Tag: pubmed

PLoS One. 2022 Oct 24;17(10):e0276609. doi: 10.1371/journal.pone.0276609. eCollection 2022.

ABSTRACT

Drug-target protein interaction (DTI) identification is fundamental for drug discovery and drug repositioning, because therapeutic drugs act on disease-causing proteins. However, the DTI identification process often requires expensive and time-consuming tasks, including biological experiments involving large numbers of candidate compounds. Thus, a variety of computation approaches have been developed. Of the many approaches available, chemo-genomics feature-based methods have attracted considerable attention. These methods compute the feature descriptors of drugs and proteins as the input data to train machine and deep learning models to enable accurate prediction of unknown DTIs. In addition, attention-based learning methods have been proposed to identify and interpret DTI mechanisms. However, improvements are needed for enhancing prediction performance and DTI mechanism elucidation. To address these problems, we developed an attention-based method designated the interpretable cross-attention network (ICAN), which predicts DTIs using the Simplified Molecular Input Line Entry System of drugs and amino acid sequences of target proteins. We optimized the attention mechanism architecture by exploring the cross-attention or self-attention, attention layer depth, and selection of the context matrixes from the attention mechanism. We found that a plain attention mechanism that decodes drug-related protein context features without any protein-related drug context features effectively achieved high performance. The ICAN outperformed state-of-the-art methods in several metrics on the DAVIS dataset and first revealed with statistical significance that some weighted sites in the cross-attention weight matrix represent experimental binding sites, thus demonstrating the high interpretability of the results. The program is freely available at https://github.com/kuratahiroyuki/ICAN.

PMID:36279284 | DOI:10.1371/journal.pone.0276609

JMIR Mhealth Uhealth. 2022 Oct 24;10(10):e35722. doi: 10.2196/35722.

ABSTRACT

BACKGROUND: Sensors and digital devices have revolutionized the measurement, collection, and storage of behavioral and physiological data, leading to the new term digital biomarkers.

OBJECTIVE: This study aimed to investigate the scope of clinical evidence covered by systematic reviews (SRs) of randomized controlled trials involving digital biomarkers.

METHODS: This scoping review was organized using the PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews) guidelines. With the search limited to English publications, full-text SRs of digital biomarkers included randomized controlled trials that involved a human population and reported changes in participants’ health status. PubMed and the Cochrane Library were searched with time frames limited to 2019 and 2020. The World Health Organization’s classification systems for diseases (International Classification of Diseases, Eleventh Revision), health interventions (International Classification of Health Interventions), and bodily functions (International Classification of Functioning, Disability, and Health [ICF]) were used to classify populations, interventions, and outcomes, respectively.

RESULTS: A total of 31 SRs met the inclusion criteria. The majority of SRs studied patients with circulatory system diseases (19/31, 61%) and respiratory system diseases (9/31, 29%). Most of the prevalent interventions focused on physical activity behavior (16/31, 52%) and conversion of cardiac rhythm (4/31, 13%). Looking after one’s health (physical activity; 15/31, 48%), walking (12/31, 39%), heart rhythm functions (8/31, 26%), and mortality (7/31, 23%) were the most commonly reported outcomes. In total, 16 physiological and behavioral data groups were identified using the ICF tool, such as looking after one’s health (physical activity; 14/31, 45%), walking (11/31, 36%), heart rhythm (7/31, 23%), and weight maintenance functions (7/31, 23%). Various digital devices were also studied to collect these data in the included reviews, such as smart glasses, smartwatches, smart bracelets, smart shoes, and smart socks for measuring heart functions, gait pattern functions, and temperature. A substantial number (24/31, 77%) of digital biomarkers were used as interventions. Moreover, wearables (22/31, 71%) were the most common types of digital devices. Position sensors (21/31, 68%) and heart rate sensors and pulse rate sensors (12/31, 39%) were the most prevalent types of sensors used to acquire behavioral and physiological data in the SRs.

CONCLUSIONS: In recent years, the clinical evidence concerning digital biomarkers has been systematically reviewed in a wide range of study populations, interventions, digital devices, and sensor technologies, with the dominance of physical activity and cardiac monitors. We used the World Health Organization’s ICF tool for classifying behavioral and physiological data, which seemed to be an applicable tool to categorize the broad scope of digital biomarkers identified in this review. To understand the clinical value of digital biomarkers, the strength and quality of the evidence on their health consequences need to be systematically evaluated.

PMID:36279171 | DOI:10.2196/35722

Clin Chem Lab Med. 2022 Oct 24. doi: 10.1515/cclm-2022-0642. Online ahead of print.

ABSTRACT

OBJECTIVES: Vitamin D-binding protein (VDBP), a serum transport protein for 25-hydroxyvitamin D [25(OH)D], has three common proteoforms which have co-localized amino acid variations and glycosylation. A monoclonal immunoassay was found to differentially detect VDBP proteoforms and methods using liquid chromatography-tandem mass spectrometry (LC-MS/MS) might be able to overcome this limitation. Previously developed multiple reaction monitoring LC-MS/MS methods for total VDBP quantification represent an opportunity to probe the potential effects of proteoforms on proteolysis, instrument response and quantification accuracy.

METHODS: VDBP was purified from homozygous human donors and quantified using proteolysis or acid hydrolysis and LC-MS/MS. An interlaboratory comparison was performed using pooled human plasma [Standard Reference Material^® 1950 (SRM 1950) Metabolites in Frozen Human Plasma] and analyses with different LC-MS/MS methods in two laboratories.

RESULTS: Several shared peptides from purified proteoforms were found to give reproducible concentrations [≤2.7% coefficient of variation (CV)] and linear instrument responses (R²≥0.9971) when added to human serum. Total VDBP concentrations from proteolysis or amino acid analysis (AAA) of purified proteoforms had ≤1.92% CV. SRM 1950, containing multiple proteoforms, quantified in two laboratories resulted in total VDBP concentrations with 7.05% CV.

CONCLUSIONS: VDBP proteoforms were not found to cause bias during quantification by LC-MS/MS, thus demonstrating that a family of proteins can be accurately quantified using shared peptides. A reference value was assigned for total VDBP in SRM 1950, which may be used to standardize methods and improve the accuracy of VDBP quantification in research and clinical samples.

PMID:36279170 | DOI:10.1515/cclm-2022-0642

J Med Internet Res. 2022 Oct 24;24(10):e39614. doi: 10.2196/39614.

ABSTRACT

BACKGROUND: In the past decade, patient-accessible electronic health record (PAEHR) systems have emerged as an important tool for health management both at the hospital level and individual level. However, little is known about the effects of PAEHR portals on the survivorship of patients with chronic health conditions (eg, cancer).

OBJECTIVE: This study aims to investigate the effects of the use of PAEHR portals on cancer survivors’ health outcomes and to examine the mediation pathways through patient-centered communication (PCC) and health self-efficacy.

METHODS: Data for this study were derived from the Health Information National Trends Survey (HINTS 5, Cycle 4) collected from February 2020 to June 2020. This study only involved respondents who reported having been diagnosed with cancer (N=626). Descriptive analyses were performed, and the mediation models were tested using Model 6 from the SPSS macro PROCESS. Statistically significant relationships among PAEHR portal use, PCC, health self-efficacy, and physical and psychological health were examined using bootstrapping procedures. In this study, we referred to the regression coefficients generated by min-max normalization as percentage coefficients (b_p). The 95% bootstrapped CIs were used with 10,000 resamplings.

RESULTS: No positive direct associations between PAEHR portal use and cancer survivors’ health outcomes were found. The results supported the indirect relationship between PAEHR portal use and cancer survivors’ psychological health via (1) PCC (b_p=0.029; β=.023, 95% CI .009-.054), and (2) PCC and health self-efficacy in sequence (b_p=0.006; β=.005, 95% CI .002-.014). Besides, the indirect association between PAEHR portal use and cancer survivors’ physical health (b_p=0.006; β=.004, 95% CI .002-.018) via sequential mediators of PCC and health self-efficacy was also statistically acknowledged.

CONCLUSIONS: This study offers empirical evidence about the significant role of PAEHR portals in delivering PCC, improving health self-efficacy, and ultimately contributing to cancer survivors’ physical and psychological health.

PMID:36279157 | DOI:10.2196/39614

Int J Biostat. 2022 Oct 24. doi: 10.1515/ijb-2022-0010. Online ahead of print.

ABSTRACT

In genome wide association studies (GWAS), researchers are often dealing with dichotomous and non-normally distributed traits, or a mixture of discrete-continuous traits. However, most of the current region-based methods rely on multivariate linear mixed models (mvLMMs) and assume a multivariate normal distribution for the phenotypes of interest. Hence, these methods are not applicable to disease or non-normally distributed traits. Therefore, there is a need to develop unified and flexible methods to study association between a set of (possibly rare) genetic variants and non-normal multivariate phenotypes. Copulas are multivariate distribution functions with uniform margins on the [0, 1] interval and they provide suitable models to deal with non-normality of errors in multivariate association studies. We propose a novel unified and flexible copula-based multivariate association test (CBMAT) for discovering association between a genetic region and a bivariate continuous, binary or mixed phenotype. We also derive a data-driven analytic p-value procedure of the proposed region-based score-type test. Through simulation studies, we demonstrate that CBMAT has well controlled type I error rates and higher power to detect associations compared with other existing methods, for discrete and non-normally distributed traits. At last, we apply CBMAT to detect the association between two genes located on chromosome 11 and several lipid levels measured on 1477 subjects from the ASLPAC study.

PMID:36279152 | DOI:10.1515/ijb-2022-0010

J Clin Child Adolesc Psychol. 2022 Oct 24:1-23. doi: 10.1080/15374416.2022.2127104. Online ahead of print.

ABSTRACT

OBJECTIVE: Meta-analyses were used to test associations of parental depression with child internalizing and externalizing problems, based on 107 cross-sectional and 127 longitudinal effects for 164,047 parent-child pairs in 112 studies published between 2009 and 2020.

METHOD: For each child, internalizing and externalizing problems were assessed with the same measure and source of data. Meta-analyses were conducted with random effects, multi-level Structural Equation Modeling with Bayesian estimation.

RESULTS: Mean Pearson rs between parental depression and children’s internalizing and externalizing problems were statistically significant in both cross-sectional (rs = .267 and .264) and longitudinal (rs = .207 and .194) analyses. The difference between the correlations of parental depression with internalizing versus externalizing problems was not statistically significant for cross-sectional or longitudinal effects. For both internalizing and externalizing problems, the cross-sectional correlation was significantly larger than the longitudinal correlation. Using the Lag as Moderator Meta-Analyses (LAMMA), evidence of a linear negative effect of the measurement interval between parental depression and child internalizing problems was found. In addition, several significant methodological moderators were found, with most implicating informant factors. Significant non-methodological moderators included the proportion of girls in a sample and children’s White ethnicity.

CONCLUSIONS: Overall, the study provided evidence of small but consistent associations between parental depression and child internalizing and externalizing problems, including that these associations are present over substantial periods of development.

PMID:36279145 | DOI:10.1080/15374416.2022.2127104

JAMA Netw Open. 2022 Oct 3;5(10):e2238191. doi: 10.1001/jamanetworkopen.2022.38191.

ABSTRACT

IMPORTANCE: Colony-stimulating factors are prescribed to patients undergoing chemotherapy to reduce the risk of febrile neutropenia. Research suggests that 55% to 95% of colony-stimulating factor prescribing is inconsistent with national guidelines.

OBJECTIVE: To examine whether a guideline-based standing order for primary prophylactic colony-stimulating factors improves use and reduces the incidence of febrile neutropenia.

DESIGN, SETTING, AND PARTICIPANTS: This cluster randomized clinical trial, the Trial Assessing CSF Prescribing Effectiveness and Risk (TrACER), involved 32 community oncology clinics in the US. Participants were adult patients with breast, colorectal, or non-small cell lung cancer initiating cancer therapy and enrolled between January 2016 and April 2020. Data analysis was performed from July to October 2021.

INTERVENTIONS: Sites were randomized 3:1 to implementation of a guideline-based primary prophylactic colony-stimulating factor standing order system or usual care. Automated orders were added for high-risk regimens, and an alert not to prescribe was included for low-risk regimens. Risk was based on National Comprehensive Cancer Network guidelines.

MAIN OUTCOMES AND MEASURES: The primary outcome was to find an increase in colony-stimulating factor use among high-risk patients from 40% to 75%, a reduction in use among low-risk patients from 17% to 7%, and a 50% reduction in febrile neutropenia rates in the intervention group. Mixed model logistic regression adjusted for correlation of outcomes within a clinic.

RESULTS: A total of 2946 patients (median [IQR] age, 59.0 [50.0-67.0] years; 2233 women [77.0%]; 2292 White [79.1%]) were enrolled; 2287 were randomized to the intervention, and 659 were randomized to usual care. Colony-stimulating factor use for patients receiving high-risk regimens was high and not significantly different between groups (847 of 950 patients [89.2%] in the intervention group vs 296 of 309 patients [95.8%] in the usual care group). Among high-risk patients, febrile neutropenia rates for the intervention (58 of 947 patients [6.1%]) and usual care (13 of 308 patients [4.2%]) groups were not significantly different. The febrile neutropenia rate for patients receiving high-risk regimens not receiving colony-stimulating factors was 14.9% (17 of 114 patients). Among the 585 patients receiving low-risk regimens, colony-stimulating factor use was low and did not differ between groups (29 of 457 patients [6.3%] in the intervention group vs 7 of 128 patients [5.5%] in the usual care group). Febrile neutropenia rates did not differ between usual care (1 of 127 patients [0.8%]) and the intervention (7 of 452 patients [1.5%]) groups.

CONCLUSIONS AND RELEVANCE: In this cluster randomized clinical trial, implementation of a guideline-informed standing order did not affect colony-stimulating factor use or febrile neutropenia rates in high-risk and low-risk patients. Overall, use was generally appropriate for the level of risk. Standing order interventions do not appear to be necessary or effective in the setting of prophylactic colony-stimulating factor prescribing.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02728596.

PMID:36279134 | DOI:10.1001/jamanetworkopen.2022.38191

JAMA Netw Open. 2022 Oct 3;5(10):e2238240. doi: 10.1001/jamanetworkopen.2022.38240.

ABSTRACT

IMPORTANCE: Minoritized racial and ethnic groups remain underrepresented in medicine (UIM) compared with the general population. Although many residency programs want to train a diverse group of individuals, methods for implementation are not fully established.

OBJECTIVE: To describe the implementation and restructuring of the Boston Combined Residency Program (BCRP) Diversity Council and evaluate the association between restructuring the BCRP Diversity Council and the number of UIM interns.

DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study was conducted on a large academic pediatric residency program at Boston Children’s Hospital and Boston Medical Center. Interns who matched in the BCRP from March 17, 2011, to March 18, 2021, were included. Interns who matched in an affiliated medicine-pediatrics residency were excluded because they are not universally exposed to the same recruitment efforts as individuals in the other BCRP tracks.

EXPOSURE: Because the BCRP Diversity Council was restructured in 2016, 2011-2016 was defined as the prerestructuring era and 2017-2021 as the postrestructuring era.

MAIN OUTCOMES AND MEASURES: The primary outcome was the proportion of interns who self-identified as UIM.

RESULTS: A total of 516 BCRP interns from 2011 to 2021 were included. A total of 62 individuals (12.0%) identified as racial and ethnic identities UIM (ie, American Indian/Alaska Native, Black/African American, Hispanic/Latino, and Native Hawaiian/Pacific Islander). During the 6-year prerestructuring Diversity Council era, 27 of the 275 BCRP interns (9.8%) were UIM; 35 of 241 BCRP interns (14.5%) were UIM during the 5-year restructured Diversity Council era (χ2 P = .10).

CONCLUSIONS AND RELEVANCE: In this cohort study, the number of UIM interns was higher after the BCRP Diversity Council was restructured, although the difference was not statistically significant. As the magnitude of the Diversity Council’s influence is multidimensional, perhaps studying additional aspects would have better captured its impact. The BCRP Diversity Council has expanded innovative recruitment initiatives, supported efforts to improve the resident experience, and collaborated with the residency and institutional leadership to promote an inclusive and antiracist learning environment.

PMID:36279132 | DOI:10.1001/jamanetworkopen.2022.38240

J Periodontol. 2022 Oct 24. doi: 10.1002/JPER.22-0075. Online ahead of print.

ABSTRACT

BACKGROUND: The aim of this systematic review was to assess the efficacy of three biologics, namely autologous blood-derived products (ABPs), enamel matrix derivatives (EMD) and recombinant human platelet-derived growth factor BB (rhPDGF-BB), in root coverage and gingival augmentation therapy.

METHODS: The protocol of this PRISMA 2020-compliant systematic review was registered in PROSPERO (CRD42021285917). After study selection, data of interest were extracted. A network meta-analysis (NMA) was conducted to assess the effect of different surgical interventions on the main clinical outcomes of interest (i.e., mean root coverage [MRC%], complete root coverage [CRC%], keratinized tissue width [KTW], gingival thickness [GT] change, and recession depth [RD] reduction).

RESULTS: A total of 48 trials reported in 55 articles were selected. All studies reported on the treatment of gingival recession defects for root coverage purposes. Forty-six treatment arms from 24 trials were included in the NMA. These arms consisted of treatment with coronally advanced flap (CAF) alone, EMD + CAF, platelet-rich fibrin (PRF) + CAF, and subepithelial connective tissue graft (SCTG) + CAF. Regarding MRC%, SCTG+CAF was associated with a significant higher estimate (13.41%, 95% CI [8.06-18.75], P < 0.01), while EMD+CAF (6.68%, 95% CI [-0.03 to 13.4], P = 0.061) and PRF+CAF (1.03%, 95% CI [-5.65 to 7.72], P = 0.71) failed to show statistically significant differences compared with CAF alone (control group) or with each other. Similarly, only SCTG+CAF led to a significantly higher CRC% (14.41%, 95% CI [4.21 to 24.61], P < 0.01), while treatment arms EMD + CAF (13.48%, 95% CI [-3.34 to 30.32], P = 0.11) and PRF+CAF (-0.91%, 95% CI [-15.38, 13.57], p = 0.81) did not show significant differences compared with CAF alone or with each other. Differences in the CI of PRF+CAF (symmetrical around a zero adjunctive effect) and EMD+CAF (non-symmetrical) suggest that EMD could have some additional value compared with PRF. Treatment with SCTG+CAF led to a statistically significant higher RD reduction (-0.39 mm, 95% CI [-0.55 to 0.22], P < 0.01), however EMD+CAF (-0.13 mm, 95% CI [-0.29 to 0.01], P = 0.08) and PRF+CAF (-0.06 mm, 95% CI [-0.23 to 0.09], P = 0.39) failed to show significant differences compared with CAF or with each other. While SCTG+CAF was associated with a statistically significant higher gain of KTW (0.71 mm, 95% CI [0.48 to 0.93], P < 0.01), EMD+CAF (0.24 mm, 95% CI [-0.02 to 0.51], P = 0.08) and PRF+CAF (0.08 mm, 95% CI [-0.23 to 0.41], P = 0.58) did not result into significant changes compared with CAF alone or with each other. Regarding the use of rhPDGF-BB+CAF, although available studies have reported equivalent results compared with SCTG+CAF, evidence is very limited.

CONCLUSIONS: The use of ABPs, EMD, or rhPDGF-BB in conjunction with a CAF for root coverage purposes is safe and generally promotes significant improvements respective to baseline clinical parameters. However, the adjunctive use of ABPs and EMD does not provide substantial additional improvements in terms of clinical outcomes and patient-reported outcome measures to those achieved using CAF alone, when baseline KTW is >2 mm. Both PRF+CAF and EMD+CAF rendered inferior MRC%, CRC%, RD reduction, and KTW gain compared with SCTG+CAF, which should still be considered the gold-standard in root coverage therapy. Although some studies have reported equivalent results for rhPDGF-BB+CAF compared with the gold-standard intervention, limited evidence precludes formal comparisons with CAF or SCTG+CAF that could be extrapolated to guide clinical practice.

PMID:36279123 | DOI:10.1002/JPER.22-0075

J Periodontol. 2022 Oct 24. doi: 10.1002/JPER.22-0120. Online ahead of print.

ABSTRACT

BACKGROUND: A large variety of biomaterials, biologics and membranes have been utilized in the past 40 years for the regenerative treatment of periodontal infrabony defects. Biologic agents have progressively gained popularity among clinicians and are routinely used for periodontal regeneration. In alignment with the goals of the American Academy of Periodontology (AAP) Best Evidence Consensus (BEC) on the use of biologic mediators in contemporary clinical practice, the aim of this sytematic review was to evaluate the effect of biologic agents, specifically autogenous blood-dervied products (ABPs), enamel matrix derivative (EMD) and recombinant human platelet-derived growth factor-BB (rhPDGF-BB), on the regenerative outcomes of infrabony defects.

METHODS: A detailed systematic search was conducted to identify eligible randomized control trials (RCTs) reporting the outcomes of periodontal regenerative therapy using biologics for the treatment of infrabony defects. A frequentist mixed-modeling approach to network meta-analysis (NMA), characterized by the assessment of three individual components for the treatment of an infrabony defect (the bone graft material [BG], the biologic agent, the application of a barrier membrane) was performed to evaluate and compare the relative efficacy of the different components, on the outcomes of different therapeutic modalities of periodontal regeneration.

RESULTS: A total of 153 eligible RCTs were included, with 150 studies contributing to the NMA. The quantitative analysis showed that the addition of biologic agents to bone graft significantly improves the clinical and radiographic outcomes, as compared to BG and flap procedures alone. Barrier membranes enhanced the regenerative outcomes of BG but did not provide further benefits in combination with biologics. The type of BG (autogenous, allogeneic, xenogeneic or alloplastic) and the biologic agent (EMD, platelet-rich fibrin [PRF], platelet-rich plasma [PRP] or rhPDGF-BB) played a significant role on the final outcomes of infrabony defects. Allogeneic and xenogeneic BGs exhibited statistically significantly superior clinical gain than synthetic and autogenous BGs (p < 0.05 in all the comparisons), while rhPDGF-BB and PRF demonstrated significantly higher stability of the gingival margin (p < 0.01) and radiographic bone fill/gain (p < 0.05), together with greater, although not statistically significant, clinical attachment level gain and pocket depth reduction, than EMD and PRP. Overall, rhPDGF-BB exhibited the largest effect size for most parameters, including clinical attachment level gain, pocket depth reduction, less gingival recession and radiographic linear bone gain. Considering the relatively high number of trials presenting an unclear or high risk of bias, the strength of recommendation supporting the use of PRP was judged weak, while the recommendation for EMD, PRF and rhPDGF-BB was deemed in favor.

CONCLUSIONS: Biologics enhance the outcomes of periodontal regenerative therapy. Combination therapies involving BGs + biologics or BGs + barrier membrane demonstrated to be superior to monotherapies. The choice of the type of BG and biologic agent seems to have significant impact on the clinical and radiographic outcomes of infrabony defects.

PMID:36279121 | DOI:10.1002/JPER.22-0120