Test Trials Research Articles

The NExT trial: Protocol for a two-phase randomized controlled trial testing transcranial magnetic stimulation to augment exposure therapy for youth with OCD

BackgroundExposure with Response Prevention (ERP) is a first-line treatment for OCD, but even when combined with first-line medications it is insufficiently effective for approximately half of patients. Compulsivity in OCD is thought to arise from an imbalance of two distinct neural circuits associated with specific subregions of striatum. Targeted modulation of these circuits via key cortical nodes (dorsolateral prefrontal cortex [dlPFC] or presupplementary motor area [pSMA]) has the potential to improve ERP efficacy by decreasing compulsions during therapy.MethodsThe NExT (Neuromodulation + Exposure Therapy) trial is a two-phase, multisite early-stage randomized controlled trial designed to examine whether TMS augmentation of ERP alters activity in dlPFC and/or pSMA-associated circuitry and reduces compulsions during therapy in youth with OCD age 12–21 years. Phase 1 (N = 60) will compare two different active TMS regimens with sham: A. continuous theta burst stimulation (cTBS) to pSMA vs. B. intermittent theta burst stimulation (iTBS) to dlPFC. A priori “Go/No-Go” criteria will inform a decision to proceed to Phase 2 and the choice of TMS regimen. Phase 2 (N = 60) will compare the selected TMS regimen vs. sham in a new sample.DiscussionThis trial is the first to test TMS augmentation of ERP in youth with OCD. Results will inform the potential of TMS to enhance ERP efficacy and enhance knowledge about mechanisms of change.Trial registrationClinicalTrials.gov NCT05931913. Registered prospectively on July 5, 2023.

In Vivo Cardiovascular Molecular Imaging: Contributions to Precision Medicine and Drug Development.

Conventional forms of noninvasive cardiovascular imaging that evaluate morphology, function, flow, and metabolism play a vital role in individual treatment decisions, often based on guidelines. Innovations in molecular imaging have enhanced our ability to spatially quantify the expression of a wider array of disease-related proteins, genes, or cell types, or the activity of specific pathogenic pathways. These techniques, which usually rely on design of targeted imaging probes, have already been used extensively in cancer medicine and have now become part of cardiovascular care in conditions such as amyloidosis and sarcoidosis. The recognition that common cardiovascular conditions are caused by a substantial diversity of pathobiologic pathways and the diversity of therapies available for use have rekindled interest in expanding the role of molecular imaging of tissue phenotype to improve precision in diagnosis and therapeutic decision-making. The intent of this article is to raise awareness and understanding of approaches to molecular or cellular imaging of phenotype with targeted probes, and their potential to promote the principles of precision medicine. Also addressed are the diverse roles of molecular imaging to improve precision and efficiency of new drug development at the stages of candidate identification, preclinical testing, and clinical trials.

Trajectory priming through obstacle avoidance in motor imagery – does motor imagery comprise the spatial characteristics of movement?

Motor imagery and execution often indicate a similar trend in the temporal characteristics of movements. This finding supports the notion of functional equivalence, whereby imagery and execution use a common neural representation. However, there is comparatively limited evidence related to the spatial characteristics of movements; no doubt owing to the absence of an actual spatial trajectory during imagery. Therefore, we adapted the trajectory priming paradigm involving an obstacle, where the trajectory adopted in a trial (n) is directly contaminated by a previous trial (n-1). If imagery accurately represents the spatial characteristics, then we would predict a similar priming effect as execution. Participants completed a series of trial blocks under different imagery/execution protocols, where the test trial (n) comprised execution alone, while the previous trial (n-1) involved imagery or execution. Each block comprised pairs of trials with alternate or consistent presentations of a virtual obstacle (O) or no obstacle (N): N-N, N-O, O-N, O-O. For trial n-1 (imagery/execution), there was a more prolonged reaction and movement time for imagery compared execution. Most importantly for trial n (execution), there was an increase in early angular and peak deviation following an obstacle compared to no obstacle in trial n-1, but only when it was execution and not imagery. These findings suggest imagery holds a limited representation of the spatial characteristics, while functional equivalence may be limited to the temporal characteristics.

Radiomic features of primary retroperitoneal sarcomas: a prognostic study

BackgroundRisk-stratification of patients with retroperitoneal sarcomas (RPS) relies on validated nomograms, such as Sarculator. This retrospective study investigated whether radiomic features extracted from computed tomography (CT) imaging could i) enhance the performance of Sarculator and ii) identify G3 dedifferentiated liposarcoma (DDLPS) or leiomyosarcoma (LMS), which are currently consider in a randomized clinical trial testing neoadjuvant chemotherapy. MethodsPatients with primary localized RPS treated with curative-intent surgery (2011-2015) and available pre-operative CT imaging were included. Regions of interest (ROIs) were manually annotated on both unenhanced and portal venous phase acquisitions. Top performing radiomic features were selected with outcome-specific random forest models, through generation of replicative experiments (contexts) where patients were split into training and testing sets. Endpoints were overall and disease-free survival (OS, DFS).Prognostic models for DFS and OS included the top five selected radiomic features and the Sarculator nomogram score.Models accuracy was assessed with Harrell’s Concordance (C-)index. ResultsThe study included 112 patients, with a median follow-up of 77 months (IQR 65-92 months).Sarculator alone achieved a C-index of 0.622 and 0.686 for DFS and OS, respectively. Radiomic features only marginally enhanced the prediction accuracy of Sarculator for OS (C-index=0.726, C-index gain: 0.04) or DFS (C-index=0.639, C-index gain: 0.017). Finally, radiomic features identified patients with G3 DDLPS or LMS with an accuracy of 0.806. ConclusionRadiomic features marginally improved the performance of Sarculator in RPS.However, they accurately identified G3 DDLPS or LMS at diagnosis, potentially improving patients selection for neoadjuvant treatments.

The Relationship of Diuretics and Dietary Sodium in Patients with Heart Failure: An Analysis of the SODIUM-HF Trial

BackgroundSODIUM-HF was a large clinical trial testing dietary sodium restriction compared to usual care in patients with heart failure that showed no reduction in clinical events. It has been suggested that diuretic doses in response to dietary sodium modification may have influenced the trial results. ObjectiveWe assessed the effects of baseline diuretic dose and diuretic dose changes on clinical outcomes in the SODIUM-HF trial. MethodsDiuretics were converted to furosemide-equivalent diuretic total daily doses. Furosemide dose was treated as a continuous variable and also stratified into 0 mg, 1–39 mg, 40 mg, 41–80 mg, and >80 mg daily. The baseline diuretic dose and change in diuretic dose were assessed and correlated with dietary sodium restriction and changes in dietary sodium intake. We then examined the relationship between diuretic dosing and the primary outcomes of SODIUM-HF (cardiovascular-related emergency department visit, cardiovascular-related hospitalization, and all-cause mortality). ResultsOf the 806 patients enrolled in the SODIUM-HF trial, 784 had known diuretic status at baseline: 209 patients (26.7%) with 0 mg, 134 patients (17%) with 1-39 mg, 205 patients (26.1%) with 40 mg, 118 patients (15.1%) with 41-80 mg, and 118 patients (15.1%) with >80 mg. No correlation was found between dietary sodium intake and diuretic dose, either at baseline or change throughout the study (P>0.05). For the primary outcomes, the 2-year risk of primary outcomes was strongly correlated with diuretic dose at baseline across the overall SODIUM-HF population (P<0.001). No significant association was found between the treatment arm and the risk of primary outcomes, within each baseline diuretic dose range or with change in diuretic dose (both P>0.05). ConclusionsAlthough a higher baseline diuretic dose was associated with worse clinical outcomes, no association was found between dietary sodium restriction, baseline or change in diuretic dose and the primary outcomes.

Examining children’s verb learning in the United States and Japan: Do comparisons help?

Learning verbs is an important part of learning one’s native language. Prior studies have shown that children younger than 5 years can have difficulty in learning and extending new verbs. The current study extended these studies by showing children multiple events that can be compared during learning, including Japanese- and English-speaking children. In the study, 2-, 3-, and 4-year-olds saw two similar events and then one varied (progressive alignment) or three varied (low alignable) events in a learning phase before test, and this was repeated for four sets. Children were asked to extend these novel verbs in easy (non-cross-mapping) and difficult (cross-mapping) test trials. A repeated-measures analysis of variance showed a significant Age by Condition interaction. In contrast to prior results, the 4-year-olds in both languages did well in both conditions and across test trial types. The 3-year-olds, especially in Japanese, performed best in the progressive alignment condition, showing that experience in seeing similar events was useful for verb learning. The 2-year-olds mostly struggled in this task, showing success only in the low-alignment condition, non-cross-mapping (easy) test trial. These are new findings given that no previous study has examined the role of different levels of variability during learning in a cross-language sample, and no prior study has examined the impact of objects at test in this way. This study shows that an important mechanism for verb learning—the comparison of events—could be useful across languages.

Pengembangan Game Edukasi Berbasis Android PADA Materi Jenis Konektivitas Internet Kelas X TKJ SMKN 1 Sepulu

The development of technology in the world of education can produce learning innovations, one of which is educational games. This study aims to develop an Android-based educational game application as a learning medium on the material of internet connectivity types for class X TKJ students at SMKN 1 Sepulu. This study uses the Research and Development (RD) method with the ADDIE development model consisting of five stages: analysis, design, development, implementation, and evaluation. The results of the study indicate that this educational game application has succeeded in increasing the effectiveness of learning through validation testing and user trials. Validation by media experts obtained a percentage of 96.3% and material experts 98.4%, both in the "very good" category. User trials involving students were carried out in three stages, namely individual trials 95.7%, small groups 96.0%, and large groups 90.7%, all in the "very good" category. With these results, this Android-based educational game application is considered suitable for use as a learning medium to increase student motivation and learning outcomes. This study shows that the development of educational game-based learning media can be an innovative solution to support more interesting and effective learning.

INNOVATIVE SOLUTIONS FOR IMPROVING THE EXISTING HEAT EXCHANGE EQUIPMENT OF METALLURGICAL ENTERPRISES

Considered issues regarding the refusal to use natural gas in the technological process of air heating in air heaters ofblast furnaces (coopers) of metallurgical enterprises. An innovative solution is proposed – a technological schemeusing a heat generator for heating flue gases and improving the system of their heat utilization in order to increase thetemperature of air and gas entering the air heater by 150–200°C. The results of the test trials of the technologicalscheme, which were carried out under the following conditions, are presented: calorific value of the mixture of naturaland blast furnace gas – 826.4 kcal/m3 (3,459.3104 KJ); calorific value of blast furnace gas – 750.7 kcal/m3 (3,142.43KJ); air consumption per unit of air heaters – 58 thousand m3/h; temperature of combustion components in front ofheat exchangers: air – 10 °С; fuel – 35 °C; smoke temperature: at the exit from the air heaters – 230 °C; in front of thechimney – 130 °C. The results showed that its application will ensure an increase in the average temperature of blastheating by 60-110°С without the use of natural gas, the duration of operation of heat exchangers can be increased byat least 10 years, and the technical and economic indicators of the blast furnace process will also improve. Theproposed innovative solutions will allow: to abandon the use of natural gas for air heaters; ensure coke savings up to14 kg/t; increase the average heating temperature of blowing by 110°C; stable, long-term provision of the necessaryair heating temperatures. The use of these technical solutions will allow to increase the production of cast iron andreduce the consumption of natural gas to increase the temperature of hot blasting. In the future, similar schemes maybe used in the fuel preparation system for multi-fuel boiler units of metallurgical enterprises

Evaluation and randomised controlled trial of home urinalysis testing in patients with SLE at elevated risk for developing lupus nephritis: a study protocol

IntroductionLupus nephritis (LN) is a frequent complication of SLE, occurring in up to 60% of adult patients and ultimately progressing from acute inflammation to chronicity with fibrosis and end-stage kidney...

Demographic, morphological and coat factors in dogs after exercise at a fast course ability test (FCAT) trial.

Domestic dogs are a widely diverse species of endothermic mammals that show a positive correlation between body mass and whole-animal metabolic rate, but a negative correlation between body mass and lifespan, making them an interesting system for determining thermoregulatory patterns in relation to body mass, body morphology, and age within a single mammalian species. Though previous work has found differences in thermoregulation across seasons and with training in dogs of different sizes, we now seek to determine (1) whether sampling event-related temperature differences remained when dogs exercised intensely and acutely outdoors and (2) whether thermal differences were also expressed in short-term burst exercise in athletic dogs compared to long-term exercise in non-athletic dogs, as previously found. Here, we measured tympanic membrane temperature (Tear) as a correlate of core or internal body temperature (Tb). We also measured changes in body temperature across different body surfaces using thermal imaging (Teye, Tnose, and Tmouth) in dogs after exercise during Fast Course Agility Trial (FCAT) competitions between spring and summer months in Central New York State, USA (N = 20, July and August N = 26). We correlated these data to each dog's body mass (average(± standard error) = 29.97(± 0.24) lbs.), age (5.99(± 0.78) years), and various aspects of body part measurements and coat characteristics, such as length, type, and color. First, in our overall dataset, being sampled in May was the most significant predictor of temperature slope (p < 0.001), and we identified far more significant predictor variables in the May event dataset than in other datasets. Second, as we gave special attention to our study population, we found that running an outdoor, burst exercise course (FCAT trial) shows a different pattern of thermoregulation compared with previous work. Thus, our data may offer preliminary insights that thermoregulation in dogs varies with sampling event and exercise type, though additional research is needed to understand the complexity of these observed patterns. Our data also provides evidence that responses can be plastic depending on the dog's individual phenotype and that athleticism may affect thermoregulation in dogs, similar to humans.

Operationalizing implementation science frameworks to plan a hybrid effectiveness-implementation study of a digital health intervention.

Background Evaluating implementation of digital health interventions (DHIs) in practice settings is complex, involving diverse users and multistep processes. Proactive planning can ensure desired implementation determinants and outcomes are captured for hybrid studies, but operational guidance for DHI studies is limited. Methods We planned a cluster randomized, type II hybrid effectiveness-implementation trial testing PositiveLinks, a smartphone application for HIV care, compared to usual care (n = 6 sites per arm), among HIV outpatient sites in the DC Cohort Longitudinal HIV Study in Washington, DC. Our process included: 1) Defining components of the DHI and associated implementation strategy, 2) Selecting implementation science frameworks to accomplish evaluation aims, 3) Mapping framework dimensions, domains, and constructs to implementation strategy steps, 4) Modifying/creating instruments to collect data for implementation outcome measures and determinants and 5) Developing a compatible implementation science data collection and management plan. Results Specification of components of the DHI and implementation strategy identified relevant platform usage data and necessary implementer actions, toward planning measurement of program reach and adoption. A priori mapping of implementation strategy steps to the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) framework identified how data would be collected for each step/corresponding outcome measure. The multi-site cohort study provided infrastructure for prospective, scaled implementation research, including site research assistants (RAs) coordinating implementation. Existing cohort tools (periodic site assessments, patient consent logs) were adapted for the evaluation to further capture representativeness and reach/adoption 'denominators.' New survey instruments allowed for framework-guided evaluation of provider adaptations/dose/fidelity to planned implementation across a large number of participants and multiple timepoints. Some aspects of real-world implementation were challenging to mirror within the planned hybrid trial (e.g. RAs selected as de facto site implementation leads) or were modified to preserve internal validity of effectiveness measurement (e.g. PositiveLinks 'community of practice'). Conclusions Challenges and opportunities arose in planning the implementation evaluation for PositiveLinks within a hybrid trial in a cohort population. Prospective hybrid trial planning must balance generalizability of implementation processes to 'real world' conditions, with rigorous trial procedures to measure intervention effectiveness. Rapid, scalable tools require further study to enable evaluations within large, multi-site hybrid studies. Trial registration : ClinicalTrials.gov NCT04998019, August 10, 2021.https://classic.clinicaltrials.gov/ct2/show/NCT04998019.

Distinguishing Doors and Floors on All Fours: Landmarks as Tools for Vertical Navigation Learning in Domestic Dogs (Canis familiaris).

Spatial navigation allows animals to understand their environment position and is crucial to survival. An animal's primary mode of spatial navigation (horizontal or vertical) is dependent on how they naturally move in space. Observations of the domestic dog (Canis familiaris) have shown that they, like other terrestrial animals, navigate poorly in vertical space. This deficit is visible in their use of multi-story buildings. To date, no research has been conducted to determine if dogs can learn how to navigate in an anthropogenic vertical environment with the help of a landmark. As such, we herein investigate the effect of the addition of a visual or olfactory landmark on dogs' ability to identify when they are on their home floor. Subject behaviors toward their home door and a contrasting floor door were compared before and after exposure to a landmark outside of their home door. While subjects initially showed no difference in latency to approach an apartment door on their home or a wrong floor, we found a significant difference in latency to approach the doors in the test trials for subjects who approached the doors in every trial. Other findings are equivocal, but this result is consistent with the hypothesis that dogs can learn to navigate in vertical space.

Ill-structured on respiratory system: How does the contextual problem improve students’ problem-solving skills by developing electronic worksheet?

This research aims to develop an electronic student worksheet based on respiratory problem to improve problem-solving skills on the respiratory system concept. This research and development (R&amp;D) using 4D model proposed by Thiagarajan consist of define, design, develop, and disseminate. E-worksheets were validated by three experts, i.e. the material experts, media experts, and biology teacher as a practitioner. The result of the research showed that the e-worksheet developed had an average validity percentage of 81.85% with a very good category. While the e-worksheet readability was 96.67% (very good). Furthermore, either the teacher or students shows that the field trial test of the e-worksheet had good criteria due to their responses of 94.58% and 88.39%, respectively. The research results shows that there is an increase on students’ problem-solving skills based on the N-gain score of 0.47 and classified as medium category. Based on these results, it can be concluded that e-worksheet is very suitable for use in learning activities and can improve student’s problem-solving skills.

HSD3B1, prostate cancer mortality and modifiable outcomes.

Androgen receptor stimulation by testosterone and dihydrotestosterone is crucial for prostate cancer progression. Despite the initial effectiveness of androgen deprivation therapy (ADT), castration-resistant prostate cancer eventually develops in most men. A common germline missense-encoding polymorphism in HSD3B1 increases extra-gonadal androgen biosynthesis from adrenal precursors owing to increased availability of the encoded enzyme 3β-hydroxysteroid dehydrogenase 1 (3βHSD1) - hence, it is called the adrenal-permissive enzyme. This mechanism explains the more rapid progression to castration-resistant prostate cancer in men who inherit this allele than in men without it via sustained androgen receptor activation despite ADT. Multiple clinical studies, including data derived from prospective phase III studies, have linked adrenal-permissive allele inheritance to inferior clinical responses to ADT and increased mortality, but reversal is possible with upfront adrenal androgen blockade. The adrenal-permissive allele exhibits divergent frequencies across various groups worldwide, which could contribute to differences in clinical outcomes among these populations. Large-scale data from the Million Veteran Program have shown homozygous HSD3B1 adrenal-permissive allele inheritance to be an independent biomarker of prostate cancer-specific mortality. Together, these observations support the integration of HSD3B1 into germline testing and clinical trials as it might help to identify groups at increased likelihood of benefiting from early, intensified, AR-targeting interventions. Lastly, 3βHSD1 is a promising target for pharmacological inhibition, which enables new strategies for systemic prostate cancer therapy.

Performance of the Healthy Aging Brain Care Monitor Self Report in Monitoring Post-Intensive Care Syndrome Among Acute Respiratory Failure Survivors.

To describe the performance of the Healthy Aging Brain Care Monitor Self Report (HABC-M SR) in assessment of post-intensive care syndrome (PICS) among Acute Respiratory Failure ICU survivors. Secondary data analysis of a randomized controlled trial. Patients evaluated by a nurse care coordinator in an out-of-hospital setting. English-speaking adults 18 years old or older who were admitted to the ICU with acute respiratory failure requiring invasive or noninvasive mechanical ventilation for greater than or equal to 24 hours. Patients randomized to the intervention arm of the mobile critical care recovery program, a negative trial testing multidisciplinary care to improve quality of life. HABC-M SR scale was used to assess PICS in the intervention group at ICU discharge, 3, and 6 months post-discharge. Hospital Anxiety and Depression Scale; Pain, Enjoyment of Life, and General Activity Scale; Timed Up and Go; and Patient-Reported Outcomes Measurement Information System sleep scores were obtained at the same time. Mini-Mental State Examination (MMSE) was administered at baseline and 6 months. ICU survivors reported mild PICS symptoms, which improved over 6 months (mean HABC-M SR scores: baseline [8.5, sd 7.6], 3 mo [5.3 mo, sd 6.6 mo], and 6 mo [5.2 mo, sd 6.9 mo; p < 0.001]). HABC-M SR total score had moderate internal consistency that improved over time (Cronbach's alpha = 0.78 at baseline and 0.84 at 6 mo). The psychological subscale of HABC-M SR was moderately correlated with standardized scales for mood, pain, and sleep. The cognitive subscale was not significantly correlated with MMSE. While HABC-M SR correlated with mood, physical, and sleep symptoms, the cognitive subscale was less sensitive compared with standardized scales.

Can self-testing be enhanced to hasten safe return of healthcare workers in pandemics? Random order, open label trial using two manufacturers’ SARS-CoV-2 lateral flow devices concurrently and nested viral culture study

BackgroundCovid-19 healthcare worker testing, isolation and quarantine policies had to balance risks to patients from the virus and from staff absence. The emergence of the Omicron variant led to dangerous levels of key-worker absence globally.We evaluated whether using two manufacturers’ lateral flow tests (LFTs) concurrently improved SARS-CoV-2 Omicron detection significantly and was acceptable to hospital staff. In a nested study, to understand risks of return to work after a 5-day isolation/quarantine period, we examined virus culture 5–7 days after positive test or significant exposure.MethodsFully-vaccinated Liverpool (UK) University Hospitals staff participated (February-May 2022) in a random-order, open-label trial testing whether dual LFTs improved SARS-CoV-2 detection, and whether dual swabbing was acceptable to users. Participants used nose-throat swab Innova and nose-only swab Orient Gene LFTs in daily randomised order for 10 days. A user-experience questionnaire was administered on exit. Selected participants gave swabs for viral culture on days 5–7 after symptom onset or first positive test. Cultures were considered positive if cytopathic effect was apparent or SARS-CoV-2 N gene sub-genomic RNA was detected.ResultsTwo hundred and twenty-six individuals reported 1466 pairs of LFT results. Tests disagreed in 127 cases (8.7%). Orient Gene was more likely (78 cf. 49; OR: 2.1, 1.1–4.1; P = 0.03) to be positive. If Innova was swabbed second, it was less likely to agree with a positive Orient Gene result (OR: 2.7, 1.3–5.2; P = 0.005); swabbing first with Innova made no significant difference (OR: 1.1, 0.5–2.3; P = 0.85). Orient Gene positive Innova negative result-pairs became more frequent over time (OR: 1.2, 1.1–1.3; P < 0.001).Of individuals completing the exit questionnaire, 90.7% reported dual swabbing was easy, 57.1% said it was no barrier to their daily routine and 65.6% preferred dual testing. Respondents had more confidence in dual versus single test results.Viral cultures from days 5–7 were positive for 6/31 (19.4%, 7.5%-37.5%) and indeterminate for 11/31 (35.5%, 19.2%-54.6%) LFT-positive participants, indicating they were likely still infectious.ConclusionsDual brand testing increased LFT detection of SARS-CoV-2 antigen by a small but meaningful margin and was acceptable to hospital workers. Viral cultures demonstrated that policies recommending safe return to work ~ 5 days after Omicron infection/exposure were flawed. Key-workers should be prepared for dynamic self-testing protocols in future pandemics.Trial registrationhttps://www.isrctn.com/ISRCTN47058442 (26 January 2022).

CTNI-44. NCT03643549 PHASE IB/II TRIAL: EFFICACY, SAFETY, AND BIOLOGICAL MECHANISMS OF OBJECTIVE RESPONSES IN RECURRENT GBM PATIENTS WITH UNMETHYLATED MGMT PROMOTER TREATED WITH SEQUENTIAL BORTEZOMIB AND TEMOZOLOMIDE

Abstract BACKGROUND Glioblastoma (GBM) is amongst the deadliest malignancies in adults, but especially for patients with unmethylated MGMT promoter (uMGMT) who gain limited benefit from the standard treatment. We previously demonstrated that proteosome inhibitor bortezomib (BTZ), inhibited NFkB activation,depleted MGMT protein and sensitized uMGMT GBM cells to Temozolomide (TMZ). Thus, a phase I/II trial testing sequential combination BTZ+TMZ was launched to investigate safety and clinical benefit. METHODS Recurrent GBM patients with uMGMT promoter, progressing ≥12 weeks after radiotherapy, KPS≥70 and radiologically measurable lesions were enrolled. The trial was powered for n=63 patients compared with n=102 historical controls. Patients received BTZ 1.3mg/m² IV on days 1, 4, and 7 of each 4-week cycle, starting on day 3 with oral 200mg/m² TMZ for 5 days/week. Whole exome sequencing (WES) of tumor DNA was conducted to identify genetic changes and LC-MS/MS used to asses proteomic changes in plasma collected during treatment. RESULTS As of January 2024, 54 patients (median 55y (25-70); 38 males, 16 females) were treated. The median KPS 90 (range 70-100) and NANO score was 1 (range 0-7). QoL was preserved, with mild /moderate adverse events. Adjusted analyses showed overall survival (OS) of 16.2 months compared to 8.4 months for uMGMT control patients, HR0.48, 95%CI[1.057-2.74],P=0.028. Objective radiological responses stable disease or better were observed in 22% (12/54) patients. Survival from recruitment was 10.5 months for responders vs. 4.8 months for rest of cohort, P=0.054 HR2.55, 95%CI[0.984-5.94]. Preliminary data indicate 78% (7/9) of responders harboured amplified EGFR vs. 38% in rest-of-the patients. The responders differentially expressed proteins critical for cellular processes, including ADAMTSL4, NCAM1, AZGP1, MMP2, CD163, and IL6ST. CONCLUSION Sequential BTZ+TMZ therapy is safe, effective and showed clinical benefit. EGFR amplification may be a predictive biomarker for response through NFκB activation, that is targeted by BTZ thereby depleting MGMT protein and enhancing treatment efficacy. Sequential BTZ+TMZ treamtment may represent additional treatment option at recurrence.

Characterization of the Biological Variability of the Angiome Biomarkers over Time in Healthy Subjects.

Biomarker analyses are an integral part of cancer research. Despite the intense efforts to identify and characterize biomarkers in cancer patients, little is known regarding the natural variation of biomarkers in healthy populations. Here we conducted a clinical study to evaluate the natural variability of biomarkers over time in healthy participants. The angiome multiplex array, a panel of 25 circulating protein biomarkers, was assessed in 28 healthy participants across 8 timepoints over the span of 60 days. We utilized the intraclass correlation coefficient (ICC) to quantify the reliability of the biomarkers. Adjusted ICC values were calculated under the framework of a linear mixed-effects model, taking into consideration age, sex, body mass index (BMI), fasting status, and sampling factors. ICC was calculated to determine the reliability of each biomarker. HGF was the most stable marker (ICC=0.973), while PDGF-BB was the most variable marker (ICC=0.167). In total, ICC analyses revealed that 22 out of 25 measured biomarkers display good (≥0.4) to excellent (>0.75) ICC values. Three markers (PDGF-BB, TGF-1, PDGF-AA) had ICC values <0.4. Greater age was associated with higher IL-6 (p=0.0114). Higher BMI was associated with higher levels of IL-6 (p=0.0003) and VEGF-R3 (p=0.0045). Of the 25 protein biomarkers measured over this short time period, 22 markers were found to have good or excellent ICC values, providing additional validation for this biomarker assay. This data further supports the validation of the angiome biomarker assay and its application as an integrated biomarker in clinical trial testing.

Preventing Allogeneic Stem Cell Transplant-Related Cardiovascular Dysfunction: ALLO-Active Trial.

Allogeneic stem cell transplantation (allo-SCT) is an efficacious treatment for hematologic malignancies but can be complicated by cardiac dysfunction and exercise intolerance impacting quality of life and longevity. We conducted a randomized controlled trial testing whether a multicomponent activity intervention could attenuate reductions in cardiorespiratory fitness and exercise cardiac function (co-primary end points) in adults undergoing allo-SCT. Sixty-two adults scheduled for allo-SCT were randomized to a 4-month activity program (n=30) or usual care (UC; n=32). Activity comprised multicomponent exercise training (3 days/week) and sedentary time reduction (≥30 min/day) program and was delivered throughout hospitalization (≈4 weeks) and for 12 weeks after discharge. Physiological assessments conducted before admission and at 12 weeks after discharge included cardiopulmonary exercise testing to quantify peak oxygen uptake ([Formula: see text]), exercise cardiac magnetic resonance imaging for peak cardiac volume (CIpeak) and stroke volume (SVIpeak) index, echocardiography-derived left ventricular ejection fraction and global longitudinal strain, and cardiac biomarkers (cTn-I [troponin-I] and BNP [B-type natriuretic peptide]). Fifty-two participants (84%) completed follow-up (25 activity and 27 UC); median (interquartile range [IQR]) adherence to the activity program was 74% (41-96%). There was a marked decline in [Formula: see text] in the UC program (-3.4 mL‧kg-1‧min-1 [95% CI, -4.9 to -1.8]) that was attenuated with activity (-0.9 mL‧kg-1‧min-1 [95% CI, -2.5 to 0.8]; interaction P=0.029). Activity preserved exercise cardiac function, with preservation of CIpeak (0.30 L‧min-1‧m-2 [95% CI, -0.34 to 0.41]) and SVIpeak (0.6 mL/m2 [95% CI, -1.3 to 2.5]), both of which declined with UC (CIpeak, -0.68 L‧min-1‧m-2 [95% CI, -1.3 to -0.32]; interaction P=0.008; SVIpeak, -2.7 mL/m2 [95% CI, -4.6 to -0.9]; interaction P=0.014). There were no treatment effects of activity on cardiac biomarkers or echocardiographic indices. Multicomponent activity intervention during and after allo-SCT is beneficial for preserving patient cardiorespiratory fitness and exercise cardiac function. These results may have important implications for cardiovascular morbidity and mortality after allo-SCT. URL: https://anzctr.org.au/; Unique identifier: ACTRN12619000741189.

Biomarkers of glucose-insulin homeostasis and incident type 2 diabetes and cardiovascular disease: results from the Vitamin D and Omega-3 trial

BackgroundDysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.MethodsVITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).ResultsWe identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.ConclusionsEach of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.