Conditioning Trials Research Articles

Presenting JAK inhibitor safety information to dermatology patients

AbstractJanus Kinase (JAK) inhibitors are treatment options for dermatologic conditions such as atopic dermatitis, psoriasis, vitiligo, and alopecia areata. Guidance on how to counsel patients on these novel treatments is limited. The purpose of this review is to provide options providers can use to discuss JAK inhibitors with dermatology patients. The PubMed database was searched for terms including “dermatology JAK inhibitor safety” and “presenting information to patients.” Relevant literature was selected for inclusion. Black box warnings were placed on JAK inhibitors after a large, controlled trial in rheumatoid arthritis patients did not prove that tofacitinib was as safe as tumor necrosis factor inhibitors; in clinical trials for dermatologic conditions, JAK inhibitors had low risks of serious adverse events. Patient barriers to comprehending treatment information include conflicting information and limited time for discussion of risks. To address these barriers, suggested approaches have included speaking in simple phrases, providing reliable sources, and offering educational materials appropriate for different cultures. When discussing risks, physicians may use anecdotes and frame risks and side effects in ways that decrease anxiety. JAK inhibitors have uncommon severe side effects and related concerns that may be hard for patients to overcome, even when benefits exceed risks. Standard educational approaches can be complemented by anecdotes and framing to help diminish patients' anxiety.

Revolutionising Neurological Therapeutics: Investigating Drug Repurposing Strategies.

Repurposing drugs (DR) has become a viable approach to hasten the search for cures for neurodegenerative diseases (NDs). This review examines different off-target and on-target drug discovery techniques and how they might be used to find possible treatments for non-diagnostic depressions. Off-target strategies look at the known or unknown side effects of currently approved drugs for repositioning, whereas on-target strategies connect disease pathways to targets that can be treated with drugs. The review highlights the potential of experimental and computational methodologies, such as machine learning, proteomic techniques, network and genomics-based approaches, and in silico screening, in uncovering new drug-disease correlations. It also looks at difficulties and failed attempts at drug repurposing for NDs, highlighting the necessity of exact and standardised procedures to increase success rates. This review's objectives are to address the purpose of drug repurposing in human disorders, particularly neurological diseases, and to provide an overview of repurposing candidates that are presently undergoing clinical trials for neurological conditions, along with any possible causes and early findings. We then include a list of drug repurposing strategies, restrictions, and difficulties for upcoming research.

Effect of Task Constraints on Neurobiological Systems Involved in Postural Control in Individuals with and without Chronic Ankle Instability.

The purpose of this study is to investigate the effect of task constraints on the neurobiological systems while maintaining postural control under various sensory feedback manipulations in individuals with and without Chronic Ankle Instability (CAI). Forty-two physically active individuals, with and without CAI, were enrolled in a case-control study conducted at a biomechanics research laboratory. All participants underwent the Sensory Organization Test (SOT), which assesses individuals' ability to integrate somatosensory, visual, and vestibular feedback to maintain postural control in double-, uninjured-, and injured-limb stances under six different conditions in which variations in the sway-referenced support surface (platform) and visual surroundings, with and without vision, are manipulated to affect somatosensory and visual feedback. Center-of-Pressure (COP) path length was computed from raw data collected during trials of each SOT condition. Sample Entropy (SampEN) values were extracted from the COP path length time series to examine neurobiological systems complexity, with lower SampEN values indicating more predictable and periodic (rigid) neurobiological systems, while higher SampEN values indicate more unpredictable and random systems. The results show that specific task constraints affect the neurobiological systems. Specifically, individuals with CAI demonstrated reduced complexity (decreased SampEN values) in the neurobiological systems during the uninjured-limb stance when all sensory feedback was intact and during both uninjured- and injured-limb stances when they were forced to rely on vestibular feedback. These results highlight the interplay between sensory feedback and task constraints in individuals with CAI and suggest potential adaptations in the neurobiological systems involved in postural control.

Target and Gene-Based Therapeutic Strategies against Pancreatic Cancer: Current and Future Prospects.

Despite tremendous advancements in knowledge, diagnosis, and availability of both traditional and innovative treatments, pancreatic cancer remains a dangerous disease with a high death rate and dismal prognosis. The traditional strategy in adjuvant and palliative settings is still cytotoxic chemotherapy predicated on the purine derivative gemcitabine; nevertheless, there is an increasing need for new medicines that target the primary molecular pathways and pathophysiological abnormalities implicated. There is now just a tiny amount of evidence of therapeutic benefit when the targeted drug erlotinib is added to the conventional gemcitabine treatment. In preclinical and clinical trials, novel medications targeting mTOR, NF-κB, and proteasome, including the enzyme histone deacetylase, are currently being studied alongside the well-established monoclonal antibody treatments and small-molecule protein tyrosine kinase inhibitors. These novel medications may change the negative natural progression of this illness in conjunction with gene therapy and immunotherapy, both of which are undergoing clinical study. In this regard, leveraging miRNA manipulation to combat cancer is appealing due to its promise to deliver personalized treatment tailored to an individual's distinct gene or miRNA expression profile. Preclinical studies involving animals have showcased the effectiveness of miRNA-based therapies, with several of these treatments now progressing into human clinical trials for various malignancies and other medical conditions. This review describes the important developments of targeted therapeutics that are associated with pancreatic cancer and the discoveries which can help in dealing with this fatal malignancy in a more significant manner.

Antisense oligonucleotides and their applications in rare neurological diseases.

Rare diseases affect almost 500 million people globally, predominantly impacting children and often leading to significantly impaired quality of life and high treatment costs. While significant contributions have been made to develop effective treatments for those with rare diseases, more rapid drug discovery strategies are needed. Therapeutic antisense oligonucleotides can modulate target gene expression with high specificity through various mechanisms determined by base sequences and chemical modifications; and have shown efficacy in clinical trials for a few rare neurological conditions. Therefore, this review will focus on the applications of antisense oligonucleotides, in particular splice-switching antisense oligomers as promising therapeutics for rare neurological diseases, with key examples of Duchenne muscular dystrophy and spinal muscular atrophy. Challenges and future perspectives in developing antisense therapeutics for rare conditions including target discovery, antisense chemical modifications, animal models for therapeutic validations, and clinical trial designs will also be briefly discussed.

The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF): Rationale and design.

Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a unique pragmatic registry-based randomized controlled trial. SPIRRIT-HFpEF is a multicentre, prospective, randomized, open-label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N-terminal pro-B-type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre-specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event-driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. SPIRRIT-HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry-based trials in heart failure and other chronic conditions.

Patient acceptance of care of a novel care pathway for those at risk of poor outcomes from musculoskeletal pain: A mixed methods study

ObjectiveInvestigate people's acceptance of specialist musculoskeletal care within a new care pathway for common musculoskeletal conditions (low back pain, neck pain/whiplash, knee osteoarthritis). DesignConvergent parallel mixed methods design referencing the Theoretical Framework of Acceptability. The study included a subset of participants (n = 29) at-risk of poor outcomes from the intervention arm of the PAthway of CarE for common musculoskeletal conditions (PACE-MSK) trial. In the PACE-MSK arm, participants received specialist physiotherapist care as an adjunct to the care provided by their primary healthcare professional(s). One-to-one semi-structured interviews were conducted around 3-months after commencing in the trial. Quantitative data were collected at baseline and 3-month follow-up (health-related quality of life, pain self-efficacy, global perceived change, satisfaction). ResultsFive themes were identified (Expectations and beliefs shaped patient experience; Clinical expertise and competence influence acceptance; Person-centred care; Mechanisms facilitating beneficial responses to care; Gaps in care pathway implementation). There were positive individual changes in physical quality of life for 17/29 (59%) participants, mental health quality of life for 12/29 (41%), pain self-efficacy for 8/29 (28%) and global perceived change for 19/29 (66%). Management met expectations with the majority reporting high levels of satisfaction. Integrating the qualitative and quantitative data with the Theoretical Framework of Acceptability, there were complementary meta-inferences in the constructs of ‘ethicality’, ‘intervention coherence’, ‘self-efficacy’ and ‘affective attitude’. Divergence was identified in ‘perceived effectiveness’. DiscussionIn general, there was positive acceptance of the care pathway by participants. Specialist physiotherapists’ care was perceived as a positive addition to usual care.

β-glucans, SAM, and GSH fluctuations in barley anther tissue culture conditions affect regenerants’ DNA methylation and GPRE

BackgroundMicrospore embryogenesis is a process that produces doubled haploids in tissue culture environments and is widely used in cereal plants. The efficient production of green regenerants requires stresses that could be sensed at the level of glycolysis, followed by the Krebs cycle and electron transfer chain. The latter can be affected by Cu(II) ion concentration in the induction media acting as cofactors of biochemical reactions, indirectly influencing the production of glutathione (GSH) and S-adenosyl-L-methionine (SAM) and thereby affecting epigenetic mechanisms involving DNA methylation (demethylation—DM, de novo methylation—DNM). The conclusions mentioned were acquired from research on triticale regenerants, but there is no similar research on barley. In this way, the study looks at how DNM, DM, Cu(II), SAM, GSH, and β-glucan affect the ability of green plant regeneration efficiency (GPRE).ResultsThe experiment involved spring barley regenerants obtained through anther culture. Nine variants (trials) of induction media were created by adding copper (CuSO4: 0.1; 5; 10 µM) and silver salts (AgNO3: 0; 10; 60 µM), with varying incubation times for the anthers (21, 28, and 35 days). Changes in DNA methylation were estimated using the DArTseqMet molecular marker method, which also detects cytosine methylation.Phenotype variability in β-glucans, SAM and GSH induced by the nutrient treatments was assessed using tentative assignments based on the Attenuated Total Reflectance-Fourier Transform Infrared (ATR-FTIR) spectroscopy. The effectiveness of green plant regeneration ranged from 0.1 to 2.91 plants per 100 plated anthers. The level of demethylation ranged from 7.61 to 32.29, while de novo methylation reached values ranging from 6.83 to 32.27. The paper demonstrates that the samples from specific in vitro conditions (trials) formed tight groups linked to the factors contributing to the two main components responsible for 55.05% of the variance (to the first component DNM, DM, to the second component GSH, β-glucans, Cu(II), GPRE).ConclusionsWe can conclude that in vitro tissue culture conditions affect biochemical levels, DNA methylation changes, and GPRE. Increasing Cu(II) concentration in the IM impacts the metabolism and DNA methylation, elevating GPRE. Thus, changing Cu(II) concentration in the IM is fair to expect to boost GPRE.

The influence of repetitive thoughts of CS-US pairing on expectancy learning and evaluative conditioning: a fundamental study.

Repetitive thinking is a common phenomenon, also implicated in a variety of mental disorders. The content of repetitive thoughts can take the form of prediction of aversive events (in worry) or evoking negatively valenced information (in rumination), for instance. Investigating the influence of repetitive thinking through the lens of associative learning could help deepen our understanding of the mechanisms involved in its effects.In two experiments, non-clinical participants were exposed to CS-US pairings with the aim of creating non-threatening expectancy learning (Experiment 1) or evaluative conditioning (Experiment 2). After each conditioning trial, participants were instructed to initiate repetitive thoughts about the pairing (i.e. rehearse) or follow control instructions.Experiment 1 (N = 64) showed that such intervention strengthen the association between the mental representations of the CS and the US, leading to a stronger US expectancy in response to the CS. In Experiment 2 (N = 107), an evaluative conditioning effect was observed; however, it was not influenced by instructions.The study demonstrated that simulated repetitive thinking strengthens the CS-US association and leads to greater US expectancy in expectancy learning, despite appearing not to influence the evaluative conditioning effect. The potential implications of these findings on repetitive thinking are discussed.

Partner-Specific Adaptation in Disfluency Processing.

Speakers tend to produce disfluencies when naming unexpected or complex items; in turn, when perceiving disfluency, listeners tend to expect upcoming reference to items that are unexpected or complex to name. In two experiments, we examined if these disfluency-based expectations are routine, or instead, if they adapt to the way the speaker uses disfluency in the current context in a talker-specific manner. Participants listened to instructions to look at objects in contexts with several images, some of which lacked conventional names. We manipulated the co-occurrence of disfluency and reference to novel versus familiar objects in a single talker situation (Experiment 1) and in a multi-talker situation (Experiment 2). In the predictive condition, disfluent expressions referred to novel objects, and fluent expressions referred to familiar objects. In the nonpredictive condition, fluent and disfluent trials referred to either familiar or novel objects. Participants' gaze revealed that listeners more readily predicted familiar images for fluent trials and novel images for disfluent trials in the predictive condition than in the nonpredictive condition. In sum, listeners adapted their expectations about upcoming words based on recent experience with disfluency. Disfluency is not invariably processed, but instead a cue that is flexibly interpreted depending on the local context even in a multi-talker setting.

Potential Use of MicroRNA Technology in Thalassemia Therapy.

Thalassemia encompasses a group of inherited hemoglobin disorders characterized by reduced or absent production of the α- or β-globin chains, leading to anemia and other complications. Current management relies on lifelong blood transfusions and iron chelation, which is burdensome for patients. This review summarizes the emerging therapeutic potential of modulating microRNAs (miRNAs) to treat thalassemia. MiRNAs are small non-coding RNAs that regulate gene expression through sequence-specific binding to messenger RNAs (mRNAs). While they commonly repress gene expression by binding to the 3' untranslated regions (UTRs) of target mRNAs, miRNAs can also interact with 5'UTRs and gene promoters to activate gene expression. Many miRNAs are now recognized as critical regulators of erythropoiesis and are abnormally expressed in β-thalassemia. Therapeutically restoring levels of deficient miRNAs or inhibiting overexpression through miRNA mimics or inhibitors (antagomir), respectively, has shown preclinical efficacy in ameliorating thalassemic phenotypes. The miR-144/451 cluster is especially compelling for targeted upregulation to reactivate fetal hemoglobin synthesis. Advances in delivery systems are addressing previous challenges in stability and targeting of miRNA-based drugs. While still early, gene therapy studies suggest combinatorial approaches with miRNA modulation may provide synergistic benefits. Several key considerations remain including enhancing delivery, minimizing off-target effects, and demonstrating long-term safety and efficacy. While no miRNA therapies have yet progressed to clinical testing for thalassemia specifically, important lessons are being learned through clinical trials for other diseases and conditions, such as cancer, cardiovascular diseases, and viral. If limitations can be overcome through multi-disciplinary collaboration, miRNAs hold great promise to expand and transform treatment options for thalassemia in the future by precisely targeting pathogenic molecular networks. Ongoing innovations, such as advancements in miRNA delivery systems, improved targeting mechanisms, and enhanced understanding of miRNA biology, continue to drive progress in this emerging field towards realizing the clinical potential of miRNA-based medicines for thalassemia patients.

Aerobic Exercise: Randomized Controlled Trial Data Suggest Qualified Benefits for Erectile Dysfunction.

Erectile dysfunction (ED) refers to the difficulty in achieving and maintaining a degree of penile erection that suffices for satisfactory sexual activity. ED is multifactorial in origin; its prevalence therefore varies with the population studied. In the general population, ED is present in 18-52% of men in younger to older age groups and in 43-76% of men with different medical conditions. Phosphodiesterase-5 inhibitor drugs are gold standard treatments for ED. However, because many lifestyle disorders predispose to ED and because aerobic exercise is beneficial for these lifestyle disorders, aerobic exercise may be a possible intervention for ED. In this context, a recent systematic review and meta-analysis identified 11 randomized controlled trials (RCTs; pooled N = 1,147) of aerobic exercise vs nonexercising control conditions for the treatment of ED. These RCTs had been conducted in men with different medical and surgical conditions, commonly obesity, metabolic syndrome, diabetes mellitus, and cardiovascular disease. The exercise interventions were varied but mostly involved 30-60 minutes sessions of activity, 3-5 times a week, for a median duration of 6 months. Advice for diet and weight loss was also commonly provided. The meta analysis found that aerobic exercise was significantly superior to nonexercising control conditions, with greater improvement in erectile functioning observed in subjects with greater baseline impairment. Limitations of the findings were that subjects could not be blinded to the nature of the intervention and that the magnitude of benefit with exercise, although statistically significant, fell below thresholds suggested for clinical significance. Aerobic exercise might therefore be more useful for the primary prevention of ED, for which preliminary evidence already exists. Exercise can also be recommended, along with other lifestyle guidance, to improve sexual functioning in both men and women and to improve health across a range of domains.

Digital health technologies to strengthen patient-centred outcome assessment in clinical trials in inflammatory arthritis.

Common to all inflammatory arthritides, namely rheumatoid arthritis, psoriatic arthritis, axial spondyloarthritis, and juvenile idiopathic arthritis, is a potential for reduced mobility that manifests through joint pain, swelling, stiffness, and ultimately joint damage. Across these conditions, consensus has been reached on the need to capture outcomes related to mobility, such as functional capacity and physical activity, as core domains in randomised controlled trials. Existing endpoints within these core domains rely wholly on self-reported questionnaires that capture patients' perceptions of their symptoms and activities. These questionnaires are subjective, inherently vulnerable to recall bias, and do not capture the granularity of fluctuations over time. Several early adopters have integrated sensor-based digital health technology (DHT)-derived endpoints to measure physical function and activity in randomised controlled trials for conditions including Parkinson's disease, Duchenne's muscular dystrophy, chronic obstructive pulmonary disease, and heart failure. Despite these applications, there have been no sensor-based DHT-derived endpoints in clinical trials recruiting patients with inflammatory arthritis. Borrowing from case studies across medicine, we outline the opportunities and challenges in developing novel sensor-based DHT-derived endpoints that capture the symptoms and disease manifestations most relevant to patients with inflammatory arthritis.

IBAT inhibitors in pediatric cholestatic liver diseases: Transformation on the horizon?

Historically, the therapeutic options available to hepatologists managing cholestasis have been limited. Apart from bile acid--binding resins and the choleretic ursodeoxycholic acid, the medical management of cholestasis in children has been predominately focused on managing the complications of cholestasis, namely pruritus, malnutrition, fat-soluble vitamin deficiencies, and portal hypertension. As such, invasive surgical procedures such as biliary diversion and liver transplantation may become the only options for progressive and unremitting cases of cholestasis. Particularly in the pediatric population, where debilitating pruritus is a common indication for a liver transplant, effective anti-cholestatic medications have the potential to prolong native liver survival without the need for biliary diversion. Ileal bile acid transporter (IBAT) inhibitors are a relatively new class of drugs which that target the ileal re-uptake of bile acids, thus interrupting the enterohepatic circulation and reducing the total bile acid pool size and exposure of the liver. Oral, minimally absorbed IBAT inhibitors have been demonstrated to reduce serum bile acid levels and pruritus with a minimal side effect profile in clinical trials in Alagille Ssyndrome and progressive familial intrahepatic cholestasis, leading to FDA and EMA approval. The indications for IBAT inhibitors will likely expand in the coming years as clinical trials in other adult and pediatric cholestatic conditions are ongoing. This review will summarize the published clinical and pre-clinical data on IBAT inhibitors and offer providers guidance on their practical use.

Absence of differential protection from extinction in human causal learning.

Elemental models of associative learning typically employ a common prediction-error term. Following a conditioning trial, they predict that the change in the strength of an association between a cue and an outcome is dependent upon how well the outcome was predicted. When multiple cues are present, they each contribute to that prediction. The same rule applies both to increases in associative strength during excitatory conditioning and the loss of associative strength during extinction. In five experiments using an allergy prediction task, we tested the involvement of a common error term in the extinction of causal learning. Two target cues were each paired with an outcome prior to undergoing extinction in compound either with a second excitatory cue or with a cue that had previously undergone extinction in isolation. At test, there was no difference in the causal ratings of the two target cues. Manipulations designed to bias participants toward elemental processing of cue compounds, to promote the acquisition of inhibitory associations, or to reduce generalization decrement between training and test were each without effect. These results are not consistent with common error term models of associative learning. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Insight into Olfactory Learning, Memory, and Mortality of Apis mellifera jemenitica after Exposure to Acetamiprid Insecticide.

The honey bee, a significant crop pollinator, encounters pesticides through various routes of exposure during foraging and flower visitation. Considering the potential threat of pesticide poisoning, the indigenous Saudi bee Apis mellifera jemenitica is susceptible to the risks associated with acetamiprid, a neonicotinoid insecticide. This study investigates the acetamiprid-induced effects on the survival, olfactory learning, and memory formation of A. m. jemenitica through two exposure routes: topical application and oral ingestion. Field-realistic and serially diluted concentrations (100, 50, 25, and 10 ppm) of acetamiprid led to notable mortality at 4, 12, 24, and 48 h after treatment, with peak mortality observed at 24 h and 48 h for both exposure routes. Bee mortality was concentration-dependent, increasing with the rising concentration of acetamiprid at the tested time intervals. Food consumption following oral exposure exhibited a concentration-dependent pattern, steadily decreasing with increasing concentrations of acetamiprid. Oral exposure resulted in a substantially higher cumulative mortality (55%) compared to topical exposure (15%), indicating a significant disparity in bee mortality between the two exposure routes. The 24 h post-treatment LC50 values for acetamiprid were 160.33 and 12.76 ppm for topical application and oral ingestion, respectively. The sublethal concentrations (LC10, LC20, and LC30) of acetamiprid were 15.23, 34.18, and 61.20 ppm, respectively, following topical exposure, and 2.85, 4.77, and 6.91 ppm, respectively, following oral exposure. The sublethal concentrations of acetamiprid significantly decreased learning during the 2nd-3rd conditioning trials and impaired memory formation at 2, 12, and 24 h following both topical and oral exposure routes, compared to the control bees. Notably, the sublethal concentrations were equally effective in impairing bee learning and memory. Taken together, acetamiprid exposure adversely affected bee survival, hindered learning, and impaired the memory retention of learned tasks.

IMG-29. IMPLICATIONS OF IMAGE HARMONIZATION FOR BRAIN TUMOR CLINICAL TRIALS

Abstract BACKGROUND Clinical trials for rare pediatric conditions like optic pathway gliomas associated with NF1 (NF1-OPGs) require numerous sites that utilize different MRI scanners and protocols. These MRIs must be harmonized for reliable comparison using machine learning tools. We propose a deep-learning based MRI harmonization that enables reproducible data analysis across multiple sites and MRI platforms. METHODS One-hundred eighty clinical T1-weighted-MRIs of pediatric NF1-OPG subjects were acquired from three sites [Children’s National Hospital (site A, N=60), Children’s Hospital Colorado (site B, N=60), and Children’s Hospital of Philadelphia (site C, N=60)] using different MR scanners (GE, Phillips, and Siemens, respectively). MRIs from A and B were used to train a branched neural network and C were used for testing. Using unsupervised learning, the neural network identified differences in imaging protocols and harmonized data to a chosen protocol, e.g., that of site A, while preserving the patient anatomy. The harmonization was evaluated using Wasserstein distance (nWD), which measured similarity between two gray scale appearances of MRI intensity histograms. Anatomy preservation metric (AP) measured relative volume changes in gray matter (GM) segmented using Freesurfer, before and after harmonization. For both metrics, 100% means the best possible harmonization was achieved. RESULTS Before harmonization, nWD between grayscale appearance of MRIs from sites A and B was 27.3±3.1%. After harmonization, the similarity became 94.2±2.0% with a GM volume error of 3.11±0.56ml which corresponded to AP of 93.1±4.7%. For the test data, nWD similarity post harmonization improved from 38.2±3.9% to 93.4±2.2% with GM volume error of 4.12±0.47ml which corresponded to AP of 90.3±3.5%. CONCLUSIONS Our approach enables MRI harmonization while preserving anatomy for precise analysis using machine learning tools. It scales to new sites to support multisite clinical trials that utilize imaging outcomes for brain tumors and other rare diseases.

Conditioning of Motor Evoked Responses After Anterior Cruciate Ligament Reconstruction: Effects of Stimulus Intensity.

Operant conditioning of motor evoked torque (MEPTORQUE) can directly target the corticospinal pathway in patients with anterior cruciate ligament (ACL) reconstruction. However, it remains unclear whether operant conditioning can elicit short-term improvements in corticospinal excitability and whether these improvements are influenced by stimulus intensity. Quadriceps MEPTORQUE responses can be upconditioned in a single session and will elicit short-term adaptations in corticospinal excitability, with higher stimulus intensities eliciting greater effects. Randomized controlled laboratory study. Level 2. Thirty-six participants were assessed during a single session of an operant conditioning protocol. Participants were randomized into 1 of 3 groups for stimulus intensity used during operant conditioning based on the participant's active motor threshold (AMT: 100%, 120%, and 140%). Quadriceps MEPTORQUE amplitude was evaluated during a block of control transcranial magnetic stimulation trials (CTRL) to establish baseline corticospinal excitability, and 3 blocks of conditioning trials (COND) during which participants trained to upcondition their MEPTORQUE. MEPTORQUE recruitment curves were collected to evaluate the effect of operant conditioning on acute corticospinal adaptations. Participants with ACL reconstruction could upcondition their MEPTORQUE in a single session (P < 0.01; CTRL, 17.27 ± 1.28; COND, 21.35 ± 1.28 [mean ± standard error [SE] in N·m]), but this ability was not influenced by the stimulus intensity used during training (P = 0.84). Furthermore, significant improvements in corticospinal excitability were observed (P = 0.05; PRE, 687.91 ± 50.15; POST, 761.08 ± 50.15 [mean ± SE in N·m %AMT]), but stimulus intensity did not influence corticospinal adaptations (P = 0.67). Operant conditioning can elicit short-term neural adaptations in ACL-reconstructed patients. Future operant conditioning paradigms may effectively use any of the 3 stimulus intensities studied herein. Operant conditioning may be a feasible approach to improve corticospinal excitability after ACL reconstruction.

Telehealth cognitive-behavioral therapy for cancer-related cognitive impairment: 2024 update of a model for remote clinical trial participation.

TPS12147 Background: Cancer-related cognitive impairment (CRCI) consists of persistent memory symptoms that adversely affects survivor quality of life (QOL). Memory and Attention Adaptation Training (MAAT) is an evidence-based cognitive behavioral therapy (CBT) for CRCI with demonstrated efficacy in telehealth delivery. MAAT consists of 8 weekly (45 minute) video visits. The aims of this study are to confirm MAAT telehealth efficacy in a phase III RCT (MAAT vs Supportive Therapy; ST) across large catchment areas of two comprehensive cancer centers. A secondary aim is to evaluate treatment-induced brain activation as assessed by functional MRI (fMRI). We present remote treatment and data capture methods of this open NCI-sponsored (R01CA244673) randomized clinical trial (NCT 04586530). These methods have high success in participant accrual despite starting the trial in COVID-19 pandemic conditions and can be readily adopted to other clinical trials to enhance rural/underserved enrollment. Methods: We are enrolling 200 adult, stage I-III breast cancer survivors 1-5 years post-chemotherapy with cognitive complaints. Individuals with CNS disease, previous brain injury, dementia or psychiatric disorder are excluded. All study procedures are completed from the participant’s home (except fMRI). Eligibility screening is a structured phone interview followed by detailed informed consent online (Research Electronic Data Capture: REDCap) with phone guidance. Consented participants complete baseline brief phone-based neurocognitive assessment and validated patient-reported outcome measures (PROs) of cognition and quality of life via REDCap. Participants are randomized to MAAT or ST and assigned treating clinicians at respective cancer centers. All 8 visits are completed through secure telehealth platforms, followed by repeat phone/online assessment post-treatment and again at 6 months. Enrollment began 3/2021. As of 12/12/2023 (33.5 months), 116 participants are enrolled (58% of the planned sample), 116 randomized (MAAT 58; ST 58), with 81 completing post-treatment assessments. If all assessments and treatment visits were in person, travel burden per participant is 977 miles/22 hours driven, and $640 (US 2023 Federal rate). Thus, study travel savings to date are $74,240. Participant feedback indicates telehealth makes participation possible, similar to previous MAAT research. The current RCT demonstrates utility, efficiency and cost-savings of telehealth and remote data capture technology in the conduct of cancer control research. Methods described here can also be adopted for cancer therapeutic trials. Comprehensive cancer centers, where most clinical trials are based, can enhance participation of remote and/or underserved populations that have higher rates of cancer, more disease burden and less opportunity for trial participation. Clinical trial information: NCT04586530 .

Transgender people in clinical trials of drugs and biologics: An analysis of ClinicalTrials.gov from 2007 to 2023.

Transgender people have unmet health needs related to chronic conditions such as dementia, osteoporosis and hypertension. Community-driven advocacy increased transgender representation in phase III trials for pharmacological prevention of HIV, but the extent to which drug trials for other conditions have included transgender people is unknown. We investigated the extent to which trials of drugs and biologics represented transgender people across therapeutic areas on ClinicalTrials.gov. Cross-sectional analysis of trials of drugs and biologics registered on ClinicalTrials.gov from 2007-2023. We included efficacy and effectiveness trials (phase II-IV) with transgender-related terms (e.g. 'transgend*'). We labelled trials as Inclusive or Exclusive of transgender people using the trial eligibility criteria. We compared trials (therapeutic area, trial design, enrolment), summarized trials registered from 2008 onward and characterized participant enrolment for Inclusive trials with primary trial publications. We summarized continuous data using median (range), categorical data using frequencies and percentages and compared trial characteristics using Fisher's exact test. Ninety-seven trials represented transgender people. Characteristics were similar between 85 Inclusive and 12 Exclusive trials. Among Inclusive trials, 58% focused on infectious diseases (e.g. treatment or prevention of HIV and COVID-19), 15% on mental health (e.g. post-traumatic stress disorder, substance use-related disorders), and the remainder focused on endocrine (9%), pain (5%), digestive system disorders (1%) and neoplasms (1%). Twenty (of 25) trials reported enrolment of transgender participants in primary trial publications or reported results. Transgender-inclusive trials have increased since 2008. Most trials focused on infectious diseases and mental health. Investigators should increase opportunities to include of transgender people in trials of drugs and biologics for chronic diseases.