Detection of atrial fibrillation by implantable loop recorders following cryptogenic stroke: A retrospective study of predictive factors and outcomes.

PURPOSE: Cryptogenic strokes account for 40% of ischemic strokes. Atrial fibrillation (AF) is a known cause of stroke. Current data shows that occult AF is detected by implantable devices at higher rates than conventional monitoring. The objective of this study was to investigate risk factors and outcomes associated with AF detection by implantable loop recorders (ILRs) in patients with cryptogenic stroke. METHODS: We conducted a retrospective study of 172 patients admitted with cryptogenic stroke at Ascension St John and Macomb-Oakland Hospitals who had ILRs placed from 1/1/2016 to 1/31/2020. AF detection was defined as sustained AF for 30 s. RESULTS: The incidence of AF detection by ILR was 14% (24/172) over a mean follow-up of 12.75 ± 10.71 months. The mean duration of monitoring prior to AF detection was 4.5 months. The median duration of AF was 6 min. With univariable analysis, older age (p = 0.03), male sex (p = 0.09), embolic stroke pattern on imaging (p = 0.06), and presence of symptoms (p = 0.001) were associated with AF detection. Using multivariable analysis, patients with AF were more likely to be older (OR = 1.04, p = 0.04), male (OR = 3.6, p = 0.03), symptomatic (OR = 6.3, p = 0.01), and had embolic stroke pattern (OR = 3.3, p = 0.04). 95.8% of patients with AF were started on anticoagulation for secondary stroke prevention. CONCLUSION: In patients with cryptogenic stroke, age, sex, stroke pattern, and presence of AF symptoms are independent predictors of AF detection by ILR. Most patients with AF were started on anticoagulation for secondary stroke prevention.

miRNAs dysregulated in association with Gleason grade regulate extracellular matrix, cytoskeleton and androgen receptor pathways.

The Gleason grading system is an important determinant of treatment decisions and prognosis in prostate cancer. It has a number of limitations, including significant inter-observer variability, creating a need for biological parameters to accurately assess the Gleason grade. The objective of this study was to determine the molecular correlates of the different Gleason grades. Global miRNA expression was analysed in pure regions of each Gleason grade. Bioinformatics analysis was performed to predict miRNA-mediated signalling. We experimentally validated the effect of miRNAs on target gene expression and cellular functions using cell line models. We also examined the correlation of miRNAs with biochemical failure, metastasis and prognosis. We identified miRNAs that are differentially expressed between grades 3 and 5, and the top biological processes associated with Gleason grade transition were extracellular matrix (ECM)-mediated signalling, focal adhesion kinase- and mitogen-activated kinase pathways. Transfection with miR-29c, miR-34a and miR-141 repressed genes involved in ECM-mediated pathways, such as SRC, PRKCA, COL1A1, ITGB1 and MAPK13, and decreased cell proliferation and migration. Furthermore, miR-29c and miR-34a influenced downstream pathways that affect actin cytoskeleton organization and androgen receptor localization. Finally, miR-29c, miR-34a, miR-141 and miR-148a showed inverse correlations with biochemical recurrence, but were independent of other clinical parameters. Our results demonstrate the potential role of miRNAs as independent prognostic markers and pave the road for a biological-based reclassification of the Gleason grading system.

Kallikreins are involved in an miRNA network that contributes to prostate cancer progression.

MicroRNAs (miRNAs) are short RNA nucleotides that negatively regulate their target genes. They are differentially expressed in prostate cancer. Kallikreins are genes that encode serine proteases and are dysregulated in cancer. We elucidated a miRNA-kallikrein network that can be involved in prostate cancer progression. Target prediction identified 23 miRNAs that are dysregulated between high and low risk biochemical failure and are predicted to target five kallikreins linked to prostate cancer; KLK2, KLK3, KLK4, KLK14 and KLK15. We also identified 14 miRNAs that are differentially expressed between Gleason grades and are predicted to target these kallikreins. This demonstrates that kallikreins are downstream effectors through which miRNAs influence tumor progression. We show, through in-silico and experimental analysis, that miR-378/422a and its gene targets PIK3CG, GRB2, AKT3, KLK4 and KLK14 form an integrated circuit in prostate cancer. Our analysis shows that a minisatellite sequence in the kallikrein locus consists of a number of microsatellite repeats that represent predicted miRNA response elements. A number of kallikrein and non-kallikrein prostate cancer-related genes share these microsatellite repeats. We validated some of these interactions in prostate cancer cell lines. Finally, we provide preliminary evidence on the presence of a miRNA-mediated cross-talk between kallikreins, including a kallikrein pseudogene.

Genomic medicine: new frontiers and new challenges.

BACKGROUND: The practice of personalized medicine has made large strides since the introduction of high-throughput technologies and the vast improvements in computational biotechnology. The personalized-medicine approach to cancer management holds promise for earlier disease detection, accurate prediction of prognosis, and better treatment options; however, the early experience with personalized medicine has revealed important concerns that need to be addressed before research findings can be translated to the bedside. CONTENT: We discuss several emerging "practical" or "focused" applications of personalized medicine. Molecular testing can have an important positive impact on health and disease management in a number of ways, and the list of specific applications is evolving. This list includes improvements in risk assessment, disease prevention, identification of new disease-related mutations, accurate disease classification based on molecular signatures, selection of patients for enrollment in clinical trials, and development of new targeted therapies, especially for metastatic tumors that are refractory to treatment. Several challenges remain to be addressed before genomics information can be applied successfully in the routine clinical management of cancers. Further improvements and investigations are needed in data interpretation, extraction of actionable items, cost-effectiveness, how to account for patient heterogeneity and ethnic variation, and how to handle the risk of "incidental findings" in genetic testing. SUMMARY: It is now clear that personalized medicine will not immediately provide a permanent solution for patient management and that further refinement in the applications of personalized medicine will be needed to address and focus on specific issues.

The Impact of Metabolic Syndrome on Quality of Life Among Individuals With Knee Osteoarthritis Living in Egypt.

Background: Several studies have linked metabolic syndrome (MetS) to osteoarthritis (OA), but they have not looked into how MetS can affect the health-related quality of life (HRQOL) of OA individuals. Objectives: We aimed to assess the association of MetS and its components, including obesity, hypertension, hyperglycemia, and dyslipidemia, with HRQOL among Egyptians with knee OA. Methods: This cross-sectional study comprised 116 adult Egyptian participants with knee OA. They were divided into 2 groups based on whether or not they had the MetS. All participants were subjected to a thorough medical history taking and a detailed medical examination. The Kellgren and Lawrence (K/L) scale evaluated OA in all individuals using anteroposterior knee radiographs. The Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were used to assess participants' HRQOL; their higher scores indicate more disability. Spearman rank and Pearson's correlation analyses were used to assess the association between variables. Results: Diabetes, hypertension, dyslipidemia, and obesity were significantly associated with the OA + MetS group with a prevalence of 77.6%, 82.8%, 77.6%, and 50.0%, respectively. According to the K/L scale, 70.7% of the OA + MetS group had grade IV knee affection. The HAQ-DI and WOMAC scores were significantly (P < .001) higher among the OA + MetS individuals compared with the OA individuals. Interleukin (IL)-6 serum levels were also significantly higher in the OA + MetS group (P = .036) and increased significantly with the more serious radiological damage and functional disability. We found significant positive correlations between HAQ-DI and WOMAC with waist circumference (P = .004, .001), as well as triglycerides (P = .006, .008), cholesterol (P = .041, .048), fasting blood sugar (P < .001, < .001) and significant negative correlations with high-density lipoprotein levels (P = .628, .002). Conclusions: Individuals with knee OA with MetS showed more significant radiological damage, severe functional disability, and poor HRQOL. They also had higher levels of IL-6, which correlated significantly with the degree of disability, promoting it as a significant therapeutic target.

Can Complete Blood Count Picture Tell Us More About the Activity of Rheumatological Diseases?

Background: In clinical practice, distinguishing disease activity in patients with rheumatological illnesses is challenging. Objectives: We aimed to investigate clinical associations of hemogram-derived indices, namely: red cell distribution width (RDW), mean platelet volume (MPV), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) with disease activity in patients with rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS). Methods: In 250 patients with rheumatological disease and 100 healthy age-matched controls, we investigated disease activity scores and indicators and evaluated their association with hemogram-derived indices values. Results: Compared with the control group, RDW, MPV, and PLR significantly increased (P < .001) in the three studied disorders (RA, SLE, and AS), but LMR dramatically decreased. SII was considerably higher in RA and AS patients compared with controls but not in SLE patients. On the other hand, NLR rose dramatically in SLE patients compared with controls (P = .043), but did not change much in RA and AS patients (P > .05). RDW and MPV showed significant changes (P < .001) in the three studied diseases (RA, SLE, and AS) according to disease activity. They significantly increased across worsening activity scores. Only in the SLE group, PLR was significantly increased with disease activity (P < .001), while LMR showed a significant decrease (P = .016). Conclusions: Clinicians must pay close attention to complete blood count (CBC) analysis and its various derived ratios to better characterize the activity of rheumatological disorders and anticipate the disease course and prognosis.

Post-COVID-19 arthritis: is it hyperinflammation or autoimmunity?

BACKGROUND:  Various musculoskeletal and autoimmune manifestations have been described in patients with coronavirus disease 2019 (COVID-19). Objectives: This study aims to investigate the prevalence and etiology of arthritis in post-COVID Egyptian patients. Methods: We included 100 post-COVID Egyptian patients who recovered 6 months ago and assessed several inflammatory and autoimmune markers. Results: The prevalence of post-COVID arthritis was 37%. Ankle, knee, and wrist were the most commonly affected joints. Old age (P = 0.010), smoking (P = 0.001), and arthralgia (P = 0.049) were all linked with post-COVID arthritis. Levels of pretreatment (baseline) interleukin (IL)-6 (46.41 ± 3.67 vs. 24.03 ± 2.46; P = 0.001), as well as 6-month post-COVID C-reactive protein (CRP; 98.49 ± 67.55 vs. 54.32 ± 65.73; P = 0.002), and erythrocyte sedimentation rate (ESR; 109.08 ± 174.91 vs. 58.35 ± 37.87; P = 0.029) were significantly higher in patients with arthritis compared to those without. On the other hand, complement C3 (P = 0.558) and C4 (P = 0.192), anti-nuclear antibodies (P = 0.709), and anti-cyclic citrullinated peptides (anti-CCP; P = 0.855) did not show significant differences. Only pretreatment IL-6 level was the significant single predictor of post-COVID arthritis with an odds ratio (95% confidence interval) of 3.988 (1.460-10.892) and a P-value of 0.007. CONCLUSION:  The strong association observed with inflammatory markers (ESR and CRP) and the insignificant association with serologic markers of autoimmunity (ANA and anti-CCP) in our study support the notion that the underlying mechanism of post-COVID-19 arthritis is primarily due to the hyperinflammatory process associated with COVID-19 infection, and not the result of an autoimmune reaction. IL-6 levels before therapy can predict post-COVID arthritis allowing for early management.

Evaluation of human tissue kallikrein-related peptidases 6 and 10 expression in early gastroesophageal adenocarcinoma.

Kallikreins are a family of serine proteases that are linked to malignancy of different body organs with potential clinical utility as tumor markers. In this study, we investigated kallikrein-related peptidase 6 (KLK6) and KLK10 expression in early gastroesophageal junction adenocarcinoma and Barrett esophagus (BE) with and without dysplasia. Immunohistochemistry revealed significantly increased KLK6 expression in early invasive cancer compared with dysplastic (P = .009) and nondysplastic BE (P = .0002). There was a stepwise expression increase from metaplasia to dysplasia and invasive tumors. Significantly higher KLK10 was seen in dysplastic lesions compared with metaplasia but not between dysplastic lesions and invasive cancers. KLK6 staining intensity was increased at the invasive front (P = .006), suggesting its role in tumor invasiveness. Neither KLK6 nor KLK10 was significantly associated with other prognostic markers, including depth of invasion, indicating their potential as independent biomarkers. Our results should be interpreted with caution due to limited sample size. There was a significant correlation between KLK6 and KLK10 expression both at the invasive front and within the main tumor, indicating a collaborative effect. We then compared KLK6 and KLK10 messenger RNA expression between metaplastic and cancerous tissues in an independent data set of esophageal carcinoma from The Cancer Genome Atlas. KLK6 and KLK10 may be useful markers and potential therapeutic targets in gastroesophageal junction tumors.

miR-210 is a prognostic marker in clear cell renal cell carcinoma.

Accurate assessment of prognosis of clear cell renal cell carcinoma (ccRCC) is key in optimizing management plans to fit individual patient needs. miRNAs are short noncoding single-stranded RNAs that control the expression of target genes and may act as cancer biomarkers. We analyzed the expression of miR-210 in 276 cases of primary ccRCC and compared its expression in 40 pairs of adjacent normal and cancerous tissues. We assessed its expression in primary and metastatic tumors, in the common RCC subtypes, and the benign oncocytoma. The results were validated with an independent data set from The Cancer Genome Atlas. miR-210 was significantly overexpressed in ccRCC compared with normal kidney. miR-210(+) patients had a statistically higher chance of disease recurrence [hazard ratio (HR), 1.82; P = 0.018] and shorter overall survival (HR, 2.46; P = 0.014). In multivariate analysis, miR-210 lost its statistically significant association with shorter disease-free survival and overall survival after adjusting for tumor size and tumor, node, metastasis stage. Papillary RCC showed comparable miR-210 overexpression, whereas decreased up-regulation was seen in chromophobe RCC and oncocytoma. A number of predicted targets that might be involved in carcinogenesis and aggressive tumor behavior were identified. miR-210 is a potential therapeutic target and independent marker of poor prognosis of ccRCC.

miRNAs can predict prostate cancer biochemical relapse and are involved in tumor progression.

Prostate cancer is the leading cancer diagnosed and the second most common cause of cancer related death in the western world. For prognostic monitoring after prostatectomy, recurrent increase of prostate-specific antigen (PSA), the so-called PSA or biochemical relapse remains the leading biomarker. There is currently no biomarker that can accurately predict the risk of relapse at the time of surgery. We analyzed formalin-fixed and paraffin-embedded tissue samples from 52 primary prostate cancers and normal adjacent tissues obtained after radical prostatectomy. Patients were grouped into two categories: i) patients with early biochemical relapse (<1 year after radical prostatectomy) and ii) patients with late or no biochemical relapse (>2 years after surgery). Multiplex real-time quantitative polymerase chain reaction (RT-qPCR) analysis was performed to identify a miRNA signature that can predict relapse. Results were validated by quantitative RT-PCR analysis. We identified 63 miRNAs that were differentially expressed among the same categories of patients, of whom 35 miRNAs were up-regulated and 28 were down-regulated. Literature search shows that many of these miRNAs have an established prognostic significance in other cancers and can be actively involved in tumor progression. Target prediction analysis showed that predicted targets of these miRNAs could be involved in biological processes and pathways that enhance tumor progression. We experimentally validated the role of one of the dysregulated miRNAs (miR-10b) in relapse using proliferation and wound-healing assay. miRNAs can be reliable predictive markers for biochemical relapse of prostate cancer at the time of radical prostatectomy. This should have significant impact on patient managing plans.