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This study aims to establish an optimal ratio of Mineral Oil (MO) and Neem Oil After Esterification (NOAE)to develop a Mixed Insulation (MXI) that effectively replaces the MO for oil-filled transformers and other oil-filled electrical equipments. The effective use of two-stage esterification technique using Neem Oil (NO) as a base oil and concentrated sulfuric acid (H2SO4) and potassium hydroxide (KOH) as acid and base catalysts had been adopted to transform NO into NOAE. Further, the FAME formation is confirmed using the 1H-NMR. By lowering the impact of MO in oil-cooled transformers, the proposed MXI's dielectric properties are critically analysed using its AC breakdown voltage (BDV) in sphere-sphere and point-plane, kinematic viscosity (KVIS), corona inception voltage (CIV) and interfacial tension (IFT), and other dielectric properties. The MXI proportions are subject to accelerated thermal ageing in the presence of a pressboard and copper plate. The changes in their dielectric properties are reported along with the information about the material characteristics using an FTIR. Further, the validation of the samples is verified using Weibull distribution and Kurtosis and Skewness values. The current study on MXI is given credence by the discovery that sample X30, or the optimal MO: NOAE blending ratio, is 70:30. The X30's dielectric properties showed a notable level of durability after ageing, which helped to explain its high resistance and low conductivity.

Advances in clinical neurophysiology have transformed the understanding and assessment of myoclonus. Neurophysiological techniques have made it possible to identify the neural generators of myoclonus and have provided the foundation for modern classification systems that integrate clinical phenomenology with physiological mechanisms. Many of these developments were shaped by the work of several research groups worldwide, with major influence from the contributions of Professor Mark Hallett. His studies helped to establish the central role of neurophysiology in the investigation of myoclonus. Through careful neurophysiological experiments and clinical observations, his work clarified the mechanisms underlying cortical and brainstem myoclonus and contributed substantially to the characterization of functional jerks. This review summarizes current approaches to the clinical neurophysiological evaluation of myoclonus and outlines the evolution of classification systems leading to the recent consensus framework proposed by the International Association of Parkinsonism and Related Disorders. Key neurophysiological techniques used in clinical practice are discussed, and emerging quantitative approaches, including machine-learning of neurophysiological signals, are also highlighted as potential tools to improve diagnostic precision and standardization in the evaluation of myoclonus.

Early and ongoing stakeholder engagement is critical to the development and implementation of scalable behavioral health interventions. Our overarching goal in this implementation research study was to understand and document the process of planning and rolling out Common Elements Treatment Approach (CETA), a transdiagnostic mental health intervention, in Uganda. Guided by the Consolidated Framework for Implementation Research (CFIR) 2.0, we conducted in-depth interviews with multilevel stakeholders (healthcare providers, MOH members, clinic managers, implementing partners, n = 20) to understand and document the process of planning and rolling out CETA in Western Uganda. All interviews were audio recorded, transcribed, and analyzed thematically in Dedoose using a codebook based on CFIR 2.0 domains and constructs. Multilevel stakeholder engagement supported strategic decision making at each stage. Early endorsement of CETA by Uganda's MOH was instrumental in facilitating program integration. Ministry of Health leadership guided facility selection, while clinic leaders identified trainees positioned to implement CETA. Training incorporated both didactic and participatory methods, including real-time adaptation of intervention content for contextual relevance and identification of "champion" trainees to serve as supervisors as part of the ongoing support supervision infrastructure. During rollout, an incremental implementation strategy facilitated integration into clinic workflows. Ongoing multilevel stakeholder supervision and technical assistance helped CETA deliverers troubleshoot challenges, maintain fidelity, and gain confidence. Together, these processes enabled expansion beyond the initial pilot sites, providing early evidence of stakeholder-perceived feasibility and identifying foundational conditions for scalability. Continued engagement with policymakers, those delivering CETA, and community stakeholders will be essential to refine CETA implementation and support integration into national mental health strategies. By reframing stakeholder engagement as an implementation strategy that builds enduring, locally led infrastructures, this study offers a replicable model for preparing behavioral health interventions for scale-up in low resource settings and advances implementation research in global mental health.

The error-related negativity (ERN) is a measurable brain response to mistakes that is thought to reflect a modifiable cognitive/emotional bias contributing to the development of anxiety disorders. We previously demonstrated that a psychosocial intervention to reduce error sensitivity can reduce the ERN among (nonclinical) adults and children who have relatively large ERNs. We have also demonstrated that a brain response (balance N1) evoked by a disturbance to standing balance shares the ERN's relationship to anxiety. We hypothesized that if ERN and N1 reflect the same underlying brain mechanisms, then an intervention to reduce the ERN should similarly reduce the balance N1. In this pre-registered randomized controlled trial, 54 children with anxiety disorders (age 9-12 years) were randomized into either a brief (45-min) single-session computerized psychosocial intervention to reduce error sensitivity, or a similarly formatted control condition. Primary outcome measures were changes in the ERN (measured in a Go/NoGo task) and balance N1 (measured in a lean-and-release balance task). The ERN was reduced after the psychosocial intervention, while the balance N1 remained unchanged. A brief computerized psychosocial intervention to reduce error sensitivity can reduce the ERN among clinically anxious children, but the limited effect may warrant a larger dosage. Discrepant outcomes between the ERN and balance N1 suggest the intervention targets mechanisms not shared between these brain responses. We speculate the intervention may have helped children manage overreactions to trivial mistakes while preserving the inherent significance of a loss of balance. CLINICAL TRIAL REGISTRATION: Computerized intervention targeting the error-related negativity and balance N1 in anxious children. https://clinicaltrials.gov/study/NCT05503017.

Inborn errors of immunity (IEIs) are rare diseases that affect the immune system. Variants in over 500 genes have been identified as causative of 555 IEIs, with clinical phenotypes that can be heterogeneous within the same gene or even within the same variant. Therefore, these challenges make it difficult to determine the cause of IEI in individuals with immune disorders and to link clinical phenotypes to the precise genetic damage. An incorrect diagnosis can miss approximately 25% of IEI patients with overlapping initial manifestations. Accurate diagnosis and timely treatment are essential to improving quality of life and prolonging the lives of patients, as these patients often suffer from severe, life-threatening infections if left untreated. In this study, whole exome sequencing (WES) was used to identify potentially pathogenic variants in six Vietnamese IEI patients. Variants in genes associated with IEIs were screened from WES data using criteria for known and/or novel pathogenic variants, and variants with minor allele frequency (MAF) < 0.001. The pathogenicity of the novel variant was assessed using The American College of Medical Genetics and Genomics (ACMG) criteria and in silico predictive software. Six variants were identified as causative in six study patients, including c.116-2A>G (in the IL2RG gene); c.215delA, p.Asn72Ilefs*49 and c.83G>A, p.Arg28His (in the BTK gene); c.1110-3C>A (in the STAT3 gene); c.1114G>A, p.Glu372Lys (in the STAT6 gene); and c.526C>T, p.Arg176* (in the NHEJ1 gene). Of these, the variant c.1110-3C>A in the STAT3 gene was newly identified in an IEI patient. Although this study has limitations in analyzing the WES of six patients with different types of IEI, the results will contribute to a better understanding of the genetic causes of IEIs. Furthermore, the study emphasizes the importance of accurate diagnosis, which helped improve treatment outcomes and enhance the quality of care for individuals with IEIs.

Although large-scale populations are used to detect genes for polygenic traits, few studies integrate genes and gene-by-environment interactions (GEIs) into breeding by design. Here, we present Fast3VmrMLM, which uses eight big-data techniques to analyze climatic, phenomic and genomic data together to detect GEIs, decipher plasticity and guide breeding. In multi-environment joint analysis (MEJA) of maize, rice and soybean datasets, a total of 396 known genes and 84 known GEIs validated Fast3VmrMLM. In a 12-environment maize dataset, six GEIs interacting with five meteorological factors and two MEJA-detected GEIs helped to explain flowering time plasticity. Thirteen known genes, eight known GEIs and seven plasticity genes advanced flowering by 1.10-6.61&#xa0;days, whereas nine known genes, one known GEI and three plasticity genes increased yield by 0.51-3.56&#xa0;Mg&#xb7;ha-1, identifying 15 high breeding potential hybrids and 29 genes. By incorporating single nucleotide polymorphisms, haplotypes and structural variations, Fast3VmrMLM offers a big-data platform for identifying GEIs and developing climate-adaptive cultivars.

While sleep inequities exist worldwide, interventions to improve sleep and well-being have rarely been developed through an indigenous lens. This article outlines the development of a M&#x101;ori-led (indigenous people of Aotearoa New Zealand) intervention aiming to improve sleep in families with p&#x113;pi (infants) aged 2-12&#x202f;months and thus well-being in the wider wh&#x101;nau (family). Interviews were held with 20 experts in M&#x101;ori tikanga (customs) and te reo (language) and 20 wh&#x101;nau regarding what helped ensure healthy sleep for their wh&#x101;nau. Interviews were transcribed and analyzed thematically. Interviews yielded a number of themes including 1) that ritual plays a crucial role in fostering connection, cultural identity, and well-being in wh&#x101;nau; 2) that ritual assisted movement between transitions such as wake to sleep through the lens of whakanoa (a cleansing of restrictions as move from one state to another); 3) that water-based activities in particular facilitate the transition to sleep; 4) the importance of intergenerational knowledge as sources of support; and 5) that shared meals prior to sleep symbolize Manaaki (hospitality) and connectedness as well as nourishment. Our findings suggest that culturally grounded approaches that honor the lived realities of wh&#x101;nau may help foster healthy sleep patterns and enhance overall well-being. Prioritizing cultural relevance and intergenerational wisdom has the potential to lead to more effective and meaningful approaches to supporting the sleep and well-being of wh&#x101;nau. Australian New Zealand Clinical Trials Registry (anzctr.org.au, AACTRN12622000921785, 28 June 2022).

To assess the impact of virtual case conferences on referring primary care clinician knowledge, prescribing, and patient care practices. Paper-based postal survey. The USask Chronic Pain Clinic (UCPC) in Saskatoon, Sask. All referring health professionals who participated in a USask Chronic Pain Clinic case conference between July 2023 and December 2024 were included. Participants included family physicians (87.3%, n=48 of 55) and nurse practitioners (12.7%, n=7 of 55). The questionnaire collected data regarding participant demographic characteristics and various aspects of participants' chronic pain management knowledge, prescribing, and chronic pain care practices. A total of 168 questionnaires were mailed and the response rate was 32.7% (n=55 of 168). Most participants found case conferences to be a useful resource to their practices (94.5%) and reported that the service helped them with the management of their patients (92.7%). Many respondents reported improved knowledge about safe opioid prescribing (70.9%) and the process for opioid tapering (49.1%). Most agreed the knowledge they acquired from the case conference had been applied to additional patients in their practice (74.5%). Many respondents also felt more confident managing chronic pain (74.5%), more confident prescribing buprenorphine-naloxone for chronic pain (41.8%), and more willing to prescribe buprenorphine-naloxone for chronic pain (36.4%). Some had even prescribed buprenorphine-naloxone for chronic pain for the first time because of the case conference (30.9%). Case conferences between UCPC interdisciplinary chronic pain team members and referring primary care clinicians may be a valuable service to support referring providers in the care of their patients and to increase the capacity of the primary care system to manage chronic pain.

Clostridioides difficile infection (CDI) is one of the most common healthcare-associated infections in the US, and recurrence remains a major clinical challenge, as standard-of-care antibiotics fail to prevent recurrence in up to one-third of cases. Fecal microbiota, live-jslm (RBL) is the first single-dose, microbiota-based product approved by the US Food and Drug Administration and Health Canada for the prevention of recurrent CDI (rCDI) following standard-of-care antibiotics. The RBL clinical development program is the largest to date for any microbiota-based product, encompassing seven studies and enrolling over 1700 participants to evaluate the safety and efficacy of RBL in preventing rCDI. Although the RBL development program consistently evaluated both efficacy and safety outcomes across all studies, this review summarizes the study designs, with a primary focus on the efficacy outcomes. The program consists of randomized controlled trials, open-label cohorts, retrospective analyses, and real-world data, each contributing unique insights across different patient populations and treatment settings. All studies enrolled adults aged&#x2009;&#x2265;&#x2009;18&#xa0;years with rCDI who received antibiotics for their enrolling CDI episode before RBL administration. Most studies administered RBL rectally, except for an open-label study and a retrospective study, which evaluated colonoscopic administration of RBL. Treatment success was evaluated at 8&#xa0;weeks, and sustained clinical response was evaluated at 6 or 24&#xa0;months after RBL and/or placebo administration, depending on the study design. Overall, the study designs for all seven studies were consistent, with slight differences between number of CDI episodes (specifically, 2 studies allowed enrollment after the first CDI recurrence), blinding, controls, and administration routes. Efficacy data of RBL reported across all studies consistently demonstrated RBL is efficacious for the prevention of rCDI in a broad adult population. TRIAL REGISTRATION: ClinicalTrials.gov. NCT01925417; NCT02299570; NCT02589847; NCT03244644; NCT03931941; NCT05831189. Antibiotics used to treat bacterial infections can also damage good bacteria in the gut (dysbiosis). When these good bacteria are damaged, a bacterium called Clostridioides difficile can overgrow and release toxins that harm the colon. This can cause severe diarrhea and may become life-threatening. Antibiotics used to treat C. difficile infection contribute to dysbiosis and increase the chance the infection will return. Microbiota-based products are treatments comprising a wide variety of gut microbes. They help restore the natural balance of bacteria in the gut and have been shown to prevent C. difficile infection from returning. RBL, also known as REBYOTA&#xae; or fecal microbiota, live-jslm, is one of these microbiota-based products developed to prevent recurrent C. difficile infection in adults. The RBL clinical development program is currently the largest group of studies for any microbiota-based product. More than 1700 people have taken part in these studies to test the safety of RBL and its efficacy in preventing recurrent C. difficile infections. This review summarizes all the RBL studies and results seen so far. Across the different studies, which were similar in design and included a wide range of adult participants, RBL consistently helped prevent C. difficile infections from returning. Overall, the evidence shows RBL is effective for many adults at risk of recurrent C. difficile infection.

This article reconstructs Stanis&#x142;aw Ulam's significance for postwar biology and cognition not as the author of a single biological theory but as a contributor to a transformation in representational form. Drawing on Los Alamos reports, Ulam's retrospective framing in Analogies Between Analogies, and the 1974 Mathematical Biosciences article "A Molecular Sequence Metric and Evolutionary Trees," it shows how discrete mathematical models became credible vehicles of biological meaning in the postwar decades. Two examples anchor the argument: cellular automata and recursive growth models, where simple local rules generated growth-like, periodic, and replication-like behavior; and sequence metrics, where molecular relatedness was expressed through the distance between strings. Ulam's work helped normalize two interconnected operations: local rule-based dynamics on lattices and graphs, and metric comparison among structured objects such as pictures and sequences. The article argues that these practices made "information" operational by treating emergence and relatedness as calculable properties of explicit representations. Ulam's influence was frequently indirect and mediated, but historically consequential in widening the range of biological phenomena that could be treated as tractable objects of computation.

This article provides a historical account of collaborative efforts of Japanese, and the United States scientists helped commercialization of the first animal-derived surfactant. Specific details of how collaborative efforts among researchers from Japan, Chicago, Boston, and Vermont was instrumental in helping surfactant commercialization. The article underscores the lasting value of scientific collaboration beyond national boundaries.

This study explored the utilization of medication for addiction treatment (MAT) by participants in one state physician health program (PHP) over the course of 30 years, and reviewed patterns of use and monitoring outcomes. Data were extracted from the PHP records of 45 physicians and 37 pharmacists with substance use disorder (SUD), with or without co-occurring pain disorder, who used opioid [partial] agonist or antagonist medication, with or without other MAT. Variables of interest included demographics, type/length of monitoring, use of medications during monitoring, results of neurocognitive testing, and monitoring outcomes. Descriptive statistics were used to characterize PHP participants. &#x3c7;2 tests, Fisher exact test, and t tests were used for group comparisons. Findings demonstrated positive outcomes among the PHP participants, regardless of MAT use status, with over 70% graduating monitoring or currently in good standing. A minority completed their initial monitoring but returned to the PHP due to return-to-use (n=4, 4.9%), discontinued monitoring against recommendations (n=4, 4.9%), or were turned over to the licensing board due to noncompliance with monitoring (n=4, 4.9%). There were 5 deaths (unrelated to substance use). Periods of MAT use were not associated with worse outcomes or additional impairment. All FDA-approved MAT should be considered for physicians and pharmacists monitored by a PHP, on an individual basis, when deemed clinically appropriate. Extended-release formulations may be particularly helpful for this population. Results may help clarify misunderstandings and controversies surrounding the use of MAT for PHP participants, while also advancing patient-centered, evidence-based care.

Finite Element Analysis (FEA) helps to visualize stress, strain and displacement and biomechanics of a system. Therefore, it is of interest to assess the effects of various methods on simultaneous intrusion and retraction of maxillary anterior teeth by Three-dimensional FEA. For this investigation, the 3D Computer Aided Design (CAD) models simulating Maxilla, three-piece intrusion arch, K-SIR arch and TADs were modeled in the computer finite element program. The software used for geometric modelling was Autodesk AutoCAD 2017 and Inventor 2017. The von Mises stress, principal compressive and tensile stress on PDL and alveolar bone and initial displacement of the teeth in bucco- palatal, mesio- distal and vertical direction were analyzed. Thus, the three-piece intrusion arch showed better stress distribution and controlled tooth movement compared to K-SIR arch and TADs model.

This review conducts a critical assessment of artemisinin oligomers as multivalent agents against pharmacokinetic resistance, rather than presenting a simple literature summary. Dimerization and trimerization are hypothesized to strengthen the binding ability to limited heme within PfKelch13-mutant parasites through the mechanism of 'heme hijacking'. This mode of action relies on affinity-driven molecular capture. Nevertheless, direct biophysical evidence that integrates stoichiometric ratios with kinetic and thermodynamic data is still absent. Three key scientific issues remain insufficiently clarified. First, it remains unclear whether multivalence can effectively reverse drug resistance or only enhance binding affinity in drug-susceptible strains. Second, relevant ADME research on higher-order oligomers is far from adequate. Third, the imprecise definition of multitarget pharmacology leads to ambiguous differentiation between antimalarial and anticancer mechanisms. Notably, no existing research has validated the antimalarial potency of artemisinin trimers. This review evaluates mainstream hypotheses with current research findings and highlights critical knowledge gaps in this field. It thereby provides a solid foundation for rational molecular design. It also helps transform relevant research paradigms. Research focus can shift from empirical linker optimization to the verification of target binding behaviors and comprehensive pharmacokinetic characterization.

Magnetic Resonance Imaging can be a challenging experience for many, despite improvements in scanner design and acquisition speed. A key area of importance to patients is communication about what is happening throughout their scan experience, which can be overlooked in increasingly busy departments. With the new scanner technology available in this community diagnostic centre, there is an updated autovoice function that automatically provides the patient with an update on the expected scan duration. A post-scan survey was administered to patients attending for MRI scanning. Open and closed questions were used to explore patients' views on the usefulness of this autovoice functionality and to better understand how it was received and how it influenced their experience. A total of 313 questionnaires were collected during the two-month period. Most participants perceived the autovoice prompt as useful, with one in five patients preferring the auto prompt over that of a radiographer, and the majority having no preference either way (68%). Entry into the scanner and preference for the delivery of information during the scan were not significant (p = 0.054), with no strong preference one way or the other, although a greater number of headfirst opted for autovoice. Age was not significant (p = 0.063), but those aged 50 years or less showed a greater preference for autovoice than those over 50. Those reporting heightened perceived anxiety on the day suggested greater benefit from the autovoice during the examination. Content analysis of the survey responses indicates a generally positive experience and response towards the autovoice, with some criticisms and suggestions for improvement highlighted. The feedback underscores the importance of clear communication, time awareness, and supportive staff in improving the patient experience during scans. For many, automated systems seem to be perceived as beneficial, offering consistent information, helping them anticipate what to expect, and reducing the likelihood of miscommunication or omission. Findings from this evaluation indicate that patients generally report a positive MRI experience, with the integration of autovoice prompts contributing meaningfully to their sense of communication and reassurance. MRI scans can be stressful, and clear communication during the scan is important for patient comfort. This study asked people to complete a survey after their MRI scan to understand their views on an automated voice system that gives updates about scan timing. This study found that most people felt the automated messages were helpful, especially those who felt more anxious, and many had no strong preference between automated messages and staff communication. This matters because improving how information is shared during scans can help people feel more reassured and improve their overall experience.

Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is a highly contagious disease that severely threatens the global pig industry. A significant symptom of PRRS is severe pneumonia. At present, studies have shown that IL-1&#x3b2; is upregulated by PRRSV infection in vivo and in vitro, while the underlying mechanism remains unknown. Here, we explored how PRRSV regulated IL-1&#x3b2; production. We found that HP-PRRSV nsp1 upregulated the expression of IL-1&#x3b2;. Overexpression of nsp1 induced IL-1&#x3b2; production in a dose-dependent manner. Subsequently, we demonstrated that nsp1 enhanced IL-1&#x3b2; expression by activating JNK/p38 signaling pathways, as the addition of p38 and JNK inhibitors reduced IL-1&#x3b2; production induced by nsp1. Moreover, deleting the AP-1 binding motif in porcine IL-1&#x3b2; promoter impaired IL-1&#x3b2; expression induced by nsp1, suggesting that AP-1 is essential for IL-1&#x3b2; production. In addition, we showed that TRAF6 was required for nsp1 to activate the TAK1/JNK/p38/AP-1 signaling pathway by interacting with each other. Truncation and deletion mutation analysis indicated that R308 and R375 amino acids were important for nsp1 to interact with TRAF6 and induce IL-1&#x3b2; production. Finally, we constructed the recombinant viruses mutated at R308 and R375 and found that the mutated virus PRRSV-R308/375A exhibited a significantly reduced replication rate and impaired the ability to induce IL-1&#x3b2; compared to the wild-type strain. These findings provide new insights into the molecular mechanisms of IL-1&#x3b2; production induced by PRRSV and help us further understand the pathogenesis of PRRSV infection.IMPORTANCEHighly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has been prevalent in China since 2006, causing severe pneumonia in pigs. IL-1&#x3b2; is a proinflammatory cytokine secreted by various cells. In this study, we demonstrated that PRRSV protein nsp1 interacted with TRAF6 to activate the TAK1/JNK/p38/AP-1 signaling pathway, consequently inducing the expression of IL-1&#x3b2;. Additionally, our findings revealed that R308 and R375 in nsp1 were critical amino acid residues for nsp1 to interact with TRAF6 and induce IL-1&#x3b2; production. Notably, the recombinant virus PRRSV-R308/375A exhibited a significantly reduced replication rate and impaired ability to induce proinflammatory cytokines in vitro compared to the wild-type strain HP-PRRSV. This study helps us further understand HP-PRRSV pathogenesis and provides a new idea for the development of PRRSV vaccines.

Accelerating permafrost thaw may release vast deep (>3 meters) frozen soil carbon as carbon dioxide (CO2), but this magnitude remains uncertain because current Earth system models (ESMs) lack deep carbon processes. Using an updated ORCHIDEE-MICT model simulating Pleistocene Yedoma formation and Holocene peatland development, we project northern (>30&#xb0;N) carbon responses under climate change. Compared to the original model, including these deep carbon pools improves agreement with observations and reduces net CO2 uptake by 47 to 74 petagrams of carbon from 1900 to 2100 across three future scenarios because of deep carbon decomposition with accelerated active-layer deepening. Under high-emission pathways, the northern soil carbon balance shifts from a sink to a source of 32 petagrams of carbon, advancing the reversal reported in earlier studies into the 21st century. Consistent with field data, our model shows that colder soils retain more labile carbon-contrary to assumptions in many Coupled Model Intercomparison Project (CMIP) models-helping explain their persistent sink bias. Our results highlight the need to represent both the quantity and quality of permafrost carbon in ESMs.

New technologies developed by a California company are expanding upon raw coronary computed tomography angiography (CCTA) data with artificial intelligence (AI) and computational fluid dynamics to model the coronary arteries and identify arterial narrowing and the types of plaque present. An integrated, AI-driven planning tool also helps interventional cardiologists optimize stent placement.

A prominent symptom of post-acute sequelae of SARS-CoV-2 infection (i.e., Long COVID) is exercise intolerance with or without post-exertional malaise (PEM). PEM is characterized by the worsening of both symptoms and function following even minor physical or mental exertion, with symptoms typically worsening 12 to 48 hours after activity and lasting for days or even weeks. Individualized, supervised cardiopulmonary rehabilitation is considered a safe and effective intervention for many cardiac and pulmonary conditions, and has been effective in gradually improving function in previously hospitalized and nonhospitalized patients with severe COVID-19. While traditional cardiopulmonary rehabilitation approaches appear helpful in some situations, the exercise intolerance symptoms experienced by many individuals with Long COVID may require a different approach, especially when attempts to increase physical activity result in PEM. No clear consensus exists on the optimal treatment of PEM, and no major studies have evaluated the efficacy in individuals with Long COVID of either carefully supervised, individualized cardiopulmonary rehabilitation programs for exercise intolerance without significant PEM or activity pacing interventions designed to treat or prevent PEM. The Researching COVID to Enhance Recovery Clinical Trials (RECOVER-CT) initiative funded by the National Institutes of Health (NIH) included a prospective, multicenter, randomized controlled platform trial (RECOVER-ENERGIZE) designed to assess two interventions in patients with Long COVID and exercise intolerance: (1) cardiopulmonary rehabilitation for patients without significant PEM and (2) structured activity pacing to prevent or reduce PEM in participants who experience the symptom. The intervention duration will be 12 weeks. The primary endpoints for the trial include the Endurance Shuttle Walk Test as a measure of endurance capacity for the cardiopulmonary rehabilitation intervention and a modified version of the DePaul Symptom Questionnaire-Post-Exertional Malaise for the pacing intervention. Assessments will be completed at baseline, middle of intervention, end of intervention, and 12 weeks after completion of the intervention, and include physical performance measures and patient-reported surveys. The RECOVER-ENERGIZE trial protocol has been approved by an institutional review board (Advarra), and written informed consent will be obtained from all participants prior to enrollment. The trial is registered on ClinicalTrials.gov ( NCT06404047 ). Formally assessing PEM and developing a structured activity pacing intervention delivered by local pacing coaches are novel features of this trial. Results will be disseminated through peer-reviewed publications, presentations at scientific conferences, and communication with participants, patient advocacy organizations, and the broader Long COVID community. De-identified participant data will be made available through the NIH RECOVER data repository in accordance with NIH data-sharing policies. If successful, this protocol will provide accessible tools that clinicians can use to address exercise intolerance and PEM in patients with Long COVID. ClinicalTrials.gov - Platform: NCT06404047 ; Appendix A: NCT06404060 ; Appendix B: NCT06404073 . Registered on May 6, 2024. RECOVER-ENERGIZE is a large, multicenter, randomized controlled platform trial that stratifies participants by PEM status, separately evaluating cardiopulmonary rehabilitation in those without significant PEM and structured activity pacing in those with PEM, while mitigating the risk of exertional harm.The structured activity pacing intervention is novel and has not previously been tested in a randomized trial in Long COVID. Its coach-delivered, video-conference format is designed to be easily implemented and scalable across diverse clinical settings.Patient, caregiver, and community representatives were integrally involved throughout protocol development, shaping eligibility criteria, intervention design, and selection of outcome measures, which strengthens the relevance of the trial to the Long COVID community.The trial combines a performance-based measure of endurance capacity (the Endurance Shuttle Walk Test) with a modified, PEM-specific patient-reported instrument (mDSQ-PEM). However, the nature of the interventions precludes blinding of participants and providers, and several key outcomes rely on self-report, which may introduce bias.