molecules, doing so can threaten the validity and generalizability of the trials, thereby weakening translational research. Another possibility is to stratify and include patients with less advanced disease who demonstrate certain biomarkers or cancer genotypes and who have a disease profile similar to that tested in preclinical studies. The latter approach could be a step toward personalized medical research and targeted drug development. Such a patient selection approach requires multi-stakeholder discussion to reach scientific and ethics consensus.

Exercise as Therapy for Diabetic and Prediabetic Neuropathy.

Length-dependent neuropathy is the most common and costly complication of diabetes and frequently causes injury primarily to small-diameter cutaneous nociceptive fibers. Not only persistent hyperglycemia but also metabolic, endocrine, and inflammatory effects of obesity and dyslipidemia appear to play an important role in the development of diabetic neuropathy. Rational therapies aimed at direct control of glucose or its increased entry into the polyol pathway, oxidative or nitrosative stress, advanced glycation end product formation or signaling, microvascular ischemia, or adipocyte-derived toxicity have each failed in human trials of diabetic neuropathy. Aerobic exercise produces salutary effects in many of these pathogenic pathways simultaneously and, in both animal models and human trials, has been shown to improve symptoms of neuropathy and promote re-growth of cutaneous small-diameter fibers. Behavioral reduction in periods of seated, awake inactivity produces multimodal metabolic benefits similar to exercise, and the two strategies when combined may offer sustained benefit to peripheral nerve function.

Pharmacological and stem cell therapy of stroke in animal models: Do they accurately reflect the response of humans?

Cerebrovascular diseases are the second leading cause of death worldwide. Despite significant research investment, the only available therapeutic options are mechanical thrombectomy and tissue plasminogen activator thrombolysis. None of the more than a thousand drugs tested on animal models have proven successful in human clinical trials. Several factors contribute to this poor translation of data from stroke-related animal models to human stroke patients. Firstly, our understanding of the molecular and cellular processes involved in recovering from an ischemic stroke is severely limited. Secondly, although the risk of stroke is particularly high among older patients with comorbidities, most drugs are tested on young, healthy animals in controlled laboratory conditions. Furthermore, in animal models, the tracking of post-stroke recovery typically spans only 3 to 28 days, with occasional extensions to 60 days, whereas human stroke recovery is a more extended and complex process. Thirdly, young animal models often exhibit a considerably higher rate of spontaneous recovery compared to humans following a stroke. Fourth, only a very limited number of animals are utilized for each condition, including control groups. Another contributing factor to the much smaller beneficial effects in humans is that positive outcomes from numerous animal studies are more readily accepted than results reported in human trials that do not show a clear benefit to the patient. Useful recommendations for conducting experiments in animal models, with increased chances of translatability to humans, have been issued by both the STEPS investigative team and the STAIR committee. However, largely, due to economic factors, these recommendations are largely ignored. Furthermore, one might attribute the overall failures in predicting and subsequently developing effective acute stroke therapies beyond thrombolysis to potential design deficiencies in clinical trials.

Neuralink and Brain-Computer Interface-Exciting Times for Artificial Intelligence.

Purvish Mahendra ParikhBrain-computer interfaces are becoming a tangible reality, capable of significantly aiding patients in real-world scenarios. The recent approval by the U.S. Food and Drug Administration for clinical human trials of Neuralink marks a monumental stride, comparable to Mr. Armstrong's moonwalk. Numerous other companies are also pioneering innovative solutions in this domain. Presently, over 150,000 patients in the United States possess brain implants. As technology advances, it holds the potential to alleviate various conditions, notably motor paralysis, cerebral palsy, and involuntary movements.

Unveiling the Nutritional Veil of Sulforaphane: With a Major Focus on Glucose Homeostasis Modulation.

Abnormal glucose homeostasis is associated with metabolic syndromes including cardiovascular diseases, hypertension, type 2 diabetes mellitus, and obesity, highlighting the significance of maintaining a balanced glucose level for optimal biological function. This highlights the importance of maintaining normal glucose levels for proper biological functioning. Sulforaphane (SFN), the primary bioactive compound in broccoli from the Cruciferae or Brassicaceae family, has been shown to enhance glucose homeostasis effectively while exhibiting low cytotoxicity. This paper assesses the impact of SFN on glucose homeostasis in vitro, in vivo, and human trials, as well as the molecular mechanisms that drive its regulatory effects. New strategies have been proposed to enhance the bioavailability and targeted delivery of SFN in order to overcome inherent instability. The manuscript also covers the safety evaluations of SFN that have been documented for its production and utilization. Hence, a deeper understanding of the favorable influence and mechanism of SFN on glucose homeostasis, coupled with the fact that SFN is abundant in the human daily diet, may ultimately offer theoretical evidence to support its potential use in the food and pharmaceutical industries.

Does the use of platelet-rich fibrin enhance the rate of orthodontic tooth movement? A systematic review and meta-analysis.

Introduction: This review synthesizes the available evidence pertinent to the effect of platelet-rich fibrin on the rate of orthodontic tooth movement during comprehensive orthodontic treatment. Method: This review followed the Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Nine electronic databases were searched until January 2024 without restrictions, followed by a hand search of the reference lists. Controlled randomized split-mouth human studies assessing the effect of platelet-rich fibrin on the rate of orthodontic tooth movement were included. All relevant data from the included studies were extracted and pooled for qualitative and quantitative analysis. Risk-of-Bias was assessed using the Cochrane Risk of Bias tool. The certainty of the evidence was graded using the Grading of Recommendations, Assessment, Development, and Evaluation tool. Results: From 515 studies, eleven randomized clinical trials were included for qualitative analysis and nine for quantitative analysis. The certainty of the evidence for these studies was low to moderate. The overall risk of bias for most studies was of some concern. The pooled estimate of the data from ten studies has a mean revealed difference of 1.31 (0.13-2.48) at a 95 % confidence interval with significant heterogeneity. Conclusions: This systematic review suggest that platelet-rich fibrin enhances the orthodontic tooth movement rate, but the evidence quality was moderate. Further, based on the currently available evidence, the effectiveness of platelet-rich fibrin on the acceleration of orthodontic tooth movement could not be fully established. Trial registration: PROSPERO: (CRD42021261836).

Ethics of gene and cell therapy development for neurologic disorders.

In this chapter, I provide a condensed overview of nine recurring policy and ethical challenges encountered with the development of gene and cell therapies for neurologic disease. These include the question of when to initiate first-in-human trials, the ethics and policy of expanded/special access, the conduct of individualized therapy trials, subject selection in trials, designing trials for negative results, unintended effects of interventions on personal identity, comparator choice in randomized trials, consent and therapeutic misestimation, and cost and access for effective therapies. Broadly speaking, I argue that early in their development, the justification of risk in trials of gene and cell therapies derives from the social and scientific value of a trial and not the therapeutic value for trial participation. This generates strong imperatives to justify, design, and report trials appropriately and select patient populations that incur the least burden and opportunity cost for trial participation. Late in intervention development, policy makers must contend with the fact that proven effective interventions will almost certainly amplify strains in healthcare budgets as well as the ethical justifications standing behind reimbursement decisions.