A novel activated-zinc antiseptic solution effective against MRSA and Pseudomonas aeruginosa: a pig model.

OBJECTIVE: The purpose of this study was to investigate the antimicrobial efficacy of a novel activated zinc solution against meticillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa after one hour, and to evaluate any untoward effect of the solution on local wound tissue at 24 hours after solution exposure in a pig wound model. METHOD: A pathogen-free, commercially raised, Yorkshire-cross female pig was acquired 12 days prior to the procedure. Within one week prior to the procedure, a small loopful of test bacteria, Pseudomonas aeruginosa (pig-isolate) and MRSA (ATCC-6538), were streaked and cultured on a non-selective agar. Full-thickness wounds (n=24) were created and evenly divided into three groups: control wounds (exposed to bacteria but untreated, n=8); wounds treated with Compound 1 (n=8), and wounds treated with Compound 2 (n=8). All wounds were dressed and monitored for one hour and 24 hours. RESULTS: After one hour, the wounds treated with Compound 1 and Compound 2 had a mean recoverable total bacteria of 2.8 log colony forming units (CFUs) and 3.5 logCFUs, respectively. After one hour, the wounds treated with Compound 1 and Compound 2 had a mean recoverable MRSA of 2.3 logCFUs and 1.6 logCFUs, respectively (p=0.009). After one hour, the wounds treated with Compound 1 and Compound 2 had a mean recoverable Pseudomonas aeruginosa of 0.3 logCFUs and 0.0 logCFUs, respectively (p=0.000). After 24 hours of exposure to Compound 1 and Compound 2, there was no statistically significant increased necrosis (p=0.12, p=0.31, respectively) or neutrophilic infiltrate (Compound 2, p=0.12) when compared with control wounds. CONCLUSION: The novel activated-zinc compound used in this study demonstrated a 99.5-99.9% reduction in total bacteria, a 99.9-99.98% reduction in MRSA, and 100% eradication of Pseudomonas aeruginosa one hour after exposure. This novel solution may provide another significant tool to treat and/or prevent wound infections.

Metadata Framework to Support Deployment of Digital Health Technologies in Clinical Trials in Parkinson's Disease.

Sensor data from digital health technologies (DHTs) used in clinical trials provides a valuable source of information, because of the possibility to combine datasets from different studies, to combine it with other data types, and to reuse it multiple times for various purposes. To date, there exist no standards for capturing or storing DHT biosensor data applicable across modalities and disease areas, and which can also capture the clinical trial and environment-specific aspects, so-called metadata. In this perspectives paper, we propose a metadata framework that divides the DHT metadata into metadata that is independent of the therapeutic area or clinical trial design (concept of interest and context of use), and metadata that is dependent on these factors. We demonstrate how this framework can be applied to data collected with different types of DHTs deployed in the WATCH-PD clinical study of Parkinson's disease. This framework provides a means to pre-specify and therefore standardize aspects of the use of DHTs, promoting comparability of DHTs across future studies.

A Novel Activated Zinc Solution with Improved Efficacy Against Pseudomonas and MRSA Biofilm Compared to Chlorhexidine and Povidone-Iodine.

INTRODUCTION: The search for the optimal agent for infection eradication in periprosthetic joint infection (PJI) remains challenging as there are limited efficacious and safe options. The ideal solution should have significant bactericidal and anti-biofilm activity to be able to eradicate infection with the preservation of prosthetic components. Therefore, the purpose of this study was to 1) investigate the anti-biofilm efficacy of a novel activated zinc solution against Pseudomonas aeruginosa and methicillin-resistant Staphylococcus aureus (MRSA) biofilm in vitro and 2) compare its efficacy against two leading commercially available antimicrobial irrigants (CHG and 0.35% povidone-iodine [PI]). MATERIALS AND METHODS: A modified Robbins device (MRD) was utilized to replicate Pseudomonas aeruginosa and MRSA biofilms. The primary outcome was to determine bacterial reduction after two hours of biofilm exposure to an activated zinc solution, CHG, and PI, and compare to untreated controls. RESULTS: Against Pseudomonas biofilm, activated zinc demonstrated a 4.5-log (99.996%) reduction, chlorhexidine demonstrated a 0.9-log (87.4%) reduction (p<0.001), and PI demonstrated a 0.8-log (83.1%) reduction (p<0.001). After two hours of exposure, activated zinc had undetectable MRSA with a 7.08-log (100%) reduction, chlorhexidine had a 1.9-log (98.7%) reduction (p<0.01), and PI had a 3.2-log (99.9%) reduction (p<0.01). CONCLUSIONS: Our novel activated zinc compound demonstrated a 99.996% reduction in Pseudomonas biofilm and a 100% reduction in MRSA biofilm. This novel solution may provide a significant tool in the arsenal to treat and/or prevent PJI and other wound infections. Future in vivo studies are warranted to demonstrate clinical utility, efficacy, and safety.

A standard system phantom for magnetic resonance imaging.

PURPOSE: A standard MRI system phantom has been designed and fabricated to assess scanner performance, stability, comparability and assess the accuracy of quantitative relaxation time imaging. The phantom is unique in having traceability to the International System of Units, a high level of precision, and monitoring by a national metrology institute. Here, we describe the phantom design, construction, imaging protocols, and measurement of geometric distortion, resolution, slice profile, signal-to-noise ratio (SNR), proton-spin relaxation times, image uniformity and proton density. METHODS: The system phantom, designed by the International Society of Magnetic Resonance in Medicine ad hoc committee on Standards for Quantitative MR, is a 200 mm spherical structure that contains a 57-element fiducial array; two relaxation time arrays; a proton density/SNR array; resolution and slice-profile insets. Standard imaging protocols are presented, which provide rapid assessment of geometric distortion, image uniformity, T1 and T2 mapping, image resolution, slice profile, and SNR. RESULTS: Fiducial array analysis gives assessment of intrinsic geometric distortions, which can vary considerably between scanners and correction techniques. This analysis also measures scanner/coil image uniformity, spatial calibration accuracy, and local volume distortion. An advanced resolution analysis gives both scanner and protocol contributions. SNR analysis gives both temporal and spatial contributions. CONCLUSIONS: A standard system phantom is useful for characterization of scanner performance, monitoring a scanner over time, and to compare different scanners. This type of calibration structure is useful for quality assurance, benchmarking quantitative MRI protocols, and to transition MRI from a qualitative imaging technique to a precise metrology with documented accuracy and uncertainty.

The Dementias Platform UK (DPUK) Data Portal.

The Dementias Platform UK Data Portal is a data repository facilitating access to data for 3 370 929 individuals in 42 cohorts. The Data Portal is an end-to-end data management solution providing a secure, fully auditable, remote access environment for the analysis of cohort data. All projects utilising the data are by default collaborations with the cohort research teams generating the data. The Data Portal uses UK Secure eResearch Platform infrastructure to provide three core utilities: data discovery, access, and analysis. These are delivered using a 7 layered architecture comprising: data ingestion, data curation, platform interoperability, data discovery, access brokerage, data analysis and knowledge preservation. Automated, streamlined, and standardised procedures reduce the administrative burden for all stakeholders, particularly for requests involving multiple independent datasets, where a single request may be forwarded to multiple data controllers. Researchers are provided with their own secure 'lab' using VMware which is accessed using two factor authentication. Over the last 2 years, 160 project proposals involving 579 individual cohort data access requests were received. These were received from 268 applicants spanning 72 institutions (56 academic, 13 commercial, 3 government) in 16 countries with 84 requests involving multiple cohorts. Projects are varied including multi-modal, machine learning, and Mendelian randomisation analyses. Data access is usually free at point of use although a small number of cohorts require a data access fee.

Quantitative magnetic resonance imaging phantoms: A review and the need for a system phantom.

The MRI community is using quantitative mapping techniques to complement qualitative imaging. For quantitative imaging to reach its full potential, it is necessary to analyze measurements across systems and longitudinally. Clinical use of quantitative imaging can be facilitated through adoption and use of a standard system phantom, a calibration/standard reference object, to assess the performance of an MRI machine. The International Society of Magnetic Resonance in Medicine AdHoc Committee on Standards for Quantitative Magnetic Resonance was established in February 2007 to facilitate the expansion of MRI as a mainstream modality for multi-institutional measurements, including, among other things, multicenter trials. The goal of the Standards for Quantitative Magnetic Resonance committee was to provide a framework to ensure that quantitative measures derived from MR data are comparable over time, between subjects, between sites, and between vendors. This paper, written by members of the Standards for Quantitative Magnetic Resonance committee, reviews standardization attempts and then details the need, requirements, and implementation plan for a standard system phantom for quantitative MRI. In addition, application-specific phantoms and implementation of quantitative MRI are reviewed. Magn Reson Med 79:48-61, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Mechanisms of vascular disease in dementia: what does industry want to know?

Despite recent advances in basic and clinical science, dementia remains an area of high unmet medical need. The role of cerebrovascular mechanisms in the pathogenesis and progression of cognitive and functional impairment in dementia is being revived. In order to facilitate the development of therapeutic approaches, it is critical that a number of fundamental elements are integrated into research strategies investigating cerebrovascular pathologies as these will maximize the opportunity of bringing medicines to patients in a timely manner.

Design, operation, and safety of single-room interventional MRI suites: practical experience from two centers.

The design and operation of a facility in which a magnetic resonance imaging (MRI) scanner is incorporated into a room used for surgical or endovascular cardiac interventions presents several challenges. MR safety must be maintained in the presence of a much wider variety of equipment than is found in a diagnostic unit, and of staff unfamiliar with the MRI environment, without compromising the safety and practicality of the interventional procedure. Both the MR-guided cardiac interventional unit at Kings College London and the intraoperative imaging suite at the National Hospital for Neurology and Neurosurgery are single-room interventional facilities incorporating 1.5 T cylindrical-bore MRI scanners. The two units employ similar strategies to maintain MR safety, both in original design and day-to-day operational workflows, and between them over a decade of incident-free practice has been accumulated. This article outlines these strategies, highlighting both similarities and differences between the units, as well as some lessons learned and resulting procedural changes made in both units since installation.

Percutaneous sclerotherapy for treatment of tumoral calcinosis.

Massive tumoral calcinosis developed in a 29-year-old woman with type 1 diabetes and failed pancreas and kidney transplant on peritoneal dialysis. The patient had a symptomatic calcified, fluid-filled posterior thigh mass. After percutaneous drainage of 260 mL of milky fluid, she had rapid recurrence of the collection. She underwent catheter-based sclerotherapy first with 110 mL of povidone-iodine followed 2 days later by 40 mL of 3% sodium tetradecyl sulfate foam. At 5.5 months after the procedure, the patient remained asymptomatic, and computed tomography imaging showed complete resolution of the collection.

Robustness of automated hippocampal volumetry across magnetic resonance field strengths and repeat images.

BACKGROUND: Low HCV has recently been qualified by the European Medicines Agency as a biomarker for enrichment of clinical trials in predementia stages of Alzheimer's disease. For automated methods to meet the necessary regulatory requirements, it is essential they be standardized and their performance be well characterized. METHODS: The within-image and between-field strength reproducibility of automated hippocampal volumetry using the Learning Embeddings for Atlas Propagation (or LEAP) algorithm was assessed on 153 Alzheimer's Disease Neuroimaging Initiative subjects. RESULTS: Tests/retests at 1.5 T and 3 T, and a comparison between 1.5 T and 3 T, yielded average unsigned variabilities in HCVs of 1.51%, 1.52%, and 2.68%. A small bias between field strengths (mean signed difference, 1.17%; standard deviation, 3.07%) was observed. CONCLUSIONS: The measured reproducibility characteristics confirm the suitability of using automated magnetic resonance imaging analyses to assess HCVs quantitatively and to represent a fundamental characterization that is critical to meet the regulatory requirements for using hippocampal volumetry in clinical trials and health care.

Coalition Against Major Diseases/European Medicines Agency biomarker qualification of hippocampal volume for enrichment of clinical trials in predementia stages of Alzheimer's disease.

BACKGROUND: Regulatory qualification of a biomarker for a defined context of use provides scientifically robust assurances to sponsors and regulators that accelerate appropriate adoption of biomarkers into drug development. METHODS: The Coalition Against Major Diseases submitted a dossier to the Scientific Advice Working Party of the European Medicines Agency requesting a qualification opinion on the use of hippocampal volume as a biomarker for enriching clinical trials in subjects with mild cognitive impairment, incorporating a scientific rationale, a literature review and a de novo analysis of Alzheimer's Disease Neuroimaging Initiative data. RESULTS: The literature review and de novo analysis were consistent with the proposed context of use, and the Committee for Medicinal Products for Human Use released an opinion in November 2011. CONCLUSIONS: We summarize the scientific rationale and the data that supported the first qualification of an imaging biomarker by the European Medicines Agency.

AI in imaging: the regulatory landscape.

Artificial intelligence (AI) methods have been applied to medical imaging for several decades, but in the last few years, the number of publications and the number of AI-enabled medical devices coming on the market have significantly increased. While some AI-enabled approaches are proving very valuable, systematic reviews of the AI imaging field identify significant weaknesses in a significant proportion of the literature. Medical device regulators have recently become more proactive in publishing guidance documents and recognizing standards that will require that the development and validation of AI-enabled medical devices need to be more rigorous than required for tradition "rule-based" software. In particular, developers are required to better identify and mitigate risks (such as bias) that arise in AI-enabled devices, and to ensure that the devices are validated in a realistic clinical setting to ensure their output is clinically meaningful. While this evolving regulatory landscape will mean that device developers will take longer to bring novel AI-based medical imaging devices to market, such additional rigour is necessary to address existing weaknesses in the field and ensure that patients and healthcare professionals can trust AI-enabled devices. There would also be benefits in the academic community taking into account this regulatory framework, to improve the quality of the literature and make it easier for academically developed AI tools to make the transition to medical devices that impact healthcare.

Understanding patterns of fatigue in health and disease: protocol for an ecological momentary assessment study using digital technologies.

INTRODUCTION: Fatigue is prevalent across a wide range of medical conditions and can be debilitating and distressing. It is likely that fatigue is experienced differently according to the underlying aetiology, but this is poorly understood. Digital health technologies present a promising approach to give new insights into fatigue.The aim of this study is to use digital health technologies, real-time self-reports and qualitative interview data to investigate how fatigue is experienced over time in participants with myeloma, long COVID, heart failure and in controls without problematic fatigue. Objectives are to understand which sensed parameters add value to the characterisation of fatigue and to determine whether study processes are feasible, acceptable and scalable. METHODS AND ANALYSIS: An ecological momentary assessment study will be carried out over 2 or 4 weeks (participant defined). Individuals with fatigue relating to myeloma (n=10), heart failure (n=10), long COVID (n=10) and controls without problematic fatigue or a study condition (n=10) will be recruited. ECG patches will measure heart rate variability, respiratory rate, body temperature, activity and posture. A wearable bracelet accompanied by environment beacons will measure physical activity, sleep and room location within the home. Self-reports of mental and physical fatigue will be collected via smartphone app four times daily and on-demand. Validated fatigue and affect questionnaires will be completed at baseline and at 2 weeks. End-of-study interviews will investigate experiences of fatigue and study participation. A feedback session will be offered to participants to discuss their data.Data will be analysed using multilevel modelling and machine learning. Interviews and feedback sessions will be analysed using content or thematic analyses. ETHICS AND DISSEMINATION: This study was approved by the East of England-Cambridge East Research Ethics Committee (22/EE/0261). The results will be disseminated in peer-reviewed journals and at international conferences. TRIAL REGISTRATION NUMBER: NCT05622669.

Standardization of analysis sets for reporting results from ADNI MRI data.

The Alzheimer's Disease Neuroimaging Initiative (ADNI) three-dimensional T1-weighted magnetic resonance imaging (MRI) acquisitions provide a rich data set for developing and testing analysis techniques for extracting structural endpoints. To promote greater rigor in analysis and meaningful comparison of different algorithms, the ADNI MRI Core has created standardized analysis sets of data comprising scans that met minimum quality control requirements. We encourage researchers to test and report their techniques against these data. Standard analysis sets of volumetric scans from ADNI-1 have been created, comprising screening visits, 1-year completers (subjects who all have screening, 6- and 12-month scans), 2-year annual completers (screening, 1-year and 2-year scans), 2-year completers (screening, 6-months, 1-year, 18-months [mild cognitive impaired (MCI) only], and 2-year scans), and complete visits (screening, 6-month, 1-year, 18-month [MCI only], 2-year, and 3-year [normal and MCI only] scans). As the ADNI-GO/ADNI-2 data become available, updated standard analysis sets will be posted regularly.

Regulation of muscle protein synthesis in humans.

PURPOSE OF REVIEW: Investigations into the regulation of muscle protein synthesis (MPS) are a cornerstone of understanding the control of muscle mass. Rates of MPS are finely tuned according to levels of activity, nutrient availability and health status. For instance, rates of MPS are positively regulated by exercise and nutrition, and negatively regulated by inactivity (e.g. disuse), ageing (i.e. sarcopenia) and in muscle-wasting related diseases (e.g. cancer). RECENT FINDINGS: Skeletal muscles display a high degree of intrinsic regulation. Increases in MPS after exercise occur independently of the systemic milieu for example growth hormone/testosterone concentrations. In the absence of exercise, increases in MPS after feeding are of finite duration despite enduring precursor availability; that is muscles can sense they are 'full'. Intriguingly, exercise delays this 'muscle-full' response to allow for building and repair. In contrast, muscle-wasting conditions exhibit a premature 'muscle-full' response to nutrition and exercise (i.e. anabolic resistance), which may cause atrophy. Observations of 'dissociations' between MPS and anabolic signalling pathways have cast doubt on how much we understand of the molecular regulation of human MPS. SUMMARY: Anabolic and anticatabolic interventions in health and disease should be aimed at manipulating the 'muscle-full' set point to maximize muscle maintenance/hypertrophy.

The long-term impact of loneliness and social isolation on depression and anxiety in memory clinic attendees and their care partners: A longitudinal actor-partner interdependence model.

Introduction: This study examined the long-term influence of loneliness and social isolation on mental health outcomes in memory assessment service (MAS) attendees and their care partners, with a focus on interdependence and bidirectionality. Methods: Longitudinal data from 95 clinic attendees with cognitive impairment, and their care partners (dyads), from four MAS in the North of England were analyzed. We applied the actor-partner interdependence model, seeking associations within the dyad. At baseline and 12-month follow-up, clinic attendees and care partners completed measures of loneliness and social isolation, depression, and anxiety. Results: Social isolation at baseline was more prevalent in care partners compared to MAS attendees. Social isolation in MAS attendees was associated with higher anxiety symptoms (ß = 0.28, 95% confidence intervals [CIs] = 0.11 to 0.45) in themselves at 12 months. We found significant positive actor and partner effects of loneliness on depression (actor effect: ß = 0.36, 95% CIs = 0.19 to 0.53; partner effect: ß = 0.23, 95% CIs = 0.06 to 0.40) and anxiety (actor effect: ß = 0.39, 95% CIs = 0.23 to 0.55; partner effect: ß = 0.22, 95% CIs = 0.05 to 0.39) among MAS attendees 1 year later. Loneliness scores of the care partners have a significant and positive association with depressive (ß = 0.36, 95% CIs = 0.19 to 0.53) and anxiety symptoms (ß = 0.32, 95% CIs = 0.22 to 0.55) in themselves at 12 months. Discussion: Loneliness and social isolation in MAS clinic attendees had a downstream effect on their own and their care partners' mental health. This highlights the importance of including care partners in assessments of mental health and social connectedness and expanding the remit of social prescribing in the MAS context.

Identifying and characterising sources of variability in digital outcome measures in Parkinson's disease.

Smartphones and wearables are widely recognised as the foundation for novel Digital Health Technologies (DHTs) for the clinical assessment of Parkinson's disease. Yet, only limited progress has been made towards their regulatory acceptability as effective drug development tools. A key barrier in achieving this goal relates to the influence of a wide range of sources of variability (SoVs) introduced by measurement processes incorporating DHTs, on their ability to detect relevant changes to PD. This paper introduces a conceptual framework to assist clinical research teams investigating a specific Concept of Interest within a particular Context of Use, to identify, characterise, and when possible, mitigate the influence of SoVs. We illustrate how this conceptual framework can be applied in practice through specific examples, including two data-driven case studies.

Steps to standardization and validation of hippocampal volumetry as a biomarker in clinical trials and diagnostic criterion for Alzheimer's disease.

BACKGROUND: The promise of Alzheimer's disease biomarkers has led to their incorporation in new diagnostic criteria and in therapeutic trials; however, significant barriers exist to widespread use. Chief among these is the lack of internationally accepted standards for quantitative metrics. Hippocampal volumetry is the most widely studied quantitative magnetic resonance imaging measure in Alzheimer's disease and thus represents the most rational target for an initial effort at standardization. METHODS AND RESULTS: The authors of this position paper propose a path toward this goal. The steps include the following: (1) Establish and empower an oversight board to manage and assess the effort, (2) adopt the standardized definition of anatomic hippocampal boundaries on magnetic resonance imaging arising from the European Alzheimer's Disease Centers-Alzheimer's Disease Neuroimaging Initiative hippocampal harmonization effort as a reference standard, (3) establish a scientifically appropriate, publicly available reference standard data set based on manual delineation of the hippocampus in an appropriate sample of subjects (Alzheimer's Disease Neuroimaging Initiative), and (4) define minimum technical and prognostic performance metrics for validation of new measurement techniques using the reference standard data set as a benchmark. CONCLUSIONS: Although manual delineation of the hippocampus is the best available reference standard, practical application of hippocampal volumetry will require automated methods. Our intent was to establish a mechanism for credentialing automated software applications to achieve internationally recognized accuracy and prognostic performance standards that lead to the systematic evaluation and then widespread acceptance and use of hippocampal volumetry. The standardization and assay validation process outlined for hippocampal volumetry was envisioned as a template that could be applied to other imaging biomarkers.

Hippocampal Neuroimaging-Informed Clinical Trial Enrichment Tool for Amnestic Mild Cognitive Impairment Using Open Data.

Our goal was to assess the enrichment utility of hippocampal volume (HV) as an enrichment biomarker in amnestic mild cognitive impairment (aMCI) clinical trials, and, hence, develop an HV neuroimaging-informed clinical trial enrichment tool. Modeling of integrated longitudinal patient-level data came from open-access natural history studies in patients diagnosed with aMCI-the Alzheimer's Disease Neuroimaging Initiative (ADNI)-1 and ADNI-2-and indicated that a decrease of 1 cm3 with respect to the analysis dataset median baseline intracranial volume-adjusted HV (ICV-HV; ~ 5 cm3 ) is associated with > 50% increase in disease progression rate as measured by the Clinical Dementia Rating Scale-Sum of Boxes. Clinical trial simulations showed that the inclusion of aMCI subjects with baseline ICV-HV below the 84th or 50th percentile allowed an approximate reduction in trial size of at least 26% and 55%, respectively. This clinical trial enrichment tool can help design more efficient and informative clinical trials.

Precompetitive Consensus Building to Facilitate the Use of Digital Health Technologies to Support Parkinson Disease Drug Development through Regulatory Science.

Innovative tools are urgently needed to accelerate the evaluation and subsequent approval of novel treatments that may slow, halt, or reverse the relentless progression of Parkinson disease (PD). Therapies that intervene early in the disease continuum are a priority for the many candidates in the drug development pipeline. There is a paucity of sensitive and objective, yet clinically interpretable, measures that can capture meaningful aspects of the disease. This poses a major challenge for the development of new therapies and is compounded by the considerable heterogeneity in clinical manifestations across patients and the fluctuating nature of many signs and symptoms of PD. Digital health technologies (DHT), such as smartphone applications, wearable sensors, and digital diaries, have the potential to address many of these gaps by enabling the objective, remote, and frequent measurement of PD signs and symptoms in natural living environments. The current climate of the COVID-19 pandemic creates a heightened sense of urgency for effective implementation of such strategies. In order for these technologies to be adopted in drug development studies, a regulatory-aligned consensus on best practices in implementing appropriate technologies, including the collection, processing, and interpretation of digital sensor data, is required. A growing number of collaborative initiatives are being launched to identify effective ways to advance the use of DHT in PD clinical trials. The Critical Path for Parkinson's Consortium of the Critical Path Institute is highlighted as a case example where stakeholders collectively engaged regulatory agencies on the effective use of DHT in PD clinical trials. Global regulatory agencies, including the US Food and Drug Administration and the European Medicines Agency, are encouraging the efficiencies of data-driven engagements through multistakeholder consortia. To this end, we review how the advancement of DHT can be most effectively achieved by aligning knowledge, expertise, and data sharing in ways that maximize efficiencies.