Nevin Manimala

J Am Heart Assoc. 2023 Nov 10:e030084. doi: 10.1161/JAHA.123.030084. Online ahead of print.

ABSTRACT

Background Sterile inflammation caused by metabolic disorders impairs endothelial function; however, the underlying mechanism by which hyperglycemia induces inflammation remains obscure. Recent studies have suggested that stimulator of interferon genes (STING), a key cytosolic DNA sensor in the innate immune system, contributes to the pathogenesis of inflammatory diseases. This study examines the role of the STING in endothelial dysfunction in streptozotocin-induced diabetic mice. Methods and Results Injection of streptozotocin promoted the expression of STING and DNA damage markers in the aorta of wild-type mice. Streptozotocin elevated blood glucose and lipid levels in both wild-type and STING-deficient mice, which showed no statistical differences. Genetic deletion of STING ameliorated endothelial dysfunction as determined by the vascular relaxation in response to acetylcholine (P<0.001) and increased endothelial nitric oxide synthase phosphorylation in the aorta (P<0.05) in STZ-injected mice. Endothelium-independent vascular response to sodium nitroprusside did not differ. Treatment with a direct STING agonist, cyclic GMP-AMP, or mitochondrial DNA increased inflammatory molecule expression (eg, VCAM1 and IFNB) and decreased endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells, partially through the STING pathway. Cyclic GMP-AMP significantly impaired endothelial function of aortic segments obtained from wild-type mice, which was ameliorated in the presence of C-176, a STING inhibitor, or a neutralizing interferon-β antibody. Furthermore, the administration of C-176 ameliorated endothelial dysfunction in STZ-induced diabetic mice (P<0.01). Conclusions The DNA damage response regulated by STING impairs endothelial function. STING signaling may be a potential therapeutic target of endothelial dysfunction caused by hyperglycemia.

PMID:37947148 | DOI:10.1161/JAHA.123.030084

Ortop Traumatol Rehabil. 2023 Aug 31;25(4):195-206. doi: 10.5604/01.3001.0053.9346.

ABSTRACT

BACKGROUND: Besides arch-supportive insoles, sensorimotor insoles are used for the treatment of flatfoot in children. The aim of this study was to compare the effect of both types of insoles on the arch-supporting muscles and clinical aspects in children with flexible flatfoot.

MATERIAL AND METHODS: 52 children with flexible flatfoot (mean age of 8.22.7 years) were enrolled. Supportive, sensorimotor, and placebo insoles were compared. Muscle activity was detected by surface electromyography during the midstance phase. Valgus index, foot and ankle disability index (FADI) and pain were assessed at enrolment and after 6 and 12 months. Mixed-design ANOVA was used for statistical evaluation.

RESULTS: Supportive and sensorimotor insoles caused significantly lower activity in the tibialis anterior in comparison to placebo insoles regarding the parameter Mean. No significant differences could be detected between both types of therapeutic insoles. Supportive insoles showed a significant decrease regarding the parameter Amplitude of the peroneus longus. Placebo insoles produced an increase in the valgus index, while both therapeutic insoles did not induce any changes. The sensorimotor insoles induced an increase in FADI, while the supportive and placebo insoles had no significant effect on this parameter.

CONCLUSIONS: 1. Supportive and sensorimotor insoles potentially influence muscle activity in the lower leg. 2. Both could influence the longitudinal arch in flat feet. 3. While placebo insoles caused a deterioration of the valgus index, both kinds of therapeutic insoles could possibly prevent the progression of the flatfoot. 4. Clinical studies including more clinical aspects and long-term observations are necessary.

PMID:37947144 | DOI:10.5604/01.3001.0053.9346

J Periodontal Res. 2023 Nov 10. doi: 10.1111/jre.13206. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate, in vivo, the effect of local application of Resolvin E1 (RvE1) on the bone regeneration of critical-size defects (CSDs) in Wistar rats utilizing gene expression and micro-computed tomographic (micro-CT) analysis.

BACKGROUND: The inflammation-resolving actions of RvE1 are well established. The molecular mechanism of its bone-regenerative actions has been of significant interest in recent years; however, there is limited information regarding the same.

MATERIALS AND METHODS: Thirty Wistar rats with a 5 mm induced critical-size calvarial defect were randomly allocated into four groups: no treatment/negative control (n = 5), treatment using bovine bone grafts/positive control (n = 5), treatment using local delivery of RvE1 (n = 11) and treatment using RvE1 mixed with bovine bone graft (n = 9). After 4 weeks, RNA isolation, complementary DNA synthesis and real-time polymerase chain reaction were used for genetic expression of alkaline phosphatase (ALP), osteocalcin (OCN) and osteopontin (OPN). The rats were sacrificed after 12 weeks and micro-CT imaging was performed to analyse the characteristics of the newly formed bone (NFB). The data were analysed using ANOVA and the least significant difference tests (α ≤ .05).

RESULTS: The RvE1 + bovine graft group had statistically highest mean NFB (20.75 ± 2.67 mm³ ) compared to other groups (p < .001). Similarly, RvE1 + bovine graft group also demonstrated statistically highest mean genetic expression of ALP (31.71 ± 2.97; p = .008) and OPN (34.78 ± 3.62; p < .001) compared to negative control and RvE1 groups.

CONCLUSION: Resolvin E1 with adjunct bovine bone graft demonstrated an enhanced bone regeneration compared to RvE1 or bovine graft alone in the calvarial defect of Wistar rats.

PMID:37947141 | DOI:10.1111/jre.13206

J Ment Health. 2023 Nov 10:1-9. doi: 10.1080/09638237.2023.2278107. Online ahead of print.

ABSTRACT

BACKGROUND: Latent disease classification is currently the accepted approach to mental illness diagnosis. In the United States, this takes the form of the Diagnostic and Statistical Manual of Mental Disorders-5-Text Revision (DSM-5-TR). Latent disease classification has been criticized for reliability and validity problems, particularly regarding diagnostic heterogeneity. No authors have calculated the scope of the heterogeneity problem of the entire DSM-5-TR.

AIMS: We addressed this issue by calculating the unique diagnostic profiles that exist for every DSM-5-TR diagnosis.

METHODS: We did this by applying formulas previously used in smaller heterogeneity analyses to all diagnoses within the DSM-5-TR.

RESULTS: We found that there are 10,130,814 ways to be diagnosed with a mental illness using DSM-5-TR criteria. When specifiers are considered, this number balloons to over 161 septillion unique diagnostic presentations (driven mainly by bipolar II disorder). Additionally, there are 1,951,065 ways to present with psychiatric symptoms, yet not meet diagnostic criteria.

CONCLUSIONS: Latent disease classification leads to considerable heterogeneity in possible presentations. We provide examples of how latent disease classification harms research and treatment programs. We echo recommendations for the dismissal of latent disease classification as a mental illness diagnostic program.

PMID:37947129 | DOI:10.1080/09638237.2023.2278107

J Am Heart Assoc. 2023 Nov 10:e030117. doi: 10.1161/JAHA.123.030117. Online ahead of print.

ABSTRACT

Background Mortality from cardiovascular diseases in Asian populations is considerable. Menopause is a risk-enhancing factor for cardiovascular disease, but it is unclear whether menopause is an independent risk factor for cardiovascular disease and mortality in Asian women. Methods and Results A total of 1 159 405 postmenopausal women, who had participated in the health examinations of the Korean National Health Insurance Service in 2009, were analyzed, and their reproductive histories were taken. A multivariable Cox proportional hazard model assessed the hazard ratios (HRs) of myocardial infarction (MI), ischemic stroke, and all-cause mortality, according to the history of premature menopause and age at menopause. After an average 10-year follow-up, there were 31 606, 45 052, and 77 680 new cases of MI, ischemic stroke, and all-cause mortality, respectively. The women with premature menopause exhibited increased risks of MI (HR, 1.40 [95% CI, 1.31-1.50]), ischemic stroke (HR, 1.24 [95% CI, 1.17-1.31]), and all-cause mortality (HR, 1.19 [95% CI, 1.14-1.24]) when compared with women with menopause aged ≥50 years. The highest risk was evident with menopause between the ages of 30 and 34 years (HR for MI, 1.52 [95% CI, 1.30-1.78]; HR for ischemic stroke, 1.29 [95% CI, 1.12-1.48]; HR for all-cause mortality, 1.33 [95% CI, 1.20-1.47]) when compared with women with menopause aged ≥50 years. Conclusions Earlier age at menopause was associated with increased risks for MI, ischemic stroke, and all-cause mortality. Future guidelines and risk assessment tools should consider menopause as an independent risk factor of cardiovascular disease in Korean women.

PMID:37947103 | DOI:10.1161/JAHA.123.030117

J Am Heart Assoc. 2023 Nov 10:e030211. doi: 10.1161/JAHA.123.030211. Online ahead of print.

ABSTRACT

Background Patients with rheumatoid arthritis (RA) have a 2- to 10-fold increased risk of cardiovascular disease (CVD), but the biological mechanisms and existence of causality underlying such associations remain to be investigated. We aimed to investigate the genetic associations and underlying mechanisms between RA and CVD by leveraging large-scale genomic data and genetic cross-trait analytic approaches. Methods and Results Within UK Biobank data, we examined the genetic correlation, shared genetics, and potential causality between RA (N_cases=6754, N_controls=452 384) and cardiovascular diseases (CVD, N_cases=44 238, N_controls=414 900) using linkage disequilibrium score regression, cross-trait meta-analysis, and Mendelian randomization. We observed significant genetic correlations of RA with myocardial infarction (r_g:0.40 [95% CI, 0.24-0.56), angina (r_g:0.42 [95% CI, 0.28-0.56]), coronary heart diseases (r_g:0.41 [95% CI, 0.27-0.55]), and CVD (r_g:0.43 [95% CI, 0.29-0.57]) after correcting for multiple testing (P<0.05/5). When stratified by frequent use of analgesics, we found increased genetic correlation between RA and CVD among participants without aspirin usage (r_g:0.54 [95% CI, 0.30-0.78] for angina; P_value=6.69×10^-6) and among participants with paracetamol usage (r_g:0.75 [95% CI, 0.20-1.29] for myocardial infarction; P_value=8.90×10^-3), whereas others remained similar. Cross-trait meta-analysis identified 9 independent shared loci between RA and CVD, including PTPN22 at chr1p13.2, BCL2L11 at chr2q13, and CCR3 at chr3p21.31 (P_{single trait}<1×10^-3 and P_meta<5×10^-8), highlighting potential shared pathogenesis including accelerating atherosclerosis, upregulating oxidative stress, and vascular permeability. Finally, Mendelian randomization estimates showed limited evidence of causality between RA and CVD. Conclusions Our results supported shared genetic pathogenesis rather than causality in explaining the observed association between RA and CVD. The identified shared genetic factors provided insights into potential novel therapeutic target for RA-CVD comorbidities.

PMID:37947095 | DOI:10.1161/JAHA.123.030211

Circulation. 2023 Nov 10. doi: 10.1161/CIRCULATIONAHA.123.067626. Online ahead of print.

ABSTRACT

Background: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the AHA Predicting Risk of CVD EVENTs (PREVENT) equations among US adults aged 30-79 years without known CVD. Methods: The derivation sample included individual-level participant data from 25 datasets (N=3,281,919) between 1992-2017. The primary outcome was CVD (atherosclerotic CVD [ASCVD] and heart failure [HF]). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, anti-hypertensive or statin use, diabetes) and estimated glomerular filtration rate [eGFR]. Models were sex-specific, race-free, developed on the age-scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each dataset and meta-analyzed. Discrimination was assessed using Harrell’s C-statistic. Calibration was calculated as the slope of the observed vs. predicted risk by decile. Additional equations to predict each CVD subtype (ASCVD, HF) and include optional predictors (urine albumin-to-creatinine ratio [UACR], hemoglobin A1c [HbA1c]), and social deprivation index [SDI]) were also developed. External validation was performed in 3,330,085 participants from 21 additional datasets. Results: Among 6,612,004 adults included, mean (SD) age was 53 (12) years and 56% were female. Over a mean (SD) follow-up of 4.8 (3.1) years, there were 211,515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval [IQI]: 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (IQI 0.81 -1.16) and 0.94 (0.81-1.13) among females and males, respectively. Similar estimates for discrimination and calibration were observed for ASCVD- and HF-specific models. The improvement in discrimination was small but statistically significant when UACR, HbA1c, and SDI were added together to the base model to total CVD (ΔC-statistic [IQI] 0.004 [0.004, 0.005] and 0.005 [0.004, 0.007] among females and males, respectively). Calibration improved significantly when UACR was added to the base model among those with marked albuminuria (>300mg/g) (1.05 [0.84-1.20] vs. 1.39 [1.14-1.65], p=0.01). Conclusions: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults using routinely available clinical variables.

PMID:37947085 | DOI:10.1161/CIRCULATIONAHA.123.067626

APL Bioeng. 2023 Nov 7;7(4):046112. doi: 10.1063/5.0153461. eCollection 2023 Dec.

ABSTRACT

Fractional-pixel CO₂ laser therapy shows promise for treating the genitourinary syndrome of menopause (GSM). Nevertheless, it remains controversial in the field of female pelvic medicine. This is due to the inherent difficulties in obtaining noninvasive biopsies to evaluate the treatment’s efficacy and safety objectively. To address this challenge, we developed a noninvasive intravaginal optical coherence tomography (OCT)/OCT angiography (OCTA) endoscopic system, whose probe features a shape identical to the laser treatment probe. This system can provide high-resolution OCT images to identify the microstructure of vaginal tissue and visualize the vasculature network in vivo. We conducted clinical research on 25 post-menopausal patients with GSM. OCT/OCTA scans were acquired at four different locations of the vagina (distal anterior, distal posterior, proximal anterior, and proximal posterior) during the whole laser treatment session. A U-Net deep learning model was applied to segment the vaginal epithelium for assessing vaginal epithelial thickness (VET). Blood vessel density and VET were quantified to monitor the efficacy of fractional-pixel CO₂ laser therapy. Statistical correlation analyses between these metrics and other clinical scores were conducted, validating the utility of our system. This OCT/OCTA endoscopic system has great potential to serve as a noninvasive biopsy tool in gynecological studies to screen, evaluate, and guide laser treatment for GSM.

PMID:37946874 | PMC:PMC10631816 | DOI:10.1063/5.0153461

World J Clin Cases. 2023 Oct 16;11(29):7075-7081. doi: 10.12998/wjcc.v11.i29.7075.

ABSTRACT

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma that affects B lymphocytes. It can develop in the lymph nodes and can be localized or generalized. Despite DLBCL being considered potentially curable, little research has been conducted on the relationship between the body’s immune response and DLBCL.

AIM: To study the expression and significance of T-regulatory cells (Tregs) interleukin (IL)-35, IL-10, and transforming growth factor-beta (TGF-β) in DLBCL.

METHODS: Data from 82 patients with DLBCL who were initially admitted to The First Affiliated Hospital of Ningbo University (Zhejiang Province, China) between January 2017 and June 2022 and treated with standard first-line regimens were reviewed. Three patients were lost to follow-up; thus, 79 patients were included in the statistical analysis and then divided into three groups according to the evaluation of clinical efficacy: Incipient (new-onset and treatment-naïve), effectively treated, and relapsed-refractory. Thirty healthy individuals were included in the control group. The expression of peripheral blood T lymphocytes and their associated factors IL-35, IL-10, and TGF-β in the four groups were observed.

RESULTS: In contrast to the successfully treated and normal control groups, both the incipient and relapse-refractory groups exhibited greater proportions of CD4-positive (+) Tregs (P < 0.05), whereas the proportion of CD8+ Tregs did not differ substantially between the groups. Serum levels of IL-35 and IL-10 in the incipient and relapsed-refractory groups were higher than those in the effectively treated and normal control groups (P < 0.05). There was no statistically significant distinction in the expression level of TGF-β between the groups (P > 0.05). The correlation between IL-35 and IL-10 concentrations was significantly positive, with a correlation coefficient of 0.531 (P < 0.05). The correlation between IL-35 and TGF-β concentration was significantly positive, with a correlation coefficient of 0.375 (P < 0.05). The correlation between IL-10 and TGF-β concentration was significantly positive, with a correlation coefficient of 0.185 (P < 0.05). The expression concentrations of IL-35, IL-10 and TGF-β were apparently and positively correlated (P < 0.05).

CONCLUSION: Tregs IL-35, and IL-10 may be closely associated with the occurrence and development of DLBCL and the detection of related indices may be helpful in the analysis of disease prognosis.

PMID:37946782 | PMC:PMC10631411 | DOI:10.12998/wjcc.v11.i29.7075

World J Clin Cases. 2023 Oct 16;11(29):7004-7016. doi: 10.12998/wjcc.v11.i29.7004.

ABSTRACT

BACKGROUND: The incidence of chronic kidney disease (CKD) has dramatically increased in recent years, with significant impacts on patient mortality rates. Previous studies have identified multiple risk factors for CKD, but they mostly relied on the use of traditional statistical methods such as logistic regression and only focused on a few risk factors.

AIM: To determine factors that can be used to identify subjects with a low estimated glomerular filtration rate (L-eGFR < 60 mL/min per 1.73 m²) in a cohort of 1236 Chinese people aged over 65.

METHODS: Twenty risk factors were divided into three models. Model 1 consisted of demographic and biochemistry data. Model 2 added lifestyle data to Model 1, and Model 3 added inflammatory markers to Model 2. Five machine learning methods were used: Multivariate adaptive regression splines, eXtreme Gradient Boosting, stochastic gradient boosting, Light Gradient Boosting Machine, and Categorical Features + Gradient Boosting. Evaluation criteria included accuracy, sensitivity, specificity, area under the receiver operating characteristic curve (AUC), F-1 score, and balanced accuracy.

RESULTS: A trend of increasing AUC of each was observed from Model 1 to Model 3 and reached statistical significance. Model 3 selected uric acid as the most important risk factor, followed by age, hemoglobin (Hb), body mass index (BMI), sport hours, and systolic blood pressure (SBP).

CONCLUSION: Among all the risk factors including demographic, biochemistry, and lifestyle risk factors, along with inflammation markers, UA is the most important risk factor to identify L-eGFR, followed by age, Hb, BMI, sport hours, and SBP in a cohort of elderly Chinese people.

PMID:37946770 | PMC:PMC10631406 | DOI:10.12998/wjcc.v11.i29.7004