Paradigm For Therapy Research Articles

Novel balloon catheter containing therapeutic mRNA with smart RNA switch alleviate restenosis after vascular injury

Abstract Background Cardiovascular diseases are the leading cause of death worldwide, and vascular intervention is an effective method for ischemic heart diseases. However, vascular restenosis significantly affects the long-term therapeutic outcomes, which mainly caused by excessive proliferation of vascular smooth muscle cells (VSMCs). While drug-eluting stents and drug-coated balloons have successfully decreased the incidence of restenosis by inhibiting the VSMCs proliferation, they concurrently suppress the repair of endothelial cells (ECs) and re-endothelialization, thereby increasing the risk of late thrombotic events and mortality. Consequently, it is urged to develop novel high-selectively therapeutic devices to overcome vascular restenosis. In current mRNA therapies of cardiovascular diseases, there are few effective systems for cell-specific expression. Therefore, we propose to utilize RNA editing (based on ADAR1 RNA editing) to investigate a smart RNA molecular switch capable of cell-specific recognition and selectively releasing payload in targeted cells or tissues for cell precision therapy. However, the application of gene editing in the cardiovascular system faces challenge of low delivery efficiency. We innovatively take the balloon as a specific and efficient tool to delivery therapeutic mRNA, which may be a potential therapy for vascular restenosis. Objective We investigated therapeutic mRNA containing a smart RNA switch to selectively suppress the VSMCs proliferation while promoting re-endothelialization and delivered by balloon as a novel therapy in vascular restenosis animal models. Results For RNA switch high-throughput screening, we utilized PiggyBac transposon system to establish monoclonal overexpressing cell lines and chose the cell strain with expression levels closely mimicking VSMCs and ECs. We found the most effective RNA switch from dozens of potential candidates which could specifically recognize VSMCs but not ECs. Therapeutic mRNA sequences containing the RNA switch efficiently initiated payload translation in VSMCs while maintaining payload silence in primary vascular endothelial cells, which effectively and selectively inhibited VSMCs excessive proliferation and promoted endothelial repair. Additionally, we developed an interventional balloon delivery system for mRNA drugs, achieving in situ delivery to cardiovascular lesions in vivo, demonstrating therapeutic effects consistent with cellular phenotypes in animal models. Conclusion We suggest that the smart RNA switch can serve as a novel, cell-specific therapeutic tool for restenosis and other cardiovascular diseases. Additionally, utilizing a balloon for mRNA delivery represents a new paradigm for mRNA therapy and gene editing in the cardiovascular field.

How Psychedelics Modulate Multiple Memory Mechanisms in Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) is a psychiatric disorder with defining abnormalities in memory, and psychedelics may be promising candidates for the treatment of PTSD given their effects on multiple memory systems. Most PTSD and psychedelic research has investigated memory with fear conditioning and extinction. While fruitful, conditioning and extinction provide a limited model of the complexity of PTSD and phenomenology of psychedelics, thereby limiting the refinement of therapies. In this review, we discuss abnormalities in fear conditioning and extinction in PTSD and review 25 studies testing psychedelics on these forms of memory. Perhaps the most reliable effect is that the acute effects of psychedelics can enhance extinction learning, which is impaired in PTSD. However, the post-acute effects may also enhance extinction learning, and the acute effects can also enhance fear conditioning. We then discuss abnormalities in episodic and semantic memory in PTSD and review current knowledge on how psychedelics impact these memory systems. Although PTSD and psychedelics acutely impair the formation of hippocampal-dependent episodic memories, psychedelics may acutely enhance cortical-dependent learning of semantic memories that could facilitate the integration of trauma memories and disrupt maladaptive beliefs. More research is needed on the acute effects of psychedelics on episodic memory consolidation, retrieval, and reconsolidation and post-acute effects of psychedelics on all phases of episodic memory. We conclude by discussing how targeting multiple memory mechanisms could improve upon the current psychedelic therapy paradigm for PTSD, thereby necessitating a greater emphasis on assessing diverse measures of memory in translational PTSD and psychedelic research.

Perioperative systemic therapy, current paradigm and ongoing clinical trials in upper tract urothelial cancer.

To provide of comprehensive overview of existing and future paradigms for perioperative systemic therapy in the treatment of upper tract urothelial carcinoma. Contemporary treatment paradigms for the management of upper tract urothelial carcinoma focus on use of neoadjuvant cisplatin based chemotherapy for high grade disease primarily based on two small single arm phase II clinical trials. More robust evidence from a phase III randomized clinical trial exists for the use of adjuvant platinum based chemotherapy for invasive disease after radical nephroureterectomy, but there are significant concerns about renal function and platinum eligibility after nephroureterectomy. There are currently ongoing clinical trials for nonplatinum based perioperative systemic therapies including checkpoint inhibitors/immunotherapy as well as antibody-drug conjugates, but currently no recommendation can be made for these approaches. Current evidence supports neoadjuvant cisplatin chemotherapy in the setting of high grade disease or concern for significant renal dysfunction after radical nephroureterectomy or platinum based adjuvant chemotherapy in eligible patients with advanced disease after surgery. While there is no established role for nonplatinum based therapies yet, multiple ongoing trials exploring use of immunotherapies and antibody-drug conjugates as monotherapy or combination may provide new therapeutic options in this population.

ROS‐Activatable Prodrug of Doxazolidine as Novel Cancer Therapy Paradigm

AbstractOvercoming severe side effects from anticancer agents without decreasing their effects on tumor growth is a major challenge. A prodrug technology is reported using agents that are spatiotemporally activated primarily in tumors while the extratumoral toxicity to healthy cells is minimized. A ROS‐activatable prodrug of a strong anticancer agent, doxazolidine (doxaz), is developed. Doxaz is a DNA alkylating agent with a half‐life of 3 min and significantly higher cytotoxicity than the clinically used parental compound doxorubicin (dox). Importantly, doxaz is not affected by p‐glycoprotein expression since it irreversibly alkylates DNA while dox inhibits the topoisomerase II DNA complex. As drug activators, reactive oxygen species (ROS) are already produced inside cancer cells in higher abundance than in normal cells but additionally generated by external stimuli such as radionuclides (via radiolysis of water) and/or ROS‐inducing drugs. We synthesized the prodrug, Doxaz‐BA, and evaluated its efficacy in vitro in cell cultures and then in vivo in xenograft mouse models. Doxaz‐BA is effective in a broad range of cancer cells since most cancer cells produce higher levels of ROS. Combining with clinically relevant radiotracers such as 18F‐FDG or other tumor‐tropic agents / ROS inducing drugs results in a tumor‐specific and enhanced localized therapy paradigm.

Advancements in Pancreatic Cancer Treatment: A Comprehensive Review of Current Therapies and Future Directions

Pancreatic cancer still has a 5-year survival rate in the single digits, making it one of the most aggressive and deadly cancers. The therapy of pancreatic cancer presents considerable hurdles because of its late diagnosis, fast development, and resistance to traditional therapies, even with advancements in oncological research. This study offers a thorough summary of the various treatment options available today, including as radiation therapy, chemotherapy, surgery, and the newly recognized roles of immunotherapy and targeted medicines. We examine the most recent advancements in personalized medicine and molecular profiling, which are starting to challenge established therapy paradigms and provide fresh hope for bettering patient outcomes. The study also outlines ongoing clinical trials that attempt to address the shortcomings of current therapy, such as the toxicity and limited efficacy of chemotherapeutic drugs. This study aims to provide a comprehensive overview of the pancreatic cancer therapy landscape by analyzing both conventional and cutting-edge treatments. It also identifies promising directions for future research and clinical practice.

Near-infrared remote triggering of bio-enzyme activation to control intestinal colonization by orally administered microorganisms

Oral biotherapeutics hold significant promise, but their lack of controllability and targeting poses a major challenge, particularly for intestinal bacterial biotherapeutics. In response, we have developed a nanoencapsulation approach that responds to the release of enzyme activity in the organism and activates the enzyme in situ, allowing for controlled colonization of microbes in the gut. The nano-coating comprises a two-layer structure: an inner layer of polydopamine with photothermal and adhesive properties, and an outer layer of gelatin–sodium carboxymethylcellulose, which is hydrolyzed by cellulases in the gut following photothermal interaction with dopamine. We have successfully achieved controlled colonization of a wide range of microorganisms. Furthermore, in a diabetes model, this approach has had a profound impact on regulating glucagon-like peptide-1 (GLP-1) production, β-cell physiology, and promoting insulin secretion. This nanocoating is achieved by in situ activation of cellulase without the need for genetic or targeted molecular modification, representing a new paradigm and alternative strategy for microbial therapy. It not only enables precise and controlled colonization of probiotics but also demonstrates great potential for broader application in the field of oral biotherapy. Statement of significanceWe have developed a nano-encapsulation method that triggers enzyme activity in response to enzymatic activity, resulting in the controlled release and adhesion of a wide range of microorganisms in the gut. The nano coating comprises two layers: an inner layer of polydopamine with photothermal and adhesion properties, and an outer layer of a gelatin-sodium carboxymethylcellulose polymer, which can be hydrolyzed by cellulases in the intestine. Additionally, this method allows for the preparation of various microbial coatings. This approach holds significant promise for regulating GLP-1 production, the physiological function of pancreatic β-cells, and promoting insulin secretion in diabetes models.

On the significance of the different geometrical and dosimetric parameters in microbeam and minibeam radiation therapy a retrospective evaluation.

Spatially Fractionated Radiation Therapy (SFRT) is an unconventional therapeutic approach with the potential to disrupt the classical paradigms of conventional radiation therapy. The high spatial dose modulation in SFRT is believed to activate distinct radiobiological mechanisms which lead to remarkable increases in normal tissue tolerance. To make optimal use of SFRT and its benefits, a deeper understanding of the biological response and its relationship with the complex dosimetric and geometric components of SFRT is essential. A retrospective evaluation of preclinical studies was conducted to gain insight into the dosimetric and geometric parameters that are most correlated with normal tissue response. Current literature evaluates the response of tissue to MBRT and MRT according to various end points, e.g. the level of desquamation, degree of necrosis, or the amount of malcalcification. A set of metrics was developed to allow a quantitative comparison of these results. The strongest correlations were observed with the doses in both the peaks and valleys as well as the ratio of the area covered by the peak over the total area. This emphasises the geometry of the beam. MBRT challenged previous uniform dose-distribution paradigms by highlighting the critical role of Peak Dose alongside Valley Dose in tissue sparing whereas MRT underscores the significant influence of geometric beam parameters on tissue preservation. The data exhibits variability in the results obtained using different animal models and endpoints and additional research is warranted to explore the trends observed in this study under controlled conditions.

Concanavalin: A Loaded Chitosan Nanoparticles Synthesis and Characterization to Inhibit the Proliferation of Lung Cancer

Background Non-small-cell lung cancer is the most ubiquitous malignancy, and the present treatments do not offer the most effective outcomes for therapy. Natural drug therapy, which directly targets tumor cells, is now recognized as a safe technique for cancer treatment. The use of tailored nanoparticles also improves the efficacy of cancer therapy. Purpose To synthesize, characterize, and evaluate the natural drug concanavalin A (ConA) coated with chitosan nanoparticles (ConA-CS NPs) for cytotoxicity against lung cancer cell line (NCI-H358). Methods The current study demonstrates the development of ConA-CS NPs as well as their unique characteristics, anticancer processes, and possible applications in treatment. Using UV–Vis, Fourier transform infrared, X-ray diffraction, field emission scanning electron microscopy, and dynamic light scattering studies, ConA-CS NPs were generated and evaluated. The mitochondrial toxicity test assay was used to examine ConA-CS NP-induced cytotoxicity. Dual (acridine orange/ethidium bromide) staining was performed to examine apoptotic modifications, and mitochondrial membrane potential levels in NCI-H358 cells were examined using the appropriate fluorescence staining assays. Results and Conclusion The use of ConA-CS NPs for enhanced tumor treatment, which combines natural drugs to eradicate the tumor and prevent relapses, is supported by in vitro investigations. The ability of ConA-encapsulated CS NPs to impede human lung carcinoma cell growth has not yet been investigated. Therefore, this investigation may provide a new paradigm for cancer detection and therapy, and the results may surely help to enhance the quality of life for cancer patients.

“Internal Trouble and Outside Aggression” Strategy: Energy Deprivation Synergized With cGAS‐STING Pathway Activation for Stimuli‐Responsive Photodynamic‐Metal‐Metabolic Immunotherapy

AbstractThe aberrant metabolic activities of tumor cells not only facilitate tumor proliferation but also impair immune cell function and cause an immunosuppressive tumor microenvironment (TME). Thus, reshaping the metabolic TME while activating innate immunity is highly desirable but challenging. Herein, a multifunctional immunomodulator is engineered for near‐infrared light (NIR)‐triggered photodynamic‐metal‐metabolic immunotherapy via the “internal trouble and outside aggression” strategy. Specifically, an endogenous and exogenous stimuli‐responsive nanoagent is prepared consisting of photosensitizer chlorin e6 (Ce6) modified dense silica‐coated rare earth‐doped nanoparticles (ReNPs@SiO2(Ce6)), with in situ grown ZIF‐8 on the surface for loading glucose transporter‐1 (GLUT‐1) inhibitor Fasentin and glutaminase‐1 inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl sulfide (BPTES). The as‐obtained final product is denoted as ReSZ(FB). ReSZ(FB) induces‐ mitochondrial damage and releases mitochondrial DNA (mtDNA) via NIR‐mediated PDT. Subsequently, Zn2+ from ZIF‐8 collaborates with mtDNA to activate the cGAS‐STING pathway, initiating a robust tumor‐specific immune response. Concurrently, Fasentin and BPTES triggeres energy deprivation by blocking glucose uptake and inhibiting glutamine decomposition, thereby reprogramming the metabolic TME, and alleviating immunosuppression. Tumor cells are damaged and trapped into “internal trouble” by combining PDT and energy deprivation, while the sharply enhanced immune cell lethality exposes cancer cells to “outside aggression”. Overall, this photodynamic‐metal‐metabolic immunotherapy provides a promising paradigm for cancer therapy.

Radiotherapeutic advances in the management of glioblastoma.

Glioblastoma remains a fatal diagnosis despite continuous efforts to improve upon the current standard backbone management paradigm of surgery, radiation therapy, systemic therapy and Tumor Treating Fields. Radiation therapy (RT) plays a pivotal role, with progress recently achieved in multiple key areas of research. The evolving landscape of dose and fractionation schedules and dose escalation options for different patient populations is explored, offering opportunities to better tailor treatment to a patient's overall status and preferences; novel efforts to modify treatment volumes are presented, such as utilizing state-of-the-art MRI-based linear accelerators to deliver adaptive therapy, hoping to reduce normal tissue exposure and treatment-related toxicity; specialized MR techniques and functional imaging using novel PET agents are described, providing improved treatment accuracy and the opportunity to target areas at risk of disease relapse; finally, the role of particle therapy and new altered dose-rate photon and proton therapy techniques in the treatment paradigm of glioblastoma is detailed, aiming to improve tumor control and patient outcome by exploiting novel radiobiological pathways. Improvements in each of these aforementioned areas are needed to make the critical necessary progress and allow for new approaches combining different advanced treatment modalities. This plethora of multiple new treatment options currently under investigation provides hope for a new outlook for patients with glioblastoma in the near future.

Cardioprotection strategies for anthracycline cardiotoxicity.

Thanks to the fantastic progress in cancer therapy options, there is a growing population of cancer survivors. This success has resulted in a need to focus much effort into improving the quality of life of this population. Cancer and cardiovascular disease share many common risk factors and have an interplay between them, with one condition mechanistically affecting the other and vice versa. Furthermore, widely prescribed cancer therapies have known toxic effects in the cardiovascular system. Anthracyclines are the paradigm of efficacious cancer therapy widely prescribed with a strong cardiotoxic potential. While some cancer therapies cardiovascular toxicities are transient, others are irreversible. There is a growing need to develop cardioprotective therapies that, when used in conjunction with cancer therapies, can prevent cardiovascular toxicity and thus improve long-term quality of life in survivors. The field has three main challenges: (i) identification of the ultimate mechanisms leading to cardiotoxicity to (ii) identify specific therapeutic targets, and (iii) more sensible diagnostic tools to early identify these conditions. In this review we will focus on the cardioprotective strategies tested and under investigation. We will focus this article into anthracycline cardiotoxicity since it is still the agent most widely prescribed, the one with higher toxic effects on the heart, and the most widely studied.

Introducing a New Paradigm in Occupational Therapy for Mental Health in Bangladesh

Bangladesh is making strides in supporting mental health needs by incorporating occupational therapy into rehabilitation care. Despite challenges like social stigma and limited resources, a shift toward a socio-humanistic approach is underway. Occupational therapy practitioners have set up a mental health day treatment service to help individuals transition from hospitals to the community, focusing on daily living skills and meaningful activities. Integrating mental health day treatment service with government psychiatric hospitals and improving rehabilitation and home care follow-up can significantly enhance support for people with mental health needs in low-resource settings.

A cuproptosis-based nanomedicine suppresses triple negative breast cancers by regulating tumor microenvironment and eliminating cancer stem cells

Cuproptosis is a new kind of cell death that depends on delivering copper ions into mitochondria to trigger the aggradation of tricarboxylic acid (TCA) cycle proteins and has been observed in various cancer cells. However, whether cuproptosis occurs in cancer stem cells (CSCs) is unexplored thus far, and CSCs often reside in a hypoxic tumor microenvironment (TME) of triple negative breast cancers (TNBC), which suppresses the expression of the cuproptosis protein FDX1, thereby diminishing anticancer efficacy of cuproptosis. Herein, a ROS-responsive active targeting cuproptosis-based nanomedicine CuET@PHF is developed by stabilizing copper ionophores CuET nanocrystals with polydopamine and hydroxyethyl starch to eradicate CSCs. By taking advantage of the photothermal effects of CuET@PHF, tumor hypoxia is overcome via tumor mechanics normalization, thereby leading to enhanced cuproptosis and immunogenic cell death in 4T1 CSCs. As a result, the integration of CuET@PHF and mild photothermal therapy not only significantly suppresses tumor growth but also effectively inhibits tumor recurrence and distant metastasis by eliminating CSCs and augmenting antitumor immune responses. This study presents the first evidence of cuproptosis in CSCs, reveals that disrupting hypoxia augments cuproptosis cancer therapy, and establishes a paradigm for potent cancer therapy by simultaneously eliminating CSCs and boosting antitumor immunity.

Enhanced neural recovery and reduction of secondary damage in spinal cord injury through modulation of oxidative stress and neural response

Spinal cord injury (SCI) presents a critical medical challenge, marked by substantial neural damage and persistent functional deficits. This study investigates the therapeutic potential of cold atmospheric plasma (CAP) for SCI, utilizing a tailored dielectric barrier discharge (DBD) device to conduct comprehensive in vivo and in vitro analyses. The findings show that CAP treatment significantly improves functional recovery after SCI, reduces neuronal apoptosis, lowers inflammation, and increases axonal regeneration. These findings illustrate the efficacy of CAP in fostering a conducive environment for recovery by modulating inflammatory responses, enhancing neuronal survival, and encouraging regenerative processes. The underlying mechanism involves CAP’s reactive oxygen species (ROS) reduction, followed by activating antioxidant enzymes. These findings position CAP as a pioneering approach for spinal cord injury (SCI) treatment, presenting opportunities for improved neural recovery and establishing a new paradigm in SCI therapy.

A Splice Form of VEGF, a Potential Anti-Angiogenetic Form of Head and Neck Squamous Cell Cancer Inhibition.

Angiogenesis, primarily mediated by vascular endothelial growth factor (VEGF), is a fundamental step in the progression and metastasis of head and neck squamous cell carcinoma (HNSCC). Traditional anti-angiogenic therapies that target the VEGF pathway have shown promise but are often associated with significant side effects and variable efficacy due to the complexity of the angiogenic signaling pathway. This review highlights the potential of a specific VEGF splice form, VEGF165b, as an innovative therapeutic target for HNSCC. VEGF165b, unlike standard VEGF, is a natural inhibitor that binds to VEGF receptors without triggering pro-angiogenic signaling. Its distinct molecular structure and behavior suggest ways to modulate angiogenesis. This concept is particularly relevant when studying HNSCC, as introducing VEGF165b's anti-angiogenic properties offers a novel approach to understanding and potentially influencing the disease's dynamics. The review synthesizes experimental evidence suggesting the efficacy of VEGF165b in inhibiting tumor-induced angiogenesis and provides insight into a novel therapeutic strategy that could better manage HNSCC by selectively targeting aberrant vascular growth. This approach not only provides a potential pathway for more targeted and effective treatment options but also opens the door to a new paradigm in anti-angiogenic therapy with the possibility of reduced systemic toxicity. Our investigation is reshaping the future of HNSCC treatment by setting the stage for future research on VEGF splice variants as a tool for personalized medicine.

Triple Combinations of AAV9-Vectors Encoding Anti-HIV bNAbs Provide Long-Term In Vivo Expression of Human IgG Effectively Neutralizing Pseudoviruses from HIV-1 Global Panel.

Anti-human immunodeficiency virus (HIV) broadly neutralizing antibodies (bNAbs) offer a promising approach for the treatment of HIV-1. The current paradigm for antibody therapy involves passive antibody transfer, requiring regular delivery of bNAbs in treating chronic diseases such as HIV-1. An alternative strategy is to use AAV-mediated gene transfer to enable in vivo production of desirable anti-HIV-1 antibodies. In this study, we investigated two sets of triple combinations of AAV9-vectors encoding different bNAbs: N6, 10E8, 10-1074 (CombiMab1), and VRC07-523, PGDM1400, 10-1074 (CombiMab2). We used CBAxC57Bl and C57BL/6 mouse models to characterize rAAV-induced antibody expression and to evaluate the neutralization capacity of mouse sera against a global panel of HIV-1 viral strains. rAAV9-mediated IgG expression varied between bNAb clones and mouse strains, with C57BL/6 mice exhibiting higher bNAb titers following rAAV delivery. Although CombiMab2 treatment elicited a higher IgG titer than CombiMab1, both combinations resulted in neutralization of all the viral strains from the global HIV-1 panel. Our data highlight the potential of AAV vectors as a long-term option for HIV-1 therapy.

Boosting ferroptosis by intervention of redox balance and synergetic with photothermal/photodynamic therapy for suppression of pancreatic cancer

Metal-doped iron oxide nanoparticles have attracted increasing attention for their Fenton reaction ability, which converts H2O2 to cytotoxic reactive oxygen species (ROS) and is recently utilized as ferroptosis activator in pancreatic cancer therapy. However, low intracellular H2O2 level hinders ferroptosis effect and leads to unsatisfactory efficacy. Herein, a transferrin coated and tumor homing peptide decorated bimetallic magnetic nanoparticles copper-doped iron oxide nanosystems embedded with photothermal agent IR820 and iron ions (denoted as PCTIFL) is constructed for synergistic treatment for pancreatic cancer by combining ferroptosis and photothermal/photodynamic therapy (PTT/PDT) under 808 nm laser irradiation. Benefiting from the homologous targeting property of LyP-1, the nanosystems can be precisely delivered and gradually accumulate at tumor site. For the synergistic therapy, IR820 generates ROS via photodynamic effect and enables cancer cell temperature elevation via PTT effect upon 808 nm laser irradiation on the one hand and metal ions such as Fe2+, Fe3+ and Cu2+ catalyze H2O2 into ROS and finally triggered ferroptosis on the other hand. Moreover, PCTIFL nanosystems can be applied in pancreatic cancer diagnosis for their MRI/NIR dual imaging function. Overall, this work not only presents a promising strategy for augmenting the ferroptosis induced by iron oxide, but also a fantastic paradigm for pancreatic cancer diagnosis and synergistic therapy.

An artificial metabzyme for tumour-cell-specific metabolic therapy.

Metabolic dysregulation constitutes a pivotal feature of cancer progression. Enzymes with multiple metal active sites play a major role in this process. Here we report the first metabolic-enzyme-like FeMoO4 nanocatalyst, dubbed 'artificial metabzyme'. It showcases dual active centres, namely, Fe2+ and tetrahedral Mo4+, that mirror the characteristic architecture of the archetypal metabolic enzyme xanthine oxidoreductase. Employing spatially dynamic metabolomics in conjunction with the assessments of tumour-associated metabolites, we demonstrate that FeMoO4 metabzyme catalyses the metabolic conversion of tumour-abundant xanthine into uric acid. Subsequent metabolic adjustments orchestrate crosstalk with immune cells, suggesting a potential therapeutic pathway for cancer. Our study introduces an innovative paradigm in cancer therapy, where tumour cells are metabolically reprogrammed to autonomously modulate and directly interface with immune cells through the intervention of an artificial metabzyme, for tumour-cell-specific metabolic therapy.

Physical Therapy Paradigms in Athletic Return to Play After Hip Surgery

Hip arthroscopy has become the predominant surgical approach for managing femoroacetabular impingement (FAI) and associated intra-articular pathologies, particularly in athletes. Despite advancements in surgical techniques, rehabilitation protocols, especially those governing return to play (RTP), have not kept pace in terms of specificity and objectivity. This article reviews current practices and introduces a comprehensive, multi-factorial continuum for RTP that extends beyond mere time-based criteria to include an athlete's overall readiness, encompassing both physical and psychological aspects. Through a phased rehabilitation strategy beginning in the preoperative phase and extending through to full return to competition, this paper aims to present a more nuanced continuum for RTP that accounts for an athlete's readiness beyond temporal benchmarks. The phases outlined include preoperative preparation, immediate postoperative care, early rehabilitation, reconditioning, performance enhancement, and final return to play, each phase tailored to integrate clinical milestones with biomechanical and psychosocial factors. This approach advocates for a shift towards personalized rehabilitation protocols that align with the biological healing processes and functional milestones essential for a successful return to sports.

Desensitizing Anxiety Through Imperceptible Change: Feasibility Study on a Paradigm for Single-Session Exposure Therapy for Fear of Public Speaking.

Exposure therapy (ET) for anxiety disorders involves introducing the participant to an anxiety-provoking situation over several treatment sessions. Each time, the participant is exposed to a higher anxiety-provoking stimulus; for example, in the case of fear of heights, the participant would successively experience being at a greater height. ET is effective, and its counterpart, virtual reality (VR) exposure therapy (VRET), where VR substitutes real-world exposure, is equally so. However, ET is time-consuming, requiring several sessions. This study aimed to compare the results of single-session exposure with those of traditional VRET with regard to reducing public speaking anxiety. We introduced a paradigm concerned with public speaking anxiety where the VR exposure occurred in a single session while the participant interacted with a virtual therapist. Over time, the therapist transformed into an entire audience with almost imperceptible changes. We carried out a feasibility study with 45 participants, comparing 3 conditions: single-session exposure (n=16, 36%); conventional multiple-session exposure (n=14, 31%), where the same content was delivered in successive segments over 5 sessions; and a control group (n=15, 33%), who interacted with a single virtual character to talk about everyday matters. A week later, the participants were required to speak on a stage in front of a large audience in VR. Across most of the series of conventional public speaking anxiety measures, the single-session exposure was at least as effective in reducing anxiety as the multiple-session exposure, and both these conditions were better than the control condition. The 12-item Personal Report of Confidence as a Speaker was used to measure public speaking anxiety levels, where higher values indicated more anxiety. Using a Bayesian model, the posterior probabilities of improvement compared to a high baseline were at least 1.7 times greater for single- and multiple-session exposures compared to the control group. The State Perceived Index of Competence was used as a measure of anticipatory anxiety for speaking on a stage in front of a large audience, where lower values indicated higher anxiety. The probabilities of improvement were just over 4 times greater for single- and multiple-session exposures compared to the control group for a low baseline and 489 (single) and 53 (multiple) times greater for a middle baseline. Overall, the results of this feasibility study show that for moderate public speaking anxiety, the paradigm of gradual change in a single session is worth following up with further studies with more severe levels of anxiety and a larger sample size, first with a randomized controlled trial with nonpatients and subsequently, if the outcomes follow those that we have found, with a full clinical trial with patients.