Measuring implementation fidelity in a cluster-randomized pragmatic trial: development and use of a quantitative multi-component approach

Background In pragmatic trials, on-site partners, rather than researchers, lead intervention delivery, which may result in implementation variation. There is a need to quantitatively measure this variation. Applying the Framework for Implementation Fidelity (FIF), we develop an approach for measuring variability in site-level implementation fidelity. This approach is then applied to measure site-level fidelity in a cluster-randomized pragmatic trial of Music & MemorySM (M&M), a personalized music intervention targeting agitated behaviors in residents living with dementia, in US nursing homes (NHs). Methods Intervention NHs (N = 27) implemented M&M using a standardized manual, utilizing provided staff trainings and iPods for participating residents. Quantitative implementation data, including iPod metadata (i.e., song title, duration, number of plays), were collected during baseline, 4-month, and 8-month site visits. Three researchers developed four FIF adherence dimension scores. For Details of Content, we independently reviewed the implementation manual and reached consensus on six core M&M components. Coverage was the total number of residents exposed to the music at each NH. Frequency was the percent of participating residents in each NH exposed to M&M at least weekly. Duration was the median minutes of music received per resident day exposed. Data elements were scaled and summed to generate dimension-level NH scores, which were then summed to create a Composite adherence score. NHs were grouped by tercile (low-, medium-, high-fidelity). Results The 27 NHs differed in size, resident composition, and publicly reported quality rating. The Composite score demonstrated significant variation across NHs, ranging from 4.0 to 12.0 [8.0, standard deviation (SD) 2.1]. Scaled dimension scores were significantly correlated with the Composite score. However, dimension scores were not highly correlated with each other; for example, the correlation of the Details of Content score with Coverage was τb = 0.11 (p = 0.59) and with Duration was τb = − 0.05 (p = 0.78). The Composite score correlated with CMS quality star rating and presence of an Alzheimer’s unit, suggesting face validity. Conclusions Guided by the FIF, we developed and used an approach to quantitatively measure overall site-level fidelity in a multi-site pragmatic trial. Future pragmatic trials, particularly in the long-term care environment, may benefit from this approach. Trial registration Clinicaltrials.gov NCT03821844. Registered on 30 January 2019, https://clinicaltrials.gov/ct2/show/NCT03821844.

Design and rationale for a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy (OVOID) trial: study protocol for a randomized controlled trial

Background Dilated cardiomyopathy (DCMP) is characterized by ventricular chamber enlargement and systolic dysfunction which may cause heart failure. Patients with DCMP have overactivation of the renin-angiotensin-aldosterone systems, which can also adversely affect myocardial metabolism in heart failure. The impairment of myocardial metabolism can contribute to the progression of left ventricular remodeling and contractile dysfunction in heart failure. Although angiotensin II receptor blockers (ARBs) have been used to treat patients with DCMP, there has been no direct comparison of the efficacy of these agents. The objective of this study is to compare the effects of olmesartan and valsartan on myocardial metabolism in patients with DCMP. Methods/design The OVOID study (a comparison study of Olmesartan and Valsartan On myocardial metabolism In patients with Dilated cardiomyopathy) is designed as a non-blinded, open-label, parallel-group, prospective, randomized, controlled, multicenter clinical trial. A total of 40 DCMP patients aged between 20 and 85 years will be randomly allocated into the olmesartan or the valsartan group. 18F-fluoro-2-deoxyglucose (FDG) cardiac positron emission tomography (PET) will be performed at baseline and six months after receiving the study agent. The primary endpoint is myocardial glucose consumption per square meter, measured using 18F-FDG PET 6 months after receiving the study agent. Discussion The purpose of this trial is to compare the efficacy between olmesartan and valsartan in improving myocardial metabolism in DCMP patients. This will be the first randomized comparative study investigating the differential effects of ARBs on heart failure. Trial registration ClinicalTrials.govNCT04174456. Registered on 18 November 2019

Assigning protein function from domain-function associations using DomFun

Background Protein function prediction remains a key challenge. Domain composition affects protein function. Here we present DomFun, a Ruby gem that uses associations between protein domains and functions, calculated using multiple indices based on tripartite network analysis. These domain-function associations are combined at the protein level, to generate protein-function predictions. Results We analysed 16 tripartite networks connecting homologous superfamily and FunFam domains from CATH-Gene3D with functional annotations from the three Gene Ontology (GO) sub-ontologies, KEGG, and Reactome. We validated the results using the CAFA 3 benchmark platform for GO annotation, finding that out of the multiple association metrics and domain datasets tested, Simpson index for FunFam domain-function associations combined with Stouffer’s method leads to the best performance in almost all scenarios. We also found that using FunFams led to better performance than superfamilies, and better results were found for GO molecular function compared to GO biological process terms. DomFun performed as well as the highest-performing method in certain CAFA 3 evaluation procedures in terms of $$F_{max}$$ F max and $$S_{min}$$ S min We also implemented our own benchmark procedure, Pathway Prediction Performance (PPP), which can be used to validate function prediction for additional annotations sources, such as KEGG and Reactome. Using PPP, we found similar results to those found with CAFA 3 for GO, moreover we found good performance for the other annotation sources. As with CAFA 3, Simpson index with Stouffer’s method led to the top performance in almost all scenarios. Conclusions DomFun shows competitive performance with other methods evaluated in CAFA 3 when predicting proteins function with GO, although results vary depending on the evaluation procedure. Through our own benchmark procedure, PPP, we have shown it can also make accurate predictions for KEGG and Reactome. It performs best when using FunFams, combining Simpson index derived domain-function associations using Stouffer’s method. The tool has been implemented so that it can be easily adapted to incorporate other protein features, such as domain data from other sources, amino acid k-mers and motifs. The DomFun Ruby gem is available from https://rubygems.org/gems/DomFun. Code maintained at https://github.com/ElenaRojano/DomFun. Validation procedure scripts can be found at https://github.com/ElenaRojano/DomFun_project.

Care Outcomes for Chiropractic Outpatient Veterans (COCOV): a qualitative study with veteran stakeholders from a pilot trial of multimodal chiropractic care

Background Low back pain (LBP) is common among military veterans seeking treatment in Department of Veterans Affairs (VA) healthcare facilities. As chiropractic services within VA expand, well-designed pragmatic trials and implementation studies are needed to assess clinical effectiveness and program uptake. This study evaluated veteran stakeholder perceptions of the feasibility and acceptability of care delivery and research processes in a pilot trial of multimodal chiropractic care for chronic LBP. Methods The qualitative study was completed within a mixed-method, single-arm, pragmatic, pilot clinical trial of chiropractic care for LBP conducted in VA chiropractic clinics. Study coordinators completed semi-structured, in person or telephone interviews with veterans near the end of the 10-week trial. Interviews were audiorecorded and transcribed verbatim. Qualitative content analysis using a directed approach explored salient themes related to trial implementation and delivery of chiropractic services. Results Of 40 participants, 24 completed interviews (60% response; 67% male gender; mean age 51.7 years). Overall, participants considered the trial protocol and procedures feasible and reported that the chiropractic care and recruitment methods were acceptable. Findings were organized into 4 domains, 10 themes, and 21 subthemes. Chiropractic service delivery domain encompassed 3 themes/8 subthemes: scheduling process (limited clinic hours, scheduling future appointments, attendance barriers); treatment frequency (treatment sufficient for LBP complaint, more/less frequent treatments); and chiropractic clinic considerations (hire more chiropractors, including female chiropractors; chiropractic clinic environment; patient-centered treatment visits). Outcome measures domain comprised 3 themes/4 subthemes: questionnaire burden (low burden vs. time-consuming or repetitive); relevance (items relevant for LBP study); and timing and individualization of measures (questionnaire timing relative to symptoms, personalized approach to outcomes measures). The online data collection domain included 2 themes/4 subthemes: user concerns (little difficulty vs. form challenges, required computer skills); and technology issues (computer/internet access, junk mail). Clinical trial planning domain included 2 themes/5 subthemes: participant recruitment (altruistic service by veterans, awareness of chiropractic availability, financial compensation); and communication methods (preferences, potential barriers). Conclusions This qualitative study highlighted veteran stakeholders’ perceptions of VA-based chiropractic services and offered important suggestions for conducting a full-scale, veteran-focused, randomized trial of multimodal chiropractic care for chronic LBP in this clinical setting. Trial registration ClinicalTrials.govNCT03254719

Assessing Neurofilaments as Biomarkers of Neuroprotection in Progressive Multiple Sclerosis

Background and ObjectivesImproved biomarkers of neuroprotective treatment are needed in progressive multiple sclerosis (PMS) to facilitate more efficient phase 2 trial design. The MS-STAT randomized controlled trial supported the neuroprotective potential of high-dose simvastatin in secondary progressive MS (SPMS). Here, we analyze serum from the MS-STAT trial to assess the extent to which neurofilament light (NfL) and neurofilament heavy (NfH), both promising biomarkers of neuroaxonal injury, may act as biomarkers of simvastatin treatment in SPMS.MethodsThe MS-STAT trial randomized patients to 80 mg simvastatin or placebo. Serum was analyzed for NfL and NfH using Simoa technology. We used linear mixed models to investigate the treatment effects of simvastatin compared with placebo on NfL and NfH. Additional models examined the relationships between neurofilaments and MRI and clinical measures of disease severity.ResultsA total of 140 patients with SPMS were included. There was no evidence for a simvastatin treatment effect on NfL or NfH: compared with placebo, NfL was 1.2% lower (95% CI 10.6% lower to 9.2% higher; p = 0.820) and NfH was 0.4% lower (95% CI 18.4% lower to 21.6% higher; p = 0.969) in the simvastatin treatment group. Secondary analyses suggested that higher NfL was associated with greater subsequent whole brain atrophy, higher T2 lesion volume, and more new/enlarging T2 lesions in the previous 12 months, as well as greater physical disability. There were no significant associations between NfH and MRI or clinical variables.DiscussionWe found no evidence of a simvastatin treatment effect on serum neurofilaments. While confirmation of the neuroprotective benefits of simvastatin is awaited from the ongoing phase 3 study (NCT03387670), our results suggest that treatments capable of slowing the rate of whole brain atrophy in SPMS, such as simvastatin, may act via mechanisms largely independent of neuroaxonal injury, as quantified by NfL. This has important implications for the design of future phase 2 clinical trials in PMS.Trial Registration InformationMS-STAT: NCT00647348.Classification of EvidenceThis study provides class I evidence that simvastatin treatment does not have a large impact on either serum NfL or NfH, as quantified in this study, in SPMS.

A randomized crossover study of functional electrical stimulation during walking in spastic cerebral palsy: the FES on participation (FESPa) trial

Background Spastic cerebral palsy is the most common cause of motor disability in children. It often leads to foot drop or equinus, interfering with walking. Ankle-foot orthoses (AFOs) are commonly used in these cases. However, AFOs can be too restrictive for mildly impaired patients. Functional electrical stimulation (FES) of the ankle-dorsiflexors is an alternative treatment as it could function as a dynamic functional orthosis. Despite previous research, high level evidence on the effects of FES on activities and participation in daily life is missing. The primary aim of this study is to evaluate whether FES improves the activity and participation level in daily life according to patients, and the secondary aim is to provide evidence of the effect of FES at the level of body functions and activities. Furthermore, we aim to collect relevant information for decisions on its clinical implementation. Methods A randomized crossover trial will be performed on 25 children with unilateral spastic cerebral palsy. Patients aged between 4 and 18 years, with Gross Motor Functioning Classification System level I or II and unilateral foot drop of central origin, currently treated with AFO or adapted shoes, will be included. All participants will undergo twelve weeks of conventional treatment (AFO/adapted shoes) and 12 weeks of FES treatment, separated by a six-week washout-phase. FES treatment consists of wearing the WalkAide® device, with surface electrodes stimulating the peroneal nerve during swing phase of gait. For the primary objective, the Goal Attainment Scale is used to test whether FES improves activities and participation in daily life. The secondary objective is to prove whether FES is effective at the level of body functions and structures, and activities, including ankle kinematics and kinetics measured during 3D-gait analysis and questionnaire-based frequency of falling. The tertiary objective is to collect relevant information for clinical implementation, including acceptability using the device log file and side effect registration, cost-effectiveness based on quality adjusted life years (QALYs) and clinical characteristics for patient selection. Discussion We anticipate that the results of this study will allow evidence-based use of FES during walking in children with unilateral spastic cerebral palsy. Trial registration ClinicalTrials.gov: NCT03440632.

Central Vein Sign Profile of Newly Developing Lesions in Multiple Sclerosis

Background and ObjectivesThe central vein sign (CVS), a central linear hypointensity within lesions on T2*-weighted imaging, has been established as a sensitive and specific biomarker for the diagnosis of multiple sclerosis (MS). However, the CVS has not yet been comprehensively studied in newly developing MS lesions. We aimed to identify the CVS profiles of new white matter lesions in patients with MS followed over time and investigate demographic and clinical risk factors associated with new CVS+ or CVS− lesion development.MethodsIn this retrospective longitudinal cohort study, adults from the NIH MS Natural History Study were considered for inclusion. Participants with new T2 or enhancing lesions were identified through review of the radiology report and/or longitudinal subtraction imaging. Each new lesion was evaluated for the CVS. Clinical characteristics were identified through chart review.ResultsA total of 153 adults (95 relapsing-remitting MS, 27 secondary progressive MS, 16 primary progressive MS, 5 clinically isolated syndrome, and 10 healthy; 67% female) were included. Of this cohort, 96 had at least 1 new T2 or contrast-enhancing lesion during median 3.1 years (Q1–Q3: 0.7–6.3) of follow-up; lesions eligible for CVS evaluation were found in 62 (65%). Of 233 new CVS-eligible lesions, 159 (68%) were CVS+, with 30 (48%) individuals having only CVS+, 12 (19%) only CVS−, and 20 (32%) both CVS+ and CVS− lesions. In gadolinium-enhancing (Gd+) lesions, the CVS+ percentage increased from 102/152 (67%) at the first time point where the lesion was observed, to 92/114 (82%) after a median follow-up of 2.8 years. Younger age (OR = 0.5 per 10-year increase, 95% CI = 0.3–0.8) and higher CVS+ percentage at baseline (OR = 1.4 per 10% increase, 95% CI = 1.1–1.9) were associated with increased likelihood of new CVS+ lesion development.DiscussionIn a cohort of adults with MS followed over a median duration of 3 years, most newly developing T2 or enhancing lesions were CVS+ (68%), and nearly half (48%) developed new CVS+ lesions only. Importantly, the effects of edema and T2 signal changes can obscure small veins in Gd+ lesions; therefore, caution and follow-up is necessary when determining their CVS status.Trial Registration InformationClinical trial registration number NCT00001248.Classification of EvidenceThis study provides Class III evidence that younger age and higher CVS+ percentage at baseline are associated with new CVS+ lesion development.

Aird: a computation-oriented mass spectrometry data format enables a higher compression ratio and less decoding time

Background With the precision of the mass spectrometry (MS) going higher, the MS file size increases rapidly. Beyond the widely-used open format mzML, near-lossless or lossless compression algorithms and formats emerged in scenarios with different precision requirements. The data precision is often related to the instrument and subsequent processing algorithms. Unlike storage-oriented formats, which focus more on lossless compression rate, computation-oriented formats concentrate as much on decoding speed as the compression rate. Results Here we introduce “Aird”, an opensource and computation-oriented format with controllable precision, flexible indexing strategies, and high compression rate. Aird provides a novel compressor called Zlib-Diff-PforDelta (ZDPD) for m/z data. Compared with Zlib only, m/z data size is about 55% lower in Aird average. With the high-speed decoding and encoding performance of the single instruction multiple data technology used in the ZDPD, Aird merely takes 33% decoding time compared with Zlib. We have downloaded seven datasets from ProteomeXchange and Metabolights. They are from different SCIEX, Thermo, and Agilent instruments. Then we convert the raw data into mzML, mgf, and mz5 file formats by MSConvert and compare them with Aird format. Aird uses JavaScript Object Notation for metadata storage. Aird-SDK is written in Java, and AirdPro is a GUI client for vendor file converting written in C#. They are freely available at https://github.com/CSi-Studio/Aird-SDK and https://github.com/CSi-Studio/AirdPro. Conclusions With the innovation of MS acquisition mode, MS data characteristics are also constantly changing. New data features can bring more effective compression methods and new index modes to achieve high search performance. The MS data storage mode will also become professional and customized. ZDPD uses multiple MS digital features, and researchers also can use it in other formats like mzML. Aird is designed to become a computing-oriented data format with high scalability, compression rate, and fast decoding speed.

Efficacy of repetitive transcranial magnetic stimulation (rTMS) for reducing consumption in patients with alcohol use disorders (ALCOSTIM): study protocol for a randomized controlled trial

Background The number of people with an alcohol use disorder (AUD) was recently estimated to be 63.5 million worldwide. The global burden of disease and injury attributable to alcohol is considerable: about 3 million deaths, namely one in 20, were caused by alcohol in 2015. At the same time, AUD remains seriously undertreated. In this context, alternative or adjunctive therapies such as brain stimulation could play an important role. The early results of studies using repetitive transcranial magnetic stimulation (rTMS) suggest that stimulations delivered to the dorsolateral prefrontal cortex significantly reduce cravings and improve decision-making processes in various addictive disorders. We therefore hypothesize that rTMS could lead to a decrease in alcohol consumption in patients with AUD. Methods/design We report the protocol of a randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the efficacy of rTMS on alcohol reduction in individuals diagnosed with AUD. The study will be conducted in 2 centers in France. Altogether, 144 subjects older than 18 years and diagnosed with AUD will be randomized to receive 5 consecutive twice-daily sessions of either active or sham rTMS (10 Hz over the right DLPFC, 2000 pulses per day). The main outcomes of the study will be changes in alcohol consumption within the 4 weeks after the rTMS sessions. Secondary outcome measures will include changes in alcohol consumption within the 24 weeks, alcohol cravings, clinical and biological improvements, effects on mood and quality of life, and cognitive and safety assessments, and, for smokers, an assessment of the effects of rTMS on tobacco consumption. Discussion Several studies have observed a beneficial effect of rTMS on substance use disorders by reducing craving, impulsivity, and risk-taking behavior and suggest that rTMS may be a promising treatment in addiction. However, to date, no studies have included sufficiently large samples and sufficient follow-up to confirm this hypothesis. The results from this large randomized controlled trial will give a better overview of the therapeutic potential of rTMS in AUD. Trial registration ClinicalTrials.gov NCT04773691. Registered on 26 February 2021 https://clinicaltrials.gov/ct2/show/NCT04773691?term=trojak&draw=2&rank=5.

Genomic evolution of the globally disseminated multidrug-resistant Klebsiella pneumoniae clonal group 147

The rapid emergence of multidrug-resistant Klebsiella pneumoniae is being driven largely by the spread of specific clonal groups (CGs). Of these, CG147 includes 7-gene multilocus sequence typing (MLST) sequence types (STs) ST147, ST273 and ST392. CG147 has caused nosocomial outbreaks across the world, but its global population dynamics remain unknown. Here, we report a pandrug-resistant ST147 clinical isolate from India (strain DJ) and define the evolution and global emergence of CG147. Antimicrobial-susceptibility testing following European Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines and genome sequencing (Illumina and Oxford Nanopore Technologies, Unicycler assembly) were performed on strain DJ. Additionally, we collated 217 publicly available CG147 genomes [National Center for Biotechnology Information (NCBI), May 2019]. CG147 evolution was inferred within a temporal phylogenetic framework (beast) based on a recombination-free sequence alignment (Roary/Gubbins). Comparative genomic analyses focused on resistance and virulence genes and other genetic elements (BIGSdb, Kleborate, PlasmidFinder, phaster, ICEfinder and CRISPRCasFinder). Strain DJ had a pandrug-resistance phenotype. Its genome comprised the chromosome, seven plasmids and one linear phage-plasmid. Four carbapenemase genes were detected: bla NDM-5 and two copies of bla OXA-181 in the chromosome, and a second copy of bla NDM-5 on an 84 kb IncFII plasmid. CG147 genomes carried a mean of 13 acquired resistance genes or mutations; 63 % carried a carbapenemase gene and 83 % harboured bla CTX-M. All CG147 genomes presented GyrA and ParC mutations and a common subtype I-E CRISPR-Cas system. ST392 and ST273 emerged in 2005 and 1995, respectively. ST147, the most represented phylogenetic branch, was itself divided into two main clades with distinct capsular loci: KL64 (74 %, DJ included, emerged in 1994 and disseminated worldwide, with carbapenemases varying among world regions) and KL10 (20 %, emerged in 2002, predominantly found in Asian countries, associated with carbapenemases NDM and OXA-48-like). Furthermore, subclades within ST147-KL64 differed at the yersiniabactin locus, OmpK35/K36 mutations, plasmid replicons and prophages. The absence of IncF plasmids in some subclades was associated with a possible activity of a CRISPR-Cas system. K. pneumoniae CG147 comprises pandrug-resistant or extensively resistant isolates, and carries multiple and diverse resistance genes and mobile genetic elements, including chromosomal bla NDM-5. Its emergence is being driven by the spread of several phylogenetic clades marked by their own genomic features and specific temporo–spatial dynamics. These findings highlight the need for precision surveillance strategies to limit the spread of particularly concerning CG147 subsets.