Integrative analysis of liver-specific non-coding regulatory SNPs associated with the risk of coronary artery disease.

Genetic factors underlying coronary artery disease (CAD) have been widely studied using genome-wide association studies (GWASs). However, the functional understanding of the CAD loci has been limited by the fact that a majority of GWAS variants are located within non-coding regions with no functional role. High cholesterol and dysregulation of the liver metabolism such as non-alcoholic fatty liver disease confer an increased risk of CAD. Here, we studied the function of non-coding single-nucleotide polymorphisms in CAD GWAS loci located within liver-specific enhancer elements by identifying their potential target genes using liver cis-eQTL analysis and promoter Capture Hi-C in HepG2 cells. Altogether, 734 target genes were identified of which 121 exhibited correlations to liver-related traits. To identify potentially causal regulatory SNPs, the allele-specific enhancer activity was analyzed by (1) sequence-based computational predictions, (2) quantification of allele-specific transcription factor binding, and (3) STARR-seq massively parallel reporter assay. Altogether, our analysis identified 1,277 unique SNPs that display allele-specific regulatory activity. Among these, susceptibility enhancers near important cholesterol homeostasis genes (APOB, APOC1, APOE, and LIPA) were identified, suggesting that altered gene regulatory activity could represent another way by which genetic variation regulates serum lipoprotein levels. Using CRISPR-based perturbation, we demonstrate how the deletion/activation of a single enhancer leads to changes in the expression of many target genes located in a shared chromatin interaction domain. Our integrative genomics approach represents a comprehensive effort in identifying putative causal regulatory regions and target genes that could predispose to clinical manifestation of CAD by affecting liver function.

Lipophilic statins inhibit YAP coactivator transcriptional activity in HCC cells through Rho-mediated modulation of actin cytoskeleton.

Hepatocellular carcinoma (HCC) is the third leading cause of liver-related death. Lipophilic statins have been associated with a decrease in HCC incidence, raising the possibility of their use as chemoprevention agents. The Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have emerged as an important pro-oncogenic mechanism in HCC. Statins modulate YAP/TAZ in other solid tumors, but few studies have assessed their mechanisms in HCC. We aimed to delineate how lipophilic statins regulate YAP protein localization by interrogating the mevalonate pathway in a stepwise manner using pharmacological and genetical approaches in HCC cells. Huh7 and Hep3B HCC cells were treated with the lipophilic statins cerivastatin and atorvastatin. YAP protein localization was determined using quantitative immunofluorescence (IF) imaging. The gene expression of CTGF and CYR61, known YAP/TEA-domain DNA-binding factor (TEAD)-regulated genes, was measured using quantitative real-time PCR. Rescue experiments were conducted using metabolites of the mevalonate pathway including mevalonic acid and geranylgeranyl pyrophosphate (GG-PP). The cellular cytoskeleton was assessed using F-actin IF staining. YAP protein was extruded from the nucleus to the cytoplasm with statin treatment. Consistently, CTGF and CYR61 mRNA expression significantly decreased with statins. Cytoskeletal structure was also compromised with statins. Gene expression, YAP protein localization, and cytoskeletal structure were all restored to baseline with exogenous GG-PP but not with other metabolites of the mevalonate pathway. Direct Rho GTPase inhibitor treatment mirrored the statin effects on YAP. YAP protein localization is regulated by lipophilic statins via Rho GTPases, causing cytoskeletal structural changes and is independent of cholesterol metabolites.NEW & NOTEWORTHY Statins are widely used for the treatment of cardiovascular diseases. Recently, their use has been associated with a decrease in the incidence of hepatocellular carcinoma (HCC); however, their mechanism(s) has remained elusive. In this study, we delineate the mechanism by which statins affect the Yes-associated protein (YAP), which has emerged as a key oncogenic pathway in HCC. We investigate each step of the mevalonate pathway and demonstrate that statins regulate YAP via Rho GTPases.

Increased diagnostic yield from negative whole genome-slice panels using automated reanalysis.

We evaluated the diagnostic yield using genome-slice panel reanalysis in the clinical setting using an automated phenotype/gene ranking system. We analyzed whole genome sequencing (WGS) data produced from clinically ordered panels built as bioinformatic slices for 16 clinically diverse, undiagnosed cases referred to the Pediatric Mendelian Genomics Research Center, an NHGRI-funded GREGoR Consortium site. Genome-wide reanalysis was performed using Moon™, a machine-learning-based tool for variant prioritization. In five out of 16 cases, we discovered a potentially clinically significant variant. In four of these cases, the variant was found in a gene not included in the original panel due to phenotypic expansion of a disorder or incomplete initial phenotyping of the patient. In the fifth case, the gene containing the variant was included in the original panel, but being a complex structural rearrangement with intronic breakpoints outside the clinically analyzed regions, it was not initially identified. Automated genome-wide reanalysis of clinical WGS data generated during targeted panels testing yielded a 25% increase in diagnostic findings and a possibly clinically relevant finding in one additional case, underscoring the added value of analyses versus those routinely performed in the clinical setting.

The causal effect of obesity on prediabetes and insulin resistance reveals the important role of adipose tissue in insulin resistance.

Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10-3 and p = 3.1×10-24). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10-5 in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals' adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

Adipose Tissue Gene Expression Associations Reveal Hundreds of Candidate Genes for Cardiometabolic Traits.

Genome-wide association studies (GWASs) have identified thousands of genetic loci associated with cardiometabolic traits including type 2 diabetes (T2D), lipid levels, body fat distribution, and adiposity, although most causal genes remain unknown. We used subcutaneous adipose tissue RNA-seq data from 434 Finnish men from the METSIM study to identify 9,687 primary and 2,785 secondary cis-expression quantitative trait loci (eQTL; <1 Mb from TSS, FDR < 1%). Compared to primary eQTL signals, secondary eQTL signals were located further from transcription start sites, had smaller effect sizes, and were less enriched in adipose tissue regulatory elements compared to primary signals. Among 2,843 cardiometabolic GWAS signals, 262 colocalized by LD and conditional analysis with 318 transcripts as primary and conditionally distinct secondary cis-eQTLs, including some across ancestries. Of cardiometabolic traits examined for adipose tissue eQTL colocalizations, waist-hip ratio (WHR) and circulating lipid traits had the highest percentage of colocalized eQTLs (15% and 14%, respectively). Among alleles associated with increased cardiometabolic GWAS risk, approximately half (53%) were associated with decreased gene expression level. Mediation analyses of colocalized genes and cardiometabolic traits within the 434 individuals provided further evidence that gene expression influences variant-trait associations. These results identify hundreds of candidate genes that may act in adipose tissue to influence cardiometabolic traits.

Reverse GWAS: Using genetics to identify and model phenotypic subtypes.

Recent and classical work has revealed biologically and medically significant subtypes in complex diseases and traits. However, relevant subtypes are often unknown, unmeasured, or actively debated, making automated statistical approaches to subtype definition valuable. We propose reverse GWAS (RGWAS) to identify and validate subtypes using genetics and multiple traits: while GWAS seeks the genetic basis of a given trait, RGWAS seeks to define trait subtypes with distinct genetic bases. Unlike existing approaches relying on off-the-shelf clustering methods, RGWAS uses a novel decomposition, MFMR, to model covariates, binary traits, and population structure. We use extensive simulations to show that modelling these features can be crucial for power and calibration. We validate RGWAS in practice by recovering a recently discovered stress subtype in major depression. We then show the utility of RGWAS by identifying three novel subtypes of metabolic traits. We biologically validate these metabolic subtypes with SNP-level tests and a novel polygenic test: the former recover known metabolic GxE SNPs; the latter suggests subtypes may explain substantial missing heritability. Crucially, statins, which are widely prescribed and theorized to increase diabetes risk, have opposing effects on blood glucose across metabolic subtypes, suggesting the subtypes have potential translational value.

Colocalization of GWAS and eQTL signals at loci with multiple signals identifies additional candidate genes for body fat distribution.

Integration of genome-wide association study (GWAS) signals with expression quantitative trait loci (eQTL) studies enables identification of candidate genes. However, evaluating whether nearby signals may share causal variants, termed colocalization, is affected by the presence of allelic heterogeneity, different variants at the same locus impacting the same phenotype. We previously identified eQTL in subcutaneous adipose tissue from 770 participants in the Metabolic Syndrome in Men (METSIM) study and detected 15 eQTL signals that colocalized with GWAS signals for waist-hip ratio adjusted for body mass index (WHRadjBMI) from the Genetic Investigation of Anthropometric Traits consortium. Here, we reevaluated evidence of colocalization using two approaches, conditional analysis and the Bayesian test COLOC, and show that providing COLOC with approximate conditional summary statistics at multi-signal GWAS loci can reconcile disagreements in colocalization classification between the two tests. Next, we performed conditional analysis on the METSIM subcutaneous adipose tissue data to identify conditionally distinct or secondary eQTL signals. We used the two approaches to test for colocalization with WHRadjBMI GWAS signals and evaluated the differences in colocalization classification between the two tests. Through these analyses, we identified four GWAS signals colocalized with secondary eQTL signals for FAM13A, SSR3, GRB14 and FMO1. Thus, at loci with multiple eQTL and/or GWAS signals, analyzing each signal independently enabled additional candidate genes to be identified.

Genetic Regulation of Adipose Gene Expression and Cardio-Metabolic Traits.

Subcutaneous adipose tissue stores excess lipids and maintains energy balance. We performed expression quantitative trait locus (eQTL) analyses by using abdominal subcutaneous adipose tissue of 770 extensively phenotyped participants of the METSIM study. We identified cis-eQTLs for 12,400 genes at a 1% false-discovery rate. Among an approximately 680 known genome-wide association study (GWAS) loci for cardio-metabolic traits, we identified 140 coincident cis-eQTLs at 109 GWAS loci, including 93 eQTLs not previously described. At 49 of these 140 eQTLs, gene expression was nominally associated (p < 0.05) with levels of the GWAS trait. The size of our dataset enabled identification of five loci associated (p < 5 × 10-8) with at least five genes located >5 Mb away. These trans-eQTL signals confirmed and extended the previously reported KLF14-mediated network to 55 target genes, validated the CIITA regulation of class II MHC genes, and identified ZNF800 as a candidate master regulator. Finally, we observed similar expression-clinical trait correlations of genes associated with GWAS loci in both humans and a panel of genetically diverse mice. These results provide candidate genes for further investigation of their potential roles in adipose biology and in regulating cardio-metabolic traits.

ASElux: an ultra-fast and accurate allelic reads counter.

Motivation: Mapping bias causes preferential alignment to the reference allele, forming a major obstacle in allele-specific expression (ASE) analysis. The existing methods, such as simulation and SNP-aware alignment, are either inaccurate or relatively slow. To fast and accurately count allelic reads for ASE analysis, we developed a novel approach, ASElux, which utilizes the personal SNP information and counts allelic reads directly from unmapped RNA-sequence (RNA-seq) data. ASElux significantly reduces runtime by disregarding reads outside single nucleotide polymorphisms (SNPs) during the alignment. Results: When compared to other tools on simulated and experimental data, ASElux achieves a higher accuracy on ASE estimation than non-SNP-aware aligners and requires a much shorter time than the benchmark SNP-aware aligner, GSNAP with just a slight loss in performance. ASElux can process 40 million read-pairs from an RNA-sequence (RNA-seq) sample and count allelic reads within 10 min, which is comparable to directly counting the allelic reads from alignments based on other tools. Furthermore, processing an RNA-seq sample using ASElux in conjunction with a general aligner, such as STAR, is more accurate and still ∼4× faster than STAR + WASP, and ∼33× faster than the lead SNP-aware aligner, GSNAP, making ASElux ideal for ASE analysis of large-scale transcriptomic studies. We applied ASElux to 273 lung RNA-seq samples from GTEx and identified a splice-QTL rs11078928 in lung which explains the mechanism underlying an asthma GWAS SNP rs11078927. Thus, our analysis demonstrated ASE as a highly powerful complementary tool to cis-expression quantitative trait locus (eQTL) analysis. Availability and implementation: The software can be downloaded from https://github.com/abl0719/ASElux. Contact: zmiao@ucla.edu or a5ko@ucla.edu. Supplementary information: Supplementary data are available at Bioinformatics online.

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected ß-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.

Molecular Characterization of the Lipid Genome-Wide Association Study Signal on Chromosome 18q11.2 Implicates HNF4A-Mediated Regulation of the TMEM241 Gene.

OBJECTIVE: We recently identified a locus on chromosome 18q11.2 for high serum triglycerides in Mexicans. We hypothesize that the lead genome-wide association study single-nucleotide polymorphism rs9949617, or its linkage disequilibrium proxies, regulates 1 of the 5 genes in the triglyceride-associated region. APPROACH AND RESULTS: We performed a linkage disequilibrium analysis and found 9 additional variants in linkage disequilibrium (r(2)>0.7) with the lead single-nucleotide polymorphism. To select the variants for functional analyses, we annotated the 10 variants using DNase I hypersensitive sites, transcription factor and chromatin states and identified rs17259126 as the lead candidate variant for functional in vitro validation. Using luciferase transcriptional reporter assay in liver HepG2 cells, we found that the G allele exhibits a significantly lower effect on transcription (P<0.05). The electrophoretic mobility shift and ChIPqPCR (chromatin immunoprecipitation coupled with quantitative polymerase chain reaction) assays confirmed that the minor G allele of rs17259126 disrupts an hepatocyte nuclear factor 4 α-binding site. To find the regional candidate gene, we performed a local expression quantitative trait locus analysis and found that rs17259126 and its linkage disequilibrium proxies alter expression of the regional transmembrane protein 241 (TMEM241) gene in 795 adipose RNAs from the Metabolic Syndrome In Men (METSIM) cohort (P=6.11×10(-07)-5.80×10(-04)). These results were replicated in expression profiles of TMEM241 from the Multiple Tissue Human Expression Resource (MuTHER; n=856). CONCLUSIONS: The Mexican genome-wide association study signal for high serum triglycerides on chromosome 18q11.2 harbors a regulatory single-nucleotide polymorphism, rs17259126, which disrupts normal hepatocyte nuclear factor 4 α binding and decreases the expression of the regional TMEM241 gene. Our data suggest that decreased transcript levels of TMEM241 contribute to increased triglyceride levels in Mexicans.

Rates and patterns of great ape retrotransposition.

We analyzed 83 fully sequenced great ape genomes for mobile element insertions, predicting a total of 49,452 fixed and polymorphic Alu and long interspersed element 1 (L1) insertions not present in the human reference assembly and assigning each retrotransposition event to a different time point during great ape evolution. We used these homoplasy-free markers to construct a mobile element insertions-based phylogeny of humans and great apes and demonstrate their differential power to discern ape subspecies and populations. Within this context, we find a good correlation between L1 diversity and single-nucleotide polymorphism heterozygosity (r(2) = 0.65) in contrast to Alu repeats, which show little correlation (r(2) = 0.07). We estimate that the "rate" of Alu retrotransposition has differed by a factor of 15-fold in these lineages. Humans, chimpanzees, and bonobos show the highest rates of Alu accumulation--the latter two since divergence 1.5 Mya. The L1 insertion rate, in contrast, has remained relatively constant, with rates differing by less than a factor of three. We conclude that Alu retrotransposition has been the most variable form of genetic variation during recent human-great ape evolution, with increases and decreases occurring over very short periods of evolutionary time.

Remote Ischemic Conditioning Alters Methylation and Expression of Cell Cycle Genes in Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND AND PURPOSE: Remote ischemic conditioning (RIC) is a phenomenon in which short periods of nonfatal ischemia in 1 tissue confers protection to distant tissues. Here we performed a longitudinal human pilot study in patients with aneurysmal subarachnoid hemorrhage undergoing RIC by limb ischemia to compare changes in DNA methylation and transcriptome profiles before and after RIC. METHODS: Thirteen patients underwent 4 RIC sessions over 2 to 12 days after rupture of an intracranial aneurysm. We analyzed whole blood transcriptomes using RNA sequencing and genome-wide DNA methylomes using reduced representation bisulfite sequencing, both before and after RIC. We tested differential expression and differential methylation using an intraindividual paired study design and then overlapped the differential expression and differential methylation results for analyses of functional categories and protein-protein interactions. RESULTS: We observed 164 differential expression genes and 3493 differential methylation CpG sites after RIC, of which 204 CpG sites overlapped with 103 genes, enriched for pathways of cell cycle (P<3.8×10(-4)) and inflammatory responses (P<1.4×10(-4)). The cell cycle pathway genes form a significant protein-protein interaction network of tightly coexpressed genes (P<0.00001). CONCLUSIONS: Gene expression and DNA methylation changes in aneurysmal subarachnoid hemorrhage patients undergoing RIC are involved in coordinated cell cycle and inflammatory responses.

Copy number variation detection and genotyping from exome sequence data.

While exome sequencing is readily amenable to single-nucleotide variant discovery, the sparse and nonuniform nature of the exome capture reaction has hindered exome-based detection and characterization of genic copy number variation. We developed a novel method using singular value decomposition (SVD) normalization to discover rare genic copy number variants (CNVs) as well as genotype copy number polymorphic (CNP) loci with high sensitivity and specificity from exome sequencing data. We estimate the precision of our algorithm using 122 trios (366 exomes) and show that this method can be used to reliably predict (94% overall precision) both de novo and inherited rare CNVs involving three or more consecutive exons. We demonstrate that exome-based genotyping of CNPs strongly correlates with whole-genome data (median r(2) = 0.91), especially for loci with fewer than eight copies, and can estimate the absolute copy number of multi-allelic genes with high accuracy (78% call level). The resulting user-friendly computational pipeline, CoNIFER (copy number inference from exome reads), can reliably be used to discover disruptive genic CNVs missed by standard approaches and should have broad application in human genetic studies of disease.

Integration of Mindfulness Educational Innovation in Nursing Programs.

Purpose: The study's purpose was to assess: (1) Students' perceptions toward mindfulness interventions, and (2) Instructors' perceptions in implementing mindfulness interventions in their classes. Study design: Descriptive study. Methods: A total of 96 students from the second-degree option and BSN programs in the host institution participated in a mindfulness intervention prior to course activities. The four mindfulness interventions utilized in this study included: music, meditation, guided breathing, and positive affirmation. The data were analyzed using descriptive statistics on postintervention surveys. Findings: The mindfulness intervention was overwhelmingly received by the students and faculty as reflected in the result of the confidential postsurveys. The majority of the students and faculty felt that this mindfulness intervention was worth implementing in their course. Conclusion: The mindfulness intervention can promote students' feelings of "at ease" and confidence prior to a nursing course activity.

Using Simulation Training to Reduce Skill Decay Among Certified Registered Nurse Anesthetists.

BACKGROUND: Skill decay refers to the loss of skills and knowledge resulting from lack of consistent use. Among certified registered nurse anesthetists (CRNAs), skill decay can lead to negative results. One method that has been shown to mitigate skill decay is low-dose, high-frequency (LDHF) simulation. There is a gap in the LDHF simulation literature regarding CRNAs to determine its effectiveness in reducing skill decay or increasing confidence levels. METHOD: This study used a quasi-experimental pretest-posttest follow-up design. The pretests and posttests were evaluated using a Wilcoxon signed rank test to determine CRNAs' proficiency and confidence in central venous catheter (CVC) insertion before and after a simulated refresher training course. RESULTS: The CRNAs showed a significant improvement in CVC insertion proficiency, from a 50% pretest average to a 94% posttest average (p < .0001), and they retained proficiency 6 months later (91%, p = .0109). There was no significant change in CRNAs' confidence level following the training (p = .4486). CONCLUSION: A program of LDHF simulation training is an important activity in meeting the continuing education/training needs of CRNAs in improving and retaining CVC insertion proficiency. This study demonstrates the efficacy of a LDHF simulation program for CRNAs and helps to bridge the gap in the literature on the use of LDHF simulation among CRNAs. [J Contin Educ Nurs. 2024;55(4):187-194.].

Strengthening DNP Business Acumen: An Educational Intervention.

BACKGROUND: As reflected in the literature, business acumen for Doctor of Nursing Practice (DNP) students is lacking. Foundational business concepts and applications in the curriculum necessitate the understanding of core business requirements in health care applicable toward DNP leadership roles. METHOD: Course pedagogy used evidence-based materials as well as activities that included the development of business innovation proposals, stakeholder presentations, and business plans, as well as practicum hours. RESULTS: Successful course delivery increased DNP students' knowledge and skills related to business acumen. In addition, students fully grasped the need to sustain and have fully developed scholarly projects that consider the clinical and financial aspects of health care. CONCLUSION: Development of a business course strengthens the needed skills and acumen toward quality and financial performance critical in the DNP leadership role as well as in contributing toward institutions' growth. [J Nurs Educ. 2021;61(4):201-204.].

Brilliant at the Basics: An Academic Practice Partnership to Build Nursing Management Expertise.

This article describes the importance of building academic and practice partnerships, and the process in developing and implementing a successful leadership academy in transforming emerging nurse leaders. In addition, this article highlighted the value on the evaluation and outcomes of the educational program pertaining to positive changes in the workplace. In its initial phase, the health system conducted a needs assessment that provided vital information to enhance nursing management development skills through the initiation of a leadership training academy for nurse leaders. The vital information obtained in the needs assessment was used as a framework in working on topical outline and content objectives developed as a joint initiative between the university-based school of nursing and health professions and the health system that shared a similar mission, vision, and goals. Thus, "Brilliant at the Basics" nursing leadership academy was formed. [J Contin Educ Nurs. 2021;52(3):136-141.].

Dealing with Anxious Patients: A Systematic Review of the Literature on Nonpharmaceutical Interventions to Reduce Anxiety in Patients Undergoing Medical or Dental Procedures.

Objectives: State (situational) anxiety can create suboptimal outcomes for patients across a variety of health care specializations. While anxiolytic medications reduce anxiety, problematic side effects can compromise outcomes. These challenges have spurred searches for nonpharmaceutical approaches to alleviate patient anxiety. This systematic literature review, largely following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, aimed to determine patterns and effectiveness of interventions across medical health care specialty areas, including dentistry. Methods: A systematic review was conducted, using PubMed, CINAHL, and PsycINFO databases, with search terms related to anxiety, specific interventions, and medical or dental procedures. Hand searching for additional citations was performed on the bibliographies of dissertations, meta-analyses, and systematic reviews that met article inclusion criteria. The search process yielded 48,324 articles and 257 dissertations published in English between 1974 and 2018. Each abstract was evaluated for inclusion by two reviewers, yielding 718 articles that were read and evaluated for outcomes, risk of bias, pretest and post-test, controls and quality, using a Critical Appraisal Skills Programme instrument. Of these, 408 articles, describing 501 experimental trials, were accepted for inclusion in this analysis. Results: A total of 50,343 patients were included in these experiments, with an overall success rate of 71% for reducing patient anxiety. Results are summarized by health care specialty area: surgery, oncology, cardiology, obstetrics/gynecology, dentistry, and pain/trauma, and the following diagnostic testing and intervention areas: imaging, colonoscopy, mechanical ventilation, and other. The largest number of experiments (114) was in the surgery category. The types of interventions included music, education, relaxation, cognitive behavioral therapy (CBT), massage, distraction, hypnosis, acupuncture/acupressure, social support, aromatherapy, nature sounds, natural visual stimuli, special garment, and other. The largest numbers of experiments were done with music (143) and education (130). Discussion: The following interventions were most successful, reducing anxiety in over 70% of experiments: music, CBT, relaxation, massage, acupuncture/acupressure, hypnosis, and natural sounds. Confidence in results is limited by publication bias, small sample sizes, and the lack of placebo controls. Directions for future research are discussed.

Dealing with Anxious Patients: An Integrative Review of the Literature on Nonpharmaceutical Interventions to Reduce Anxiety in Patients Undergoing Medical or Dental Procedures.

Objectives: A previous systematic literature review (SLR) evaluated 501 experiments on reducing patient anxiety across medical and dental environments. This integrative review examines those interventions and explores possible mechanisms leading to relative success or failure within those environments, in the interest of interprofessional education and communication. Methods: Reviewers evaluated 501 experiments testing interventions for reducing patient anxiety in a variety of medical and dental health care settings. Methodology for the SLR, largely following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, is briefly reviewed. Results: A total of 501 experiments (from 408 articles) met review criteria. One hundred and forty-three Music experiments were included, and Music interventions were largely effective, except in the case of colonoscopy. Education is the only intervention that occasionally (5 times of 130 experiments) raised patient anxiety in the face of a procedure; the discussion focuses on the wisdom of assessing patient need for information. Thirty-seven Cognitive Behavioral Therapy (CBT) experiments of various types are included, with a success rate of 89%, with a particularly high rate of success (12 of 12 experiments) in dentistry. Massage has a success rate that is similar to that of CBT, but Massage has been tested in far fewer specialty areas. Relaxation has been tested in every specialty area, except mechanical ventilation, with promising results. Acupuncture and Acupressure have not been widely tested, but their effectiveness rate is 100% when it comes to reducing patient anxiety in various procedural settings. Similarly, experiments show Hypnosis to be successful in 90% of trials. In contrast, Distraction was successful in only 40% of the experiments summarized, although it was more effective in dentistry. A variety of Nature-based Interventions (Aromatherapy, Nature Sounds, and Visual Stimuli) were highly successful across a variety of settings. Discussion: Possible mechanisms are discussed, along with commentary on feasibility. Limitations include publication bias, small sample sizes, and the lack of placebo controls. Future areas of research are pointed out.