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An FPGA-based hardware accelerator supporting sensitive sequence homology filtering with profile hidden Markov models

Abstract Background Sequence alignment lies at the heart of genome sequence annotation. While the BLAST suite of alignment tools has long held an important role in alignment-based sequence database search, greater sensitivity is achieved through the use of profile hidden Markov models (pHMMs). Here, we describe an FPGA hardware accelerator, called HAVAC, that targets a key bottleneck step (SSV) in the analysis pipeline of the popular pHMM alignment tool, HMMER. Results The HAVAC kernel calculates the SSV matrix at 1739 GCUPS on a $$\sim$$ ∼ $3000 Xilinx Alveo U50 FPGA accelerator card, $$\sim$$ ∼ 227× faster than the optimized SSV implementation in nhmmer . Accounting for PCI-e data transfer data processing, HAVAC is 65× faster than nhmmer’s SSV with one thread and 35× faster than nhmmer with four threads, and uses $$\sim$$ ∼ 31% the energy of a traditional high end Intel CPU. Conclusions HAVAC demonstrates the potential offered by FPGA hardware accelerators to produce dramatic speed gains in sequence annotation and related bioinformatics applications. Because these computations are performed on a co-processor, the host CPU remains free to simultaneously compute other aspects of the analysis pipeline.

59 BASIC BIOLOGICAL SCIENCES↗

Chimera Spectrum Diagnostics for Peptides Using Two-Dimensional Partial Covariance Mass Spectrometry

The rate of successful identification of peptide sequences by tandem mass spectrometry (MS/MS) is adversely affected by the common occurrence of co-isolation and co-fragmentation of two or more isobaric or isomeric parent ions. This results in so-called `chimera spectra’, which feature peaks of the fragment ions from more than a single precursor ion. The totality of the fragment ion peaks in chimera spectra cannot be assigned to a single peptide sequence, which contradicts a fundamental assumption of the standard automated MS/MS spectra analysis tools, such as protein database search engines. This calls for a diagnostic method able to identify chimera spectra to single out the cases where this assumption is not valid. Here, we demonstrate that, within the recently developed two-dimensional partial covariance mass spectrometry (2D-PC-MS), it is possible to reliably identify chimera spectra directly from the two-dimensional fragment ion spectrum, irrespective of whether the co-isolated peptide ions are isobaric up to a finite mass accuracy or isomeric. We introduce ‘3-57 chimera tag’ technique for chimera spectrum diagnostics based on 2D-PC-MS and perform numerical simulations to examine its efficiency. We experimentally demonstrate the detection of a mixture of two isomeric parent ions, even under conditions when one isomeric peptide is at one five-hundredth of the molar concentration of the second isomer.

47 OTHER INSTRUMENTATION↗

Improving Peptide-Level Mass Spectrometry Analysis via Double Competition

A critical statistical task in the analysis of shotgun proteomics data involves controlling the false discovery rate (FDR) among the reported set of discoveries. This task is most commonly solved at the peptide-spectrum match (PSM) level by using target-decoy competition (TDC), in which a set of observed spectra are searched against a database containing a mixture of real (target) and decoy peptides. The PSM-level procedure can be adapted to the peptide level by selecting the top-scoring PSM per peptide prior to FDR estimation. Here, we investigate both PSM-level and peptide-level FDR control methods and come to two conclusions. First, although the TDC procedure is provably correct under certain assumptions, we observe that one of these assumptions - that incorrect PSMs are independent of one another - is frequently violated. Hence, we empirically demonstrate that TDC-based PSM-level FDR estimates can be liberally biased. Further, we propose that researchers avoid PSM-level results and instead focus on peptide-level analysis. Second, we investigate three ways to carry out peptide level TDC and show that the most common method ("PSM-only") offers the lowest statistical power in practice. The most powerful method, peptide-level FDR with PSM competition ("PSM-and-peptide"), carries out competition first at the PSM level and then again at the peptide level. In our experiments, this approach yields an average increase of 17% more discovered peptides at a1% FDR threshold relative to the PSM-only method.

59 BASIC BIOLOGICAL SCIENCES↗

RNAcentral 2021: secondary structure integration, improved sequence search and new member databases

RNAcentral is a comprehensive database of non-coding RNA (ncRNA) sequences that provides a single access point to 44 RNA resources and >18 million ncRNA sequences from a wide range of organisms and RNA types. RNAcentral now also includes secondary (2D) structure information for >13 million sequences, making RNAcentral the world’s largest RNA 2D structure database. The 2D diagrams are displayed using R2DT, a new 2D structure visualization method that uses consistent, reproducible and recognizable layouts for related RNAs. The sequence similarity search has been updated with a faster interface featuring facets for filtering search results by RNA type, organism, source database or any keyword. This sequence search tool is available as a reusable web component, and has been integrated into several RNAcentral member databases, including Rfam, miRBase and snoDB. To allow for a more fine-grained assignment of RNA types and subtypes, all RNAcentral sequences have been annotated with Sequence Ontology terms. The RNAcentral database continues to grow and provide a central data resource for the RNA community. RNAcentral is freely available at https://rnacentral.org.

59 BASIC BIOLOGICAL SCIENCES↗

Patient-Reported Outcomes in Pediatric Cancer Registration Trials: A US Food and Drug Administration Perspective

Pediatric patient-reported outcome (PRO) data can help inform the US Food and Drug Administration’s (FDA’s) benefit-risk assessment of cancer therapeutics by quantifying symptom and functional outcomes from the patient’s perspective. This study assessed use of PROs in commercial pediatric oncology trials submitted to the FDA for regulatory review. FDA databases were searched to identify pediatric oncology product applications approved between 1997 and 2020. Sponsor-submitted documents were reviewed to determine whether PRO data were collected, which instruments were used, and the quality of collected data (ie, sample size, completion rates, and use of fit-for-purpose instruments). The role of PROs in each trial (endpoint hierarchy) was also recorded in addition to whether any PRO endpoints were included in product labeling. We reviewed 17 pediatric oncology applications, 4 of which included PRO data: denosumab, tisagenlecleucel, larotrectinib, and selumetinib. In these 4 instances, PROs served as exploratory endpoints and were not incorporated in product labeling. Trials that collected PRO data were phase II or phase I/II single-arm studies with sample sizes of 28 to 88 patients. Symptomatic adverse events (AEs) were characterized using clinician-reported Common Terminology Criteria for Adverse Events (CTCAE) without additional patient self-report. PROs were infrequently used in pediatric cancer registration trials. When PROs were used, PRO data were limited by lack of a clear research objective and corresponding prospective statistical analysis plan. Contemporary PRO symptom libraries, such as the National Cancer Institute’s Pediatric PRO-CTCAE, may provide an opportunity to better evaluate the occurrence and impact of symptomatic AEs, from the patient’s perspective, in pediatric oncology trials.

Oncology↗

Untargeted, tandem mass spectrometry (LC/MS-MS) metaproteomes from soil samples in control and warming plots in Blodgett Forest, CA (2014-2021)

The pathways of carbon transport and loss through and from soils—soil organic matter (SOM) depolymerization to dissolved organic carbon and mineralization to carbon dioxide (CO2)—are fundamentally driven by microbial activity, which is strongly regulated by environmental conditions. As part of Lawrence Berkeley National Laboratory (LBNL) Terrestrial Ecosystem Science (TES) Belowground Biogeochemistry Science Focus Area (SFA), we have established a novel whole-soil long-term warming experiment at the University of California (UC) Blodgett Forest Research Station (Sierra Nevada) in 2014, where we study the role of biogeochemical, microbial and geochemical process interactions in SOM decomposition and stabilization. This package contains soil metaproteomics data in the context of site specific metagenomes from soil depth profiles in three paired control and warming plots from a temperate mixed forest in Northern California. Each paired plot had been subjected to experimental warming since June 2014 to simulate a predicted climate change scenario for northern California. These metaproteomes were collected in 2018 after 4.5 years of warming from five depth intervals (0-10 cm, 10-30 cm, 30-45 cm, 45-60 cm, 60-80 cm). For protein identification, the collected spectra were searched following a target-decoy search strategy against a database of metagenome predicted proteins (covering 96 samples from 2014 to 2021) representing the complete sequence diversity at the site. Data was searched with mass spectrometry database search tool (MS-GF+) using Pacific Northwest National Laboratory (PNNL)'s Data Management System (DMS) Processing pipeline. The metagenomes are published as part of another data package. Raw metaproteomic data and the data products from MS-GF+ are deposited in the Mass Spectrometry Interactive Virtual Environment (MassIVE) database under accession no. MSV000097826. Here we present a dataset that includes spectral counts for the detected proteins across samples (EMSL50964_BrodieAllMAGs_Globals_SC.txt), the sequences of the detected proteins, and sample metadata file that contains site information for the soil metaproteome samples.

Belowground Biogeochemistry Science Focus Area↗

MultiPhATE2: code for functional annotation and comparison of phage genomes

To address a need for improved tools for annotation and comparative genomics of bacteriophage genomes, we developed multiPhATE2. As an extension of multiPhATE, a functional annotation code released previously, multiPhATE2 performs gene finding using multiple algorithms, compares the results of the algorithms, performs functional annotation of coding sequences, and incorporates additional search algorithms and databases to extend the search space of the original code. MultiPhATE2 performs gene matching among sets of closely related bacteriophage genomes, and uses multiprocessing to speed computations. MultiPhATE2 can be re-started at multiple points within the workflow to allow the user to examine intermediate results and adjust the subsequent computations accordingly. In addition, multiPhATE2 accommodates custom gene calls and sequence databases, again adding flexibility. MultiPhATE2 was implemented in Python 3.7 and runs as a command-line code under Linux or MAC operating systems. Full documentation is provided as a README file and a Wiki website.

59 BASIC BIOLOGICAL SCIENCES↗

Search for Solar Flare Neutrinos with the KamLAND Detector

Abstract We report the result of a search for neutrinos in coincidence with solar flares from the GOES flare database. The search was performed on a 10.8 kton-year exposure of KamLAND collected from 2002 to 2019. This large exposure allows us to explore previously unconstrained parameter space for solar flare neutrinos. We found no statistical excess of neutrinos and established 90% confidence level upper limits of 8.4 × 10 7 cm −2 (3.0 × 10 9 cm −2 ) on the electron antineutrino (electron neutrino) fluence at 20 MeV normalized to the X12 flare, assuming that the neutrino fluence is proportional to the X-ray intensity.

79 ASTRONOMY AND ASTROPHYSICS↗

Expansion of the tmRNA sequence database and new tools for search and visualization

Abstract Transfer–messenger RNA (tmRNA) contributes essential tRNA-like and mRNA-like functions during the process of trans-translation, a mechanism of quality control for the translating bacterial ribosome. Proper tmRNA identification benefits the study of trans-translation and also the study of genomic islands, which frequently use the tmRNA gene as an integration site. Automated tmRNA gene identification tools are available, but manual inspection is still important for eliminating false positives. We have increased our database of precisely mapped tmRNA sequences over 50-fold to 97 179 unique sequences. Group I introns had previously been found integrated within a single subsite within the TψC-loop; they have now been identified at four distinct subsites, suggesting multiple founding events of invasion of tmRNA genes by group I introns, all in the same vicinity. tmRNA genes were found in metagenomic archaeal genomes, perhaps a result of misbinning of bacterial sequences during genome assembly. With the expanded database, we have produced new covariance models for improved tmRNA sequence search and new secondary structure visualization tools.

59 BASIC BIOLOGICAL SCIENCES↗

Exact and Fixed-Point Grover Search with Qudits

Grover's algorithm provides a quadratic speedup for searching unstructured databases and is traditionally implemented with qubits in Hilbert spaces whose dimensions are powers of two. With the advent of quantum platforms utilizing qudits---quantum systems with more than two levels---there is a need to generalize Grover search to these architectures, including heterogeneous systems with qudits of varying dimensions. Here, we present a unified framework for qudit-based Grover search, detailing the construction of oracles and diffusion operators with and without ancilla qubits and generalizing deterministic and fixed-point search variants that ensure exact or bounded success probabilities. We analyze phase-matching techniques and provide explicit circuit decompositions suitable for diverse hardware platforms. We also compare the corresponding trajectories on the Bloch sphere to provide an intuitive visualization of how the different phase choices amplify the target state. These results facilitate flexible, hardware-oriented protocols for implementing Grover search on qudit processors, potentially reducing circuit depth and enhancing success probabilities, thereby offering a practical toolkit for quantum computation and sensing applications leveraging multilevel quantum systems.

Roy, Tanay [Fermilab] (ORCID:000000019442862X)↗

Hit Expansion of a Noncovalent SARS-CoV-2 Main Protease Inhibitor

Inhibition of the SARS-CoV-2 main protease (M pro ) is a major focus of drug discovery efforts against COVID-19. Here we report a hit expansion of non-covalent inhibitors of M pro . Starting from a recently discovered scaffold (The COVID Moonshot Consortium. Open Science Discovery of Oral Non-Covalent SARS-CoV-2 Main Protease Inhibitor Therapeutics. bioRxiv 2020.10.29.339317) represented by an isoquinoline series, we searched a database of over a billion compounds using a cheminformatics molecular fingerprinting approach. We identified and tested 48 compounds in enzyme inhibition assays, of which 21 exhibited inhibitory activity above 50% at 20 μM. Among these, four compounds with IC 50 values around 1 μM were found. Interestingly, despite the large search space, the isoquinolone motif was conserved in each of these four strongest binders. Room-temperature X-ray structures of co-crystallized protein–inhibitor complexes were determined up to 1.9 Å resolution for two of these compounds as well as one of the stronger inhibitors in the original isoquinoline series, revealing essential interactions with the binding site and water molecules. Molecular dynamics simulations and quantum chemical calculations further elucidate the binding interactions as well as electrostatic effects on ligand binding. The results help explain the strength of this new non-covalent scaffold for M pro inhibition and inform lead optimization efforts for this series, while demonstrating the effectiveness of a high-throughput computational approach to expanding a pharmacophore library.

60 APPLIED LIFE SCIENCES↗

The Evolution of Randomized Clinical Trial Designs to Assess Therapeutics in Alzheimer Disease

Importance The success of recent randomized clinical trials (RCTs) for Alzheimer disease (AD), particularly those focusing on anti-amyloid therapies, has been discussed at length. However, the evolution of RCT design features for AD that preceded this success remain underexplored. Objective To describe temporal changes in the features of RCT design for interventions in AD. Evidence Review PubMed, Scopus, and Web of Science databases were searched in January 2025 for phase 2 and 3 AD RCTs published between January 1992 and December 2024. RCTs that investigated an intervention for AD, with a placebo or standard-of-care control group, were included. Four assessors independently reviewed full-text articles to capture study characteristics. Main Outcomes and Measures The number of participants and the duration of RCTs as well as the target population, outcomes, and funding were extracted from published reports. These features were analyzed with respect to time using linear regression and χ 2 analyses. Results The study included 203 RCTs with 79 589 participants testing interventions in AD. From 1992 to 2024, the mean sample size increased by 464% for phase 2 RCTs (from 42 to 237), and 50% for phase 3 RCTs (from 632 to 951), while the mean trial duration increased by 188% (from 16 to 46 weeks) for phase 2, and 256% (from 20 to 71 weeks) for phase 3 RCTs. This longer duration of RCTs may be partially attributed by a greater share of disease-modifying rather than symptomatic treatments. Similarly, more recent trials required AD biomarker evidence for enrollment (from 1 of 36 [2.7%] before 2006 to 40 of 76 [52.6%] since 2019). A substantial difference in the type of therapeutics researched was observed, with anti-amyloid and anti-tau RCTs being more likely to be funded by the pharmaceutical industry compared with neurotransmitter or other RCTs (anti-amyloid or anti-tau, 68 of 71 [95.8%]; neurotransmitter, 52 of 69 [77.6%]; other, 33 of 52 [63.5%]). RCT transparency improved, with more frequent data accessibility statements, registered reports, and better reporting on race and ethnicity. Conclusions and Relevance This methodology research of AD RCTs highlights substantial changes in key features of AD clinical trials from 1992 to 2024. AD RCTs have become larger and longer, such that they are powered to detect smaller clinical differences. The increased sample sizes and duration should enable the detection of smaller and more slowly occurring outcomes, which may lead to successful RCTs of therapies with slower and more subtle efficacy.

General & Internal Medicine↗

The use of teledentistry in facilitating oral health for older adults: A scoping review

Teledentistry is used in many countries to provide oral health care services. However, using teledentistry to provide oral health care services for older adults is not well documented. This knowledge gap needs to be addressed, especially when accessing a dental clinic is not possible and teledentistry might be the only way for many older adults to receive oral health care services. Nine databases were searched and 3,396 studies were screened using established eligibility criteria. Included studies were original research or review articles in which the intervention of interest was delivered to an older adult population (≥ 60 years) via teledentistry. The authors followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Review criteria. Nineteen studies were identified that met the criteria for inclusion. Only 1 study was from the United States. Seven studies had results focusing on older adult participants only, with most of those conducted in elder care facilities. The remainder consisted of studies with mixed-age populations reporting distinct results or information for older adults. The included studies used teledentistry, in both synchronous and asynchronous modes, to provide services such as diagnosis, oral hygiene promotion, assessment and referral of oral emergencies, and postintervention follow-up. Teledentistry comprises a variety of promising apps. Lastly, the authors identified and described uses, promising possibilities, and limitations of teledentistry to improve the oral health of older adults.

60 APPLIED LIFE SCIENCES↗

Seeking help for perinatal depression and anxiety: a systematic review of systematic reviews from an interdependent perspective

Abstract Background Seeking help for perinatal mood and anxiety disorders is crucial for women’s mental health and babies’ development, yet many women do not seek help for their condition and remain undiagnosed and untreated. This systematic review of systematic reviews aimed at summarizing and synthesizing findings from all systematic reviews on seeking help for PMAD in the context of interdependence theory, highlighting the interdependent relationship between women and healthcare providers and how it may impact women’s seeking-help process. Methods Four electronic databases were searched, and 18 studies published up to 2023 met inclusion criteria for review. Results The capability, opportunity and motivation model of behavior was used as a framework for organizing and presenting the results. Results demonstrate that seeking help for PMAD is a function of the interdependent relationship between perinatal women’s and healthcare providers’ psychological and physical capabilities, social and physical opportunities, and their reflective and automatic motivation. Conclusions Unmet needs in perinatal mental healthcare is an important public health problem. This systematic review of systematic reviews highlights key factors for policymakers, researchers, and practitioners to consider to optimize healthcare systems and interventions in a way that enhances perinatal women’s treatment whenever necessary.

Bina, Rena (ORCID:0000000340729229)↗

Implementation of early psychosis services in Latin America: A scoping review

Abstract Aim The evidence of the effectiveness and cost‐effectiveness of early intervention for psychosis (EIP) services has motivated their implementation worldwide. However, complex interventions of such EIP services require local adaptations to successfully match population needs and cultural differences. Latin America is a heterogenous region where EIP services are progressively being adopted. Our aim is to map such initiatives in the region with a focus on implementation outcomes. Methods A scoping review following the Preferred Reporting Items for Systematic review and Meta‐Analysis extension for Scoping Reviews guidelines was conducted. International and regional databases were searched for publications describing EIP programmes in the region. Besides mapping the services, we described implementation outcomes based on the Standards for Reporting Implementation Studies Checklist. Results Ten articles describing seven EIP initiatives from the region were found. Four countries were represented: Argentina, Brazil, Chile and Mexico. The implementation outcomes reporting was heterogenous, although it was possible to ascertain EIP services are feasible and adequate for the region's context. Also, there is some evidence of effectiveness in terms of reducing hospitalizations and improving symptoms. Information about fidelity measures was scarce and there was no information about costs or cost‐effectiveness. Conclusions Only a small proportion of Latin American countries have adopted EIP services. Although these programmes seem to be feasible and effective, data on other implementation outcomes, such as fidelity, cultural appropriateness, cost‐effectiveness and affordability are not available. This might in part explain why this effective approach has not been yet scaled‐up at nationwide levels.

Aceituno, David↗

Database of low‐temperature absorption and fluorescence spectra of native photosynthetic tetrapyrrole macrocycles

Low-temperature (77 K) absorption and fluorescence spectra of 12 naturally occurring photosynthetic tetrapyrrole macrocycles have been recorded in a frozen glass (2-methyltetrahydrofuran). The compounds encompass distinct chromophore classes: porphyrin, chlorophyll c 2 ; chlorin, chlorophylls a, b, d, f and bacteriochlorophylls c, d, e, f; and bacteriochlorin, bacteriochlorophylls a, b, g. The spectra are compared with those of the same pigment in liquid solution (predominantly 2-methyltetrahydrofuran) at room temperature (293 K). The measured Stokes shifts at 77 K across the 12 macrocycles range from ~30 to 300 cm −1 . The spectral data in digital form are made available as part of the PhotochemCAD databases. Literature searches have revealed extensive published data for Chl a (often in biological matrices) but at best rather limited data for less common macrocycles. The availability of a systematic collection of curated spectral data collected at low temperature should be useful for a variety of assessments, including reconstruction of absorption spectra of (bacterio)chlorophyll-containing protein complexes, vibrational analysis of absorption and fluorescence spectra, and calculations where knowledge of energy levels is important.

Niedzwiedzki, Dariusz M. [Washington University in↗

Pivotal trial characteristics and types of endpoints used to support Food and Drug Administration rare disease drug approvals between 2013 and 2022

Background/aims Rare disease drug development faces unique challenges, such as genotypic and phenotypic heterogeneity within small patient populations and a lack of established outcome measures for conditions without previously successful drug development programs. These challenges complicate the process of selecting the appropriate trial endpoints and conducting clinical trials in rare diseases. In this descriptive study, we examined novel drug approvals for non-oncologic rare diseases by the U.S. Food and Drug Administration’s Center for Drug Evaluation and Research over the past decade and characterized key regulatory and trial design elements with a focus on the primary efficacy endpoint utilized as the basis of approval. Methods Using the Food and Drug Administration’s Data Analysis Search Host database, we identified novel new drug applications and biologics license applications with orphan drug designation that were approved between 2013 and 2022 for non-oncologic indications. From Food and Drug Administration review documents and other external databases, we examined characteristics of pivotal trials for the included drugs, such as therapeutic area, trial design, and type of primary efficacy endpoints. Differences in trial design elements associated with primary efficacy endpoint type were assessed such as randomization and blinding. Then, we summarized the primary efficacy endpoint types utilized in pivotal trials by therapeutic area, approval pathway, and whether the disease etiology is well defined. Results One hundred and seven drugs that met our inclusion criteria were approved between 2013 and 2022. Assessment of the 107 drug development programs identified 150 pivotal trials that were subsequently analyzed. The pivotal trials were mostly randomized (80%) and blinded (69.3%). Biomarkers (41.1%) and clinical outcomes (42.1%) were commonly utilized as primary efficacy endpoints. Analysis of the use of clinical trial design elements across trials that utilized biomarkers, clinical outcomes, or composite endpoints did not reveal statistically significant differences. The choice of primary efficacy endpoint varied by the drug’s therapeutic area, approval pathway, and whether the indicated disease etiology was well defined. For example, biomarkers were commonly selected as primary efficacy endpoints in hematology drug approvals (70.6%), whereas clinical outcomes were commonly selected in neurology drug approvals (69.6%). Further, if the disease etiology was well defined, biomarkers were more commonly used as primary efficacy endpoints in pivotal trials (44.7%) than if the disease etiology was not well defined (27.3%). Discussion In the past 10 years, numerous novel drugs have been approved to treat non-oncologic rare diseases in various therapeutic areas. To demonstrate their efficacy for regulatory approval, biomarkers and clinical outcomes were commonly utilized as primary efficacy endpoints. Biomarkers were not only frequently used as surrogate efficacy endpoints in accelerated approvals, but also in traditionally approved rare disease drugs. The choice of primary efficacy endpoints varied by therapeutic area, approval pathway, and understanding of disease etiology.

Hong, Kyungwan [Rare Diseases Team, Office of New ↗

Quality appraisal of clinical practice guidelines for the management of Dysphagia after acute stroke

Objectives Dysphagia is a common complication in stroke patients, widely affecting recovery and quality of life after stroke. The objective of this systematic review is to identify the gaps that between evidence and practice by critically assessing the quality of clinical practice guidelines (CPGs) for management of dysphagia in stroke. Methods We systematically searched academic databases and guideline repositories between January 1, 2014, and August 1, 2023. The Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument was used by two authors to independently assess CPG quality. Results In a total of 14 CPGs included, we identified that three CPGs obtained a final evaluation of “high quality,” nine CPGs achieved “moderate quality” and two CPGs received “low quality.” The domain of “scope and purpose” achieved the highest mean score (91.1%) and the highest median (IQR) of 91.7% (86.1, 94.4%), while the domain of “applicability” received the lowest mean score (55.8%) and the lowest median (IQR) of 55.4% (43.2, 75.5%). Conclusion The CPG development group should pay more attention to improving the methodological quality according to the AGREE II instrument, especially in the domain of “applicability” and “stakeholder involvement;” and each item should be refined as much as possible.

Gao, Shi-Lin↗