Active Arm Research Articles

ZOom Delivered Intervention Against Cognitive decline (ZODIAC) COVID-19 pandemic adaptations to the Post-Ischaemic Stroke Cardiovascular Exercise Study (PISCES): protocol for a randomised controlled trial of remotely delivered fitness training for brain health

BackgroundStroke increases subsequent dementia risk yet there are no specific post-stroke therapies to protect cognition. Cardiorespiratory exercise is recommended for secondary prevention of stroke and may be neuroprotective. The Post Ischaemic Stroke Cardiovascular Exercise Study (PISCES) aims to reduce post-stroke secondary neurodegeneration and cognitive decline. During the pandemic, we pivoted to a ZOom Delivered Intervention Against Cognitive decline (ZODIAC) protocol, reducing pandemic-amplified barriers to exercise.MethodsWe present pandemic adaptions for a multicentre phase IIb assessor-blinded randomised controlled trial of ischaemic stroke survivors testing the efficacy and feasibility of an 8-week home-based exercise intervention delivered at 2 months post-stroke. We compare cardiorespiratory exercise (intervention arm) versus balance and stretching (active control arm). Participants are assessed with magnetic resonance imaging (MRI), fitness, blood, microbiome, and neuropsychological tests at three study visits: before and after the exercise intervention and at 12 months. Modifications to the original protocol include pre-exercise safety home visits, commercial delivery of exercise equipment to facilitate assessor blinding, and reconsideration of statistical plan to allow pooling of the studies. We have reduced in-person study visits from 27 to 3. Primary outcome remains between-group (intervention versus control) difference in brain volume change; secondary outcome is between-group difference in global cognitive ability to allow remote administration of a validated cognitive scale.DiscussionRemotely delivered exercise interventions reduce participant burden and may reduce barriers to recruitment. A decrease in the number of in-person study visits can be supported by greater information capture via self-reported questionnaires and phone surveys.Trial registrationProspectively ACTRN12616000942459. Registered on July 2016.

Skull Density Ratio as Arm-Allocation Parameter for a Controlled Focused Ultrasound Trial in Parkinson's Disease.

MR-guided focused ultrasound (FUS) thermoablation is an established therapy for movement disorders. FUS candidates must meet a predefined threshold of skull density ratio (SDR), a parameter that accounts for the efficiency in reaching ablative temperatures. Randomized sham-controlled trials to provide definitive therapeutic evidence employ pure randomization of subjects into active treatment or control arms. The latter design has several general limitations. To demonstrate that SDR values are not associated with clinically and demographically relevant variables in patients with Parkinson's disease (PD). This in turn would allow using SDR as an arm-allocation parameter, separating patients who will receive active FUS treatment and best medical management treatment (BMT). We studied a cohort of 215 PD patients who were candidates for FUS subthalamotomy to determine if the SDR was correlated with demographic or clinical variables that could introduce bias for group allocation in a controlled trial. SDR was unassociated with age, gender, and clinical motor features nor with levodopa daily dose in our cohort of PD patients. A negative association with age was found for the female subgroup. Our results show that in a PD population considered for FUS subthalamotomy treatment, the SDR may be a valid group-allocation parameter. This could be considered as the basis for a controlled study comparing FUS subthalamotomy vs BMT.

Perspectives of people experiencing homelessness with recent non-fatal street drug overdose on the Pharmacist and Homeless Outreach Engagement and Non-medical Independent prescribing Rx (PHOENIx) intervention.

In Scotland, a third of all deaths of people experiencing homelessness (PExH) are street-drug-related, and less than half of their multiple physical- and mental health conditions are treated. New, holistic interventions are required to address these health inequalities. PHOENIx (Pharmacist Homeless Outreach Engagement and Non-medical Independent prescribing Rx) is delivered on outreach by National Health Service (NHS) pharmacist independent prescribers in partnership with third sector homelessness charity workers. We describe participant's perspectives of PHOENIx. This study aims to understand experiences of the PHOENIx intervention by participants recruited into the active arm of a pilot randomised controlled trial (RCT). Semi-structured in-person interviews explored participants' evaluation of the intervention. In this study, the four components (coherence, cognitive participation, collective action, reflexive monitoring) of the Normalisation Process Theory (NPT) framework underpinned data collection and analyses. We identified four themes that were interpreted within the NPT framework that describe participant evaluation of the PHOENIx intervention: differentiating the intervention from usual care (coherence), embedding connection and consistency in practice (cognitive participation), implementation of practical and emotional operational work (collective action), and lack of power and a commitment to long-term support (reflexive monitoring). Participants successfully engaged with the intervention. Facilitators for participant motivation included the relationship-based work created by the PHOENIx team. This included operational work to fulfil both the practical and emotional needs of participants. Barriers included concern regarding power imbalances within the sector, a lack of long-term support and the impact of the intervention concluding. Findings identify and describe participants' evaluations of the PHOENIx intervention. NPT is a theoretical framework facilitating understanding of experiences, highlighting both facilitators and barriers to sustained engagement and investment. Our findings inform future developments regarding a subsequent definitive RCT of PHOENIx, despite challenges brought about by challenging micro and macro-economic and political landscapes.

Effectiveness and cost-effectiveness of a 12-month automated text message intervention for weight management in postpartum women with overweight or obesity: protocol for the Supporting MumS (SMS) multisite, parallel-group, randomised controlled trial

IntroductionThe reproductive years can increase women’s weight-related risk. Evidence for effective postpartum weight management interventions is lacking and engaging women during this life stage is challenging. Following a promising pilot...

P060 Multi-targeted therapy better in achieving a complete response in Lupus Nephritis: A systematic review and meta-analysis

Abstract Background/Aims Overall management of SLE and Lupus Nephritis (LN) has significantly improved over the last four decades. Recently great therapeutic strides have been made in management of LN using newer agents alone or combination of older therapies. With the availability of increased number of options choosing the optimal treatment regimen for LN has become challenging. Identifying the treatment regimen most effective in achieving complete response while minimizing adverse events is crucial for improving patient outcomes. We performed a systematic review and meta-analysis of clinical trials to explore optimal treatment regimen for LN. Methods The systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search was conducted using public databases, such as the Cochrane Library, Web of Science and PubMed. Only randomized controlled clinical trials with either active comparator or placebo arms were included. Studies were excluded if they were retrospective, with no comparative drug arm, or less than 20 subjects per treatment response arm. Due to lack of agreed upon outcome measures, complete response (CR) and partial response (PR) criteria were determined as per the definition used by individual studies. Severe adverse reaction (SAE) frequencies were determined for each study for safety evaluation. Publication bias was detected by using funnel plots. Forest plots were used to summarize data, generate frequencies, odds ratio (OR), relative risks (RR) and corresponding 95% confidence intervals (CI) for each subgroup. Heterogeneity was evaluated using the I2 statistic, and labelled as low (25%), moderate (50%) and high (75%). All analyses were performed using R Statistical Software meta package (v4.2.1; R Core Team 2022). Results 31 eligible studies comprising 5495 SLE patients were included in analyses, the study characteristic features are shown in Table 1. Overall significant OR for achieving CR was reported by 10 studies (Figure 1). The highest effect was reported from study by Bao et.al using a combination of tacrolimus(TAC) and mycophenolate mofetil (MMF) compared to cyclophosphamide (CYC) (OR = 10.5, 95% CI 2.27; 48.76), another study using TAC+MMF combo reported OR = 2.49, 95% CI 1.59;3.88. The study by Ginzler et.al reported OR = 5.06 (95% CI 1.6:16.02) in favor of using MMF. Studies using CYC, voclosporin + MMF, and belimumab also reported significant OR for achieving CR. Data for the frequency of SAE were available in 22 studies. The frequency of SAE was not significantly different between treatments arms (OR: 1.07, 95%CI: 0.93-1.23, p > 0.05) Conclusion Our meta-analysis suggests multi-target treatment strategies, by adding calcineurin inhibitors to MMF may be better for achieving complete response in LN. Furthermore, using this combination treatment did not seem to increase the risk of side effects. Heterogenous treatment response criteria and variable comparator arms were major limiting factors of this study. Disclosure O. Pamuk: None. B. Shaikh: None. S. Khan: None. S. Abi Doumeth: None. S. Hasni: None.

Exploring the Effects of Ixekizumab on Pain in Patients with Ankylosing Spondylitis Based on Objective Measures of Inflammation: Post Hoc Analysis from a Large Randomized Clinical Trial.

The objective of this analysis is to evaluate the improvement in spinal pain with ixekizumab, placebo, and adalimumab based on objective measures of inflammation response in patients with ankylosing spondylitis (AS). The COAST-V 52-week, double-blind, placebo-controlled, randomized phaseIII trial examined the efficacy of ixekizumab in patients with active AS; adalimumab was used as an active reference arm. Treatment effects on reduction in pain were assessed by objective measures of controlled and persisting inflammation (defined by magnetic resonance imaging [MRI], C-reactive protein [CRP], or MRI + CRP status). Pathway analysis was used to analyze treatment effect that was not attributable to reduction in inflammation biomarkers. In patients with AS, when inflammation was controlled as assessed by MRI, patients treated with ixekizumab experienced a reduction in spinal pain at night (SP-N, numeric rating scale, ixekizumab mean = - 3.9, p < 0.001, adalimumab mean = - 2.6, p < 0.05) compared to placebo (mean = - 1.6) at week16. When inflammation was controlled as assessed by MRI + CRP, ixekizumab and adalimumab had numerically greater reductions at week16 in SP-N versus placebo. All ixekizumab groups had further improvements at week52. When inflammation was persisting as assessed by MRI + CRP, ixekizumab-treated patients had significant reduction in SP-N (mean = - 3.7, p < 0.001) versus placebo (mean = - 1.7), improvement with adalimumab did not reach significance (mean = - 2.6, p = 0.06). In the pathway analysis at week16, ixekizumab had a greater effect on pain outcomes compared to adalimumab. This post hoc analysis is supportive of the hypothesis that ixekizumab reduces pain in AS by additional mechanisms other than the reduction of measurable inflammation. NCT02696785.

A hybrid brain-muscle-machine interface for stroke rehabilitation: Usability and functionality validation in a 2-week intensive intervention.

Introduction: The primary constraint of non-invasive brain-machine interfaces (BMIs) in stroke rehabilitation lies in the poor spatial resolution of motor intention related neural activity capture. To address this limitation, hybrid brain-muscle-machine interfaces (hBMIs) have been suggested as superior alternatives. These hybrid interfaces incorporate supplementary input data from muscle signals to enhance the accuracy, smoothness and dexterity of rehabilitation device control. Nevertheless, determining the distribution of control between the brain and muscles is a complex task, particularly when applied to exoskeletons with multiple degrees of freedom (DoFs). Here we present a feasibility, usability and functionality study of a bio-inspired hybrid brain-muscle machine interface to continuously control an upper limb exoskeleton with 7 DoFs. Methods: The system implements a hierarchical control strategy that follows the biologically natural motor command pathway from the brain to the muscles. Additionally, it employs an innovative mirror myoelectric decoder, offering patients a reference model to assist them in relearning healthy muscle activation patterns during training. Furthermore, the multi-DoF exoskeleton enables the practice of coordinated arm and hand movements, which may facilitate the early use of the affected arm in daily life activities. In this pilot trial six chronic and severely paralyzed patients controlled the multi-DoF exoskeleton using their brain and muscle activity. The intervention consisted of 2 weeks of hBMI training of functional tasks with the system followed by physiotherapy. Patients' feedback was collected during and after the trial by means of several feedback questionnaires. Assessment sessions comprised clinical scales and neurophysiological measurements, conducted prior to, immediately following the intervention, and at a 2-week follow-up. Results: Patients' feedback indicates a great adoption of the technology and their confidence in its rehabilitation potential. Half of the patients showed improvements in their arm function and 83% improved their hand function. Furthermore, we found improved patterns of muscle activation as well as increased motor evoked potentials after the intervention. Discussion: This underscores the significant potential of bio-inspired interfaces that engage the entire nervous system, spanning from the brain to the muscles, for the rehabilitation of stroke patients, even those who are severely paralyzed and in the chronic phase.

Abstract CT030: Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity

Abstract Background: Gut microbiota modulation shows promise in improving immune checkpoint blockade (ICB) response; however, precision biomarker-driven trials using rationally-designed consortia are lacking. To address this, we performed a multi-center, randomized placebo-controlled, biomarker-stratified phase 1 trial in patients with ICB-naïve unresectable or metastatic melanoma using SER-401, a bacterial consortia enriched for Firmicutes spores and Ruminococcaceae. Methods: MCGRAW was a multi-center, randomized, blinded, and placebo-controlled phase 1b study in patients with advanced melanoma. Patients were randomized 2:1 to the SER-401 active or placebo arm, respectively, and stratified by baseline stool Ruminococcaceae abundance. Patients received an oral vancomycin (vanco) preparative regimen+SER-401 (vanco+SER-401 arm), versus placebo antibiotic+placebo (Placebo arm), followed by nivolumab. Stool, blood and tumor samples were collected at baseline and on treatment. The primary endpoint was safety, with additional secondary endpoints (SER-401 microbiome engraftment, overall response rate (ORR), disease control rate (DCR), and other translational endpoints). The study was not powered for comparison between arms. Results: 14 patients were randomized (n=8 vanco+SER-401, n=6 placebo). In the vanco+SER-401 arm, ORR was 25.0% and DCR was 37.5%, with no Grade 3-4 treatment-related adverse events (TRAE); in the placebo arm, ORR was 66.7% and DCR was 83.3%, with 1 (17%) TRAE. Notably, pre-conditioning with vanco was associated with significant shift in the microbiome taxonomic composition, with depletion of target families such as Ruminococcaceae (p=0.008, Wilcoxon signed-rank test), and other spore-formers, followed by their recovery post dosing with SER-401. There was a significant increase in multiple ICB-resistance associated pathways (e.g. butyrate synthesis, p&amp;lt;0.0001), and a decrease in response-associated pathways after vanco preconditioning; these changes did normalize by nivolumab initiation. There was corresponding increase in systemic proteomic markers of inflammation after vanco, which also normalized by first dose of immunotherapy. Conclusions: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that SER-401 and anti-PD1 are a safe combination in melanoma patients. The study was limited by poor accrual during the COVID-19 pandemic. Nonetheless, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials. Additional placebo-controlled biomarker-driven microbiome trials are needed in this age of precision medicine. Trial registration: ClinicalTrials.gov (NCT03817125) Citation Format: Isabella C. Glitza Oliva, Yongwoo David Seo, Christine N. Spencer, Jennifer R. Wortman, Elizabeth M. Burton, Farah A. Alayli, Christopher Loo, Shikha Gautam, Ashish V. Damania, Julie Densmore, Justin Fairchild, Christopher Cabanski, Matthew C. Wong, Christine B. Peterson, Brian Weiner, Nathan Hicks, John Aunins, Christopher McChalicher, Michael T. Tetzlaff, Omid Hamid, Patrick A. Ott, Genevieve M. Boland, Ryan J. Sullivan, Kenneth F. Grossmann, Nadim J. Ajami, Theresa M. LaVallee, Matthew R. Henn, Hussein A. Tawbi, Jennifer A. Wargo. Randomized placebo-controlled, biomarker-stratified phase 1b microbiome modulation trial for metastatic melanoma demonstrates impact of antibiotic pre-conditioning regimen on the microbiome and immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT030.

JNJ-73763989 and bersacapavir treatment in nucleos(t)ide analogue-suppressed patients with chronic hepatitis B: REEF-2

Functional cure for chronic hepatitis B (CHB) requires finite treatment. Two agents under investigation with the goal of achieving functional cure are the small-interfering RNA JNJ-73763989 (JNJ-3989) and the capsid assembly modulator JNJ-56136379 (JNJ-6379; bersacapavir). REEF-2, a phase IIb, double-blind, placebo-controlled, randomized study, enrolled 130 nucleos(t)ide analogue (NA)-suppressed hepatitis B e-antigen (HBeAg)-negative patients with CHB who received JNJ-3989 (200mg subcutaneously every 4 weeks) + JNJ-6379 (250mg oral daily) + NA (oral daily; active arm) or placebos for JNJ-3989 and JNJ-6379+active NA (control arm) for 48 weeks followed by 48 weeks off-treatment follow-up. At follow-up Week 24, no patients achieved the primary endpoint of functional cure (off-treatment hepatitis B surface antigen [HBsAg] seroclearance). No patients achieved functional cure at follow-up Week 48. There was a pronounced on-treatment reduction in mean HBsAg from baseline at Week 48 in the active arm vs. no decline in the control arm (1.89 vs. 0.06 log10IU/ml; p= 0.001). At follow-up Week 48, reductions from baseline were >1 log10IU/ml in 81.5% vs. 12.5% of patients in the active and control arms, respectively, and 38/81 (46.9%) patients in the active arm achieved HBsAg <100IU/ml vs. 6/40 (15.0%) patients in the control arm. Off-treatment HBV DNA relapse and alanine aminotransferase increases were less frequent in the active arm, with 7/77 (9.1%) and 11/41 (26.8%) patients in the active and control arms, respectively, restarting NAs during follow-up. Finite 48-week treatment with JNJ-3989 + JNJ-6379 + NA resulted in fewer and less severe post-treatment HBV DNA increases and alanine aminotransferase flares, and a higher proportion of patients with off-treatment HBV DNA suppression, with or without HBsAg suppression, but did not result in functional cure. Achieving a functional cure from chronic hepatitis B (CHB) with finite treatments is a major unmet medical need. The current study assessed the rate of functional cure and clinical outcome after controlled nucleos(t)ide analogue (NA) withdrawal in patients with low levels of HBsAg induced by 48 weeks of treatment with the small-interfering RNA JNJ-3989 and the capsid assembly modulator JNJ-6379 plus NA vs. patients who only received NA treatment. Though functional cure was not achieved by any patient in either arm, the 48-week treatment regimen of JNJ-3989, JNJ-6379, and NA did result in more patients achieving pronounced reductions in HBsAg, with clinically meaningful reductions maintained for up to 48 weeks off all treatments, as well as fewer off-treatment HBV DNA increases and alanine aminotransferase flares. These findings provide valuable insights for future studies investigating potential finite treatment options, while the reported efficacy and safety outcomes may be of interest to healthcare providers making treatment decisions for patients with NA-suppressed HBeAg-negative CHB. NCT04129554.

Abstract 2246: The impact of a waitlist control group on physical activity level in the activity after cancer treatment exercise oncology randomized pilot study

Abstract Background: In randomized clinical trials, control conditions such as blinding are essential for mitigating threats to validity. In exercise oncology trials, researchers are unable to blind participants to randomization, which may confer unintended consequences (i.e., crossover or dropout) that may threaten validity. Despite prior suggestions that a waitlist control is optimal for lessening these consequences, to date there is little agreement concerning control conditions in exercise oncology. Further, the use of a waitlist control is complicated by concerns regarding the ethical implications of instructing participants to delay healthy behavior change. Herein, we leveraged data from the Activity after Cancer Treatment (ACT) study to evaluate the impact of randomization to a waitlist control group on objectively assessed physical activity (PA) levels in breast cancer (BC) survivors. Methods: The ACT Study (PI: Ambrosone) was a 12-week, four-arm pilot study at Roswell Park Comprehensive Cancer Center. Participants included 37 BC survivors who were randomized to either a waitlist control group (n=10), or one of three exercise interventions of varying intensities including home-based walking (n=9), home-based Zumba (n=9), or a supervised high-intensity interval training treadmill protocol (n=9) delivered by study personnel at Roswell Park Comprehensive Cancer Center. The waitlist group was asked to maintain their usual PA during the 12-week intervention. All participants received weekly phone calls to optimize engagement and ensure Fitbit data were properly synced. For the current analysis, the primary analytic exposure was randomization assignment (control or active intervention); the analytic outcomes included steps/day, moderate-to-vigorous PA (MVPA) minutes/week and total active minutes/week as measured by the Fitbit Charge 2. ANOVA was used to assess mean group differences in steps and active minutes. Results: At study conclusion, the control group accumulated significantly fewer steps/day [6,087 (±1,353)] than the active intervention groups [8,729 (±2,585), p=0.0003]. The control group also accumulated significantly fewer MVPA minutes/week [146.2 (±114.9) vs. 264.1 (±192.3), p=0.045] and total active minutes/week [1,478 (±291.0) vs. 1,976.8 (±658.6), p=0.003] in comparison to the active intervention groups, respectively. Conclusions: BC survivors randomized to active intervention accumulated significantly more steps, MVPA and total active minutes than the waitlist group. Although the waitlist was effective for minimizing PA relative to the active arms, waitlisted participants exceeded the national step average of 4800 steps/day by 1200 steps and nearly met the minimum PA recommendation of 150 minutes of MVPA/week, potentially assuaging ethical or public health concerns regarding the delay of health-seeking behavior. Citation Format: Rikki Cannioto, Evan Davis, Karen Hulme, Chi-Chen Hong, Carol DeNysschen, Tracey O'Connor, Christine Ambrosone. The impact of a waitlist control group on physical activity level in the activity after cancer treatment exercise oncology randomized pilot study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2246.

Unlocking the potential of synthetic patients for accelerating clinical trials: Results of the first GIMEMA experience on acute myeloid leukemia patients.

Artificial Intelligence has the potential to reshape the landscape of clinical trials through innovative applications, with a notable advancement being the emergence of synthetic patient generation. This process involves simulating cohorts of virtual patients that can either replace or supplement real individuals within trial settings. By leveraging synthetic patients, it becomes possible to eliminate the need for obtaining patient consent and creating control groups that mimic patients in active treatment arms. This method not only streamlines trial processes, reducing time and costs but also fortifies the protection of sensitive participant data. Furthermore, integrating synthetic patients amplifies trial efficiency by expanding the sample size. These straightforward and cost-effective methods also enable the development of personalized subject-specific models, enabling predictions of patient responses to interventions. Synthetic data holds great promise for generating real-world evidence in clinical trials while upholding rigorous confidentiality standards throughout the process. Therefore, this study aims to demonstrate the applicability and performance of these methods in the context of onco-hematological research, breaking through the theoretical and practical barriers associated with the implementation of artificial intelligence in medical trials.

Nature-based virtual reality intervention to manage stress in family caregivers of allogeneic hematopoietic stem cell transplant recipients: a two-phase pilot study protocol.

ClinicalTrials.gov, identifier NCT05909202.

Safety, tolerability, and efficacy estimate of evoked gamma oscillation in mild to moderate Alzheimer's disease.

Alzheimer's Disease (AD) is a multifactorial, progressive neurodegenerative disease that disrupts synaptic and neuronal activity and network oscillations. It is characterized by neuronal loss, brain atrophy and a decline in cognitive and functional abilities. Cognito's Evoked Gamma Therapy System provides an innovative approach for AD by inducing EEG-verified gamma oscillations through sensory stimulation. Prior research has shown promising disease-modifying effects in experimental AD models. The present study (NCT03556280: OVERTURE) evaluated the feasibly, safety and efficacy of evoked gamma oscillation treatment using Cognito's medical device (CogTx-001) in participants with mild to moderate AD. The present study was a randomized, double blind, sham-controlled, 6-months clinical trial in participants with mild to moderate AD. The trial enrolled 76 participants, aged 50 or older, who met the clinical criteria for AD with baseline MMSE scores between 14 and 26. Participants were randomly assigned 2:1 to receive self-administered daily, one-hour, therapy, evoking EEG-verified gamma oscillations or sham treatment. The CogTx-001 device was use at home with the help of a care partner, over 6 months. The primary outcome measures were safety, evaluated by physical and neurological exams and monthly assessments of adverse events (AEs) and MRI, and tolerability, measured by device use. Although the trial was not statistically powered to evaluate potential efficacy outcomes, primary and secondary clinical outcome measures included several cognitive and functional endpoints. Total AEs were similar between groups, there were no unexpected serious treatment related AEs, and no serious treatment-emergent AEs that led to study discontinuation. MRI did not show Amyloid-Related Imaging Abnormalities (ARIA) in any study participant. High adherence rates (85-90%) were observed in sham and treatment participants. There was no statistical separation between active and sham arm participants in primary outcome measure of MADCOMS or secondary outcome measure of CDR-SB or ADAS-Cog14. However, some secondary outcome measures including ADCS-ADL, MMSE, and MRI whole brain volume demonstrated reduced progression in active compared to sham treated participants, that achieved nominal significance. Our results demonstrate that 1-h daily treatment with Cognito's Evoked Gamma Therapy System (CogTx-001) was safe and well-tolerated and demonstrated potential clinical benefits in mild to moderate AD.Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03556280.

Critical lessons from a pragmatic randomized trial of home-based COVID-19 testing in rural Native American and Latino communities.

Native Americans and Latinos have higher COVID-19 infection and mortality rates and may have limited access to diagnostic testing. Home-based testing may improve access to care in rural and underserved populations. This study tests the effect of community health worker (CHW) support on accessibility, feasibility, and completion of COVID-19 home testing among Native American and Latino adults living on the Flathead Reservation in Montana and in Yakima Valley, Washington. A two-arm, multisite, pragmatic randomized controlled trial was conducted using block randomization stratified by site and participant age. Active arm participants received CHW assistance with online COVID-19 test kit registration and virtual swabbing support. The passive arm participants received standard-of-care support from the kit vendor. Logistic regression modeled the association between study arm and test completion (primary outcome) and between study arm and test completion with return of valid test results (secondary outcome). Responses to posttest surveys and interviews were summarized using deductive thematic analysis. Overall, 63% of participants (n=268) completed COVID-19 tests, and 50% completed tests yielding a valid result. Active arm participants had higher odds of test completion (odds ratio: 1.66, 95% confidence interval [1.01, 2.75]). Differences were most pronounced among adults ≥60years. Participants cited ease of use and not having to leave home as positive aspects, and transportation and mailing issues as negative aspects of home-based testing. CHW support led to higher COVID-19 test completion rates, particularly among older adults. Significant testing barriers included language, educational level, rurality, and test kit issues.

Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer’s disease

BackgroundThe clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer’s disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes.MethodsWe simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale–sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer’s Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years.ResultsThe PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease.ConclusionPMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.

Simultaneous Evaluation of Bone Cut and Implant Placement Accuracy in Robotic-Assisted Total Knee Arthroplasty.

Background: This study aimed to evaluate the accuracy of bone cuts and implant placements, simultaneously, for total knee arthroplasty (TKA) performed using a system with an active robotic arm. Methods: Two experienced orthopaedic surgeons performed TKA on ten cadaveric legs. Computed tomography scans were performed to compare the bone cuts and implant placements with the preoperative planning. The differences between the planned and actual bone cuts and implant placements were assessed using positional and angular errors in the three anatomical planes. Additionally, the cut-implant deviations were calculated. Statistical analysis was performed to detect systematic errors in the bone cuts and implant placements and to quantify the correlations between these errors. Results: The root-mean-square (RMS) errors of the bone cuts (with respect to the planning) were between 0.7-1.5 mm and 0.6-1.7°. The RMS implant placement errors (with respect to the planning) varied between 0.6-1.6 mm and 0.4-1.5°, except for the femur and tibia in the sagittal plane (2.9°). Systematic errors in the bone cuts and implant placements were observed, respectively, in three and two degrees of freedom. For cut-implant deviations, the RMS values ranged between 0.3-2.0 mm and 0.6-1.9°. The bone cut and implant placement errors were significantly correlated in eight degrees-of-freedom (ρ ≥ 0.67, p < 0.05). Conclusions: With most of the errors below 2 mm or 2°, this study supported the value of active robotic TKA in achieving accurate bone cuts and implant placements. The findings also highlighted the need for both accurate bone cuts and proper implantation technique to achieve accurate implant placements.

A Russian Doll of Resistance: Nested Gains and Losses of Venom Immunity in Varanid Lizards.

The interplay between predator and prey has catalyzed the evolution of venom systems, with predators honing their venoms in response to the evolving resistance of prey. A previous study showed that the African varanid species Varanus exanthematicus has heightened resistance to snake venoms compared to the Australian species V. giganteus, V. komodoensis, and V. mertensi, likely due to increased predation by sympatric venomous snakes on V. exanthematicus. To understand venom resistance among varanid lizards, we analyzed the receptor site targeted by venoms in 27 varanid lizards, including 25 Australian varanids. The results indicate an active evolutionary arms race between Australian varanid lizards and sympatric neurotoxic elapid snakes. Large species preying on venomous snakes exhibit inherited neurotoxin resistance, a trait potentially linked to their predatory habits. Consistent with the 'use it or lose it' aspect of venom resistance, this trait was secondarily reduced in two lineages that had convergently evolved gigantism (V. giganteus and the V. komodoensis/V. varius clade), suggestive of increased predatory success accompanying extreme size and also increased mechanical protection against envenomation due to larger scale osteoderms. Resistance was completely lost in the mangrove monitor V. indicus, consistent with venomous snakes not being common in their arboreal and aquatic niche. Conversely, dwarf varanids demonstrate a secondary loss at the base of the clade, with resistance subsequently re-evolving in the burrowing V. acanthurus/V. storri clade, suggesting an ongoing battle with neurotoxic predators. Intriguingly, within the V. acanthurus/V. storri clade, resistance was lost again in V. kingorum, which is morphologically and ecologically distinct from other members of this clade. Resistance was also re-evolved in V. glebopalma which is terrestrial in contrast to the arboreal/cliff dwelling niches occupied by the other members of its clade (V. glebopalma, V. mitchelli, V. scalaris, V. tristis). This 'Russian doll' pattern of venom resistance underscores the dynamic interaction between dwarf varanids and Australian neurotoxic elapid snakes. Our research, which included testing Acanthophis (death adder) venoms against varanid receptors as models for alpha-neurotoxic interactions, uncovered a fascinating instance of the Red Queen Hypothesis: some death adders have developed more potent toxins specifically targeting resistant varanids, a clear sign of the relentless predator-prey arms race. These results offer new insight into the complex dynamics of venom resistance and highlight the intricate ecological interactions that shape the natural world.

Lactoferrin in the Prevention of Recurrent Respiratory Infections in Preschool Children: A Prospective Randomized Study.

Few studies have evaluated the effect of bovine lactoferrin (bLf) on reducing respiratory infections in preschool children. This randomized controlled trial evaluated the effect of bLf in preschool children with recurrent respiratory infections. Participants were randomly assigned bLf (n = 25) or control (n = 25). Outcomes included respiratory infection episodes (RIEs), symptom duration, school absence and medication. Fifty children aged 4.2 ± 0.1 years were included. During the active 4-month phase, median number of RIEs was reduced by 50% in the bLf group [1-episode, interquartile range (IQR): 0-2] vs. control (2, IQR: 1-3; p = 0.02). The proportion of participants with >3 RIEs was significantly lower in bLf (n = 1, 4%) vs. control (n = 7, 28%) with 80% lower odds of upper RIEs in the bLf arm (odds ratio: 0.20, 95% CI:0.06-0.74, p = 0.015). The duration of symptoms (3 vs. 6, p = 0.009) and days absent from school (3 vs. 6, p = 0.15) were lower in the active arm. Over the 2-month follow-up, no significant differences were observed between groups for infection episodes, symptom duration or school absence. However, bLf-treated children received significantly less corticosteroids over the entire 6-month study period (32% vs. 60%; p = 0.047). bLf supplementation significantly reduced the frequency and duration of RIEs in children with decreased corticosteroid use.

An Algorithm for Activity Recognition and Assessment of Adults Poststroke.

Stroke is the leading cause of long-term disability in the United States. Providers have no robust tools to objectively and accurately measure the activity of people with stroke living at home. To explore the integration of validated upper extremity assessments poststroke within an activity recognition system. Exploratory descriptive study using data previously collected over 3 mo to report on algorithm testing and assessment integration. Data were collected in the homes of community-dwelling participants. Participants were at least 6 mo poststroke, were able to ambulate with or without an assistive device, and self-reported some difficulty using their arm in everyday activities. The activity detection algorithm's accuracy was determined by comparing its activity labels with manual labels. The algorithm integrated assessment by describing the quality of upper extremity movement, which was determined by reporting extent of reach, mean and maximum speed during movement, and smoothness of movement. Sixteen participants (9 women, 7 men) took part in this study, with an average age of 63.38 yr (SD = 12.84). The algorithm was highly accurate in correctly identifying activities, with 87% to 95% accuracy depending on the movement. The algorithm was also able to detect the quality of movement for upper extremity movements. The algorithm was able to accurately identify in-kitchen activities performed by adults poststroke. Information about the quality of these movements was also successfully calculated. This algorithm has the potential to supplement clinical assessments in treatment planning and outcomes reporting. Plain-Language Summary: This study shows that clinical algorithms have the potential to inform occupational therapy practice by providing clinically relevant data about the in-home activities of adults poststroke. The algorithm accurately identified activities that were performed in the kitchen by adults poststroke. The algorithm also identified the quality of upper extremity movements of people poststroke who were living at home.

A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol

BackgroundCombining multimodal lifestyle interventions and disease-modifying drugs (novel or repurposed) could provide novel precision approaches to prevent cognitive impairment. Metformin is a promising candidate in view of the well-established link between type 2 diabetes (T2D) and Alzheimer’s Disease and emerging evidence of its potential neuro-protective effects (e.g. vascular, metabolic, anti-senescence).MET-FINGER aims to test a FINGER 2.0 multimodal intervention, combining an updated FINGER multidomain lifestyle intervention with metformin, where appropriate, in an APOE ε4-enriched population of older adults (60–79 years) at increased risk of dementia.MethodsMET-FINGER is an international randomised, controlled, parallel-group, phase-IIb proof-of-concept clinical trial, where metformin is included through a trial-within-trial design. 600 participants will be recruited at three sites (UK, Finland, Sweden). Participants at increased risk of dementia based on vascular risk factors and cognitive screening, will be first randomised to the FINGER 2.0 intervention (lifestyle + metformin if eligible; active arm) or to receive regular health advice (control arm). Participants allocated to the FINGER 2.0 intervention group at risk indicators of T2D will be additionally randomised to receive metformin (2000 mg/day or 1000 mg/day) or placebo. The study duration is 2 years. The changes in global cognition (primary outcome, using a Neuropsychological Test Battery), memory, executive function, and processing speed cognitive domains; functional status; lifestyle, vascular, metabolic, and other dementia-related risk factors (secondary outcomes), will be compared between the FINGER 2.0 intervention and the control arm. The feasibility, potential interaction (between-groups differences in healthy lifestyle changes), and disease-modifying effects of the lifestyle-metformin combination will be exploratory outcomes.The lifestyle intervention is adapted from the original FINGER trial (diet, physical activity, cognitive training, monitoring of cardiovascular/metabolic risk factors, social interaction) to be consistently delivered in three countries. Metformin is administered as Glucophage®XR/SR 500, (500 mg oral tablets). The metformin/placebo treatment will be double blinded.ConclusionMET-FINGER is the first trial combining a multimodal lifestyle intervention with a putative repurposed disease-modifying drug for cognitive impairment prevention. Although preliminary, its findings will provide crucial information for innovative precision prevention strategies and form the basis for a larger phase-III trial design and future research in this field.Trial registrationClinicalTrials.gov (NCT05109169).