The gene therapy revolution in ophthalmology

AbstractThe advances in gene therapy hold significant promise for the treatment of ophthalmic conditions. Several studies using animal models have been published. Animal models on retinitis pigmentosa, Leber’s Congenital Amaurosis (LCA), and Stargardt disease have involved the use of adeno-associated virus (AAV) to deliver functional genes into mice and canines. Mice models have been used to show that a mutation in cGMP phosphodiesterase that results in retinitis pigmentosa can be corrected using rAAV vectors. Additionally, rAAV vectors have been successfully used to deliver ribozyme into mice with a subsequent improvement in autosomal dominant retinitis pigmentosa. By using dog models, researchers have made progress in studying X-linked retinitis pigmentosa which results from a RPGR gene mutation. Mouse and canine models have also been used in the study of LCA. The widely studied form of LCA is LCA2, resulting from a mutation in the gene RPE65. Mice and canines that were injected with normal copies of RPE65 gene showed signs such as improved retinal pigment epithelium transduction, visual acuity, and functional recovery. Studies on Stargardt disease have shown that mutations in the ABCA4 gene can be corrected with AAV vectors, or nanoparticles. Gene therapy for the treatment of red–green color blindness was successful in squirrel monkeys. Plans are at an advanced stage to begin clinical trials. Researchers have also proved that CD59 can be used with AMD. Gene therapy is also able to treat primary open angle glaucoma (POAG) in animal models, and studies show it is economically viable

Genoprotective and Genotoxic Effects of Thymoquinone on Doxorubicin-Induced Damage in Isolated Human Leukocytes

Purpose: To investigate the potential genoprotective effects of thymoquinone (TQ) on the cytotoxicity and genotoxicity-induced by doxorubicin (DXR), a key chemotherapeutic drug.Methods: Isolated human peripheral leukocytes were treated with varying concentrations of TQ (5.0, 10.0, or 20.0 µM) alone or in combination with DXR (0.15 ìg/mL). Comet assays and apoptotic cell studies were performed to evaluate the effect of TQ on the cytotoxicity and genotoxicity-induced by DXR.Results: TQ treatment, alone, (5.0, 10, or 20 µM) increased DNA damage index (DI) in a concentrationdependent manner (0.64 ± 0.09, 0.84 ± 0.07, and 0.93 ± 0.06, respectively). DXR (0.15 µg/mL) increased DI (1.67 ± 0.09) compared with no treatment (0.34 ± 0.03). However, when TQ was administered with DXR, DI was significantly reduced (0.96 ± 0.04, 0.80 ± 0.05, and 0.79 ± 0.04) compared with DXR alone (1.67 ± 0.09). Similarly, apoptotic cells decreased (10.8, 11.8 and 14.2 %) compared with that induced by DXR alone (27.6 %).Conclusion: TQ can be used as a genoprotective agent against  DXR-induced genotoxicity. The dual behavior of TQ observed in this study is dose-dependent and therefore its mechanism of action needs to be clarified in future studies.Keywords: Thymoquinone, Genotoxicity, Genoprotection, Doxorubicin, Apoptotic, Oxidative stress, DNA damage inde

Reproducibility of Left Ventricular Dyssynchrony Indices by Three-Dimensional Speckle-Tracking Echocardiography: The Impact of Sub-optimal Image Quality

Background: 3D speckle-tracking echocardiography (3D-STE) is a novel method to quantify left ventricular (LV) mechanical dyssynchrony. 3D-STE is influenced by image quality, but studies on the magnitude of its effect on 3D-STE derived LV systolic dyssynchrony indices (SDIs) and their test-retest reproducibility are limited. Methods: 3D-STE was performed in two groups, each comprising 18 healthy volunteers with good echocardiographic windows. In study 1, optimal and inferior-quality images, by intentionally poor echocardiographic technique, were acquired. In study 2, sub-optimal quality images were acquired by impairing ultrasound propagation using neoprene rubber sheets (thickness 2, 3, and 4 mm) mimicking mildly, moderately, and severely impaired images, respectively. Measures (normalized to cardiac cycle duration) were volume- and strain-based SDIs defined as the standard deviation of time to minimum segmental values, and volume- and strain-derived dispersion indices. For both studies test-retest reproducibility was assessed. Results: Test-retest reproducibility was better for most indices when restricting the analysis to good quality images; nevertheless, only volume-, circumferential strain-, and principal tangential strain-derived LV dyssynchrony indices achieved fair to good reliability. There was no evidence of systematic bias due to sub-optimal quality image. Volume-, circumferential strain-, and principal tangential strain-derived SDIs correlated closely. Radial strain- and longitudinal strain-SDI correlated moderately or weakly with volume-SDI, respectively. Conclusions: Sub-optimal image quality compromised the reliability of 3D-STE derived dyssynchrony indices but did not introduce systematic bias in healthy individuals. Even with optimal quality images, only 3D-STE indices based on volume, circumferential strain and principal tangential strain showed acceptable test-retest reliability

Does 3D-speckle tracking echocardiography improve prediction of major cardiovascular events in a multi-ethnic general population? A Southall and Brent Revisited (SABRE) cohort study

3D-speckle tracking echocardiography(3D-STE) allows simultaneous assessment of ejection fraction(EF) and multidirectional strains, but its prognostic utility in the general population is unknown. We investigated if 3D-STE strains predicted a composite of major cardiac endpoints(MACE) beyond cardiovascular risk factors(CVDRF), and whether they were superior to 3D-EF. 529 participants in SABRE, a UK-based tri-ethnic general population cohort (69±6y; 76.6% male) with acceptable 3D-STE imaging were studied. Associations between 3D-EF or multidirectional myocardial strains and MACE(coronary heart disease(fatal/non-fatal), heart failure hospitalization, new-onset arrhythmia and cardiovascular mortality) were determined using Cox regression including adjustment for CVDRF and 2D-EF. Whether 3D-EF, global longitudinal strain(3D-GLS) and principle tangential strain(3D-PTS/3D-strain) improved cardiovascular risk stratification over CVDRF was investigated using a likelihood ratio test on a series of nested Cox proportional hazards models and Harrell's C statistics. During follow-up(median, 12y), there were 92 events. 3D-EF, 3D-GLS and 3D-PTS and 3D-RS were associated with MACE in unadjusted and models adjusted for CVDRF but not CVDRF+2D-EF. Compared to 3D-EF, both 3D-GLS and 3D-PTS slightly improved the predictive value over CVDRF for MACE, but the improvement was modest(C statistic increased from 0.698(0.647, 0.749) to 0.715(0.663, 0.766) comparing CVDRF with CVDRF +3D-GLS). 3D-STE-derived LV myocardial strains predicted MACE in a multi-ethnic general population sample of elderly individuals from the UK; however the added prognostic value of 3D-STE myocardial strains was small

Prognostic implications of left ventricular strain by speckle-tracking echocardiography in the general population: A meta-analysis

Purpose: Left ventricular (LV) mechanics by speckle-tracking echocardiography (STE) is prognostic in patients with cardiovascular diseases, but evidence related to community-dwelling individuals is uncertain. We therefore performed a systematic review and meta-analysis of STE as a predictor of adverse outcomes in the general population. // Methods: PRISMA guidelines were followed and MEDLINE and EMBASE were searched to identify eligible studies. Primary outcome was all-cause mortality and secondary outcomes were composite cardiac and cardiovascular end-point. Random effects meta-analysis was performed, and a modified Newcastle-Ottawa Assessment Scale was used for quality assessment. // Results: Eight papers matched the predefined criteria (total number of individuals studied=11,744). All publications assessed global longitudinal strain (GLS) by two-dimensional speckle-tracking echocardiography (2D-STE), one assessed circumferential, radial and transverse strains, and one assessed GLS-derived post-systolic shortening. None assessed LV rotational measures in association with outcomes. Two studies reported associations between GLS and all-cause mortality and composite cardiovascular end-point. Six papers reported an association between GLS and composite cardiac end-point, three of which were from the same study. Four papers were suitable for meta-analysis. GLS predicted all-cause mortality (pooled minimally adjusted HR per unit strain (%)=1.07 [95% CI 1.03– 1.11], p=0.001), and composite cardiovascular (pooled maximally adjusted HR=1.18 [1.09–1.28], p<0.0001) and cardiac (HR=1.08 [1.02–1.14], p=0.006) end-points. GLS also predicted coronary heart disease (HR=1.15 [1.03–1.29], p=0.017) and heart failure (HR=1.07 [1.02–1.13], p=0.012). The quality of all studies was good. // Conclusions: This study provides some evidence that STE may have utility as a measure of cardiac function and risk in the general population. 2D-STE-based GLS predicts total mortality, major adverse cardiac and cardiovascular end-points in community-dwelling individuals in a limited number of studies. Despite this, this systematic review also highlights important knowledge gaps in the current literature and further evidence is needed regarding the prognostic value of LV mechanics in unselected older populations

Relationship Between Image Quality and Bias in 3D Echocardiographic Measures: Data From the SABRE (Southall and Brent Revisited) Study

Background: Image‐quality (IQ) compromises left ventricle assessment by 3‐dimensional echocardiography (3DE). Sicker/frailer patients often have suboptimal IQ, and therefore observed associations may be biased by IQ. We investigated its effect in an observational study of older people and when IQ was modified experimentally in healthy volunteers. / Methods and Results: 3DE feasibility by IQ was assessed in 1294 individuals who attended the second wave of the Southall and Brent Revisited study and was compared with 2‐dimensional (2D)‐echocardiography feasibility in 147 individuals. Upon successful analysis, means of ejection fraction (3D‐EF) and global longitudinal strain (3D‐GLS) (plus 2D‐EF) were compared in individuals with poor versus good IQ. In 2 studies of healthy participants, 3DE‐IQ was impaired by (1) intentionally poor echocardiographic technique, and (2) use of a sheet of ultrasound‐attenuating material (neoprene rubber; 2–4 mm). The feasibility was 41% (529/1294) for 3DE versus 61% (89/147) for 2D‐EF, P<0.0001. Among acceptable images (n=529), good IQ by the 2015 American Society of Echocardiography/European Association of Cardiovascular Imaging criteria was 33.6% (178/529) and 71.3% (377/529) for 3D‐EF and 3D‐GLS, respectively. Individuals with poor IQ had lower 3D‐EF and 3D‐GLS (absolute) than those with good IQ (3D‐EF: 52.8±6.0% versus 55.7±5.7%, Mean‐Δ −2.9 [−3.9, 1.8]; 3D‐GLS: 18.6±3.2% versus 19.2±2.9%, Mean‐Δ −0.6 [−1.1, 0.0]). In 2 experimental models of poor IQ (n=36 for both), mean differences were (−2.6 to −3.2) for 3D‐EF and (−1.2 to −2.0) for 3D‐GLS. Similar findings were found for other 3DE left ventricle volumes and strain parameters. / Conclusions: 3DE parameters have low feasibility and values are systematically lower in individuals with poor IQ. Although 3D‐EF and 3D‐GLS have potential advantages over conventional echocardiography, further technical improvements are required to improve the utility of 3DE in clinical practice

Sex-differences in associations of LV structure and function measured by echocardiography with long-term risk of mortality and cardiovascular morbidity

BACKGROUND: Three-dimensional echocardiography (3DE) measures of the left ventricle (LV) predict outcomes in high risk individuals, but their prognostic value in the general population is unknown. We aimed to establish whether 3DE was associated with mortality and morbidity in a multi-ethnic community-based sample, if associations differed by sex, and explored potential mechanisms explaining sex differences. METHODS: 922 individuals (69.7 ± 6.2 years; 717 men) from the SABRE study underwent a health examination including echocardiography. Associations between 3DE LV measures (ejection fraction (EF), end-diastolic volume (EDV), end-systolic volume (ESV), LV remodeling index (LVRI) and LV sphericity index (LVSI), and all-cause mortality and a composite cardiovascular endpoint [comprising new onset (non)fatal coronary heart disease, heart failure hospitalization, new-onset arrhythmias and cardiovascular mortality] were determined using multivariable Cox regression over a median follow-up of 8 years (all-cause mortality) and 7 years (composite cardiovascular endpoint). RESULTS: There were 123 deaths and 151 composite cardiovascular endpoints. Lower EF, higher LV volumes and LVSI were associated with increased all-cause mortality, and higher LV volumes were associated with the composite cardiovascular endpoint independent of potential confounders. Associations between LV volumes, LVRI, LVSI, and mortality differed by sex (p interaction <0.1). In men increased LV volumes and LVSI and decreased LVRI and EF were associated with higher mortality, but associations were null or reversed in women (hazard ratios (95% CI) men vs. women: EDV 1.25 (1.05, 1.48) vs. 0.54 (0.26, 1.10); ESV, 1.36 (1.12, 1.63) vs. 0.59 (0.33, 1.04); LVRI, 0.79 (0.64, 0.96) vs. 1.70 (1.03, 2.80); LVSI, 1.27 (1.05, 1.54) vs. 0.61 (0.32, 1.15); and EF, 0.78 (0.66, 0.93) vs. 1.27 (0.69, 2.33). Similar sex differences were observed for associations with the composite cardiovascular outcome. Adjustment for LV diastolic stiffness and arterial stiffness marginally attenuated these differences. CONCLUSIONS: 3DE measures of LV volume and remodeling are associated with all-cause mortality and cardiovascular morbidity; however, some associations differ by sex. Sex-differences in LV remodeling patterns may influence mortality and morbidity risk in the general population

Is carotid artery atherosclerosis associated with poor cognitive function assessed using the Mini-Mental State Examination? A systematic review and meta-analysis

OBJECTIVES: To determine associations between carotid atherosclerosis assessed by ultrasound and the Mini-Mental State Examination (MMSE), a measure of global cognitive function. DESIGN: Systematic review and meta-analysis. METHODS: MEDLINE and EMBASE databases were searched up to 1 May 2020 to identify studies assessed the associations between asymptomatic carotid atherosclerosis and the MMSE. Studies reporting OR for associations between carotid plaque or intima-media thickness (cIMT) and dichotomised MMSE were meta-analysed. Publication bias of included studies was assessed. RESULTS: A total of 31 of 378 reviewed articles met the inclusion criteria; together they included 27 738 participants (age 35-95 years). Fifteen studies reported some evidence of a positive association between measures of atherosclerosis and poorer cognitive performance in either cross-sectional or longitudinal studies. The remaining 16 studies found no evidence of an association. Seven cross-sectional studies provided data suitable for meta-analysis. Meta-analysis of three studies that assessed carotid plaque (n=3549) showed an association between the presence of plaque and impaired MMSE with pooled estimate for the OR (95% CI) being 2.72 (0.85 to 4.59). An association between cIMT and impaired MMSE was reported in six studies (n=4443) with a pooled estimate for the OR (95% CI) being 1.13 (1.04 to 1.22). Heterogeneity across studies was moderate to small (carotid plaque with MMSE, I2=40.9%; cIMT with MMSE, I2=4.9%). There was evidence of publication bias for carotid plaque studies (p=0.02), but not cIMT studies (p=0.2). CONCLUSIONS: There is some, limited cross-sectional evidence indicating an association between cIMT and poorer global cognitive function assessed with MMSE. Estimates of the association between plaques and poor cognition are too imprecise to draw firm conclusions and evidence from studies of longitudinal associations between carotid atherosclerosis and MMSE is limited. PROSPERO REGISTRATION NUMBER: CRD42021240077

A systematic review and meta-analysis of heart rate variability in COPD

Background: Chronic obstructive pulmonary disease (COPD) is associated with disruption in autonomic nervous control of the heart rhythm. We present here quantitative evidence of the reduction in HRV measures as well as the challenges to clinical application of HRV in COPD clinics. Method: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we search in June 2022 Medline and Embase databases for studies reporting HRV in COPD patients using relevant medical subject headings (MeSH) terms. The quality of included studies was assessed using the modified version of the Newcastle–Ottawa Scale (NOS). Descriptive data were extracted, while standardized mean difference was computed for changes in HRV due to COPD. Leave-one-out sensitivity test was performed to assess exaggerated effect size and funnel plots to assess publication bias. Results: The databases search yielded 512 studies, of which we included 27 that met the inclusion criteria. The majority of the studies (73%) had a low risk of bias and included a total of 839 COPD patients. Although there were high between-studies heterogeneity, HRV time and frequency domains were significantly reduced in COPD patients compared with controls. Sensitivity test showed no exaggerated effect sizes and the funnel plot showed general low publication bias. Conclusion: COPD is associated with autonomic nervous dysfunction as measured by HRV. Both sympathetic and parasympathetic cardiac modulation were decreased, but there is still a predominance of sympathetic activity. There is high variability in the HRV measurement methodology, which affects clinical applicability