The first article, written by health writer and ICU nurse Jenna Congdon, tackles a phenomenon that many hospital administrators would prefer not to name: shadow AI. In

The tension between clinical innovation and institutional oversight that defines the shadow AI phenomenon is not unique to any single health system. Across hospitals and clinics, the gap between what frontline workers need and what officially sanctioned software provides has widened as consumer-facing AI tools have become more capable and more accessible. A clinician who once might have drafted a discharge summary by hand can now paste de-identified fragments of a note into a general-purpose chatbot and receive a polished summary in seconds. The convenience is undeniable, but so is the risk: once patient information leaves a controlled environment, the organization loses visibility into where that data travels, how it is retained, and whether it could resurface in outputs shown to other users.

Researchers studying health information technology adoption have long observed a pattern in which workarounds emerge when formal systems are misaligned with the realities of practice. Barcode medication administration, electronic health records, and secure messaging platforms have each spawned their own unauthorized shortcuts when clinicians found the approved versions too slow, too rigid, or too poorly matched to their workflows. Shadow AI fits squarely within this tradition. Its rapid proliferation suggests that governance strategies built purely on prohibition are unlikely to succeed, and that institutions which engage with the underlying drivers of unauthorized use stand a better chance of channeling that demand into safer, auditable tools.

The economics of clinical documentation further illuminate why shadow AI has taken hold. Studies of physician and nurse time allocation consistently show that a substantial fraction of a clinician’s day is consumed by administrative tasks rather than direct patient care. Burnout surveys repeatedly link documentation burden to exhaustion and attrition, and staffing shortages across many health systems have intensified the pressure. In that environment, any tool that promises to reclaim even a few minutes per patient carries enormous appeal. The challenge for health systems is to capture those efficiency gains without sacrificing privacy safeguards, model transparency, or accountability for errors.

The science of vocal biomarkers, meanwhile, rests on a growing body of evidence that the human voice encodes measurable signatures of physiological and neurological state. Speech production requires the coordination of respiratory muscles, laryngeal folds, articulators, and multiple brain regions, so disruptions in motor control, cognition, or mood can alter acoustic properties such as pitch variability, speech rate, pause frequency, and spectral features. Researchers have reported that such features may change in conditions ranging from Parkinson disease and Alzheimer disease to depression and respiratory illness, sometimes before overt symptoms prompt a clinical visit.

What machine learning adds to this field is scale and pattern recognition. Traditional speech and language assessments are administered one patient at a time by trained specialists, limiting throughput and introducing subjectivity. Automated pipelines can process recordings in seconds and extract hundreds of acoustic variables simultaneously, potentially flagging subtle deviations a human listener would miss. The JMIR feature article highlights initiatives such as the Luxembourg Institute of Health’s Deep Digital Phenotyping Research Unit, which is incorporating vocal data into digital twin models, and the Weizmann Institute’s Human Phenotype Project, whose collection of more than 7000 voice recordings within a deep phenotyping cohort represents an early effort to build the large, standardized datasets that robust clinical validation will require.

Standardization is a critical hurdle for the field. Voice recordings are exquisitely sensitive to recording conditions: microphone quality, background noise, distance from the device, and compression by telecommunication software can all shift acoustic measurements. A biomarker validated on studio-quality recordings may perform very differently on a smartphone captured in a noisy hallway. Efforts to establish universal collection protocols, reference datasets, and calibration methods are therefore seen as prerequisites for moving vocal biomarkers from research curiosity to diagnostic utility. Regulatory agencies have begun to signal interest, but the pathway from an interesting acoustic correlation to an approved clinical test remains long and demands prospective validation in diverse populations.

If vocal biomarkers mature, they could reshape screening paradigms, particularly for neurodegenerative disorders where early detection may eventually matter most. Passive or semi-passive monitoring, in which a patient’s voice is analyzed during ordinary phone calls or periodic app-based prompts, could complement traditional assessments and provide longitudinal trends that single snapshots cannot. Yet the same capabilities raise questions about consent and surveillance. Voice is gathered constantly by consumer devices, and the prospect of health inferences drawn from routine audio underscores the need for clear policies on when such analysis is permissible and who may access the results.

The emergence of griefbots raises similarly unsettled questions in the domain of bereavement. These systems, trained on the texts, messages, social media posts, photographs, and other digital traces a person leaves behind, generate conversational avatars that mourners can interact with as though speaking with the deceased. Commercial services offering such interactions already exist, and the digital legacy market they anchor is expanding. What distinguishes the current moment is that the underlying language models have grown sophisticated enough to make these interactions feel genuinely responsive, amplifying both their potential comfort and their potential to complicate the grieving process.

Grief researchers have long described mourning not as a linear path toward forgetting but as an ongoing renegotiation of the relationship with the deceased. Within that framing, as psychologist Dr. Robert Neimeyer suggests, a griefbot could serve as one instrument among many, offering a controlled space for continuing bonds when used alongside counseling, ritual, and community support. Some bereaved individuals report that simulated conversations helped them articulate things left unsaid, and clinicians sympathetic to the technology argue that any tool that reduces isolation deserves study rather than reflexive dismissal.

Skeptics, including bioethicist Dr. Craig Klugman, counter that the technology may entrench avoidance and contribute to prolonged grief disorder, a condition characterized by persistent, disabling grief that impairs functioning. The mental health outcomes of griefbot use are only beginning to be researched, and no consensus yet exists on which users, if any, are most likely to benefit or be harmed. The commercial incentives behind these products add another layer of concern: Rebernik notes that scant regulations exist to promote user safety and privacy, leaving open the possibility that deeply personal data about the dead and the bereaved could be leveraged for precision marketing or retained indefinitely without meaningful consent from the deceased, who never agreed to be resurrected in algorithmic form.

Digital legacy questions extend beyond griefbots themselves. People increasingly curate what happens to their data after death, and legal frameworks for posthumous digital rights remain fragmented across jurisdictions. Whether an individual’s conversational style, likeness, and voice constitute property that can be licensed to a resurrection service is largely untested, and survivors may disagree among themselves about whether such services honor or violate the memory of the person they loved. These disputes are likely to grow as the technology improves and as more of the population leaves behind rich digital archives.

The story of EndeavorRX illustrates a different convergence of software and medicine: the treatment delivered as a game. Its FDA authorization for pediatric patients aged 8 to 17 marked a regulatory milestone, establishing that a video game designed to train attention through gameplay could satisfy the agency’s expectations for a therapeutic device. The game challenges users to attend to multiple simultaneous demands, and the developer reported improved attention measures in 73 percent of pediatric patients in its supporting studies. Importantly, it is positioned as an adjunct rather than a replacement for established treatments, reflecting a cautious regulatory posture toward a novel therapeutic category.

The broader category of serious games encompasses applications designed for purposes beyond entertainment, including rehabilitation, health education, and cognitive training. Researchers have investigated whether commercial games also confer measurable benefits, and some clinicians, such as psychologist Dr. Megan Connell, already incorporate certain commercial titles into therapeutic practice. The mechanisms proposed for therapeutic effect vary by application, ranging from attentional training and neuroplasticity to the safe exposure and rehearsal of coping strategies within engaging virtual environments. Advances in artificial intelligence and virtual reality may enable games that adapt difficulty in real time to an individual’s performance, potentially increasing both efficacy and adherence.

Open questions remain about how prescription games will fare in routine care. Questions of insurance coverage, prescriber familiarity, and adherence outside supervised trial conditions will shape real-world impact. Sceptics also caution that enthusiasm must be tempered by rigorous independent replication, since effect sizes in novel behavioral interventions sometimes shrink when tested at scale. Nonetheless, the authorization signals to developers and investors that digital therapeutics can clear regulatory hurdles, a signal already reflected in a growing pipeline of software-based treatments for psychiatric and neurological conditions.

Taken together, these four threads describe a health landscape in which the boundary between the clinical and the computational is steadily dissolving. Clinicians reach for unapproved tools because approved ones fall short; researchers mine the voice for early signals of disease; mourners converse with algorithmic echoes of the dead; and children practice attention within a game their doctor can prescribe. Each development carries promise measured against distinct risks: privacy breaches, premature clinical claims, commercial exploitation of grief, and unvalidated therapeutic enthusiasm. The common denominator is a widening recognition that software in health and human experience requires not only innovation but deliberate structures of evidence, ethics, and governance to earn the trust of the people it touches.

The task for researchers, regulators, clinicians, and the public in the coming years will be to decide, case by case, which of these technologies deserve integration into practice and under what safeguards. The JMIR Publications News and Perspectives series contributes to that deliberation by grounding emerging trends in expert analysis and open access scholarship, an approach consistent with the publisher’s broader commitment to open science and to making the evidence base for digital health decisions freely available to all who need it.

Subject of Research: Digital health technologies including shadow AI, vocal biomarkers, griefbots, and therapeutic video games

Article Title: JMIR news: Shadow AI, vocal biomarker tech, griefbots, and a prescription video game

Article References: JMIR news: Shadow AI, vocal biomarker tech, griefbots, and a prescription video game. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: shadow AI, vocal biomarkers, griefbots, digital resurrection, EndeavorRX, ADHD, FDA approval, machine learning, digital health, mental health, bereavement, digital legacy

Historically, CAR T-cell therapy trials systematically excluded patients with CNS involvement due to a well-founded concern about heightened neurologic toxicity. The administration of CD19-directed CAR T cells has been associated with neurologic adverse effects, ranging from mild confusion to severe encephalopathy, which are collectively termed immune effector cell-associated neurotoxicity syndrome (ICANS). Given the delicate and critical nature of the CNS and the pathological involvement of lymphoma in this compartment, conventional wisdom dictated a conservative approach, precluding CNS lymphoma patients from receiving this innovative immunotherapy. Nonetheless, early anecdotal evidence and data from studies in acute lymphoblastic leukemia and other lymphomas suggested that CAR T cells are capable of trafficking across the blood-brain barrier, infiltrating the CNS, and exerting their cytotoxic effects on malignant cells within this sanctuary site, prompting the need for systematic research.

Dana-Farber spearheaded a pilot, investigator-initiated trial designed to assess the safety and feasibility of axicabtagene ciloleucel in patients diagnosed with either primary or secondary CNS lymphoma that was relapsed or refractory to standard treatments. The study meticulously enrolled 18 patients in a staged manner with intensive monitoring protocols to identify dose-limiting toxicities and neurologic complications. The outcomes from this trial demonstrated not only manageable safety profiles but also encouraging signals of efficacy sufficient to persuade regulatory bodies of the therapy’s viability. These data formed the backbone of the FDA’s decision to rescind the previous exclusionary clause, thus formally endorsing the therapeutic use of axi-cel in this challenging context.

This regulatory update is transformative because it challenges and redefines our understanding of CAR T-cell therapy’s limitations and potential. Eligible patients with diffuse large B-cell lymphoma (DLBCL) confined to the CNS now have a path to receive a personalized, cellular immunotherapy option following one or more prior lines of treatment. This shift might herald a new therapeutic era for those suffering from primary CNS lymphoma, who have historically faced dismal prognoses and scant treatment alternatives.

The clinical implications of these findings are profound. Dr. Lakshmi Nayak, Director of Dana-Farber’s Center for CNS Lymphoma, presented these data at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, highlighting that nearly half of the patients treated with axi-cel in this cohort were alive and free from disease relapse at approximately one year post-therapy. While this represents a significant therapeutic breakthrough, Dr. Nayak emphasized the need for longitudinal studies to fully elucidate the durability of these responses and to assess the potential for long-term remission or cure in this population.

The success of this research at Dana-Farber is the culmination of years of careful, hypothesis-driven clinical investigation and multidisciplinary collaboration. Neuro-oncology, immunology, and cell therapy experts combined efforts to navigate the complexities of delivering engineered T cells into a previously deemed ‘immune-privileged’ site. The investigators employed rigorous patient selection criteria and bespoke safety monitoring frameworks to mitigate the risks while maximizing therapeutic benefit.

Understanding the mechanism behind CAR T-cell trafficking into the CNS involves appreciating the dynamic interplay between immune effector cells and the CNS microenvironment. The blood-brain barrier traditionally restricts passage of large molecules and cells to protect the brain from systemic insults. However, inflammation induced by lymphoma and CAR T-cell activation can transiently increase permeability, allowing CAR T cells to infiltrate the CNS parenchyma, surveil, and eliminate neoplastic cells. This ability to breach CNS sanctuaries marks a pivotal shift in cellular immunotherapy paradigms and widens the therapeutic targeting landscape.

Neurologic toxicity remains a key consideration. The research delineated strategies to identify early signs of ICANS and implemented interventions such as steroids and supportive care to manage these adverse events effectively. Encouragingly, the toxicity profile within this CNS lymphoma cohort was comparable to or only slightly elevated from that observed in systemic lymphoma patients without CNS involvement, alleviating earlier apprehensions about unacceptable risk.

From a translational science perspective, the axicabtagene ciloleucel FDA label change embodies the power of investigator-initiated studies to influence regulatory policy and clinical practice. The successful generation of prospective safety data, coupled with pharmacodynamic and clinical outcome measures, underscores the importance of academic institutions in driving innovation beyond industry-sponsored trials. Dana-Farber’s initiative illustrates how focused research efforts can break down long-standing barriers to care and redefine therapeutic standards.

With this important development, clinicians managing neuro-oncology and hematologic malignancies now have an expanded armamentarium supported by robust clinical evidence. The updated labeling allows for more inclusive treatment decisions that incorporate novel immunotherapies earlier in the disease course for primary CNS lymphoma patients, who were previously considered ineligible for such approaches. This democratization of CAR T-cell therapy access promises improved survival and quality of life for patients grappling with this particularly lethal disease subtype.

Looking ahead, ongoing and future investigations are poised to refine patient selection criteria, optimize conditioning regimens, and evaluate combinational approaches that might enhance CAR T-cell efficacy specifically within the CNS milieu. Additionally, molecular and cellular analyses derived from treated patients will offer deeper insights into resistance mechanisms and potential biomarkers predictive of response or toxicity. These efforts will collectively inform next-generation cellular therapies engineered to overcome current limitations.

In sum, the FDA’s approval of an expanded indication for axicabtagene ciloleucel represents a watershed moment in cancer immunotherapy. It validates the feasibility of harnessing engineered T cells to combat malignancies within the CNS, provides a much-needed therapeutic option for a highly vulnerable patient population, and exemplifies how rigorous clinical investigation can drive meaningful regulatory and clinical progress. As CAR T-cell technologies continue to evolve, their integration into the management of CNS lymphoma promises to accelerate therapeutic breakthroughs, ultimately translating into enhanced patient outcomes and survival.

Subject of Research:
FDA label update enabling axicabtagene ciloleucel (Yescarta) use in primary central nervous system lymphoma based on Dana-Farber’s clinical research.

Article Title:
FDA Expands Access to CAR T-Cell Therapy for Primary Central Nervous System Lymphoma Following Dana-Farber-Led Research

News Publication Date:
2024

Web References:
http://www.dana-farber.org/
https://www.dana-farber.org/find-a-doctor/caron-a-jacobson
https://www.dana-farber.org/find-a-doctor/lakshmi-nayak

Keywords:
Adoptive T cell therapy, Lymphoma, Central nervous system lymphoma, CAR T-cell therapy, Axicabtagene ciloleucel, Immune effector cell-associated neurotoxicity syndrome, Diffuse large B-cell lymphoma, Cancer immunotherapy, Hematologic malignancies, Cell-based therapy

The research team, led by cardiovascular scientist Dr. Arjun Deb, focused on the protein ENPP1, identified as a critical impediment to tissue healing. Prior studies on heart tissue from both murine models and human post-myocardial infarction samples revealed elevated ENPP1 levels that trigger a cascade of metabolic disturbances. These disruptions compromise cellular energy generation—a vital process for cell survival, function, and proliferation—thereby thwarting effective tissue regeneration. By elucidating ENPP1’s role, the team has opened a new avenue for targeted therapeutic intervention aimed at restoring the energy balance within injured tissue microenvironment.

Leveraging this insight, UCLA researchers engineered AD-NP1, a monoclonal antibody precisely formulated to neutralize ENPP1’s deleterious effects. Unlike treatments that introduce external regenerative factors such as stem cells, AD-NP1 harnesses endogenous repair mechanisms intrinsic to the body, optimizing them by alleviating the metabolic bottlenecks caused by ENPP1 overexpression. Preclinical studies demonstrated that blocking ENPP1 not only enhanced myocardial repair but also curtailed scar tissue formation, which is a primary cause of diminished cardiac function post-injury. The antibody’s specificity ensures that it targets ENPP1 exclusively without off-target effects on other proteins.

Monoclonal antibodies like AD-NP1 represent engineered immunological agents capable of imitating the body’s natural defense mechanisms. They can bind antigens with high affinity and selectivity, disrupting pathogenic pathways. In this case, the antibody’s function interrupts ENPP1’s interference with intracellular energy metabolism, effectively restoring cellular bioenergetics required for repair processes. Energy metabolism is fundamental since cells need to generate ATP through complex biochemical pathways, including glycolysis and oxidative phosphorylation, to maintain homeostasis and support regeneration. The reversal of ENPP1-induced metabolic repression enables cells to proliferate and function optimally in damaged tissues.

A remarkable aspect of this journey from discovery to clinical translation has been its foundation entirely on publicly funded research without reliance on private sector investment or commercial partnerships. This model reflects a commitment to intellectual freedom and cost-effective innovation within academic frameworks. Dr. Deb emphasizes the advantages of this strategy, highlighting reduced development costs, expedited research timelines, and preservation of scientific control. This approach challenges traditional paradigms where academic discoveries often transition into biotech startups or become licensed assets, potentially delaying therapeutic availability.

The U.S. Food and Drug Administration’s (FDA) recent approval of AD-NP1 for Phase I clinical trials marks a significant milestone, heralding the transition from preclinical promise to human application. The investigational new drug (IND) status signifies confidence in the drug’s safety and therapeutic potential based on rigorous testing in animal models, including mice and non-human primates. The anticipated initiation of clinical trials will critically assess AD-NP1’s efficacy and safety in humans, setting the stage for transformative treatment options for patients who suffer from organ damage after acute events such as heart attacks or kidney injuries.

Dr. Deb’s vision extends beyond cardiac repair, suggesting that the universal nature of energy metabolism across cell types could make AD-NP1 a versatile therapeutic candidate for multiple organs vulnerable to injury. The concept transcends regenerative medicine by integrating metabolic correction with tissue repair, potentially mitigating organ failure that arises from energy deficits following trauma or disease. This metabolic modulation may reshape existing clinical approaches by providing a novel mechanism-based intervention rather than symptomatic treatment or cell transplantation.

In addition to its scientific novelty, this research challenges existing dogma that focuses predominantly on regenerative stem cell therapies. Instead, it underscores the potential of enhancing the intrinsic reparative capacity of tissue through fine-tuning of molecular signaling pathways. The strategy underlined by AD-NP1 exemplifies precision medicine, where molecular targets are leveraged to correct biochemical abnormalities selectively, thereby minimizing adverse effects and maximizing therapeutic efficacy.

Organ failure secondary to impaired tissue repair is a pervasive cause of morbidity and mortality worldwide, especially in cardiovascular disease, the leading cause of death globally. By reversing metabolic derangements post-injury, AD-NP1 may halt or reverse progression toward heart failure, which remains a significant clinical challenge despite advances in medical care. The prospect of regenerating functional myocardium reduces dependency on mechanical support devices or transplants and represents a monumental stride toward improving patient outcomes.

The discovery of ENPP1 as a key regulator of energy metabolism in injured tissue not only advances pathophysiological understanding but also inspires a broader reevaluation of metabolic factors in tissue healing and disease. It opens avenues for future research into similar proteins and pathways that may impede repair in other contexts such as liver, lungs, or nervous tissue, thus broadening the horizon of regenerative therapeutics.

As the scientific community awaits clinical trial outcomes, the UCLA team’s work exemplifies how fundamental research, clinical expertise, and innovative drug development can converge within a university setting to produce first-in-class therapeutics. Their endeavor serves as a model, showcasing the power of sustained, grant-supported academic inquiry to generate high-impact medical breakthroughs without compromising accessibility and scientific integrity.

The impact of AD-NP1’s development extends beyond its immediate clinical implications; it embodies hope for millions worldwide affected by chronic organ dysfunctions. Its success could inaugurate a new era in regenerative medicine defined by metabolic precision and facilitated by monoclonal antibody technology, setting a precedent for future therapies aimed at overcoming the longstanding challenge of effective tissue repair.

Subject of Research: Tissue regeneration and metabolic modulation for organ repair
Article Title: UCLA Researchers Develop Monoclonal Antibody Targeting ENPP1 to Enhance Tissue Repair in Heart and Other Organs
News Publication Date: Not provided
Web References:
– https://newsroom.ucla.edu/releases/unexpected-regulator-heart-repair-cardiac-muscle
– https://newsroom.ucla.edu/releases/ucla-researchers-engineer-experimental-drug-for-preventing-heart-failure-after-heart-attacks
Keywords: Cardiology, Internal medicine, Pharmaceuticals, Human health