Radiation therapy with phenotypic medicine: towards N-of-1 personalization.

In current clinical practice, radiotherapy (RT) is prescribed as a pre-determined total dose divided over daily doses (fractions) given over several weeks. The treatment response is typically assessed months after the end of RT. However, the conventional one-dose-fits-all strategy may not achieve the desired outcome, owing to patient and tumor heterogeneity. Therefore, a treatment strategy that allows for RT dose personalization based on each individual response is preferred. Multiple strategies have been adopted to address this challenge. As an alternative to current known strategies, artificial intelligence (AI)-derived mechanism-independent small data phenotypic medicine (PM) platforms may be utilized for N-of-1 RT personalization. Unlike existing big data approaches, PM does not engage in model refining, training, and validation, and guides treatment by utilizing prospectively collected patient's own small datasets. With PM, clinicians may guide patients' RT dose recommendations using their responses in real-time and potentially avoid over-treatment in good responders and under-treatment in poor responders. In this paper, we discuss the potential of engaging PM to guide clinicians on upfront dose selections and ongoing adaptations during RT, as well as considerations and limitations for implementation. For practicing oncologists, clinical trialists, and researchers, PM can either be implemented as a standalone strategy or in complement with other existing RT personalizations. In addition, PM can either be used for monotherapeutic RT personalization, or in combination with other therapeutics (e.g. chemotherapy, targeted therapy). The potential of N-of-1 RT personalization with drugs will also be presented.

Personal and work-related factors associated with post-traumatic growth in nurses: A mixed studies systematic review.

INTRODUCTION: Nurses, assuming a wide range of clinical and patient care responsibilities in a healthcare team, are highly susceptible to direct and indirect exposure to traumatic experiences. However, literature has shown that nurses with certain traits developed a new sense of personal strength in the face of adversity, known as post-traumatic growth (PTG). This review aimed to synthesize the best available evidence to evaluate personal and work-related factors associated with PTG among nurses. DESIGN: Mixed studies systematic review. METHODS: Studies examining factors influencing PTG on certified nurses from all healthcare facilities were included. Published and unpublished studies were identified by searching 12 databases from their inception until 4th February 2023. Two reviewers independently screened, appraised, piloted a data collection form, and extracted relevant data. Meta-summary, meta-synthesis, meta-analysis, as well as subgroup and sensitivity analyses were performed. Integration of results followed result-based convergent design. RESULTS: A total of 98 studies with 29,706 nurses from 18 countries were included. These included 49 quantitative, 42 qualitative, and seven mixed-methods studies. Forty-six influencing factors were meta-analyzed, whereas nine facilitating factors were meta-summarized. A PTG conceptual map was created. Four constructs emerged from the integration synthesis: (a) personal system, (b) work-related system, (c) event-related factors, and (d) cognitive transformation. CONCLUSION: The review findings highlighted areas healthcare organizations could do to facilitate PTG in nurses. Practical implications include developing intervention programs based on PTG facilitators. Further research should examine the trend of PTG and its dynamic response to different nursing factors. CLINICAL RELEVANCE: Research on trauma-focused therapies targeting nurses' mental health is lacking. Therefore, findings from this review could inform healthcare organizations on the PTG phenomenon and developing support measures for nurses through healthcare policies and clinical practice.

How do aspects of selfhood relate to depression and anxiety among youth? A meta-analysis.

Adolescents' sense of self has important implications for their mental health. Despite more than two decades of work, scholars have yet to amass evidence across studies to elucidate the role of selfhood in the mental health of adolescents. Underpinned by the conceptual model of selfhood, this meta-analytic review investigated the strength of associations of different facets of selfhood and their associated traits with depression and anxiety, moderating factors that attenuate or exacerbate these associations, and their causal influences. Using mixed-effects modeling, which included 558 effect sizes from 298 studies and 274 370 adolescents from 39 countries, our findings revealed that adolescents' self-esteem/self-concept [r = -0.518, p < 0.0001; (95% CI -0.49 to -0.547)] and self-compassion [r = -0.455, p < 0.0001; (95% CI -0.568 to -0.343)] demonstrating largest effect sizes in their associations with depression. Self-esteem/self-concept, self-compassion, self-awareness, self-efficacy, and self-regulation had similar moderate negative associations with anxiety. Meta-regressions revealed that adolescent age and type of informants (parents v. adolescents) were important moderators. Findings on causal influences indicated bidirectional causations, particularly low self-esteem/self-concept, self-awareness and self-efficacy drive higher depression and vice-versa. In contrast, the different self traits did not demonstrate specific causal direction with anxiety. These results pinpoint self traits that are pivotal in relating to adolescent mental health functioning. We discussed the theoretical implications of our findings in terms of how they advance theory of selfhood for adolescent mental health, and the practical implications of building selfhood as cultivating psychological skills for mental health.

Economic Evaluation Associated With Clinical-Grade Mobile App-Based Digital Therapeutic Interventions: Systematic Review.

BACKGROUND: Digital therapeutics (DTx), a class of software-based clinical interventions, are promising new technologies that can potentially prevent, manage, or treat a spectrum of medical disorders and diseases as well as deliver unprecedented portability for patients and scalability for health care providers. Their adoption and implementation were accelerated by the need for remote care during the COVID-19 pandemic, and awareness about their utility has rapidly grown among providers, payers, and regulators. Despite this, relatively little is known about the capacity of DTx to provide economic value in care. OBJECTIVE: This study aimed to systematically review and summarize the published evidence regarding the cost-effectiveness of clinical-grade mobile app-based DTx and explore the factors affecting such evaluations. METHODS: A systematic review of economic evaluations of clinical-grade mobile app-based DTx was conducted following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines. Major electronic databases, including PubMed, Cochrane Library, and Web of Science, were searched for eligible studies published from inception to October 28, 2022. Two independent reviewers evaluated the eligibility of all the retrieved articles for inclusion in the review. Methodological quality and risk of bias were assessed for each included study. RESULTS: A total of 18 studies were included in this review. Of the 18 studies, 7 (39%) were nonrandomized study-based economic evaluations, 6 (33%) were model-based evaluations, and 5 (28%) were randomized clinical trial-based evaluations. The DTx intervention subject to assessment was found to be cost-effective in 12 (67%) studies, cost saving in 5 (28%) studies, and cost-effective in 1 (6%) study in only 1 of the 3 countries where it was being deployed in the final study. Qualitative deficiencies in methodology and substantial potential for bias, including risks of performance bias and selection bias in participant recruitment, were identified in several included studies. CONCLUSIONS: This systematic review supports the thesis that DTx interventions offer potential economic benefits. However, DTx economic analyses conducted to date exhibit important methodological shortcomings that must be addressed in future evaluations to reduce the uncertainty surrounding the widespread adoption of DTx interventions. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42022358616; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022358616.

Characteristics of Mobile Health Platforms for Depression and Anxiety: Content Analysis Through a Systematic Review of the Literature and Systematic Search of Two App Stores.

BACKGROUND: Mobile health (mHealth) platforms show promise in the management of mental health conditions such as anxiety and depression. This has resulted in an abundance of mHealth platforms available for research or commercial use. OBJECTIVE: The objective of this review is to characterize the current state of mHealth platforms designed for anxiety or depression that are available for research, commercial use, or both. METHODS: A systematic review was conducted using a two-pronged approach: searching relevant literature with prespecified search terms to identify platforms in published research and simultaneously searching 2 major app stores-Google Play Store and Apple App Store-to identify commercially available platforms. Key characteristics of the mHealth platforms were synthesized, such as platform name, targeted condition, targeted group, purpose, technology type, intervention type, commercial availability, and regulatory information. RESULTS: The literature and app store searches yielded 169 and 179 mHealth platforms, respectively. Most platforms developed for research purposes were designed for depression (116/169, 68.6%), whereas the app store search reported a higher number of platforms developed for anxiety (Android: 58/179, 32.4%; iOS: 27/179, 15.1%). The most common purpose of platforms in both searches was treatment (literature search: 122/169, 72.2%; app store search: 129/179, 72.1%). With regard to the types of intervention, cognitive behavioral therapy and referral to care or counseling emerged as the most popular options offered by the platforms identified in the literature and app store searches, respectively. Most platforms from both searches did not have a specific target age group. In addition, most platforms found in app stores lacked clinical and real-world evidence, and a small number of platforms found in the published research were available commercially. CONCLUSIONS: A considerable number of mHealth platforms designed for anxiety or depression are available for research, commercial use, or both. The characteristics of these mHealth platforms greatly vary. Future efforts should focus on assessing the quality-utility, safety, and effectiveness-of the existing platforms and providing developers, from both commercial and research sectors, a reporting guideline for their platform description and a regulatory framework to facilitate the development, validation, and deployment of effective mHealth platforms.

Omnichannel Communication to Boost Patient Engagement and Behavioral Change With Digital Health Interventions.

Digital health interventions are being increasingly incorporated into health care workflows to improve the efficiency of patient care. In turn, sustained patient engagement with digital health interventions can maximize their benefits toward health care outcomes. In this viewpoint, we outline a dynamic patient engagement by using various communication channels and the potential use of omnichannel engagement to integrate these channels. We conceptualize a novel patient care journey where multiple web-based and offline communication channels are integrated through a "digital twin." The principles of implementing omnichannel engagement for digital health interventions and digital twins are also broadly covered. Omnichannel engagement in digital health interventions implies a flexibility for personalization, which can enhance and sustain patient engagement with digital health interventions, and ultimately, patient quality of care and outcomes. We believe that the novel concept of omnichannel engagement in health care can be greatly beneficial to patients and the system once it is successfully realized to its full potential.

Clinical validation of a nanodiamond-embedded thermoplastic biomaterial.

Detonation nanodiamonds (NDs) are promising drug delivery and imaging agents due to their uniquely faceted surfaces with diverse chemical groups, electrostatic properties, and biocompatibility. Based on the potential to harness ND properties to clinically address a broad range of disease indications, this work reports the in-human administration of NDs through the development of ND-embedded gutta percha (NDGP), a thermoplastic biomaterial that addresses reinfection and bone loss following root canal therapy (RCT). RCT served as the first clinical indication for NDs since the procedure sites involved nearby circulation, localized administration, and image-guided treatment progress monitoring, which are analogous to many clinical indications. This randomized, single-blind interventional treatment study evaluated NDGP equivalence with unmodified GP. This progress report assessed one control-arm and three treatment-arm patients. At 3-mo and 6-mo follow-up appointments, no adverse events were observed, and lesion healing was confirmed in the NDGP-treated patients. Therefore, this study is a foundation for the continued clinical translation of NDs and other nanomaterials for a broad spectrum of applications.

Reducing posttreatment relapse in cleft lip palatal expansion using an injectable estrogen-nanodiamond hydrogel.

Patients with cleft lip and/or palate (CLP), who undergo numerous medical interventions from infancy, can suffer from lifelong debilitation caused by underdeveloped maxillae. Conventional treatment approaches use maxillary expansion techniques to develop normal speech, achieve functional occlusion for nutrition intake, and improve esthetics. However, as patients with CLP congenitally lack bone in the cleft site with diminished capacity for bone formation in the expanded palate, more than 80% of the patient population experiences significant postexpansion relapse. While such relapse has been a long-standing battle in craniofacial care of patients, currently there are no available strategies to address this pervasive problem. Estrogen, 17ß-estradiol (E2), is a powerful therapeutic agent that plays a critical role in bone homeostasis. However, E2's clinical application is less appreciated due to several limitations, including its pleiotropic effects and short half-life. Here, we developed a treatment strategy using an injectable system with photo-cross-linkable hydrogel (G) and nanodiamond (ND) technology to facilitate the targeted and sustained delivery of E2 to promote bone formation. In a preclinical expansion/relapse model, this functionalized E2/ND/G complex substantially reduced postexpansion relapse by nearly threefold through enhancements in sutural remodeling compared with unmodified E2 administration. The E2/ND/G group demonstrated greater bone volume by twofold and higher osteoblast number by threefold, compared with the control group. The E2/ND/G platform maximized the beneficial effects of E2 through its extended release with superior efficacy and safety at the local level. This broadly applicable E2 delivery platform shows promise as an adjuvant therapy in craniofacial care of patients.

Water-Soluble Nanoconjugate for Enhanced Cellular Delivery of Receptor-Targeted Magnetic Resonance Contrast Agents.

ProGlo is an efficient steroid receptor-targeted magnetic resonance (MR) imaging contrast agent (CA). It has been shown to bind to the progesterone receptor (PR) and produce enhanced image contrast in PR-positive cells and tissues in vitro and in vivo. However, the hydrophobicity of the steroid targeting domain of ProGlo (logP = 1.4) limits its formulation and delivery at clinically relevant doses. In this work, a hydrophobic moiety was utilized to drive efficient adsorption onto nanodiamond (ND) clusters to form a water-soluble nanoconstruct (logP = -2.4) with 80% release in 8 h under biological conditions. In cell culture, the ND-ProGlo construct delivered increased concentrations of ProGlo to target cells compared to ProGlo alone. Importantly, these results were accomplished without the use of solvents such as DMSO, providing a significant advance toward formulating ProGlo for translational applications. Biodistribution studies confirm the delivery of ProGlo to PR(+) tissues with enhanced efficacy over untargeted controls. These results demonstrate the potential for a noncovalent ND-CA construct as a general strategy for solubilizing and delivering hydrophobic targeted MR CAs.

Nanodiamond-Gadolinium(III) Aggregates for Tracking Cancer Growth In Vivo at High Field.

The ability to track labeled cancer cells in vivo would allow researchers to study their distribution, growth, and metastatic potential within the intact organism. Magnetic resonance (MR) imaging is invaluable for tracking cancer cells in vivo as it benefits from high spatial resolution and the absence of ionizing radiation. However, many MR contrast agents (CAs) required to label cells either do not significantly accumulate in cells or are not biologically compatible for translational studies. We have developed carbon-based nanodiamond-gadolinium(III) aggregates (NDG) for MR imaging that demonstrated remarkable properties for cell tracking in vivo. First, NDG had high relaxivity independent of field strength, a finding unprecedented for gadolinium(III) [Gd(III)]-nanoparticle conjugates. Second, NDG demonstrated a 300-fold increase in the cellular delivery of Gd(III) compared to that of clinical Gd(III) chelates without sacrificing biocompatibility. Further, we were able to monitor the tumor growth of NDG-labeled flank tumors by T1- and T2-weighted MR imaging for 26 days in vivo, longer than was reported for other MR CAs or nuclear agents. Finally, by utilizing quantitative maps of relaxation times, we were able to describe tumor morphology and heterogeneity (corroborated by histological analysis), which would not be possible with competing molecular imaging modalities.

A Chemopreventive Nanodiamond Platform for Oral Cancer Treatment.

Standard oral cancer therapy generally includes a combination of surgery with chemotherapy and/or radiotherapy. This treatment paradigm has not changed in some time. In this paper, we propose a chemopreventive nanodiamond platform for the delivery of celecoxib (Celebrex) to oral cancer lesions. This innovative platform allows for sustained drug release under physiological conditions, potentially enhancing chemopreventive efficacy of celecoxib without the physical and toxicological damage associated with conventional means of drug delivery.

Nanodiamond-based chemotherapy and imaging.

The advent of cancer nanomedicine has forged new pathways for the enhanced imaging and treatment of a broad range of cancers using new classes of materials. Among the many platforms being developed for drug delivery and imaging, nanodiamonds (NDs) possess several important attributes that may be beneficial toward improving the efficacy and safety of cancer nanomedicine applications. These include the uniquely faceted surfaces of the ND particles that result in electrostatic properties that mediate enhanced interactions with water and loaded therapeutic compounds, scalable processing and synthesis parameters, versatility as platform carriers, and a spectrum of other characteristics. In addition, comprehensive in vitro and in vivo studies have demonstrated that NDs are well tolerated. This chapter will examine several recent studies that have harnessed the ND agent as a foundation for both systemic and localized drug delivery, as well as the marked improvements in magnetic resonance imaging efficiency that has been observed following ND-contrast agent conjugation. In addition, insight into the important steps toward bringing the ND translational pathway to the clinic will be discussed.

Nanodiamond-mitoxantrone complexes enhance drug retention in chemoresistant breast cancer cells.

Chemoresistance is a prevalent issue that accounts for the vast majority of treatment failure outcomes in metastatic cancer. Among the mechanisms of resistance that markedly decrease treatment efficacy, the efflux of drug compounds by ATP-binding cassette (ABC) transporter proteins can impair adequate drug retention by cancer cells required for therapeutic cytotoxic activity. Of note, ABC transporters are capable of effluxing several classes of drugs that are clinical standards, including the anthracyclines such as doxorubicin, as well as anthracenediones such as mitoxantrone. To address this challenge, a spectrum of nanomaterials has been evaluated for improved drug retention and enhanced efficacy. Nanodiamonds (NDs) are emerging as a promising nanomaterial platform because they integrate several important properties into a single agent. These include a uniquely faceted truncated octahedral architecture that enables potent drug binding and dispersibility in water, scalably processed ND particles with uniform diameters of approximately 5 nm, and a demonstrated ability to improve drug tolerance while delaying tumor growth in multiple preclinical models, among others. This work describes a ND-mitoxantrone complex that can be rapidly synthesized and mediates marked improvements in drug efficacy. Comprehensive complex characterization reveals a complex with favorable drug delivery properties that is capable of improving drug retention and efficacy in an MDA-MB-231-luc-D3H2LN (MDA-MB-231) triple negative breast cancer cell line that was lentivirally transduced for resistance against mitoxantrone. Findings from this study support the further evaluation of ND-MTX in preclinical dose escalation and safety studies toward potentially clinical validation.

Synthesis of nanodiamond-daunorubicin conjugates to overcome multidrug chemoresistance in leukemia.

Nanodiamonds (NDs) are promising candidates in nanomedicine, demonstrating significant potential as gene/drug delivery platforms for cancer therapy. We have synthesized ND vectors capable of chemotherapeutic loading and delivery with applications towards chemoresistant leukemia. The loading of Daunorubicin (DNR) onto NDs was optimized by adjusting reaction parameters such as acidity and concentration. The resulting conjugate, a novel therapeutic payload for NDs, was characterized extensively for size, surface charge, and loading efficiency. A K562 human myelogenous leukemia cell line, with multidrug resistance conferred by incremental DNR exposure, was used to demonstrate the efficacy enhancement resulting from ND-based delivery. While resistant K562 cells were able to overcome treatment from DNR alone, as compared with non-resistant K562 cells, NDs were able to improve DNR delivery into resistant K562 cells. By overcoming efflux mechanisms present in this resistant leukemia line, ND-enabled therapeutics have demonstrated the potential to improve cancer treatment efficacy, especially towards resistant strains. FROM THE CLINICAL EDITOR: The authors of this study demonstrate superior treatment properties of resistant leukemia cell lines by utilizing nanodiamond vectors loaded with daunorubicin, paving the way to clinical studies in the hopefully not too distant future.

Convection-enhanced delivery of nanodiamond drug delivery platforms for intracranial tumor treatment.

This study examined a novel drug delivery system for treatment of malignant brain gliomas: DOX complexed with nanodiamonds (ND-Dox), and administered via convection-enhanced delivery (CED). Drug retention and toxicity were examined in glioma cell lines, and distribution, retention and toxicity were examined in normal rat parenchyma. Efficacy was assessed in a bioluminescence rodent tumor model. NDs markedly enhanced DOX uptake and retention in glioma cells. ND-Dox delivered via CED extended DOX retention and localized DOX toxicity in normal rodent parenchyma, and was significantly more efficient at killing tumor cells than uncomplexed DOX. Outcomes from this work suggest that CED of ND-Dox is a promising approach for brain tumor treatment. FROM THE CLINICAL EDITOR: In this paper, nanodiamonds were utilized to enhance delivery of DOX in a preclinical glioma model using a convection-enhanced delivery method, demonstrating remarkably enhanced efficacy.

N-of-1 health optimization: Digital monitoring of biomarker dynamics to gamify adherence to metabolic switching.

The digital health field is experiencing substantial growth due to its potential for sustained and longitudinal deployment. In turn, this may drive improved monitoring and intervention as catalysts for behavioral change compared to traditional point-of-care practices. In particular, the increase in incidence of population health challenges such as diabetes, heart disease, fatty liver disease, and other disorders coupled with rising healthcare costs have emphasized the importance of exploring technical, economics, and implementation considerations, among others in the decentralization of health and healthcare innovations. Both healthy individuals and patients stand to benefit from continued technical advances and studies in these domains. To address these points, this study reports a N-of-1 study comprised of sustained regimens of intermittent fasting, fitness (strength and cardiovascular training), and high protein, low carbohydrate diet and parallel monitoring. These regimens were paired with serial blood ketone, blood glucose (wearable and finger stick) and blood pressure readings, as well as body weight measurements using a collection of devices. Collectively this suite of platforms and approaches were used to monitor metabolic switching from glucose to ketones as energy sources-a process associated with potential cardio- and neuroprotective functions. In addition to longitudinal biomarker dynamics, this work discusses user perspectives on the potential role of harnessing digital devices to these dynamics as potential gamification factors, as well as considerations for the role of biomarker monitoring in health regimen development, user stratification, and potentially informing downstream population-scale studies to address metabolic disease, healthy aging and longevity, among other indications.

CURATE.AI-assisted dose titration for anti-hypertensive personalized therapy: study protocol for a multi-arm, randomized, pilot feasibility trial using CURATE.AI (CURATE.AI ADAPT trial).

Aims: Artificial intelligence-driven small data platforms such as CURATE.AI hold potential for personalized hypertension care by assisting physicians in identifying personalized anti-hypertensive doses for titration. This trial aims to assess the feasibility of a larger randomized controlled trial (RCT), evaluating the efficacy of CURATE.AI-assisted dose titration intervention. We will also collect preliminary efficacy and safety data and explore stakeholder feedback in the early design process. Methods and results: In this open-label, randomized, pilot feasibility trial, we aim to recruit 45 participants with primary hypertension. Participants will be randomized in 1:1:1 ratio into control (no intervention), home blood pressure monitoring (active control; HBPM), or CURATE.AI arms (intervention; HBPM and CURATE.AI-assisted dose titration). The home treatments include 1 month of two-drug anti-hypertensive regimens. Primary endpoints assess the logistical (e.g. dose adherence) and scientific (e.g. percentage of participants for which CURATE.AI profiles can be generated) feasibility, and define the progression criteria for the RCT in a 'traffic light system'. Secondary endpoints assess preliminary efficacy [e.g. mean change in office blood pressures (BPs)] and safety (e.g. hospitalization events) associated with each treatment protocol. Participants with both baseline and post-treatment BP measurements will form the intent-to-treat analysis. Following their involvement with the CURATE.AI intervention, feedback from CURATE.AI participants and healthcare providers will be collected via exit survey and interviews. Conclusion: Findings from this study will inform about potential refinements of the current treatment protocols before proceeding with a larger RCT, or potential expansion to collect additional information. Positive results may suggest the potential efficacy of CURATE.AI to improve BP control. Trial registration number: NCT05376683.

N-of-1 medicine.

ABSTRACT: The fields of precision and personalised medicine have led to promising advances in tailoring treatment to individual patients. Examples include genome/molecular alteration-guided drug selection, single-patient gene therapy design and synergy-based drug combination development, and these approaches can yield substantially diverse recommendations. Therefore, it is important to define each domain and delineate their commonalities and differences in an effort to develop novel clinical trial designs, streamline workflow development, rethink regulatory considerations, create value in healthcare and economics assessments, and other factors. These and other segments are essential to recognise the diversity within these domains to accelerate their respective workflows towards practice-changing healthcare. To emphasise these points, this article elaborates on the concept of digital health and digital medicine-enabled N-of-1 medicine, which individualises combination regimen and dosing using a patient's own data. We will conclude with recommendations for consideration when developing novel workflows based on emerging digital-based platforms.