Mesenchymal stem cell therapy for Alzheimer's disease: A novel therapeutic approach for neurodegenerative diseases.

Alzheimer's disease (AD) is one of the most progressive and prevalent types of neurodegenerative diseases in the aging population (aged >65 years) and is considered a major factor for dementia, affecting 55 million people worldwide. In the current scenario, drug-based therapies have been employed for the treatment of Alzheimer's disease but are only able to provide symptomatic relief to patients rather than a permanent solution from Alzheimer's. Recent advancements in stem cell research unlock new horizons for developing effective and highly potential therapeutic approaches due to their self-renewal, self-replicating, regenerative, and high differentiation capabilities. Stem cells come in multiple lineages such as embryonic, neural, and induced pluripotent, among others. Among different kinds of stem cells, mesenchymal stem cells are the most investigated for Alzheimer's treatment due to their multipotent nature, low immunogenicity, ability to penetrate the blood-brain barrier, and low risk of tumorigenesis, immune & inflammatory modulation, etc. They have been seen to substantially promote neurogenesis, synaptogenesis by secreting neurotrophic growth factors, as well as in ameliorating the Aß and tau-mediated toxicity. This review covers the pathophysiology of AD, new medications, and therapies. Further, it will focus on the advancements and benefits of Mesenchymal Stem Cell therapies, their administration methods, clinical trials concerning AD progression, along with their future prospective.

A comprehensive review on doxorubicin: mechanisms, toxicity, clinical trials, combination therapies and nanoformulations in breast cancer.

Doxorubicin is a key treatment for breast cancer, but its effectiveness often comes with significant side effects. Its actions include DNA intercalation, topoisomerase II inhibition, and reactive oxygen species generation, leading to DNA damage and cell death. However, it can also cause heart problems and low blood cell counts. Current trials aim to improve doxorubicin therapy by adjusting doses, using different administration methods, and combining it with targeted treatments or immunotherapy. Nanoformulations show promise in enhancing doxorubicin's effectiveness by improving drug delivery, reducing side effects, and overcoming drug resistance. This review summarizes recent progress and difficulties in using doxorubicin for breast cancer, highlighting its mechanisms, side effects, ongoing trials, and the potential impact of nanoformulations. Understanding these different aspects is crucial in optimizing doxorubicin's use and improving outcomes for breast cancer patients. This review examines the toxicity of doxorubicin, a drug used in breast cancer treatment, and discusses strategies to mitigate adverse effects, such as cardioprotective agents and liposomal formulations. It also discusses clinical trials evaluating doxorubicin-based regimens, the evolving landscape of combination therapies, and the potential of nanoformulations to optimize delivery and reduce systemic toxicity. The review also discusses the potential of liposomes, nanoparticles, and polymeric micelles to enhance drug accumulation within tumor tissues while sparing healthy organs.

Therapeutic potential of the medicinal mushroom Ganoderma lucidum against Alzheimer's disease.

Alzheimer's disease (AD) is a high-incidence neurodegenerative disorder, characterized by cognitive impairment, memory loss, and psychiatric abnormalities. Ganoderma lucidum is a famous medicinal fungus with a long history of dietary intake, containing various bioactive components, and have been documented to exhibit antioxidant, anti-inflammatory, anti-tumor, anti-aging, and immunomodulatory effects, among others. Recent studies have shown that G. lucidum and its components have promising therapeutic potential against AD from various aspects, which can delay the progression of AD, improve cognitive function and quality of life. The underlying mechanisms mainly include inhibiting tau hyperphosphorylation, inhibiting Aß formation, affecting activated microglia, regulating NF-κB/MAPK signalling pathway, inhibiting neuronal apoptosis, modulating immune system, and inhibiting acetylcholinesterase, etc. This paper systematically reviewed the relevant studies on the therapeutic potential of G. lucidum and its active components for treatment of AD, key points related with the mechanism studies and clinical trials have been discussed, and further perspectives have been proposed. Totally, as a natural medicinal mushroom, G. lucidum has the potential to be developed as effective adjuvant for AD treatment owing to its therapeutic efficacy against multiple pathogenesis of AD. Further mechanical investigation and clinical trials can help unlock the complete potential of G. lucidum as a therapeutic option for AD.

Recruitment Strategies of a Decentralized Randomized Placebo Controlled Clinical Trial: The Canagliflozin Impact on Health Status, Quality of Life and Functional Status in Heart Failure (CHIEF-HF) Trial.

BACKGROUND: There has been growing Interest in patient-centered clinical trials using mobile technologies to reduce the need for in-person visits. The CHIEF-HF (Canagliflozin Impact on Health Status, Quality of Life and Functional Status in Heart Failure) trial was designed as a double-blind, randomized, fully decentralized clinical trial (DCT) that identified, consented, treated, and followed participants without any in-person visits. Patient-reported questionnaires were the primary outcome, which were collected by a mobile application. To inform future DCTs, we sought to describe the strategies used in successful trial recruitment. METHODS: This article describes the operational structure and novel strategies employed in a completely DCT by summarizing the recruitment, enrollment, engagement, retention, and follow-up processes used in the execution of the trial at 18 centers. RESULTS: A total of 18 sites contacted 130,832 potential participants, of which 2572 (2.0%) opened a hyperlink to the study website, completed a brief survey, and agreed to be contacted for potential inclusion. Of these, 1333 were eligible, and 658 consented; there were 182 screen failures, due primarily to baseline Kansas City Cardiomyopathy Questionnaire scores' not meeting inclusion criteria, resulting in 476 participants' being enrolled (18.5%). There was significant site-level variation in the number of patients invited (median = 2976; range 73-46,920) and in those agreeing to be contacted (median = 2.4%; range 0.05%-16.4%). At the site with the highest enrollment, patients contacted by electronic medical record portal messaging were more likely to opt into the study successfully than those contacted by e-mail alone (7.8% vs 4.4%). CONCLUSIONS: CHIEF-HF used a novel design and operational structure to test the efficacy of a therapeutic treatment, but marked variability across sites and strategies for recruiting participants was observed. This approach may be advantageous for clinical research across a broader range of therapeutic areas, but further optimization of recruitment efforts is warranted. REGISTRATION: NCT04252287 https://clinicaltrials.gov/ct2/show/NCT04252287.

The clinical progress and challenges of mRNA vaccines.

Owing to the breakthroughs in the prevention and control of the COVID-19 pandemic, messenger RNA (mRNA)-based vaccines have emerged as promising alternatives to conventional vaccine approaches for infectious disease prevention and anticancer treatments. Advantages of mRNA vaccines include flexibility in designing and manipulating antigens of interest, scalability in rapid response to new variants, ability to induce both humoral and cell-mediated immune responses, and ease of industrialization. This review article presents the latest advances and innovations in mRNA-based vaccines and their clinical translations in the prevention and treatment of infectious diseases or cancers. We also highlight various nanoparticle delivery platforms that contribute to their success in clinical translation. Current challenges related to mRNA immunogenicity, stability, and in vivo delivery and the strategies for addressing them are also discussed. Finally, we provide our perspectives on future considerations and opportunities for applying mRNA vaccines to fight against major infectious diseases and cancers. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Biology-Inspired Nanomaterials > Lipid-Based Structures.

Rationale and Clinical Research Progress on PD-1/PD-L1-Based Immunotherapy for Metastatic Triple-Negative Breast Cancer.

Metastatic triple-negative breast cancer (mTNBC), a highly aggressive and malignant tumor, currently lacks an effective treatment. There has been some progress in the treatment of mTNBC with programmed death receptor-1/programmed death ligand-1 (PD-1/PD-L1) immunotherapy in recent years. The combination of PD-1/PD-L1 inhibitors with other therapies is a noteworthy treatment strategy. Immunotherapy in combination with chemotherapy or small-molecule inhibitors still faces many challenges. Additionally, there are some new immunotherapy targets in development. We aimed to further evaluate the effectiveness and usefulness of immunotherapy for treating mTNBC and to propose new immunotherapy strategies. This review explains the rationale and results of existing clinical trials evaluating PD-1/PD-L1 inhibitors alone or in combination for the treatment of mTNBC. For patients with aggressive tumors and poor health, PD-1/PD-L1 inhibitors, either alone or in combination with other modalities, have proven to be effective. However, more research is needed to explore more effective immunotherapy regimens that will lead to new breakthroughs in the treatment of mTNBC.

Dehydroepiandrosterone status and efficacy of dehydroepiandrosterone supplementation for bone health in anorexia nervosa: A systematic review and meta-analysis.

OBJECTIVE: This study was designed to determine the status of dehydroepiandrosterone (DHEA) in women with anorexia nervosa (AN) and to assess the efficacy of DHEA supplementation as a treatment for bone health in women with AN. METHOD: Studies were retrieved from the PubMed, Embase, Cochrane Library, MEDLINE, and Scopus databases from inception to February 14, 2022. Observational studies that compared serum DHEA levels between women with AN and healthy controls were included for meta-analysis, and randomized controlled trials (RCTs) that evaluated the effects of DHEA supplementation on bone mass were reviewed. RESULTS: Meta-analysis of 15 cross-sectional studies revealed that patients with AN had significantly elevated serum DHEA levels (mean difference (MD) = 311.63 ng/dl; 95% confidence interval (CI), 78.01-545.25) and reduced DHEAS levels (MD = -24.90 µg/dl; 95% CI, -41.72 to -8.07) compared with healthy controls. A systematic review of seven RCTs found that DHEA monotherapy does not improve bone mineral density (BMD) compared with placebo after adjusting for weight gain. While the combination of DHEA and conjugated oral contraceptives has led to increased bone strength and decreased bone loss, the beneficial effect appears to be limited to older adolescents and adults with closed physes. Potential detrimental effects on BMD were identified in younger adolescents with open physes in one study. DISCUSSION: Due to the lack of apparent benefit of DHEA in women with AN and its potential detrimental effect on BMD in young patients with AN, current evidence does not support the use of DHEA. PUBLIC SIGNIFICANCE: This study demonstrates that women with anorexia nervosa have abnormal levels of dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS), which have been suggested by previous studies to play a role in the development of low bone density in this condition. However, current evidence does not support the use of DHEA as a treatment to preserve bone health in patients with anorexia nervosa given the lack of clear benefit following its use and also because of a potential detrimental effect on bone mineral density in young patients with anorexia nervosa.

OBJETIVO: Este estudio fue diseñado para determinar el estado de la dehidroepiandrosterona (DHEA) en mujeres con anorexia nerviosa (AN) y para evaluar la eficacia de la suplementación con DHEA como tratamiento para la salud ósea en mujeres con AN. MÉTODO: Los estudios se obtuvieron de las bases de datos PubMed, Embase, Cochrane library, MEDLINE y Scopus desde su inicio hasta el 14 de febrero de 2022. Se incluyeron estudios observacionales que compararon los niveles séricos de DHEA entre mujeres que padecen AN y controles sanos para el metanálisis, y se revisaron los ensayos controlados aleatorios (ECA) que evaluaron los efectos de la suplementación con DHEA sobre la masa ósea. RESULTADOS: El metanálisis de 15 estudios transversales reveló que los pacientes que padecen AN tenían niveles séricos significativamente elevados de DHEA (diferencia de medias [DM] = 311,63 ng/dL; intervalo de confianza [IC] del 95%, 78,01-545,25) y niveles reducidos de DHEAS (DM = -24,90 µg/dL; IC del 95%, -41,72 a -8,07) en comparación con los controles sanos. La revisión sistemática de siete ECA encontró que la monoterapia con DHEA no mejora la densidad mineral ósea (DMO) en comparación con placebo después de ajustar el aumento de peso. Si bien la combinación de DHEA y anticonceptivos orales conjugados ha llevado a un aumento de la fuerza ósea y una disminución de la pérdida ósea, el efecto beneficioso parece limitarse a adolescentes mayores y adultos con placas de crecimiento cerradas. En un estudio se identificaron posibles efectos perjudiciales sobre la DMO en adolescentes más jóvenes con placas de crecimiento abiertas. DISCUSIÓN: Debido a la falta de beneficio aparente de la DHEA en mujeres que padecen AN y su posible efecto perjudicial sobre la DMO en pacientes jóvenes que padecen AN, la evidencia actual no apoya el uso de la DHEA.

Hype or hope of hyaluronic acid for osteoarthritis: Integrated clinical evidence synthesis with multi-organ transcriptomics.

BACKGROUND: Intra-articular injections of hyaluronic acid (HA), the United States Food and Drug Administration approved treatment and widely utilized to delay or reserve the progression of the osteoarthritis (OA) involves. However, this treatment has shown controversial results through various clinical practice guidelines and meta-analysis evaluations, warrants more advanced researches on its safety and effectiveness. METHODS: A novel strategy of integrating medical informatics and bioinformatics was utilized. An updated meta-analysis of 16 randomized controlled trials (RCTs) out of 1820 articles was conducted, in combination with a high throughput body-wide-organ-transcriptomic (BOT) RNA-sequencing (RNA-seq) and in vitro and vivo experiments to evaluate the effect of HA at local and systemic levels, revealing the underlying mechanism. RESULTS: A sensitivity analysis was performed restricting to high quality RCTs, no significant effect of HA treatment was found on pain relief and functional improvement. Descriptive analysis of RNA-seq using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed biological process related to innate immune responses and apoptosis; BOT analysis revealed differential gene expressions (DEGs) in cartilage, lymph node, spleen, kidney, and liver, with immune cell proliferation in immune-related organs. In vitro, HA-coated plates were shown to induce macrophage responses; in vivo histological images revealed knee joint, liver, and kidney with damaged/abnormal morphologies, while immune cell proliferation was observed in the lymph node and spleen and it was found that there was no significant difference in the treatment effect for OA animal model. CONCLUSION: Conclusively, integration of meta-analysis with bioinformatics analysis exhibited that HA induces inflammatory responses both locally and systematically and not benefit for OA treatment, thus limiting the regeneration and leading to some organ-specific pathogenesis. The strategy and findings will be of important for guiding future long-term clinical studies. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study illustrated that the administered HA activated both systemic and local pro-inflammatory immune responses, possibly limiting its efficacy. This novel unique strategy proposed in this study can be utilized and adapted for future meta-analysis and bioinformatics study.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. METHODS: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. RESULTS: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. CONCLUSION: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Application of marine natural products in drug research.

New diseases are emerging as the environment changes, so drug manufacturers are always on the lookout for new resources to develop effective and safe drugs. In recent years, many bioactive substances have been produced in the marine environment, which represents an alternative resource for new drugs used to combat major diseases such as cancer or inflammation. Many marine-derived medicinal substances are in preclinical or early stage of clinical development, and some marine drugs have been put on the market, such as ET743 (Yondelis®). This review presents the sources, activities, mechanisms of action and syntheses of bioactive substances based on marine natural products in clinical trials and on the market, which is helpful to understand the progress of drug research by application of marine natural products.

An adaptive method for assigning clinical trials wait-times for controls.

Wait-list control clinical trials are popular among psychologists and rehabilitation specialists partly because all participants receive the intervention. In 2 arm wait-list control trials, individuals randomized to the treatment group receive immediate treatment whereas individuals randomized to the control group wait a fixed amount of time before intervention is initiated. For interventions that have varying durations, careful consideration must be given to the period that participants in the control group have a delay until treatment begins, as incongruent wait times compared to the intervention durations of the treatment group may introduce confounding into the evaluation of the treatment differences. To alleviate this issue, we propose to adaptively assign wait times to individuals randomized to the control group based on the intervention duration of those in the treatment group. Simulations demonstrate the that our method not only results in similar timing distributions between participants in the treatment and control groups, but also allows participants in the control group to initiate treatment earlier than the traditional design. The latter characteristic may reduce dropout and result in more efficient study enrollment.

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.

Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

Relation of Gut Microbes and L-Thyroxine Through Altered Thyroxine Metabolism in Subclinical Hypothyroidism Subjects.

Thyroxine metabolism is an important topic of pathogenesis research and treatment schedule of subclinical hypothyroidism (SCH). L-Thyroxine replacement therapy (LRT) is usually recommended for severe SCH patients only. Our previous studies reported that disordered serum lipid of mild SCH people could also benefit from LRT. However, the benefits were different among individuals, as shown by the variations in drug dosage that required to maintain thyroid-stimulating hormone (TSH) stability. Alternative pathways, such as sulfation and glucuronidation of iodothyronine, may play a role in thyroid hormones metabolism in peripheral tissues aside from thyroid. Conjugated thyroxine can be hydrolyzed and reused in tissues including gastrointestinal tract, in which gut microbiota are one of the most attractive physiological components. On this site, the roles of gut microbiota in thyroidal metabolism should be valued. In this study, a cross-sectional study was performed by analyzing 16S rDNA of gut microbiota in mild SCH patients treated with L-thyroxine or not. Subjects were divided by serum lipid level, L-thyroxine treatment, or L-thyroxine dosage, respectively. Relationship between gut microbiome and serum profile, L-thyroxine treatment, and dose were discussed. Other metabolic disorders such as type 2 diabetes and hypertension were also taken into consideration. It turned out that microbiome varied among individuals divided by dose and the increment of L-thyroxine but not by serum lipid profile. Relative abundance of certain species that were associated with thyroxine metabolism were found varied among different L-thyroxine doses although in relatively low abundance. Moreover, serum cholesterol may perform relevance effects with L-thyroxine in shaping microbiome. Our findings suggested that the differences in L-thyroxine dosage required to maintain TSH level stability, as well as the SCH development, which was displayed by the increased L-thyroxine doses in subsequent follow-up, had relationship with gut microbial composition. The reason may due to the differences in thyroxine metabolic capacity in gut. In addition, the metabolic similarity of iodothyronines and bile acid in gut also provides possibilities for the correlation between host's thyroxine and cholesterol levels. This study was registered with ClinicalTrials.gov as number NCT01848171.

What is the impact of patient recruitment on offshoring of clinical trials?

The issue of globalization of research is receiving considerable attention due to the increasing number of offshored R&D activities from the United States, Europe, and Japan. This paper explores this phenomenon and provides a model to analyze the factors that will likely contribute to a global transformation of clinical trials. By identifying the main characteristics of clinical trials, I aim to clarify the main driver of the relocation process of clinical research. I reviewed the relevant published articles to address the research questions. The results of this study challenge the traditional thinking of cost-related factors as the major reason for offshoring cilinical trials and show the importance of the recruitment of human subjects in trials. Consequently, this paper suggests that "recruitment crisis" in home country as the main contribution and a key driver to offshore R&D activities, has been underestimated by previous studies. In particular, this study provides policy-decision makers with a new insight into the development issue surrounding the pharmaceutical industry.

Big Data Just Got Bigger: Implications of Real-World Evidence and Patient-Entered Data on Health Care and Health Care Policy.

Advancing care delivery in lifestyle medicine and primary care has increasingly benefited from unique data sources and points. To remain competitive and relevant in modern practice, physicians and health systems must tackle and engage the implementation of big data and advanced applications for increasingly complex care. In many cases, information is being aggregated, though barriers exist in terms of accessing, interpreting, and making it actionable. New mobile device applications have eased some barriers, yet present challenges of their own. These new applications, designed to gather patient-entered data outside of traditional clinical settings, will require new policies, systems, and workflows. From a business perspective, collecting such data has potential value to patient care and patient engagement as well as financial incentives. If handled correctly, these additional data sources, including those not previously accessible, have the potential to vastly improve patient health.

Research progress in gene therapy for wet age-related macular degeneration / 国际眼科杂志(Guoji Yanke Zazhi)

@#Wet age-related macular degeneration is a severe and blinding disease with progressive central visual impairment, accounting for about 10%-15% of age-related macular degeneration. In recent years, with the deepening understanding of its pathogenesis, especially the discovery of anti-VEGF family, the clinical popularization of new drugs has brought benefits to patients. However, this treatment mode requires frequent intraocular injection, and many patients must continue to use it indefinitely to preserve their vision. Gene therapy can provide long-term stable anti-VEGF activity, which has become a new hotspot of research. Several methods of gene therapy are summarized as follows.

[Research progress of gene therapy in clinical application].

In the 1960s, scientists first raised the idea of curing genetic diseases using gene therapy. This new conceptual strategy aimed to achieve a much longer therapeutic effect by introducing exogenous genetic materials into the patients. After more than five decades of ups and downs, gene therapy has been brought into a new era by those milestone breakthroughs in the 21st century. Here we reviewed and summarized the history and breakthroughs of gene therapy, including some critical clinical trials, approved drugs, and emerging gene editing techniques. We believe that with their unique advantages over traditional therapies, more gene therapies will become practical approaches to genetic diseases and benefit the entire human race.

Considerations for Optimal Trial Design for Rheumatoid Arthritis Prevention Studies.

The field of rheumatology has made major contributions to medicine through the identification of cellular and molecular targets and with the development of therapies for the treatment of an impressive range of immune-mediated rheumatic diseases. In recent years new milestones have been achieved. These include the recognition of an "at risk" state, defined by distinct clusters of characteristics, including disease-specific autoantibodies in serum and symptom complexes that include inflammatory joint pain. Studies seeking to prevent high-risk individuals from progressing to a state of clinically apparent arthritis have been initiated. Here, exploiting the current evidence base, an experimental framework to inform trial design is described, taking into consideration study patient phenotypes and highlighting the impact of risk stratification and the options available for therapeutic intervention according to the different phases of the preclinical syndrome. Pragmatic primary end points and suggestions for a set of risk-focused trial outcome measures are proposed, including both clinical assessments and patient-reported outcome measures. Rheumatoid arthritis prevention studies provide an important experimental framework for generating deeper insights into risk stratification and for refining trial design in the future. To this end, a research agenda is suggested, together with some considerations for imaging and for biological sampling. This commentary concludes with some of the operational issues that arise from such studies and addresses some of the challenges associated with recruitment and retention of the at-risk trial participant.