Coordination of RNA modifications in the brain and beyond.

Gene expression regulation is a critical process throughout the body, especially in the nervous system. One mechanism by which biological systems regulate gene expression is via enzyme-mediated RNA modifications, also known as epitranscriptomic regulation. RNA modifications, which have been found on nearly all RNA species across all domains of life, are chemically diverse covalent modifications of RNA nucleotides and represent a robust and rapid mechanism for the regulation of gene expression. Although numerous studies have been conducted regarding the impact that single modifications in single RNA molecules have on gene expression, emerging evidence highlights potential crosstalk between and coordination of modifications across RNA species. These potential coordination axes of RNA modifications have emerged as a new direction in the field of epitranscriptomic research. In this review, we will highlight several examples of gene regulation via RNA modification in the nervous system, followed by a summary of the current state of the field of RNA modification coordination axes. In doing so, we aim to inspire the field to gain a deeper understanding of the roles of RNA modifications and coordination of these modifications in the nervous system.

Atypical presentation of cutaneous meningioma.

Cutaneous meningiomas are rare tumors of ectopic meningeal tissue in the dermis or subcutis and are most commonly located on the scalp and around the eyes, ears, nose, and mouth. We present a case of cutaneous meningioma with an unusual presentation on the upper arm, but with positivity for epithelial membrane antigen to support the diagnosis of meningioma. Lack of pancytokeratin AE1/3 and p63 allowed us to rule out a keratinocytic tumor, such as squamous cell carcinoma and basal cell carcinoma. The absence of smooth muscle actin, FXIIIa, CD163, and CD34 allowed us to rule out a leiomyoma, dermatofibroma, and vascular neoplasm respectively. Weak staining of S100 allowed us to rule out a perineuroma. The purpose of this case report is to increase awareness of a rare presentation of cutaneous meningioma not located within the scalp/face region. This may broaden its inclusion within differential diagnoses of neoplasms of uncertain behavior and encourage correct clinical diagnosis, thus improving treatment outcomes.

Association of air pollution with dementia: a systematic review with meta-analysis including new cohort data from China.

It remains unclear whether a total exposure to air pollution (AP) is associated with an increased risk of dementia. Little is known on the association in low- and middle-income countries. Two cohort studies in China (in Anhui cohort 1402 older adults aged ≥ 60 followed up for 10 years; in Zhejiang cohort 6115 older adults followed up for 5 years) were conducted to examine particulate matter - PM2.5 associated with all dementia and air quality index (AQI) with Alzheimer's disease, respectively. A systematic literature review and meta-analysis was performed following worldwide literature searched until May 20, 2020 to identify 15 population-based cohort studies examining the association of AP with dementia (or any specific type of dementia) through PubMed, MEDLINE, PsycINFO, SocINDEX, CINHAL, and CNKI. The cohort studies in China showed a significantly increased relative risk (RR) of dementia in relation to AP exposure; in Anhui cohort the adjusted RR was 2.14 (95% CI 1.00-4.56) in people with PM2.5 exposure at ≥ 64.5 µg/m3 versus <63.5 µg/m3 and in Zhejiang cohort the adjusted RR was 2.28 (1.07-4.87) in AQI>90 versus ≤ 80. The systematic review revealed that all 15 studies were undertaken in high income countries/regions, with inconsistent findings. While they had reasonably good overall quality of studies, seven studies did not adjust smoking in analysis and 13 did not account for depression. Pooling all eligible data demonstrated that dementia risk increased with the total AP exposure (1.13, 1.08-1.19). Data analysis of air pollutants showed that the RR significantly increased with PM2.5 (1.06, 1.03-1.10 in 2nd tertile exposure; 1.13, 1.07-1.19 in 3rd tertile versus 1st tertile), PM10 (1.05, 0.86-1.29; 1.62, 0.60-4.36), carbon monoxide (1.69, 0.72-3.93; 1.52, 1.35-1.71), nitrogen dioxide (1.06, 1.03-1.09; 1.18, 1.10-1.28) and nitrogen oxides (1.09, 1.04-1.15; 1.26, 1.13-1.41), but not ozone. Controlling air pollution and targeting on specific pollutants would reduce dementia globally.

Are There Ultrasound Features to Distinguish Small (<3 cm) Peripheral Renal Angiomyolipomas From Renal Cell Carcinomas?

BACKGROUND: Small echogenic renal masses are usually angiomyolipomas (AMLs), but some renal cell carcinomas (RCCs) can be echogenic and confused with an AML. OBJECTIVES: This is a study to evaluate any distinguishing demographic and sonographic features of small (<3 cm) peripheral AMLs versus peripheral RCCs. METHODS: This is a HIPAA-compliant retrospective review of the demographics and ultrasound features of peripheral renal AMLs compared with a group of peripheral RCCs. All AMLs had confirmation of macroscopic fat as noted on thin-cut CT or fat-saturation MRI sequence images. All RCCs were pathologically proven. Statistical analysis was used to compare findings in the two groups. RESULTS: There were a total of 52 patients with 56 AMLs, compared with 42 patients with 42 RCCs. There were 42 females in the AML group versus 10 females in the RCC group (P < .0001). The AML diameters (15.7 mm × 12.0 mm) were statistically significantly smaller (Plargest = .0085, Psmallest < .001) than the diameters of the RCCs (19.9 mm × 18.5 mm). Ultrasound features found to be statistically different between the two groups were the ratio of the largest dimension to the smallest dimension (P < .001), a lobulated versus smooth margin of the AML (26 vs 30) compared with the RCC group (3 vs 39) (P = .0012), and an "unusual" versus a round shape (P < .001) of the AML group (45 vs 11) compared with the RCC group (9 vs 33). In the multivariable model, the patient sex, margin, and mass shape were predictive of AML, with an area under the receiver operating characteristic curve of 0.92. CONCLUSION: For a small (<3 cm) peripheral echogenic mass in a female patient, a lobulated lesion with an unusual shape is highly predictive of being an AML.

Did the mental health and well-being of young people increase after the COVID-19 vaccination campaign period? A cross-sectional multicentre study in Austria and Turkey.

In 2019, the global Coronavirus (COVID-19) pandemic and associated prevention measures affected the mental health and psychological well-being of young people with and without a migratory background. The present study aimed to compare the mental health and psychological well-being of migrant and non-migrant young people before and after the COVID-19 vaccination campaign period in two countries which had different policies to deal with the pandemic. The "Psychological General Well-being" of young people and their experiences during the pandemic were investigated using an anonymous online survey during two pandemic waves before the vaccination campaign and 6 months after its start. A majority of the 6154 participants (aged between 15 and 25 years in all study groups) reported a decrease of mental health from the time period before the vaccination (BV) to after the vaccination (AV) campaign (b = 0.27, p < .001). This association was higher in females (b = 0.04, p = 0.008) and in youth with financial problems (b = 0.13, p < .001). Furthermore, this decrease was more pronounced in people ≤17 years old (40% to 62%) than in those >17 years (59% to 67%). Contrary to expectation, vulnerable groups such as the economically disadvantaged, younger, and female participants did not experience a significant easing of the pandemic's psychological burden AV. Vaccination campaigns should continue emphasizing the beneficial effects of COVID-19 vaccination on general well-being, but with an acknowledgement that the road to recovery is still a long one. Concurrently, free access to psychological treatment and financial support should be offered, especially for vulnerable groups. Supplementary Information: The online version contains supplementary material available at 10.1007/s12144-023-04366-x.

Rapid Antigen Screening of Students and Staff for SARS-CoV-2 in Rural School Districts, Pierce County, WA, 2020.

During fall 2020 in rural Pierce County, Washington, school districts and the county health department offered weekly rapid antigen screening to students and staff. Asymptomatic screening identified 42.5% of confirmed cases from the population. Parents reported it was a positive experience for their children. The program supported decisions to return to in-person learning, but screening ended because of resource and technical limitations. When planning in-school screening, stakeholder engagement and resource sustainability are important factors to consider. (Am J Public Health. 2022;112(8):1134-1137. https://doi.org/10.2105/AJPH.2022.306875).

Impact of fish consumption on all-cause mortality in older people with and without dementia: a community-based cohort study.

BACKGROUND: Increased fish consumption reduces the risk of dementia. However, it is unknown whether fish consumption reduced all-cause mortality in people with dementia. The purpose of the study is to investigate the association of fish consumption with all-cause mortality in older people with dementia versus those without dementia. METHODS: Using a standard method of the Geriatric Mental State, we interviewed 4165 participants aged ≥ 60 years who were randomly recruited from five provinces in China during 2007-2009 to collect the baseline data of socio-demography, disease risk factors, histories of disease, and details of dietary intakes, and diagnosed dementia (n = 406). They were followed up for vital status until 2012. RESULTS: The cohort follow-up documented 329 deaths; 61 were in participants with dementia (55.3 per 1000 person-years) and 224 were those without dementia (22.3). In all participants, the risk of all-cause mortality was reduced with fish intake at " ≥ twice a week" (multivariate-adjusted hazard ratio 0.58, 95% CI 0.34-0.96) and at "once a week or less" (0.79, 0.53-1.18) compared to "never eat" over the past two years. In participants without baseline dementia, the corresponding HRs for all-cause mortality were 0.57 (0.33-0.98) and 0.85 (0.55-1.31), while in participants with dementia were 1.36 (0.28-6.60) and 1.05 (0.30-3.66), respectively. CONCLUSION: This study reveals that consumption of fish in older age reduced all-cause mortality in older people without dementia, but not in people with dementia. Fish intake should be increased in older people in general, prior to the development of dementia in the hope of preventing dementia and prolonging life.

Impact of air pollution exposure on the risk of Alzheimer's disease in China: A community-based cohort study.

Alzheimer's disease (AD) is the most common type of dementia. Impact of air pollution (AP) on the risk of AD is unclear. It is unknown which air pollutants are independently associated with AD and whether fish consumption mitigated the association. We carried out a community-based cohort of 6115 participants aged ≥60 years in China to examine the association of PM2.5, PM10, CO, NO2, SO2 and O3 exposure with AD, and differences in the association between people with low and high consumption of fish. The participants were randomly recruited from six counties in Zhejiang province for health survey to document socio-demographic and disease risk factors in 2014, and were followed up to diagnose AD in 2019. A total of 986 cohort members were diagnosed with AD. Based on the daily mean air pollutants monitored in 2013-2015 in the counties, participants were divided into low, middle and high AP exposure groups for subsequent analysis. The multiple adjusted odds ratio (OR) of AD in participants living with the middle and high levels of PM2.5 exposure versus the low exposure were 1.50 (95% CI 0.90-2.50) and 3.92 (2.09-7.37). The increased ORs were also with PM10 (1.74, 0.65-4.64; 3.00, 1.22-7.41) and CO (2.86, 1.32-6.20; 1.19, 0.45-3.18), but not with NO2 (0.63, 0.17-2.27; 0.95, 0.28-3.19), SO2 (0.44, 0.19-1.001; 1.21, 0.56-2.62), and O3 (0.38, 0.20-0.74; 0.50, 0.21-1.21). There were no significant interaction effects of AP with fish consumption on AD. However, participants with low consumption of fish appeared to have higher ORs in PM2.5 exposure (1.80, 1.39-2.33; 5.18, 3.93-6.82) than those high consumption (1.38, 0.78-2.47; 2.89, 1.50-5.59). Our findings of PM2.5, PM10 and CO exposure significantly increased the risk of AD and the potential mitigating effect of fish consumption on the association provide evidence for developing effective strategies for AD reduction and air pollution control.

Propranolol therapy for hemangiomas in infants with neonatal abstinence syndrome may produce intolerable side effects.

We report three infants with infantile hemangioma who experienced severe agitation and diarrhea following propranolol administration. Propranolol, a non-selective ß-adrenergic receptor blocker, is the first-line treatment for infantile hemangiomas. All three infants were exposed to opioids in utero and experienced neonatal abstinence syndrome at birth. We hypothesize that chronic opioid exposure in utero may cause protracted upregulation of ß2-adrenergic receptors in the central nervous system, resulting in increased susceptibility to adverse reactions to propranolol.

Genetic counseling student rotations in industry: How COVID-19 magnified the urgency for virtual learning options in diverse training settings.

The COVID-19 pandemic created unprecedented challenges worldwide that required rapid adaptation and transformation across the entire healthcare system. Graduate medical training programs across all specialties have moved to rapidly adjust to the virtual landscape. This created a unique opportunity for genetic counselors who work in industry and within diagnostic laboratories to develop internship and rotation programs that can be offered virtually to meet the needs of genetic counseling training programs. Myriad Genetics, Inc., was contacted by numerous graduate programs in genetic counseling beginning in March 2020 requesting the opportunity for their students to participate in remote laboratory-based rotations. As a result of these requests, a working group of genetic counselors across Myriad came together to adapt existing experiences to fully remote formats and develop new remote-based opportunities for students. We describe our experience of expanding genetic counseling student rotations during the COVID-19 pandemic with the goal of providing examples of remote learning experiences that may be applicable to other diagnostic laboratory industry-based rotations for genetic counseling students. In 2020, a total of 59 second-year genetic counseling students, from 21 different genetic counseling training programs, participated in one of five different virtual experiences. Furthermore, two new rotation experiences were created to increase capacity and highlight diversity of industry roles. Genetic counselors in industry are uniquely positioned to provide both remote training opportunities for genetic counseling students and exposure to the variety of roles that genetic counselors can occupy. Increasing the exposure to these roles is important as the genetic counseling workforce continues to expand and diversify, and it is imperative among all programs to enable access to these opportunities.

COVID-19, community response, public policy, and travel patterns: A tale of Hong Kong.

The COVID-19 outbreak has necessitated a critical review of urban transportation and its role in society against the backdrop of an exogenous shock. This article extends the transportation literature regarding community responses to the COVID-19 pandemic and what lessons can be obtained from the case of Hong Kong in 2020. Individual behavior and collective responsibility are considered crucial to ensure both personal and community wellbeing in a pandemic context. Trends in government policies, the number of infectious cases, and community mobility are examined using multiple data sources. The mobility changes that occurred during the state of emergency are revealed by a time-series analysis of variables that measure both the epidemiological severity level and government stringency. The results demonstrate a high response capability of the local government, inhabitants, and communities. Communities in Hong Kong are found to have reacted faster than the implementation of health interventions, whereas the government policies effectively reduced the number of infection cases. The ways in which community action are vital to empower flexible and adaptive community responses are also explored. The results indicate that voluntary community involvement constitutes a necessary condition to help inform and reshape future transport policy and response strategies to mitigate the pandemic.

Investigating microstructural variation in the human hippocampus using non-negative matrix factorization.

In this work we use non-negative matrix factorization to identify patterns of microstructural variance in the human hippocampus. We utilize high-resolution structural and diffusion magnetic resonance imaging data from the Human Connectome Project to query hippocampus microstructure on a multivariate, voxelwise basis. Application of non-negative matrix factorization identifies spatial components (clusters of voxels sharing similar covariance patterns), as well as subject weightings (individual variance across hippocampus microstructure). By assessing the stability of spatial components as well as the accuracy of factorization, we identified 4 distinct microstructural components. Furthermore, we quantified the benefit of using multiple microstructural metrics by demonstrating that using three microstructural metrics (T1-weighted/T2-weighted signal, mean diffusivity and fractional anisotropy) produced more stable spatial components than when assessing metrics individually. Finally, we related individual subject weightings to demographic and behavioural measures using a partial least squares analysis. Through this approach we identified interpretable relationships between hippocampus microstructure and demographic and behavioural measures. Taken together, our work suggests non-negative matrix factorization as a spatially specific analytical approach for neuroimaging studies and advocates for the use of multiple metrics for data-driven component analyses.

Goal-Oriented Attention Self-Regulation (GOALS) training in older adults.

Objectives: A common cognitive complaint of older adulthood is distractibility, or decline in ability to concentrate and maintain focus, yet few evidence-based interventions exist to address these deficits. We implemented s pilot trial of an evidence-based executive function training program, to investigate whether training in applied goal-directed attention regulation and problem solving would enhance executive control abilities in a sample of cognitively normal older adults with self-reported complaints of concentration problems.Method: Consecutively recruited participants were placed into small groups and randomized to either Goal-Oriented Attentional Self-Regulation training (GOALS; N = 15) or a closely matched Brain Health Education program (BHE; N = 15).Results: GOALS participants significantly improved on: neurocognitive measures of mental flexibility (p = 0.03, partial eta squared = 0.23); real-world setting functional performance measures of: task failures (p = 0.02, Cohen's d = 0.88), task rule breaks (p = 0.02, Cohen's d = 1.06), and execution (p = 0.04, Cohen's d = 0.76); and in-lab functional assessment of goal-directed behaviour divergent thinking scale (p = 0.03, Cohen's d = 0.95). All participants improved on a neurocognitive measure of planning (p = 0.01, partial eta squared = 0.031). BHE participants' improvement over and above GOALS participants was limited to: rule adherence on the real world task (p = 0.04, Cohen's d = 0.99), and evaluator rating (p = 0.03, Cohen's d = 0.56), and average score (p = 0.02, Cohen's d = 0.71) on the in-lab functional task.Conclusion: Participation in GOALS training can enhance executive control, and lead to real-world functional improvements, for cognitively normal older adults with self-reported attention difficulties.

Long-term effects of executive function training among veterans with chronic TBI.

Objective: To investigate long-term effects of GOALS executive function training in Veterans with chronic TBI. In a recently completed study Veterans with chronic TBI showed improvement immediately post-GOALS but not control training on measures of executive function, functional task performance, and emotion regulation. We now examine the long-term maintenance of post-GOALS training changes in the same sample. Setting: San Francisco VA Health Care System (SFVAHCS), and VA Northern California Health-Care System (VANCHS) in Martinez. Participants and Design: 24 Veterans with chronic TBI were assessed at baseline, post-GOALS training, and long-term follow-up 6+ months following completion of training with a structured telephone interview, neuropsychological and complex functional performance measures, and self-report measures of daily and emotional functioning. Results: Participants reported an increased likelihood of involvement in competitive employment/volunteering at follow-up (61%) compared to baseline (26%; χ2 = 5.66, p < .01, ѱ = .35). Repeated measures MANOVAS indicated improvement on attention/executive function (F = 13.85, p < .01, partial η2 = .42), complex functional task performance (GPS Total: F = 9.12, p < .01, partial η2 = .38) and daily functioning (MPAI Total: F = 3.23, p < .05, partial η2 = .21), and reduction in overall mood disturbance (POMS Total: F = 3.42, p < .05, partial η2 = .22) at follow-up relative to baseline. Discussion: Training in attention regulation applied to participant-defined goals is associated with meaningful long-term improvement in cognitive skills, emotion regulation, and daily functioning in Veterans with chronic TBI.

Machine learning in schizophrenia genomics, a case-control study using 5,090 exomes.

Our hypothesis is that machine learning (ML) analysis of whole exome sequencing (WES) data can be used to identify individuals at high risk for schizophrenia (SCZ). This study applies ML to WES data from 2,545 individuals with SCZ and 2,545 unaffected individuals, accessed via the database of genotypes and phenotypes (dbGaP). Single nucleotide variants and small insertions and deletions were annotated by ANNOVAR using the reference genome hg19/GRCh37. Rare (predicted functional) variants with a minor allele frequency ≤1% and genotype quality ≥90 including missense, frameshift, stop gain, stop loss, intronic, and exonic splicing variants were selected. A file containing all cases and controls, the names of genes with variants meeting our criteria, and the number of variants per gene for each individual, was used for ML analysis. The supervised machine-learning algorithm used the patterns of variants observed in the different genes to determine which subset of genes can best predict that an individual is affected. Seventy percent of the data was used to train the algorithm and the remaining 30% of data (n = 1,526) was used to evaluate its efficiency. The supervised ML algorithm, gradient boosted trees with regularization (eXtreme Gradient Boosting implementation) was the best performing algorithm yielding promising results (accuracy: 85.7%, specificity: 86.6%, sensitivity: 84.9%, area under the receiver-operator characteristic curve: 0.95). The top 50 features (genes) of the algorithm were analyzed using bioinformatics resources for new insights about the pathophysiology of SCZ. This manuscript presents a novel predictor which could potentially enable studies exploring disease-modifying intervention in the early stages of the disease.

Isocanthine Synthesis via Rh(III)-Catalyzed Intramolecular C-H Functionalization.

An efficient synthesis of substituted isocanthines has been achieved using an intramolecular Rh(III)-catalyzed C-H functionalization of alkyne-tethered indoles in the presence of catalytic tris(acetonitrile)pentamethylcyclopentadienylrhodium(III) hexafluoroantimonate and stoichiometric copper(II) acetate. This isocanthine synthesis tolerates a variety of electronically diverse 5- or 6-substituted indoles with N-tethered alkyne coupling partners and can also be extended to pyrrole derivatives for the synthesis of annulated 5-azaindoles.

RNA Interference Screen to Identify Kinases That Suppress Rescue of ΔF508-CFTR.

Cystic Fibrosis (CF) is an autosomal recessive disorder caused by mutations in the gene encoding the Cystic fibrosis transmembrane conductance regulator (CFTR). ΔF508-CFTR, the most common disease-causing CF mutant, exhibits folding and trafficking defects and is retained in the endoplasmic reticulum, where it is targeted for proteasomal degradation. To identify signaling pathways involved in ΔF508-CFTR rescue, we screened a library of endoribonuclease-prepared short interfering RNAs (esiRNAs) that target ∼750 different kinases and associated signaling proteins. We identified 20 novel suppressors of ΔF508-CFTR maturation, including the FGFR1. These were subsequently validated by measuring channel activity by the YFP halide-sensitive assay following shRNA-mediated knockdown, immunoblotting for the mature (band C) ΔF508-CFTR and measuring the amount of surface ΔF508-CFTR by ELISA. The role of FGFR signaling on ΔF508-CFTR trafficking was further elucidated by knocking down FGFRs and their downstream signaling proteins: Erk1/2, Akt, PLCγ-1, and FRS2. Interestingly, inhibition of FGFR1 with SU5402 administered to intestinal organoids (mini-guts) generated from the ileum of ΔF508-CFTR homozygous mice resulted in a robust ΔF508-CFTR rescue. Moreover, combination of SU5402 and VX-809 treatments in cells led to an additive enhancement of ΔF508-CFTR rescue, suggesting these compounds operate by different mechanisms. Chaperone array analysis on human bronchial epithelial cells harvested from ΔF508/ΔF508-CFTR transplant patients treated with SU5402 identified altered expression of several chaperones, an effect validated by their overexpression or knockdown experiments. We propose that FGFR signaling regulates specific chaperones that control ΔF508-CFTR maturation, and suggest that FGFRs may serve as important targets for therapeutic intervention for the treatment of CF.

Seekers, Finders, Settlers, and Stumblers: Identifying the Career Paths of Males in the Genetic Counseling Profession.

Genetic counseling is a female-dominated profession, with 96% of counselors self-identifying as female. Research suggests gender diversification benefits healthcare professionals and the populations they serve. Therefore, this study explored how men choose a genetic counseling career, associations between career satisfaction and their career entry dynamics and experience levels, and differences due to experience level in how they decide on this profession. Twenty-five novice, experienced, or seasoned male counselors and 8 male genetic counseling students participated in semi-structured phone interviews. Interpretive content and cross-case analyses of interview data were informed by Simpson's "Seekers, Finders, and Settlers" theory describing career entry dynamics of men in non-traditional (i.e., female-dominated) fields. Results revealed 13 interviewees were Seekers, who initially knew they wanted a career in genetic counseling, actively chose the profession, and were satisfied with their decision. Eleven were Settlers, who had tried different, traditional jobs, with limited satisfaction before actively finding and choosing genetic counseling. Two were Finders, who discovered genetic counseling while in the career decision making process and made a passive choice to pursue it as they had no feasible, satisfactory alternative. Seven men fit a new category, we termed "Stumblers," who were in another career and satisfied, but changed to genetic counseling after happening to hear about it. Prevalent themes pertaining to participants' experiences in the career include desire for a multidisciplinary career; lack of a priori knowledge of genetic counselor roles; late exposure to the profession; and varied perceptions of being in a non-traditional career. There were few differences due to experience level and career satisfaction was high across the sample. Results suggest earlier exposure to the career and availability of detailed descriptions of its multidisciplinary nature may increase the number of males in the profession.

Persistent Pulmonary Embolism Rates Following Total Knee Arthroplasty Even With Prophylactic Anticoagulants.

BACKGROUND: Symptomatic pulmonary embolism (PE), a significant and life-threatening complication following total knee arthroplasty (TKA), has been described as a "never event." Despite a number of advancements in care, PE continues to occur following TKA. This study evaluates symptomatic PE rates over time in TKA patients enrolled in multicenter randomized clinical trials assessing the efficacy of venous thromboembolism prophylaxis regimens. METHODS: The MEDLINE and Cochrane Central Register of Controlled Trials were searched to identify clinical trials assessing prophylactic anticoagulation in patients undergoing TKA between January 1995 and December 2016. A random effect model was used to combine PE rates across studies. The pooled proportion of symptomatic PEs was calculated and heterogeneity was quantified with the I2 statistic. A 95% prediction interval was constructed to examine what the expected range in the proportion of symptomatic PEs would be in future studies. Meta-regression was used to explore the effect of time on the rate of symptomatic PEs. RESULTS: A total of 18 studies representing 27,073 patients were included in the meta-analysis. The symptomatic PE rate was 0.37% (95% confidence interval, 0.24%-0.52%). There was significant heterogeneity across studies, I2 = 66%. Between 1996 and 2010, the proportion of PEs did not change in the regression analysis. The 95% prediction interval was 0.0002 to 0.0106, indicating that in similar future studies, the true proportion of symptomatic PEs would range from 0.02% to 1.06%. CONCLUSION: Over a 14-year period, the symptomatic PE rate after TKA was relatively constant even when patients received potent anticoagulation. These results suggest that some patients may have a genetic predisposition to develop a PE and more effective risk stratification protocols need to be developed to make sure patients receive appropriate anticoagulation.