Diabetic retinopathy is the most frequently occurring complication of diabetes mellitus and remains a leading cause of vision loss globally. Its aetiology and pathology have been extensively studied ...for half a century, yet there are disappointingly few therapeutic options. Although some new treatments have been introduced for diabetic macular oedema (DMO) (e.g. intravitreal vascular endothelial growth factor inhibitors (‘anti-VEGFs’) and new steroids), up to 50% of patients fail to respond. Furthermore, for people with proliferative diabetic retinopathy (PDR), laser photocoagulation remains a mainstay therapy, even though it is an inherently destructive procedure.
This review summarises the clinical features of diabetic retinopathy and its risk factors. It describes details of retinal pathology and how advances in our understanding of pathogenesis have led to identification of new therapeutic targets. We emphasise that although there have been significant advances, there is still a pressing need for a better understanding basic mechanisms enable development of reliable and robust means to identify patients at highest risk, and to intervene effectively before vision loss occurs.
Biomarkers for the identification of diabetic kidney disease (DKD) are needed as current tests lack sensitivity for detecting early kidney damage. MicroRNAs (miRNAs) are short, non-coding regulatory ...ribonucleic acid (RNA) molecules commonly found in urinary exosomes differentially expressed as renal function declines. We evaluated urinary exosomal miRNA expression in persons with type 2 diabetes mellitus and DKD (T2DKD). 87 human urinary exosomal miRNAs were profiled in a discovery cohort of patients with T2DKD (n = 14) and age and gender matched controls with type 2 diabetes mellitus and normal renal function (T2DNRF; n = 15). Independent validation of differentially expressed target miRNAs was performed in a second cohort with T2DKD (n = 22) and two control groups: T2DNRF (n = 15) and controls with chronic kidney disease (CCKD) and poor renal function without diabetes (n = 18). In the discovery cohort, urinary miR-21-5p, let-7e-5p and miR-23b-3p were significantly upregulated in T2DKD compared to T2DNRF (p < 0.05). Conversely, miR-30b-5p and miR-125b-5p expression was significantly lower in T2DKD (p < 0.05). Independent validation confirmed up-regulation of miR-21-5p in the replication cohort in T2DKD (2.13-fold, p = 0.006) and in CCKD (1.73-fold, p = 0.024). In contrast, miR-30b-5p was downregulated in T2DKD (0.82-fold, p = 0.006) and in CCKD (0.66-fold, p < 0.002). This study identified differential expression of miR-21-5p and miR-30b-5p in individuals with diabetic kidney disease and poor renal function. These miRNAs represent potential biomarkers associated with the pathogenesis of renal dysfunction.
AbstractObjectiveTo identify drug classes and individual selective serotonin reuptake inhibitors (SSRIs) with high rates of remission and low risk of adverse events in the treatment of panic disorder ...with or without agoraphobia.DesignSystematic review and network meta-analysis.Data sourcesEmbase, Medline, and ClinicalTrials.gov from inception to 17 June 2021.Eligibility criteria for study selectionRandomised controlled trials that included adults aged ≥18 years with a diagnosis of panic disorder, compared drugs used to treat the panic disorder, and measured the outcomes of interest, including remissions, dropouts, and adverse events.MethodsRisk of bias in the included studies was assessed using the revised Cochrane risk of bias tool for randomised trials. Direct meta-analyses were performed using random effects models. A two stage network meta-analysis with surface under the cumulative ranking curve (SUCRA) was used to estimate the comparative efficacy of drug classes and individual SSRIs.Results87 studies including a total of 12 800 participants and 12 drug classes were eligible for inclusion. Almost all the studies (86/87) had some concern or were at high risk of bias. Network meta-analysis of remission with consistent results indicated that tricyclic antidepressants, benzodiazepines, monoamine oxidase inhibitors, SSRIs, and serotonin-noradrenaline reuptake inhibitors (SNRIs) were associated with significantly higher remission rates than placebo, with risk ratios of 1.39 (95% confidence interval 1.26 to 1.54), 1.47 (1.36 to 1.60), 1.30 (1.00 to 1.69), 1.38 (1.26 to 1.50), and 1.27 (1.12 to 1.45), respectively. SUCRAs identified benzodiazepines (84.5%, mean rank=2.4), tricyclic antidepressants (68.7%, 3.8), and SSRIs (66.4%, 4.0) as the top three best treatments for remission. However, tricyclic antidepressants, benzodiazepines, and SSRIs were also significantly associated with increased risk of adverse events compared with placebo, with risk ratios of 1.79 (1.47 to 2.19), 1.76 (1.50 to 2.06), and 1.19 (1.01 to 1.41), respectively. Consistency assumption of adverse events was upheld but could still be present on removal of studies with high percentages of women participants and those with agoraphobia. A SUCRA cluster ranking plot considering both remission and adverse events among all drug classes indicated that SSRIs were associated with high remission and low risk of adverse events. Among individual SSRIs, sertraline and escitalopram provided high remission with an acceptable risk of adverse events.ConclusionThe findings suggest that SSRIs provide high rates of remission with low risk of adverse events for the treatment of panic disorder. Among SSRIs, sertraline and escitalopram were associated with high remission and low risk of adverse events. The findings were, however, based on studies of moderate to very low certainty levels of evidence, mostly as a result of within study bias, inconsistency, and imprecision of the findings reported.Systematic review registrationPROSPERO CRD42020180638.
Equivalent circuit analysis is a powerful tool for analysing acoustic systems where a lumped element model is valid. These equivalent circuits allow an overall impedance of the structure to be ...estimated which facilitates predictions of the reflectivity, transmissibility and/or absorptivity of the system. Complex acoustic systems are represented by non-planar equivalent circuits which are challenging to simplify to a single overall impedance value using traditional Kirchoff’s Law simplifications. A two-point impedance method using graph theory allows the impedance of a circuit to be estimated without simplification. The graph theory method is applied to a type of acoustic absorber structure named SeMSA (Segmented Membrane Sound Absorber) which had previously been investigated for a two-segment cell design. This method allows the SeMSA analysis to be expanded to multi-sector designs with a wider parameter space. A local optimisation routine is applied to the graph theory impedance estimation to maximise acoustic absorption of SeMSA under consideration of absorber depth, causal optimality and the targeted noise spectra. Analytical predictions are validated using numerical simulations. The optimised multi-sector absorber demonstrates 70.5% white noise absorption in the 20–4500 Hz frequency range with an absorber depth of 16 mm and is just 0.5 mm from the theoretical minimum depth to achieve this absorption response.
Genetic risk factors for chronic kidney disease (CKD) are being identified through international collaborations. By comparison, epigenetic risk factors for CKD have only recently been considered ...using population-based approaches. DNA methylation is a major epigenetic modification that is associated with complex diseases, so we investigated methylome-wide loci for association with CKD. A total of 485,577 unique features were evaluated in 255 individuals with CKD (cases) and 152 individuals without evidence of renal disease (controls). Following stringent quality control, raw data were quantile normalized and β values calculated to reflect the methylation status at each site. The difference in methylation status was evaluated between cases and controls with resultant P values adjusted for multiple testing. Genes with significantly increased and decreased levels of DNA methylation were considered for biological relevance by functional enrichment analysis using KEGG pathways in Partek Genomics Suite. Twenty-three genes, where more than one CpG per loci was identified with P
adjusted
< 10
−8
, demonstrated significant methylation changes associated with CKD and additional support for these associated loci was sought from published literature. Strong biological candidates for CKD that showed statistically significant differential methylation include CUX1, ELMO1, FKBP5, INHBA-AS1, PTPRN2, and PRKAG2 genes; several genes are differentially methylated in kidney tissue and RNA-seq supports a functional role for differential methylation in ELMO1 and PRKAG2 genes. This study reports the largest, most comprehensive, genome-wide quantitative evaluation of DNA methylation for association with CKD. Evidence confirming methylation sites influence development of CKD would stimulate research to identify epigenetic therapies that might be clinically useful for CKD.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common cause of chronic liver disease and can progress to nonalcoholic steatohepatitis and cirrhosis. This study aims to summarize ...the evidence for the effects of curcumin on MAFLD progression. Studies were identified from Medline and Scopus databases until April 2022. Systematic reviews and meta-analyses (SRMA) and randomized controlled trials (RCT) were selected based on pre-specified criteria. Three reviewers independently extracted data and assessed quality of included studies. Of the 427 identified records, 6 SRMAs and 16 RCTs were included in the analysis. Very high overlap was observed among SRMAs with corrected covered area of 21.9%. From an updated meta-analysis, curcumin demonstrated significant improvement in aspartate and alanine aminotransferase with pooled mean difference 95% confidence interval (CI) of -3.90 (-5.97, -1.82) and -5.61 (-9.37, -1.85) units/L, respectively. Resolution and improvement of hepatic steatosis was higher in curcumin than control group with pooled relative risk (95% CI) of 3.53 (2.01, 6.22) and 3.41 (1.36, 8.56), respectively. Curcumin supplementation also led to lower fasting blood sugar, body mass index, and total cholesterol. Further trials should be conducted to assess the effect of curcumin on liver histology, especially regarding non-invasive hepatic fibrosis and steatosis.
Historically, high levels of morbidity and mortality have been associated with cardiovascular disease in the Northern Ireland population. Previously reported associations between single nucleotide ...polymorphisms (SNPs) and cardiovascular disease within other populations have not always been consistent. To investigate associations between 33 SNPs with fatal or non-fatal incident coronary heart disease (CHD) events and all-cause mortality in the Northern Irish participants of the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Phase 2 of the PRIME study prospectively evaluated 2,010 men aged 58-74 years in Northern Ireland for more than 10 years for incident CHD events (myocardial infarction, percutaneous coronary intervention, coronary artery bypass, and cardiac death) and more than 15 years for all-cause mortality. SNPs previously reported in association with cardiovascular outcomes were evaluated against incident CHD events and all-cause mortality using Cox's proportional hazards models adjusted for established cardiovascular disease risk factors. During the follow-up period, 177 incident CHD events were recorded, and 821 men died. Both BCMO1 rs6564851 (Hazard ratio HR = 0.76; 95% confidence intervals CI: 0.60-0.96; P = 0.02) and TGFB1 rs1800469 (HR = 1.30; CI: 1.02-1.65; P = 0.04) were significantly associated with incident CHD events in adjusted models. Only IL1B rs16944 was significantly associated with all-cause mortality (HR = 1.18; CI: 1.05-1.33; P = 0.005). No associations remained significant following Bonferonni correction for multiple testing. We report a novel association between BCMO1 rs6564851 and risk of incident CHD events. In addition, TGFB1 rs1800469 and IL1B rs16944 were associated with the risk of incident CHD events and all-cause mortality outcomes respectively, supporting previously reported associations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Alzheimer disease (AD) is the most common cause of dementia worldwide. Despite the publication of numerous systematic reviews and meta-analyses that have summarized the evidence associated with ...pharmacotherapies (PTs) and non-pharmacotherapies (NPTs) for the wide range of interventions available for AD treatment, their comparative safety and efficacy remains insufficiently defined.
Systematic reviews of randomized controlled trials (RCTs) will be selected according to the following criteria: conducted in elderly patients aged 60 years or older with AD living in community or institutionalized settings, applied pairwise meta-analysis (PMA) or network meta-analysis (NMA) approaches providing pooled relative treatment effects for at least 1 pair of PTs or NPTs, and providing at least 1 of the following outcomes for patients/caregivers: cognitive, functional status, behavior, quality of life (QoL), and caregiver stress or burden. All article screening, data extraction, and risk of bias assessment will be completed independently by 2 reviewers. Relative treatment rankings will be reported with mean ranks and surface under the cumulative ranking curves.
We will determine the most efficacious treatment strategies for AD patients from the most highly ranked treatments. These results will help to guide clinical decision-making and improve patient care.
Chronic kidney disease (CKD) and hypertension are global public health problems associated with considerable morbidity, premature mortality and attendant healthcare costs. Previous studies have ...highlighted that non-invasive examination of the retinal microcirculation can detect microvascular pathology that is associated with systemic disorders of the circulatory system such as hypertension. We examined the associations between retinal vessel caliber (RVC) and fractal dimension (DF), with both hypertension and CKD in elderly Irish nuns.
Data from 1233 participants in the cross-sectional observational Irish Nun Eye Study (INES) were assessed from digital photographs with a standardized protocol using computer-assisted software. Multivariate regression analyses were used to assess associations with hypertension and CKD, with adjustment for age, body mass index (BMI), refraction, fellow eye RVC, smoking, alcohol consumption, ischemic heart disease (IHD), cerebrovascular accident (CVA), diabetes and medication use.
In total, 1122 (91%) participants (mean age: 76.3 range: 56-100 years) had gradable retinal images of sufficient quality for blood vessel assessment. Hypertension was significantly associated with a narrower central retinal arteriolar equivalent (CRAE) in a fully adjusted analysis (P = 0.002; effect size = -2.16 μm; 95% confidence intervals CI: -3.51, -0.81 μm). No significant associations between other retinal vascular parameters and hypertension or between any retinal vascular parameters and CKD were found.
Individuals with hypertension have significantly narrower retinal arterioles which may afford an earlier opportunity for tailored prevention and treatment options to optimize the structure and function of the microvasculature, providing additional clinical utility. No significant associations between retinal vascular parameters and CKD were detected.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To evaluate the risk of surgical site infection (SSI) following complicated appendectomy in individual patients receiving delayed primary closure (DPC) versus primary closure (PC) after adjustment ...for individual risk factors.
Secondary analysis of randomized controlled trial (RCT) with prediction model.
Referral centers across Thailand.
Adult patients who underwent appendectomy via a lower-right-quadrant abdominal incision due to complicated appendicitis.
A secondary analysis of a published RCT was performed applying a counterfactual prediction model considering interventions (PC vs DPC) and other significant predictors. A multivariable logistic regression was applied, and a likelihood-ratio test was used to select significant predictors to retain in a final model. Factual versus counterfactual SSI risks for individual patients along with individual treatment effect (iTE) were estimated.
In total, 546 patients (271 PC vs 275 DPC) were included in the analysis. The individualized prediction model consisted of allocated intervention, diabetes, type of complicated appendicitis, fecal contamination, and incision length. The iTE varied between 0.4% and 7% for PC compared to DPC; ∼38.1% of patients would have ≥2.1% lower SSI risk following PC compared to DPC. The greatest risk reduction was identified in diabetes with ruptured appendicitis, fecal contamination, and incision length of 10 cm, where SSI risks were 47.1% and 54.1% for PC and DPC, respectively.
In this secondary analysis, we found that most patients benefited from early PC versus DPC. Findings may be used to inform SSI prevention strategies for patients with complicated appendicitis.
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