Test Trials Research Articles

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

Objectives: 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. Design: Secondary data analysis of a randomized controlled trial. Setting: Patients evaluated by a nurse care coordinator in an out-of-hospital setting. Patients: 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. Interventions: Patients randomized to the intervention arm of the mobile critical care recovery program, a negative trial testing multidisciplinary care to improve quality of life. Measurements and Main Results: 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. Conclusions: 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

Abstract Background Covid-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. Methods Fully-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. Results Two 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. Conclusions Dual 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 registration https://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.

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.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5’ untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Tumor regression after neoadjuvant hormonal therapy in high risk prostate cancer: pathological outcomes from a randomized phase II trial.

High-risk localized prostate cancer (HRLPC) commonly progresses to metastatic disease after local treatment. Neoadjuvant androgen deprivation therapy (nADT) before radical prostatectomy (RP) has recently been suggested to improve early oncological outcomes in HRLPC. We aimed to perform an exploratory analysis of the pathological outcomes from a prospective trial testing nADT before RP. Prospective, single-centered, phase II, randomized trial performed between October 2018 and July 2021. Random assignment (1:1) for nADT modalities: goserelin (10.8mg) plus abiraterone acetate (1000mg/d) plus prednisone (5mg/d), with or without apalutamide (240mg/d) for 12 weeks, followed by RP (within 30 days) and extended lymph node dissection. Baseline clinical and pathological variables were assessed in needle biopsies before nADT. Tumor regression was histologically evaluated in surgical specimens using the residual cancer burden index (RCB). Sixty-two patients reached the surgical phase. Good response (RCB ≤ 0.25cm³) was achieved in 14 patients (22.5%). Overall stage migration rate between baseline status (MRI before nADT) and final status (after surgery) was 27.4%. Late stage detection (high tumor burden, perineural invasion) and altered PTEN/ERG immunostatus showed significant association with poor response in univariate analysis. Higher baseline tumor burden was the only independent factor related to poor response in multivariate analysis. There are subgroups of patients, such as those with low baseline cancer burden and PTEN/ERG wild-type status, more likely to achieve good response with nADT. In the case of long term oncological benefit to be proven, nADT might be an additional therapeutic resource for these patients.

Ameliorative effect of walnut oil against cognitive impairment in Alzheimers type dementia in rodent

Walnut oil (WO), known for abundant polyunsaturated fatty acids and an array of bioactive substances such as tocopherols, phytosterols, squalene, melatonin, and polyphenols, which is endowed with numerous health advantages. The primary objective of this research was to ascertain the impact of WO on cognitive deficits in learning and memory impairment mice caused by scopolamine (SCOP). The Morris water maze and the step-down avoidance test were utilized to assess the memory and learning capabilities. WO notably counteracted the detrimental effects of SCOP on learning and memory in the Morris water maze, as indicated by a reduction in escape latency and swimming distance. Likewise, WO administration led to a notably reduced number of errors in training trial and an increased latency in testing trial when compared to the SCOP group in the step-down avoidance test,. Moreover, WO activated the cholinergic system of the brain by upregulating choline acetyltransferase activity and reducing acetylcholinesterase activity. These results suggest that WO has the potential to protect against memory decline in mice, offering a promising strategy for the prevention of memory-related disorders.

Do kea parrots infer the weight of objects from their movement in a breeze?

Weight, though it cannot be seen directly, pervades nearly every aspect of an animal's life. However, the extent to which non-human animals reason about the property of weight remains poorly understood. Recent evidence highlights birds as a promising group for testing this ability: for example, New Caledonian crows can infer the weight of objects after observing their movements in a breeze. Here, we tested for similar weight inference abilities in kea (Nestor notabilis), a parrot species known for its sophisticated problem-solving skills. Subjects were trained to exchange objects of a target weight (light or heavy) for a food reward. They were then allowed to observe pairs of novel objects (one light and one heavy) hung in front of an electric fan in both an experimental condition (fan on, light object moving) and a control condition (fan off, both objects motionless). The birds were subsequently presented with test trials in which they could use the information from the demonstration to select an object of their target weight. We found that, unlike New Caledonian crows, kea did not perform significantly better on trials in which they observed the objects' movements and discussed our findings within the context of the kea's highly explorative nature.

Cancer of Unknown Primary Site: A New Era of Practice-Changing Approaches to Diagnosis, Staging, and Precision Therapy

The enigmatic syndrome of metastatic cancer of unknown primary (CUP) site has frustrated physicians and patients for decades. There has been debate whether CUP is a single biologically distinct cancer or a constellation of many different cancers with clinically undetectable anatomic primary sites. For the past 40 years, the diagnosis of a specific cancer type for most patients was indeterminate, and fit patients were usually treated as a single cancer with the same empiric chemotherapy (EC) regimens with poor overall results. The aggregate data from autopsies, clinical observations, specialized standard pathology, molecular testing, and several clinical trials support CUP as a multitude of clinically occult invasive primary tumors requiring different site-specific therapies (SSTs). In the past several years, improved genomic testing has been used, and the addition of molecular-guided therapies (MGTs) and immunotherapy (IO) has been shown to be superior for many different advanced cancers. Two older randomized prospective trials conducted before the advent of IO and most MGT failed to show a better outcome for patients with molecularly diagnosed cancers who received SST (tailored chemotherapy regimens) versus EC, although patients with more responsive tumor types appeared to benefit. Two recently reported randomized trials documented the clinical relevance of molecular diagnosis and comprehensive genomic profiling. The administration of improved precision SST guided by molecular diagnosis and characterization revealed significantly improved outcomes compared with EC. The management of patients with CUP is undergoing rapid change including the diagnosis of the presumed primary tumors, TNM staging for selected patients, molecular profiling, and an expanded improved role of precision therapies highlighting the rapid emergent new era of practice changing standards of care.

Does Implementation of Office Based Addiction Treatment by a Nurse Care Manager Increase the Duration of OUD Treatment in Primary Care? A Secondary Analysis of the PROUD Randomized Control Trial

BackgroundImplementation of office-based addiction treatment (OBAT) by nurse care managers increases overall use of OUD medication, but it is unknown whether it increases treatment duration among treated patients. MethodsThe Primary Care Opioid Use Disorders Treatment (PROUD) trial was a pragmatic, cluster-randomized trial testing whether implementation of OBAT increased OUD treatment in 12 primary care clinics in 6 systems. One of 2 clinics per system was randomized to implement OBAT (intervention), the other, usual care (UC). We evaluated treatment duration for the 3 years after nurses began seeing patients at clinics randomized to intervention vs. UC. The primary sample included patients newly initiating OUD medication; the secondary sample included patients with ongoing OUD medication. The primary outcome was percentage of days with OUD medications after treatment initiation, modeled using linear generalized estimating equations (GEE). Modified Poisson GEE models assessed secondary outcomes (≥80% of days covered, ≥6 months on treatment). ResultsIn adjusted analyses, the mean difference between intervention and UC in percent days treated was 6.3% (95% CI -9.6%, 22.1%) in the primary sample and 2.3% (95% CI -36.4%, 31.8%) in the secondary sample. There was no significant difference in treatment duration between intervention and UC patients in either primary or secondary outcomes. ConclusionsImplementation of OBAT in this trial did not measurably increase duration of medication treatment among those treated for OUD compared to UC, suggesting that benefits of OBAT, at least in this trial, largely reflect increases in treatment access.

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.

Exome sequencing in over 63,000 patients in TIMI trials uncovers pathogenic cardiomyopathy variant carriers with high risk for heart failure and cardiovascular death

Abstract Background Rare genetic variants predisposing to cardiomyopathy (CMP) confer increased risk for adverse events. The prevalence of CMP variants in contemporary cardiovascular (CV) trials and their association with prevalent heart failure (HF) and incident HF hospitalizations (HHF) is not established. Purpose We aimed to identify carriers of rare pathogenic/likely pathogenic (PLP) variants for dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) in well-phenotyped clinical trial cohorts and to evaluate their prognostic significance. Methods Rare variants were identified from high-quality exome sequencing data from 5 large clinical trials (ENGAGE AF-TIMI 48, SAVOR-TIMI 53, PEGASUS-TIMI 54, DECLARE-TIMI 58, FOURIER (TIMI 59)). Putatively pathogenic variants for cardiomyopathy were identified using phenotype- and gene-specific curation of protein-truncating variants and high-confidence variant classifications from ClinVar. We conducted logistic regression for prevalent disease and Cox proportional hazard models for incident HHF, both adjusted by age, sex, trial, and first 10 principal components and using those without CMP variants as the reference. Sensitivity analysis by history of HF at baseline was performed for prospective outcomes. Results In 63,700 participants, we identified 866 CMP variant carriers of which 518 identified as DCM carriers (age 65±9 yrs, male 66%), 194 HCM carriers (65.5±9 yrs, male 69%), and 125 ARVC carriers (66±9 yrs, male 77%). Out of the 518 DCM variant carriers, 402 had a PLP variant in TTN. DCM variant carriers had higher odds of history of HF (Odds ratio [OR] 1.94, 1.57-2.39, p<0.0001) whereas this was not observed for HCM variant carriers (OR 1.18, 0.85-1.65, p=0.33) or ARVC variant carriers (OR 1.23, 0.80-1.90, p=0.35). Over a mean follow-up of 2.5 years, the rate of HHF was significantly higher for DCM variant carriers (Hazard ratio [HR] 1.58, 1.14-2.20, p=0.006), HCM variant carriers (HR 2.78, 1.87-4.13, p<0.001), and ARVC variant carriers (HR 1.89, 1.02-3.53, p=0.04). These associations were, if anything, stronger in patients without HF at baseline (HR 2.06, 1.30-3.25) than in patients with HF at baseline (HR 1.48, 1.12-1.95). DCM variant carriers also had a higher rate of CV death (HR 1.50, 1.05-2.12, p=0.02), which was not observed for HCM (HR 1.10, 0.57-2.11, p=0.78) or ARVC (HR 0.35, 0.09-1.41, p=0.14) variant carriers. Conclusion In 5 contemporary CV trials, CMP variant carriers have an increased rate of HHF, while DCM variant carriers also have a higher rate of CV death. These findings motivate better identification of these high-risk individuals and the incorporation of genetic testing in CV trials.

Effects of nicorandil, isosorbide mononitrate or diltiazem on radial artery grafts after coronary artery bypass grafting: the randomized ASRAB-pilot trial

Abstract Background The optimal chronic oral antispastic medication after coronary artery bypass grafting (CABG) using radial artery (RA) grafts is controversial. Purpose This pilot trial aimed to preliminarily compare the efficacy and safety of nicorandil, isosorbide mononitrate, or diltiazem in patients who underwent CABG using RA grafts. Methods This was a single-center, randomized, open-label, parallel-group pilot trial. Eligible patients who underwent CABG using RA grafts within 3 days were randomized in a 1:1:1 ratio to receive oral doses of nicorandil (15 mg daily), isosorbide mononitrate (50 mg daily), or diltiazem (180 mg daily) for 24 weeks post-CABG. The primary outcomes were RA grafts failure (defined as modified FitzGibbon Grade B, S, or O) at 1- and 24-weeks, assessed by coronary computed tomography angiography (CCTA). The secondary outcomes include major adverse cardiovascular event (MACE, a composite of all-cause death, myocardial infarction, stroke, and unplanned revascularization) and angina recurrence. Results Among 150 randomized participants, 149 patients (full analysis set, mean age 56.8 years, 13.4% females, 83.9% with acute coronary syndrome, 49.7% with diabetes) with 177 RA grafts completed at least once CCTA assessment, including 50 patients with 64 RA grafts in the nicorandil group, 50 patients with 57 RA grafts in the isosorbide mononitrate group, and 49 patients with 56 RA grafts in the diltiazem group, respectively. (Figure 1). At 1-week post-CABG, the RA graft failure rates were numerically lower with nicorandil vs. diltiazem (19.4% vs. 25.0%, difference: -5.6% [95% CI -20.6% to 9.3%]; P = 0.49) and isosorbide mononitrate vs. diltiazem (18.2% vs. 25.0%, difference: -6.8% [95% CI -21.8% to 8.6%]; P =0.41). Nicorandil vs. isosorbide mononitrate showed similar rates (19.4% vs 18.2%, difference: 1.2% [95% CI −13.3% to 15.2%]; P =0.88). At 24 weeks, a numerically trend indicating a larger reduction in RA graft failure rates between nicorandil vs. diltiazem (16.1% vs 27.8%, difference: -11.7% [95% CI -26.6% to 3.4%]; P =0.17), and isosorbide mononitrate vs. diltiazem (12.5% vs 27.8%, difference: -15.3% [95% CI -29.8% to -0.2%]; P =0.06). Nicorandil vs. isosorbide mononitrate remained similar (16.1% vs 12.5%, difference: 3.6% [95% CI -9.6% to 16.4%]; P =0.59). Per-protocol set analysis results were consistent with full analysis set analysis (Table 1). During the follow-up, 6 patients with MACEs and 7 with angina recurrence were observed (MACE: 2 in nicorandil, 2 in isosorbide mononitrate, and 2 in diltiazem; angina recurrence: 1, 3, and 3 in the respective groups). Conclusions In this underpowered pilot trial, treatment with nicorandil or isosorbide mononitrate showed a numerically considerable but not statistically significant benefit on RA grafts outcome compared to diltiazem up to 24-week post-CABG. Larger hypothesis testing trial is warranted.Figure 1:The study flow diagramFigure 2:Primary outcomes in FAS and PP

SGLT2 inhibitor empagliflozin prevents anthracycline-induced cardiotoxicity in a large-animal model

Abstract Background While the development of cancer therapies has significantly improved the survival of cancer patients, more than 35% of cancer survivors treated with anthracyclines will develop cardiotoxicity. There is currently a lack of preventative therapies against anthracycline-induced cardiotoxicity (AIC). AIC is characterised by a disruption in myocardial metabolism. Sodium-glucose co-transporter (SLGT2) inhibitors represent a potential therapy as they have been shown to modulate myocardial substrate utilisation in other heart-failure contexts. Purpose We developed a highly translational large-animal model to test the ability of SGLT2 inhibitor empagliflozin to prevent AIC at different doses. Methods Female Large-White pigs were randomised (2:1:1) to no treatment (AIC-control group) or empagliflozin at a daily oral dose of 10 mg or 20 mg, beginning at the start of the doxorubicin regimen and continuing to 21 weeks. All pigs received 6 doses of doxorubicin intravenous infusion (25 mg/m2/every 3 weeks) with 2 additional off-dose visits. Pigs were assessed by cardiac magnetic resonance (CMR) and MR spectroscopy (MRS) at baseline and every 3 weeks for 21 weeks. At the end of 21-week follow-up, the LV was collected and processed for analysis by transmission electron microscopy (TEM) and mitochondrial respirometry. Results The primary outcome, final LVEF, was significantly higher in pigs receiving 20 mg empagliflozin than in the AIC-control group (57.5% (IQR=55.5, 60.3) vs 47.0% (40.8, 47.8); p=0.027). Final LVEF in pigs receiving 10 mg empagliflozin was 51% (46.5, 55.5) (p=0.020 vs 20 mg empagliflozin). The 20 mg empagliflozin dose prevented the doxorubicin-induced change in cardiac metabolic substrate utilisation and was associated with preservation of myocardial energetics (ATP/PCr ratio on MRS). TEM revealed disrupted mitochondrial structure and cristae density in AIC-control pigs, while mitochondria respirometry detected deteriorated respiratory function. Both mitochondrial structure and function were preserved in empagliflozin-treated pigs, with the 20 mg dose having the strongest cardioprotective effect. Conclusion The results from our translational large-animal model provide strong evidence that SGLT2 inhibition with empagliflozin prevents AIC by preserving LV systolic function and energetics as well as mitochondrial structural integrity and function. Our results establish the basis for clinical trial testing SGLT2i therapy in patients at high risk of AIC.

I am frail and my robot is stuck on the corridor: cohabitation of people with frailty and robots

Abstract UK and European policies promote research and innovation for people living with frailty (PLWF), as realistic strategies for independent living. Yet homes are not designed for PLWF or robots, even though robots could support PLWF with activities, i.e., exercise and companionship. Adoption of robots in homes is limited to devices such as automated vacuum cleaners and voice assistants. Robotics aimed at assisting PLWF have been thus far been tested in laboratories and the study of real homes for the co-habitation of robots and older people is often neglected. We draw on expertise from human-robot interaction, built environment, public health and clinical practice to facilitate optimisation of human and robot cohabitation for PLWF. For this, we have reviewed different robots-for-frailty, in terms of, ability to fit and move within homes. We utilised a range of methods and sources of information including meetings with allied health professionals, visited the Robot House and explored the available robots from a fit for purpose perspective, audited five flats for PLWF in Gloucester, England in accordance with the needs of those with frailty, simulated robot’s function within the home environment, using persona’s for different use case scenarios, trial testing of selected robots in the home environment for comparison with simulation, using knowledge gained to extrapolate this data to estimate suitability for frail individuals in their homes. Most robots currently available would not adequately fit in an independent living accommodation or the smaller ones could be a tripping hazard. The communal areas of independent living would be more realistic for such human robot interactions, rather than the actual households. The research informs the process facilitating the adoption of robots to benefit PLWF both feasible and desired. The research produced a framework that can lead to future research exploring robot and PLWF co-habitation in real home settings. Key messages • The cohabitation of humans and robots currently faces barriers relevant to independent living built-environment spatial restrictions. • Technologies that support independent living and frailty must develop in spatially-unobtrusive ways.

Efficiency of multivariate tests in trials in progressive supranuclear palsy

Measuring disease progression in clinical trials for testing novel treatments for multifaceted diseases as progressive supranuclear palsy (PSP), remains challenging. In this study we assess a range of statistical approaches to compare outcomes as measured by the items of the progressive supranuclear palsy rating scale (PSPRS). We consider several statistical approaches, including sum scores, a modified PSPRS rating scale that had been recommended by FDA in a pre-IND meeting, multivariate tests, and analysis approaches based on multiple comparisons of the individual items. In addition, we propose two novel approaches which measure disease status based on Item Response Theory models. We assess the performance of these tests under various scenarios in an extensive simulation study and illustrate their use with a re-analysis of the ABBV-8E12 clinical trial. Furthermore, we discuss the impact of the FDA-recommended scoring of item scores on the power of the statistical tests. We find that classical approaches as the PSPRS sum score demonstrate moderate to high power when treatment effects are consistent across the individual items. The tests based on Item Response Theory (IRT) models yield the highest power when the simulated data are generated from an IRT model. The multiple testing based approaches have a higher power in settings where the treatment effect is limited to certain domains or items. The study demonstrates that there is no one-size-fits-all testing procedure for evaluating treatment effects using PSPRS items; the optimal method varies based on the specific effect size patterns. The efficiency of the PSPRS sum score, while generally robust and straightforward to apply, varies depending on the specific patterns of effect sizes encountered and more powerful alternatives are available in specific settings. These findings can have important implications for the design of future clinical trials in PSP and similar multifaceted diseases.

Molecular Docking, Bioinformatic Analysis, and Experimental Verification for the Effect of Naringin on ADHD: Possible Inhibition of GSK-3β and HSP90

Background/Objectives: One of the most abundant and growing neurodevelopmental disorders in recent decades is attention deficit hyperactivity disorder (ADHD). Many trials have been performed on using drugs for the improvement of ADHD signs. This study aimed to detect the possible interaction of naringin with Wnt/β-catenin signaling and its putative anti-inflammatory and protective effects in the mouse ADHD model based on bioinformatic, behavioral, and molecular investigations. Furthermore, molecular docking was applied to investigate possible interactions with the GSK-3β and HSP90 proteins. Methods: Male Swiss albino mice were divided into four groups, a normal control group, monosodium glutamate (SGL) control, SGL + naringin 50 mg/kg, and SGL + naringin 100 mg/kg. The psychomotor activity of the mice was assessed using the self-grooming test, rope crawling test, and attentional set-shifting task (ASST). In addition, biochemical analyses were performed using brain samples. Results: The results of the SGL group showed prolonged grooming time (2.47-folds), a lower percentage of mice with successful crawling on the rope (only 16.6%), and a higher number of trials for compound discrimination testing in the ASST (12.83 ± 2.04 trials versus 5.5 ± 1.88 trials in the normal group). Treatment with naringin (50 or 100 mg per kg) produced significant shortening in the grooming time (31% and 27% reductions), as well as a higher percentage of mice succeeding in crawling with the rope (50% and 83%, respectively). Moreover, the ELISA assays indicated decreased dopamine levels (0.36-fold) and increased TNF-α (2.85-fold) in the SGL control group compared to the normal mice, but an improvement in dopamine level was observed in the naringin (50 or 100 mg per kg)-treated groups (1.58-fold and 1.97-fold). Similarly, the PCR test showed significant declines in the expression of the Wnt (0.36), and β-catenin (0.33) genes, but increased caspase-3 (3.54-fold) and BAX (5.36-fold) genes in the SGL group; all these parameters were improved in the naringin 50 or 100 mg/kg groups. Furthermore, molecular docking indicated possible inhibition for HSP90 and GSK-3β. Conclusions: Overall, we can conclude that naringin is a promising agent for alleviating ADHD symptoms, and further investigations are required to elucidate its mechanism of action.

Flashcard Development to Improve Learning Outcomes in Private 4th Class Science Learning

This research aims to develop flashcard products equipped with barcodes, test the feasibility of flashcard media in science learning to improve student learning outcomes; and knowing the effectiveness of using flashcard media in increasing average scores. This type of research is Research and Development (R&D) using the Borg & Gall development model which includes eight stages, namely potential and problems, gathering information, product design, design validation, design improvement, product testing, product revision, and usage trials. The subjects of this research were fourth grade students at SDN 01 Bojongkoneng. The research results showed: Flashcard learning media, product validity as seen from the validation results by material expert validators got a percentage of 90%, and media experts got a percentage of 92%; The effectiveness of the product can be seen from the results of student responses which include small group trials getting an average pretest score of 54 and posttest 82, and large group trials getting an average pretest score of 51 and posttest 85. In the small class the score is n- the gain was 0.60 in the medium category, while the large class obtained an n-gain value of 0.68 in the medium category. Thus, the research results show that learning media in the form of flashcards and equipped with barcodes is feasible and effective in learning science and technology as an improvement in student learning outcomes.

Role of Immunotherapy in Gastroesophageal Cancer with Liver Metastasis.

The role of immune checkpoint inhibitors (ICIs) for patients with gastroesophageal (GE) cancer with liver metastasis remains unclear. Our objective was to investigate if ICIs are beneficial in patients with GE cancer with liver metastasis. We searched PubMed, Embase, ESMO, and ASCO Meeting Abstracts for phase III randomized clinical trials (RCTs) testing ICIs in metastatic/advanced GE cancer from 2017 to 2023. Seven studies were included. OS was similar among all patients (HR 0.72 [0.67,0.77], p < .001), in patients without (HR 0.73 [0.67,0.81], p < .001, I2 = 0.0%), and with liver metastasis (HR 0.74 [0.67,0.81], p < .001, I2 = 0.0%). PFS was also similar among all patients (HR 0.63 [0.57,0.70], p < .001), without (HR 0.62 [0.51,0.76], p < .001), and with liver metastasis (HR 0.66 [0.57,0.76], p < .001). ICIs showed no difference in benefit in patients with GE cancer regardless of liver metastasis. Future studies could focus on deciphering the tumor microenvironment of liver metastasis as an area of translational research.