Hit discovery of potential CDK8 inhibitors and analysis of amino acid mutations for cancer therapy through computer-aided drug discovery.

Cyclin-dependent kinase 8 (CDK8) has emerged as a promising target for inhibiting cancer cell function, intensifying efforts towards the development of CDK8 inhibitors as potential cancer therapeutics. Mutations in CDK8, a protein kinase, are also implicated as a primary factor associated with tumor formation. In this study, we identified potential inhibitors through virtual screening for CDK8 and single amino acid mutations in CDK8, namely D173A (Aspartate 173 mutate to Alanine), D189N (Aspartate 189 mutate to Asparagine), T196A (Threonine 196 mutate to Alanine) and T196D (Threonine 196 mutate to Aspartate). Four databases (CHEMBEL, ZINC, MCULE, and MolPort) containing 65,209,131 molecules have been searched to identify new inhibitors for CDK8 and its single mutations. In the first step, structure-based pharmacophore modeling in the Pharmit server was used to select the compounds to know the inhibitors. Then molecules with better predicted drug-like molecule properties were selected. The final filter used to select more effective inhibitors among the previously selected molecules was molecular docking. Finally, 13 hits for CDK8, 11 hits for D173A, 11 hits for D189N, 15 hits for T196A, and 12 hits for T196D were considered potential inhibitors. A majority of the virtual screening hits exhibited satisfactorily predict pharmacokinetic characteristics and toxicity properties.

Vestibulo-Ocular Reflex Suppression: Clinical Relevance and Assessment in the Digital Age.

Background: Visual acuity and image stability are crucial for daily activities, particularly during head motion. The vestibulo-ocular reflex (VOR) and its suppression (VORS) support stable fixation of objects of interest. The VOR drives a reflexive eye movement to counter retinal slip of a stable target during head motion. In contrast, VORS inhibits this countermovement when the target stimulus is in motion. The VORS allows for object fixation when it aligns with the direction of the head's movement, or when an object within or outside the peripheral vision needs to be focused upon. Summary: Deficits of the VORS have been linked to age-related diseases such as balance deficits associated with an increased fall risk. Therefore, the accurate assessment of the VORS is of particular clinical relevance. However, current clinical assessment methods for VORS are mainly qualitative and not sufficiently standardised. Recent advances in digital health technology, such as smartphone-based videooculography, offer a promising alternative for assessing VORS in a more accessible, efficient, and quantitative manner. Moreover, integrating mobile eye-tracking technology with virtual reality environments allows for the implementation of controlled VORS assessments with different visual inputs. These assessment approaches allow the extraction of novel parameters with potential pathomechanistic and clinical relevance. Key Messages: We argue that researchers and clinicians can obtain a more nuanced understanding of this ocular stabilisation reflex and its associated pathologies by harnessing digital health technology for VORS assessment. Further research is warranted to explore the technologies' full potential and utility in clinical practice.

Modeling of Learning Processes Using Continuous-Time Markov Chain for Virtual-Reality-Based Surgical Training in Laparoscopic Surgery.

Recent usage of Virtual Reality (VR) technology in surgical training has emerged because of its cost-effectiveness, time savings, and cognition-based feedback generation. However, the quantitative evaluation of its effectiveness in training is still not studied thoroughly. This paper demonstrates the effectiveness of a VR-based surgical training simulator in laparoscopic surgery and investigates how stochastic modeling represented as Continuous-time Markov-chain (CTMC) can be used to explicit the training status of the surgeon. By comparing the training in real environments and in VR-based training simulators, the authors also explore the validity of the VR simulator in laparoscopic surgery. The study further aids in establishing learning models of surgeons, supporting continuous evaluation of training processes for the derivation of real-time feedback by CTMC-based modeling.

Virtual Reality Simulation in Pediatric Resuscitation for Pre-hospital Providers.

This technical report explored the feasibility and utility of virtual reality (VR) pediatric resuscitation simulations for pre-hospital providers during their scheduled shifts. To our knowledge, neither the pediatric resuscitation VR simulation nor the feasibility of in situ, on-shift training with VR had been previously evaluated in pre-hospital providers. VR headset was available at an urban city fire station for 10 days where a total of 60 pre-hospital providers were scheduled to work. Providers were made aware of the VR module but no formal demonstration was done. There were no facilitators. Participants filled out an anonymous retrospective pre- and post-survey using a five-point Likert scale, rating their confidence from "not confident" to "very confident" in recognizing and managing pediatric emergencies. We found that VR simulation for pediatric resuscitation was a feasible training tool to use in situ as 63% of the providers were able to use it on shift. Furthermore, self-reported confidence increased after the training where responses of "very confident" increased from 20% to 30% for emergency medical technicians and 55% to 63% for paramedics.

Sociodigital experiences and creativity in the metaverse: An integrative review.

Access to sociodigital experiences is constantly expanding, driven by the development of immersive technologies that capture the public's interest. These technological advances present a hypnotic nature, sparking curiosity, creating new experiences, and providing opportunities for expanding access and inclusion. This article aims to highlight the characteristics and requirements necessary for the development of creativity in new virtual environments, with a focus on the metaverse, a three-dimensional and interactive virtual space that offers users the sensation of existence within this environment. The study centers on the following question: what are the essential characteristics for an immersive environment to promote the development of creativity in its users? Understanding how technologies influence creativity is crucial to driving innovation, the progress of contemporary sciences, and education. This research analyzed various approaches and strategies for the use of the metaverse and immersive virtual environments to promote user creativity. Through an integrative literature review, practical characteristics that contribute to creativity in previous studies were identified. The results highlight the presence of common characteristics, organized into a model of articulation of the sociodigital analysis categories for creativity with potential for application.

Virtual Reality Distraction for Needle-Related Pain and Distress in Children: A Multicenter Randomized Controlled Trial.

This international multicenter randomized controlled trial aimed to compare the effectiveness of virtual reality (VR) distraction with an identical non-VR game in reducing needle-related pain and anxiety in children undergoing venous blood draw. The study involved 304 children aged 5-9 years undergoing a blood draw procedure, randomly allocated to one of three groups: VR distraction, non-VR distraction, and control group (usual care). The distraction task was based on the Multiple Object Tracking (MOT) paradigm, and the game was identical in design and gameplay for both VR and non-VR distraction groups. The primary outcome was self-reported pain intensity using the Faces Pain Scale-Revised (FPS-R). Secondary outcomes included child distress, attention/distraction to the blood draw, and parent and medical staff satisfaction with procedure. Analyses were conducted using analysis of variance and multivariable linear regression models. The results showed that VR distraction and non-VR distraction performed similarly, showing large effect sizes compared with standard care. There was no significant difference between the two types of distraction. The study's findings suggest that VR and non-VR distraction are similarly effective in reducing needle-related pain and anxiety in children undergoing venous blood draw. This is the first well-powered study comparing modern VR distraction with an identical task displayed on a smartphone or monitor screen. The study's results have important implications for using VR in clinical settings and suggest that investing in expensive VR equipment for acute pain management may not be necessary. The study protocol was pre-registered on Open Science Framework at https://osf.io/frsyc.

Carbon savings potential of virtual care in obstructive sleep apnea and otitis media with effusion.

Objective: To determine the carbon savings potential of incorporating virtual care into surgical care pathways for pediatric patients with obstructive sleep apnea or otitis media with effusion. Methods: Pediatric patients with obstructive sleep apnea or otitis media with effusion were not enrolled, instead, a modeling cohort study design was used. This study utilized the British Columbia healthcare system and geography to model emissions. Care pathways were developed for pediatric patients with obstructive sleep apnea or otitis media with effusion requiring care at a tertiary pediatric center. Home addresses were located at the geographical center of the two most populated municipalities within each of the 10 most populated regional districts in 2020. Virtual visits replaced up to three clinically equivalent in-person visits. Emissions (kgCO2e) for transport and virtual visits were estimated. Population-weighted means and descriptive statistics were calculated. Results: Utilizing 1, 2, or 3 virtual visits in the obstructive sleep apnea care pathway yielded potential emissions savings of 19.9%, 39.9%, and 59.8% respectively. Integrating 1, 2, or 3 virtual visits into the otitis media with effusion care pathway produced potential emissions savings of 16.6%, 33.2%, and 49.7%, respectively. Integrating 3 virtual visits can save up to 2156.8 kgCO2e per patient. Conclusions: Appropriately conducting up to 50% of clinical encounters virtually for children with obstructive sleep apnea or otitis media with effusion reduced theoretical carbon emissions. For a single child, emission savings could reach over 2150 kgCO2e. Level of Evidence: Level 5.

Use of virtual reality exercises in disaster preparedness training: A scoping review.

Background: The scope and number of disasters have increased over the years. This has called for more robust disaster preparedness training and plans. The use of virtual reality exercises in addition to tabletop exercises is considered a new approach to the preparation of disaster preparedness plans. Virtual reality exercises are being developed to either replace or complement current traditional approaches to disaster preparedness training. Objectives: To review and summarize the current existing literature regarding the effectiveness, advantages and limitations of using virtual reality exercises in disaster preparedness as a complementary/replacement mechanism for real-time drills and tabletop exercises. Methods: In this scoping review, we searched PubMed, Cochrane, EMBASE, PLOS, and Google Scholar for research publications involving virtual reality exercises in disaster training from 2008 to 2022 using "AND" and "OR" operators for the keywords "disaster," "preparedness," "virtual reality," and "tabletop." From a total of 333 articles that resulted in our search and were then evaluated by the authors, 55 articles were finally included in this review. Results: Virtual reality exercises are found to be better in the formulation of disaster preparedness plans compared to tabletop exercises. Virtual reality exercises can be used as the primary means of creating a real-life-like experience in disaster preparedness training and proved at least as better complementary to tabletop exercises. Virtual reality exercises have many advantages over traditional real-life or tabletop exercises and are more cost-effective, but some drawbacks are still identified. Conclusion: The advantages of virtual reality exercises are remarkable and underline their benefits and uses versus costs. We highly encourage decision-makers and institutions dealing in disaster preparedness to adopt using virtual reality exercises in training for disaster preparedness.

Observing heroic behavior and its influencing factors in immersive virtual environments.

Studying heroism in controlled settings presents challenges and ethical controversies due to its association with physical risk. Leveraging virtual reality (VR) technology, we conducted a three-study series with 397 participants from China to investigate heroic actions. Participants unexpectedly witnessed a criminal event in a simulated scenario, allowing observation of their tendency to physically intercept a thief. We examined situational factors (voluntariness, authority, and risk) and personal variables [gender, impulsivity, empathy, and social value orientation (SVO)] that may influence heroism. Also, the potential association between heroism and social conformity was explored. In terms of situational variables, voluntariness modulated participants' tendency to intercept the escaping thief, while perceived risk demonstrated its impact by interacting with gender. That is, in study 3 where the perceived risk was expected to be higher (as supported by an online study 5), males exhibited a greater inclination toward heroic behavior compared to females. Regarding other personal variables, the tendency to engage in heroic behavior decreased as empathy levels rose among males, whereas the opposite trend was observed for females. SVO influenced heroic behavior but without a gender interaction. Finally, an inverse relationship between heroism and social conformity was observed. The robustness of these findings was partly supported by the Chinese sample (but not the international sample) of an online study 4 that provided written descriptions of VR scenarios, indicating cultural variations. These results advance insights into motivational factors influencing heroism in the context of restoring order and highlight the power of VR technology in examining social psychological hypotheses beyond ethical constraints.

Pulmonary and Critical Care Fellowship Program Directors' Perspective on the Virtual Interview Process.

Background: Since the start of the coronavirus disease (COVID-19) pandemic, the residency and fellowship recruitment process has changed significantly with the use of virtual interview (VI) platforms. Pulmonary and critical care medicine (PCCM) candidates reported in a survey that VIs hindered their ability to evaluate their fit within the program. However, the program directors' (PDs') opinion of this process remains unknown. Objective: We aim to provide insight into the PCCM fellowship PDs' perspective regarding the virtual recruitment process since the first class of fellows undergoing this process has now completed 1 year of training. Methods: An anonymous survey was sent to the PDs of PCCM programs participating in the National Resident Matching Program match process in 2020 and 2021. The survey consisted of five sections and 26 closed-ended questions and was distributed via email using the SurveyMonkey platform. The survey was conducted for a total of 6 weeks. A follow-up email to nonrespondents was sent every week. The collected responses were divided into two categories: favoring VIs versus not favoring VIs. A multivariable logistic regression analysis was performed to determine the factors associated with favoring VIs. Results: The survey was sent to 190 email accounts from the Fellowship and Residency Electronic Interactive Database Access System website. Over the course of 6 weeks, 64 respondents participated in the survey, with a response rate of 33.68%. Of 64 respondents, 56 (87.5%) fully completed the survey and 8 (12.5%) partially completed the survey. The final sample size was 59. Thirty-six (61.02%) of the PDs favored VIs for future recruitment, and 23 (38.98%) did not (P < 0.001). Ninety-seven percent of PDs who favored VIs versus 72.73% of those who did not perceived the current fellows to fit well in the program (P = 0.007). The multivariable logistic regression analysis showed a trend toward higher odds of favoring VIs if PDs believed they were able to represent the program well virtually (adjusted odds ratio, 6.99; 95% confidence interval, 0.79 - 61.58) and if they found that the current fellows fit the program well (adjusted odds ratio, 7.15; 95% confidence interval, 0.76-66.52); however, these results were not statistically significant. Conclusion: In this survey research, we found that the majority of the PCCM fellowship PDs favored a virtual process for future recruitment.

Impact of Virtual Interviews on Pulmonary and Critical Care Fellowship Match: An Analysis of National Data.

Background: Internal Medicine residents have historically expressed hesitancy in pursuing a career in pulmonary and critical care medicine (PCCM). However, recent studies have demonstrated newfound competitiveness. The coronavirus disease (COVID-19) global outbreak prompted the implementation of a virtual interviewing model for PCCM fellowship match. The effect of this new paradigm on PCCM match results has not been studied previously. Objective: With the shift to virtual interviewing, we aim to determine how this new method of interviewing may influence the selection of candidates for fellowship training programs. Methods: We acquired data of 4,333 applicants ranking PCCM for the years 2017-2021 from the National Resident Matching Program and the Electronic Residency Application Service websites for the years 2017-2021. Chi-square (χ2) analysis of the applicants' demographics and the percentage of applicants matching at their first choice versus those who matched at lower than their third-choice program before and after the implementation of virtual interviews season was performed. Results: The matching probability for the U.S. Doctors of Osteopathic Medicine significantly increased after the implementation of virtual interviews compared with the years 2017-2020 (χ2 = 8.569; P = 0.003). The matching probability remained unchanged for U.S. Doctors of Medicine (χ2 = 2.448; P = 0.118). Overall, an applicant's probability of matching at their first choice has significantly decreased after the virtual interview format (χ2 = 4.14; P = 0.04). Conversely, the probability of matching at a program that is lower than the third choice has significantly increased (χ2 = 11.039; P < 0.001). Conclusion: Our study provides evidence regarding the effect of the virtual interview format on PCCM match results. Strikingly, applicants are more likely to match at lower-ranked programs in their rank list after the implementation of the virtual interview process. These results can be helpful for both programs and applicants, to guide their future expectations and decisions while going through the interview process.

Enhancing neuro-ophthalmic surgical education: The role of neuroanatomy and 3D digital technologies - An overview.

Background: Neuro-ophthalmology, bridging neurology and ophthalmology, highlights the nervous system's crucial role in vision, encompassing afferent and efferent pathways. The evolution of this field has emphasized the importance of neuroanatomy for precise surgical interventions, presenting educational challenges in blending complex anatomical knowledge with surgical skills. This review examines the interplay between neuroanatomy and surgical practices in neuro-ophthalmology, aiming to identify educational gaps and suggest improvements. Methods: A literature search across databases such as PubMed, Scopus, and Web of Science was conducted, focusing on the implications of neuroanatomy in neuro-ophthalmic surgery education and practice. The review synthesizes insights from both recent and foundational studies to highlight current understandings and future research directions, particularly in educational approaches. Results: Findings indicate that 3D digital modeling and virtual reality have significantly enhanced neuroophthalmic surgical education by providing immersive and engaging learning experiences. For instance, detailed 3D brain atlases offer comprehensive resources for understanding the central nervous system's normal and pathological states. Although studies show that 3D and traditional 2D methods achieve similar post-test results, 3D methods notably improve engagement and motivation, suggesting a shift toward more interactive learning environments. Conclusion: Integrating both traditional and innovative educational tools is crucial for the progression of neuro-ophthalmic surgical training. This balance helps overcome educational hurdles and better prepare future surgeons. Continuous research and collaboration are essential to refine educational strategies, ultimately aiming to enhance patient care in neuro-ophthalmology.

Real-time soft body dissection simulation with parallelized graph-based shape matching on GPU.

BACKGROUND AND OBJECTIVE: Interactive soft tissue dissection has been a fundamental procedure in virtual surgery systems. Existing cutting algorithms involve complex topology changes of simulation meshes, which can increase simulation overhead and produce visual artifacts. In this paper, we proposed a novel graph-based shape-matching method that allows for real-time, flexible, progressive, and discontinuous cuts on soft tissue. METHODS: We employed shape-matching constraints within the position-based dynamics (PBD) framework, a widely adopted approach for real-time simulation applications. The soft tissue was effectively modeled using overlapping clusters, each governed by shape-matching constraints. The dissection process was bifurcated into two distinct stages. In the first stage, the surgical scalpel presses the surface of the soft tissue. The soft tissue is cut apart when the surface pressure exceeds a threshold, entering the second stage. To address the discrepancy between the visual mesh and the simulation model during cluster separation, we developed an Aggregate Finding Connected Components (AFCC) algorithm, optimized for GPU computation and integrated with a background grid. This approach also avoids ghost forces and fragmentation artifacts. To control the increase in the number of clusters, we also propose a merging strategy that can run in parallel. RESULTS: Our simulation outcomes demonstrated that the AFCC dissection algorithm effectively manages cluster separation and expansion with robustness. There were no ghost forces between the cutting surface and unrealistic fragments. Our simulation capability extended to supporting intricate and discontinuous cutting routes. Our dissection simulation maintained real-time performance even with over 100,000 particles constituting the soft tissue. CONCLUSIONS: Our real-time and robust surgical dissection simulation technique enables the performance of complex cuts in various surgical scenarios, demonstrating its potential in virtual surgery applications.

Assessment of fragment docking and scoring with the endothiapepsin model system.

Fragment-based screening has become indispensable in drug discovery. Yet, the weak binding affinities of these small molecules still represent a challenge for the reliable detection of fragment hits. The extent of this issue was illustrated in the literature for the aspartic protease endothiapepsin: When seven biochemical and biophysical in vitro screening methods were applied to screen a library of 361 fragments, very poor overlap was observed between the hit fragments identified by the individual approaches, resulting in high levels of false positive and/or false negative results depending on the mutually compared methods. Here, the reported in vitro findings are juxtaposed with the results from in silico docking and scoring approaches. The docking programs GOLD and Glide were considered with the scoring functions ASP, ChemScore, ChemPLP, GoldScore, DSXCSD, and GlideScore. First, the ranking power and scoring power were assessed for the named scoring functions. Second, the capability of reproducing the crystallized fragment binding modes was tested in a structure-based redocking approach. The redocking success notably depended on the ligand efficiency of the considered fragments. Third, a blinded virtual screening approach was employed to evaluate whether in silico screening can compete with in vitro methods in the enrichment of fragment databases.

The development of tissue handling skills is sufficient and comparable after training in virtual reality or on a surgical robotic system: a prospective randomized trial.

BACKGROUND: Virtual reality is a frequently chosen method for learning the basics of robotic surgery. However, it is unclear whether tissue handling is adequately trained in VR training compared to training on a real robotic system. METHODS: In this randomized controlled trial, participants were split into two groups for "Fundamentals of Robotic Surgery (FRS)" training on either a DaVinci VR simulator (VR group) or a DaVinci robotic system (Robot group). All participants completed four tasks on the DaVinci robotic system before training (Baseline test), after proficiency in three FRS tasks (Midterm test), and after proficiency in all FRS tasks (Final test). Primary endpoints were forces applied across tests. RESULTS: This trial included 87 robotic novices, of which 43 and 44 participants received FRS training in VR group and Robot group, respectively. The Baseline test showed no significant differences in force application between the groups indicating a sufficient randomization. In the Midterm and Final test, the force application was not different between groups. Both groups displayed sufficient learning curves with significant improvement of force application. However, the Robot group needed significantly less repetitions in the three FRS tasks Ring tower (Robot: 2.48 vs. VR: 5.45; p < 0.001), Knot Tying (Robot: 5.34 vs. VR: 8.13; p = 0.006), and Vessel Energy Dissection (Robot: 2 vs. VR: 2.38; p = 0.001) until reaching proficiency. CONCLUSION: Robotic tissue handling skills improve significantly and comparably after both VR training and training on a real robotic system, but training on a VR simulator might be less efficient.

Evaluation of data uncertainty for deep-learning-based CT noise reduction using ensemble patient data and a virtual imaging trial framework.

Deep learning-based image reconstruction and noise reduction (DLIR) methods have been increasingly deployed in clinical CT. Accurate assessment of their data uncertainty properties is essential to understand the stability of DLIR in response to noise. In this work, we aim to evaluate the data uncertainty of a DLIR method using real patient data and a virtual imaging trial framework and compare it with filtered-backprojection (FBP) and iterative reconstruction (IR). The ensemble of noise realizations was generated by using a realistic projection domain noise insertion technique. The impact of varying dose levels and denoising strengths were investigated for a ResNet-based deep convolutional neural network (DCNN) model trained using patient images. On the uncertainty maps, DCNN shows more detailed structures than IR although its bias map has less structural dependency, which implies that DCNN is more sensitive to small changes in the input. Both visual examples and histogram analysis demonstrated that hotspots of uncertainty in DCNN may be associated with a higher chance of distortion from the truth than IR, but it may also correspond to a better detection performance for some of the small structures.

Aerodynamic evaluation of surgical design for the stenosis correction of airway.

Introduction: Congenital tracheal stenosis (CTS) is a rare but life-threatening disease that can lead to respiratory dysfunction in children. Obstructive sleep apnea syndrome (OSAS) in children is characterized by prolonged partial upper airway obstruction and/or intermittent complete obstruction. Both of the diseases require surgical intervention. Although respective treatments of these two diseases are clear, there is a lack of literature discussing the surgical treatment of patients with CTS complicated by OSAS. Methods: We conducted a patient-specific study of patient with CTS complicated by OSAS. Computer-aided design was used to simulate surgical correction under different surgical sequences. Computational fluid dynamics was used to compare the outcomes of different sequences. Results: Aerodynamic parameters, pressure drop, velocity streamlines, wall shear stress (WSS), and the ratio of airflow distribution and energy loss rate were evaluated. An obvious interaction was found between the two diseases in different surgical sequences. The order of correction for CTS or OSAS greatly affected the aerodynamic parameters and turbulence flows downstream of tracheal stenosis and upstream of epiglottis. The CTS and OSAS had mutual influences on each other on the aerodynamic parameters, such as pressure drops and WSS. Discussion: When evaluating the priority of surgical urgency of CTS and OSAS, surgeons need to pay attention to the state of both CTS and OSAS and the physiological conditions of patients. The aerodynamic performance of the uneven airflow distribution and the potential impact caused by the correction of CTS should be considered in surgical planning and clinical management.

Evolution of a Large Language Model for Preoperative Assessment Based on the Japanese Circulation Society 2022 Guideline on Perioperative Cardiovascular Assessment and Management for Non-Cardiac Surgery.

Background: The Japanese Circulation Society 2022 Guideline on Perioperative Cardiovascular Assessment and Management for Non-Cardiac Surgery standardizes preoperative cardiovascular assessments. The present study investigated the efficacy of a large language model (LLM) in providing accurate responses meeting the JCS 2022 Guideline. Methods and Results: Data on consultation requests, physicians' cardiovascular records, and patients' response content were analyzed. Virtual scenarios were created using real-world clinical data, and a LLM was then consulted for such scenarios. Conclusions: Google BARD could accurately provide responses in accordance with the JCS 2022 Guideline in low-risk cases. Google Gemini has significantly improved its accuracy in intermediate- and high-risk cases.

Feasibility of Somato-Cognitive Coordination Therapy Using Virtual Reality for Patients with Advanced Severe Parkinson's Disease.

 This feasibility study enrolled 20 patients with advanced severe Parkinson's disease (PD) to evaluate somato-cognitive coordination therapy (SCCT) using virtual reality. Focusing on the safety and tolerability of SCCT, 17 patients (76±9 years old and 64.7% male) completed the 3-month trial. Key observations included absence of adverse events and tolerability of the participants to SCCT despite initial apprehensions and minor adjustments in medication. Physical functions showed no significant deterioration, suggesting the safety of SCCT. In conclusion, SCCT emerges as feasible and well-tolerated intervention in advanced severe PD, requiring further research to assess its therapeutic efficacy.