Greater Reduction Research Articles

The upfront lipid-lowering combination therapy of statins and ezetimibe vs statin monotherapy in the reduction of cardiovascular outcomes. A meta-analysis.

Abstract Background Despite some data in last few years, there is still some inconsistency concerning the effectiveness and safety of the upfront intensive lipid lowering combination therapy (LLT; of moderate to high intensity statin therapy and ezetimibe) in comparison to high intensity statin therapy and recommended by some guidelines stepwise therapy approach. Purpose We sought to evaluate the efficacy of combination LLT compared with statin monotherapy for cardiovascular outcomes, LDL-C reduction, and associated adverse events. Methods A systematic literature search was conducted using PubMed, Embase, and ClinicalTrial.gov to identify relevant articles published from inception until 29th December 2023. The outcomes were assessed using pooled odds ratio (OR) for categorical data and mean difference (MD) for continuous data, with corresponding 95% confidence intervals (95% CI). Results A total of 11 studies (8 randomized controlled trials and 3 cohort studies) with 106,358 were involved in the analysis. The mean age of the patients in the combination LLT and statin monotherapy group was 65.3 and 65.7 years, respectively. Pooled analysis shows that combination LLT significantly reduces the LDL-C level from the baseline (MD, -12.13 mg/dl [0.31 mmol/l] (95%CI: -18.26 to -5.99 mg/dl), p<0.001), all-cause mortality (ACM) (OR, 0.75, 95%CI: 0.62 to 0.92, p=0.01), cardiovascular mortality (CVM) (OR 0.75, 95%CI: 0.66 to 0.84, p<0.001), major adverse cardiovascular events (MACE) (OR, 0.72 95%CI: 0.63 to 0.82, p<0.001), non-significant reduction in the incidence of stroke (OR 0.82, 95%CI: 0.66 to 1.01, p=0.06) when compared with statin monotherapy alone. Similarly, the therapy discontinuation rate was comparable between combination LLT and statin monotherapy groups (OR, 0.87 (95%CI: 0.53 to 1.40), p=0.56). The risk of adverse events related to the gastrointestinal tract (OR, 1.12 (95%CI: 0.93 to 1.36), p=0.23) and musculoskeletal system (OR, 0.88 (95%CI: 0.52 to 1.50), p=0.65) was comparable between both the groups of patients. Conclusion Combination LLT was associated with an overall greater reduction in LDL-C, a lower risk of ACM, MACE, and CVM compared to statin monotherapy alone.Forest Plot of desired outcomes.Central illustration with key findings.

Effect of interleukin 1b inhibition with canakinumab on inflammation and viral persistence in people with human immunodeficiency virus

Abstract Introduction Effectively treated people with HIV (PWH) have elevated risk of cardiovascular disease (CVD). Inflammatory markers are predictive of CVD and mortality among PWH. The role of the myeloid system in driving inflammation and atherosclerosis has been recently recognized. Canakinumab (a monoclonal antibody to IL-1β) reduces inflammation and CVD events among people with elevated hsCRP after myocardial infarction without HIV. We evaluated the impact of IL-1β inhibition using canakinumab on HIV parameters, inflammation, HIV persistence markers, arterial inflammation, and hematopoietic activity in PWH. Methods PWH on effective ART who had CVD or were at risk for CVD were randomized 2:1 to receive 150 mg of canakinumab subcutaneously or matched placebo at weeks 0 and 12. Arterial inflammation and bone marrow metabolic activity were assessed using F18 FDG PET/CT at baseline and week 18. T cell and monocyte activation were evaluated using multiparameter spectral cytometry. The viral reservoir was quantified using Tat/rev Induced Limiting Dilution Assay (TILDA), HIV DNA and cell-associated RNA. The primary endpoints were change in CD4 and CD8 count. We assessed group effects over time using linear mixed effects models. Results 33 individuals were randomized (median age of 60 years old (IQR 57.5, 64.5) and 94% male); 25 received canakinumab and 8 received placebo. There were no significant differences at baseline. As expected, IL-1β increased among those treated with canakinumab at weeks 4- 24 (p<0.01 for each) and returned to baseline at week 36. There was one death from sepsis in an individual aged 84 with CVD and poorly controlled diabetes who received canakinumab. There were no significant changes in CD4 count, CD8 count, platelet count, creatinine, AST, or ALT by group. Treatment was not associated with a greater reduction in arterial inflammation in the most diseased segment compared to placebo (-6.9%; 95% CI -30.4 to 24.5%; p=0.62). However, bone marrow metabolic activity decreased in the canakinumab group versus placebo (-14.4%, 95% CI -26.5% to -0.2%; p=0.047). Treatment was associated with increased CD163 expression on monocytes at weeks 24 (p=0.03) and 36 (p<0.001), and lower caspase activity at week 36 (p=0.02). There was expansion of anti-inflammatory CD16+ patrolling monocytes that co-express CD163+CX3CR1+ and a decrease in pro-inflammatory CD16+ patrolling monocytes that are Caspase1+CCR2+. Treatment was not associated with differences in hsCRP, IL-6, IL-16, IL-18, MCP-1, sCD14, sCD163, T cell subsets, NK cell subsets, or viral persistence markers. Conclusion Among treated PWH, targeted inhibition of IL-1β using canakinumab results in decreased bone marrow metabolic activity and a shift toward anti-inflammatory monocyte populations. These findings shed light on mechanisms underlying how targeted IL-1β inhibition using canakinumab prevents CVD events by altering monocyte populations and reducing systemic inflammation.

Liver function tests in patients receiving high-intensity care after hospital admission for acute heart failure: the STRONG-HF trial

Abstract Background/Introduction Episodes of acute heart failure (AHF) unfavorably affect extra-cardiac organs such as the liver due to altered hemodynamics and neurohormonal activation. In AHF, elevated levels of levels of alanine aminotransferase (ALT) and total bilirubin (tBil) may reflect congestion and impaired liver function, while lower levels of ALT (which is also produced in muscle cells) correlate with malnutrition and sarcopenia. Thus, the clinical importance of these markers in AHF and the post-discharge period is unclear. Purpose To assess circulating concentrations of ALT and tBil in patients with AHF before discharge and during high-intensity care (HIC) vs usual care follow-up in association with clinical outcomes. Methods ALT and tBil concentrations were measured 1-2 days before discharge in patients hospitalized for AHF (baseline), and again after 90 days of either HIC or usual care according to the STRONG-HF protocol. Baseline values and changes in ALT and tBil were analyzed in association with the primary outcome of all-cause death or HF readmission by day 180. Results At baseline, the median (Q1-Q3) concentrations of ALT and tBil were 21 (15-32) U/L and 14 (10-21) umol/L, respectively. Lower levels of both ALT and tBil were associated with female sex, Black race, lower BMI, higher LVEF, lower hemoglobin, lower creatinine and less frequent atrial fibrillation/flutter, while there were no significant associations with age. Patients with lower ALT, but not tBil, were more likely to have edema, elevated JVP and orthopnea, and used higher loop diuretic doses and less beta-blockers, pre-randomization (Figure, panel A). ALT was inversely associated with risk for the primary outcome (HR 0.81 [95%CI 0.65,1.00) per log increment, p=0.05), while there was no association with risk for tBil (HR 1.04 [95%Ci 0.84-1.28], p=0.73) (Figure, panel B). After 90 days, ALT and tBil concentrations were lower than at baseline, with a greater reduction in tBil in the HIC group vs usual care group (mean -1.7 [95%CI -3.0,-0.4] umol/L, p=0.01), while there was no significant between-group differences in ALT changes (mean -0.6 [95%CI -4.7,3.4] U/L, p=0.75) (Figure, panel C). The treatment effect of HIC over usual care on the primary outcome was consistent across the range of baseline ALT (P-interaction=0.30) and tBil (P-interaction=0.80) (Figure, panel D). Conclusion Contrary to our hypothesis of higher liver function tests with hepatic congestion in AHF, lower ALT was associated with more congestion and worse outcomes among patients hospitalized for AHF in STRONG-HF. There was no prognostic value from tBil levels. This suggests that ALT may be a marker of sarcopenia in these patients. Importantly, the beneficial effect of HIC on clinical outcomes is consistent irrespective of ALT and tBil levels at discharge.Figure

Nationwide trends in blood pressure control among those with and without diabetes in England over last 2 decades: Health Survey of England 2003-2019

Abstract Diabetes and hypertension are both risk factors for cardiovascular disease (CVD), and often co-exist. Over recent decades practice guidance and health policy efforts have been made to improve population wide blood pressure (BP) control, particularly amongst those with diabetes, to reduce CVD. However, the nationwide impact of these ongoing efforts is yet to be documented comprehensively in England. We used data from 11 serial nationally representative health surveys of England between 2003 and 2019 and compared BP control and presence of untreated hypertension amongst those with and without diabetes. These cross-sectional, randomly sampled surveys included 94,100 individuals cumulatively. We applied sample weights, accounting for oversampling and survey nonresponse, and transformations mitigating for survey equipment changes during this period. We used ‘period definitions’ to define those with diabetes and quantify BP control at the time of each coinciding survey, facilitating accurate comparison of trends over the sixteen-year period, while accounting for changes in understanding, variations in definitions, and shifts in medical practices. Python and STATA were used to conduct analyses and Join Point regression software was used to develop and compare trends. In England, from 2003-2019, the prevalence of hypertension amongst those with diabetes and without diabetes decreased from 74.4% to 66.5% and from 32.6% to 27.1% (7.9% vs. 5.5%), respectively. This corresponded to reductions in population-wide mean systolic (S) and diastolic (D) BPs: compared to those without diabetes, those with diabetes had greater reduction in both SBP (7.9mmHg vs. 4.8mmHg) and DBP (2.7mmHg vs. 1.9mmHg) (Figure1). Both groups showed similar temporal improvement in BP-control amongst those with diagnosed hypertension, with those with diabetes showing better improvement in BP control compared to those without diabetes (14% vs. 12%). There was a significant difference in proportions of those with undiagnosed (unaware) hypertension amongst those with and without diabetes (11.4% vs. 30.0% respectively) (Figure2). Notably, there was no change in proportion of those with hypertension unaware about the condition (i.e. detection rate for hypertension in either of the group did not show any improvement over time). These results suggest that we have been able to improve BP control over this period amongst those with and without diabetes, however, those without diabetes (more than 90% of population) have shown significantly poorer improvement. In addition, around one third of hypertensive patients amongst the no-diabetes group are unaware of the condition, and overall, the detection rates for hypertension in both groups have not improved in the last two decades. Lessons learnt from improving BP control amongst those with diabetes should be applied across the entire population, and newer strategies need to develop to improve detection of those with hypertension and are unaware.

Assessment of quality of life and ICD shock-related anxiety in Asian patients with implantable cardioverter defibrillator in the PainFree SST study

Abstract Background The implantable cardioverter defibrillator (ICD) reduces mortality in patients at risk of sudden cardiac death. However, it is not known if the psychological status of ICD patients differs by geography. The aim of this analysis is to compare Quality of Life (QoL) and ICD shock-related anxiety between ICD patients in Asian with those in other countries. Methods The PainFree SST study was a prospective, multicenter, global study that enrolled 2770 patients including 225 from from Asia (181 from Japan, 25 from India, and 19 from Malaysia). The EuroQol 5-D (EQ-5D) measured QoL and the Florida Shock Anxiety Scale (FSAS) measured ICD shock-related anxiety. These questionnaires were administered bi-annually and monthly for 6 months after a shock. Change in QoL and shock anxiety was analyzed used linear mixed models for repeated measures. Results: Both the EQ-5D health score and FSAS score were higher in Asian patients compared to patients in the other countries post-implant (EQ-5D: 69.5 ± 18.3 points vs 66.5 ± 19.3 points, p<0.0001, FSAS: 19.7 ± 9.4 points vs 16.4 ± 7.7 points, p<0.0001), and stayed higher for the entire follow-up period (Figure 1). The EQ-5D health score was significantly reduced after a shock (Asian: -18.1 points, p<0.0001; other countries: -7.5 points, p<0.0001) with a greater reduction in Asian patients (p=0.0035) . Recovery in the month following a shock was greater in Asian patients (+19.8 vs +3.6 points, p<0.0001). The FSAS score was significantly increased after a shock (Asian: +6.4 points, p<0.0001; other countries: +4.8 points, p<0.0001) and the increase was similar between geographies (p=0.20). The recovery effect at 1 month was greater in Asian patients (-5.8 vs -1.7 points, p=0.0003) (Figure 2). Conclusions Asian patients were more anxious about a shock in spite of greater QoL, compared with those in other countries. After a shock, Asian patients had a greater decrease in QoL and a similar increase in anxiety but recovery was greater in both measures in the month following a shock.Figure 1Figure 2

The projected global burden of modifiable risk factors on cardiovascular disease from 2025 to 2100

Abstract Background Cardiovascular diseases (CVDs) are the primary cause of global mortality and morbidity. Controlling modifiable risk factors driving the CVD epidemic is a vital focus of primary prevention efforts worldwide. Understanding the epidemiological trends in these risk factors is therefore essential in designing effective countermeasures against CVDs for the years to come. Purpose This study aims to forecast the disability-adjusted life years (DALYs) associated with CVDs attributable to high systolic blood pressure (SBP), high body-mass index (BMI), high fasting plasma glucose (FPG), high low-density lipoprotein (LDL) and tobacco use from 2025 to 2100, stratified by GBD super-regions, sex, sociodemographic index (SDI), and age-groups. Methods Historical data on DALYs from 1990 to 2019 from the Global Burden of Disease (GBD) study was used to project DALYs associated with modifiable risk factors of CVDs from 2025 to 2100. Trends across GBD super-regions, sex, SDI, and age-groups were also examined. Results Between 2025 and 2100, age-standardised DALY rates (ASDR) per 100,000 population are forecasted to fall across all modifiable risk factors, with the greatest decline seen in tobacco use (-76.0%) and high LDL (-66.9%). Globally, high SBP and high BMI expect the greatest ASDR in 2100 (both 891 per 100,000 population), while tobacco use expects the least (213 per 100,000 population). High BMI is expected to rise 623.0% in South Asia and 221.5% in South-east Asia, East Asia and Oceania from 2025 to 2100, while high FPG is expected to rise 114.2% in North Africa and the Middle-east and 110.6% in South Asia. Females are expected to have lower overall and greater reductions in ASDR across all modifiable risk factors when compared to males from 2025 to 2100. Notably, males expect a 11.0% rise in high BMI worldwide across this period. The age-prevalence of modifiable risk factors is expected to be bimodal in 2100, highest in those aged 50-59 as well as 75-84 years old, possibly suggesting improvements in global screening efforts or the earlier development of metabolic dysfunction. All modifiable risk factors are predicted to fall in high and high-middle SDI regions from 2025 to 2100. In contrast, low, low-middle, and middle SDI regions expect a rise in high FPG and high BMI across this same time frame. The burden of modifiable CVD risk factors is expected to be highest in low-middle SDI regions in 2100, as compared to high-middle SDI regions in 2025. Conclusion While the global decline in ASDR of modifiable risk factors suggests overall improvements in the primary prevention of CVDs, regional spikes in high BMI and FPG calls for the implementation of timely, targeted interventions accounting for local trends in CVD. Moreover, the disproportionate metabolic burden expected in lower SDI regions in the coming decades requires concerted, international support to alleviate the global burden of CVDs.

Persistent angina following revascularization for chronic coronary syndromes: a systematic review and meta-analysis of randomized controlled trials

Abstract Introduction Recent randomized clinical trials (RCTs) have demonstrated that revascularization plus optimal medical therapy for patients with chronic coronary syndromes (CCS) results in greater reduction in angina than medical therapy alone. However, the frequency of persistent angina following revascularization for CCS is not well understood. Purpose To quantify the frequency of persistent angina following revascularization in contemporary RCTs of revascularization plus medical therapy vs. medical therapy alone among patients with CCS. Methods A literature search through January of 2024 was conducted in PubMed and Cochrane Central Register of Controlled Trials for contemporary RCTs reporting angina frequency following randomization to revascularization plus medical therapy vs. medical therapy alone. The primary outcome of interest was the frequency of persistent angina in the revascularization arms of these studies at early (3-12 months) and late (3-5 years) time points. A random effects model was used to combine results from individual studies. Results From a total of 5287 citations, the search yielded 7 RCTs that met inclusion criteria. These studies randomized 5719 patients to an invasive or revascularization strategy. Revascularization was exclusively by percutaneous coronary intervention (PCI) in 4 studies and by coronary artery bypass grafting or PCI in 3 studies. At the early time point, the combined frequency of persistent angina was 39.6% (95% CI: 30.6-49.4). For the two blinded, sham-controlled studies, the rate of persistent angina was significantly greater at 67.2% (95%CI: 54.9-77.4) compared to 30.5% (95% CI: 23.1-39) in the unblinded studies (P<0.001). In the 5 studies with 3-5 years of follow-up, the frequency of persistent angina was 33.3% (95% CI: 19.2-51.2). Conclusion Persistent angina is common after revascularization for CCS and suggests alternative causes and treatments of residual angina should be considered.

High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a)

Abstract Background Early and prompt reduction of low-density lipoprotein cholesterol concentrations (LDL-C) using combination lipid-lowering therapy (LLT) is recommended to lower cardiovascular risk in patients with ischaemic heart disease (IHD) and elevated LDL-C. Lowering LDL-C is also an important cardiovascular risk mitigation strategy in patients with elevated lipoprotein(a) [Lp(a)]. However, it is unknown if combination LLT reduces mortality in patients with elevated Lp(a). Aim To undertake an observational study to investigate the effect of combination LLT using high intensity statin with ezetimibe on cardiovascular outcomes in patients with and without elevated Lp(a). Methods Serum Lp(a) concentrations were measured in 520 consecutively recruited patients with IHD admitted to hospital, half of whom were admitted for acute myocardial infarction. Patients treated with high intensity statin and ezetimibe within the 1st year from admission to hospital (‘HI statin-ezetimibe group’, n=157) were compared with the rest of patients who had less intensive lipid lowering regimen (‘Others group’, n=363) for cardiovascular outcomes. Results During the 2-year follow-up period, 14.6%, 6.5%, and 53.1% of patients had all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) respectively. Median age was 63.5 years and 82.3% were male. Multivariable Cox regression showed that baseline Lp(a) ≥70 nmol/L was associated with increased risk of all-cause mortality (HR 1.97, 95% CI 1.20-3.22, P=0.007). Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ≥70 nmol/L (HR 0.51, P=0.007) or Lp(a) ≥100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ≥70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a). Conclusion Intensification of lipid-lowering therapy with high-intensity statin and ezetimibe improves cardiovascular outcomes in patients at very high cardiovascular risk, particularly those with elevated Lp(a). Larger studies are required to confirm our findings that this cardiovascular benefit is partially independent of LDL-C lowering.

Factors Associated with Achieving HbA1c Targets in Patients with Type 2 Diabetes

Background: Diabetes mellitus is a major global public health concern, particularly due to its complications and associated mortality and morbidity. Ethnic differences in the epidemiology of diabetes necessitate population-specific studies to identify factors influencing glycemic control. Objectives: This study aimed to identify demographic and clinical factors associated with achieving HbA1c targets in patients with type 2 diabetes mellitus (T2DM) at the Yazd Diabetes Center in Iran. Methods: In this retrospective study, data were extracted from the medical records of 3,454 patients with type 2 diabetes at the Yazd Diabetes Research Center (March 2020 - December 2022). Data analysis was performed using chi-squared tests, t-tests, Mann-Whitney U tests, and logistic regression in R version 4.0.2. Results: The cohort, predominantly female (59%) and primarily educated at the elementary level (65%), had an average age of 59.5 years (SD = 10) and a mean diabetes duration of 10.7 years (SD = 7.6). In the multivariable logistic regression model, older age (B = 0.03, OR = 1.03 per year, P < 0.001) and higher education level (secondary school B = 0.664, OR = 1.94, P < 0.001; academic education B = 0.834, OR = 2.30, P < 0.001) remained significant independent predictors of achieving HbA1c < 7%. The interaction term revealed that each additional year of diabetes duration led to a 3% greater reduction in the odds of achieving HbA1c < 7% for females compared to males (B = -0.029, OR = 0.97, P = 0.011), indicating gender-specific impacts of diabetes duration. Conclusions: This study found that demographic factors, including older age and higher education levels, were significantly associated with better glycemic control. The duration of diabetes negatively affected HbA1c outcomes, with a more pronounced impact in females than in males.

Dynamic Simulation of Carbon Emission Peak in City-Scale Building Sector: A Life-Cycle Approach Based on LEAP-SD Model

Systematically predicting carbon emissions in the building sector is crucial for formulating effective policies and plans. However, the timing and potential peak emissions from urban buildings remain unclear. This research integrates socio-economic, urban planning, building technology, and energy consumption factors to develop a LEAP-SD model using Shenzhen as a case study. The model considers the interrelationship between socio-economic development and energy consumption, providing more realistic scenario simulations to predict changes in carbon emissions within the urban building sector. The study investigates potential emission peaks and peak times of buildings under different population and building area development scenarios. The results indicate that achieving carbon peaking by 2030 is challenging under a business as usual (BAU) scenario. However, a 10% greater reduction in energy intensity compared to BAU could result in peaking around 2030. The simulation analysis highlights the significant impact of factors such as population growth rate, per capita residential building area, and energy consumption per unit building area and the need for a comprehensive analysis. It provides more realistic scenario simulations that not only enhance theories and models for predicting carbon emissions but also offer valuable insights for policymakers in establishing effective reduction targets and strategies.

Real Exchange Rate Depreciation and Domestic Tax Revenue Performance in Kenya

Purpose: Taxation plays a critical role in raising the resources needed for financing government activities in developing countries. On the other hand, the volatility of real exchange rates (RERs) has generated significant concern among academics and policymakers in view of its effects on macroeconomic variables such as tax revenue generation. This study therefore focused on real exchange rate depreciation on domestic tax revenue performance in Kenya. The study was guided Theory of Constraints. Methodology: The study employed an explanatory research design. Secondary data was collected from the CBK, KRA, and the World Bank. In this study time series data ranging from 2003 – 2023 was used to analyze the determinants of domestic tax revenue performance in Kenya. The hypotheses were tested at a significance level of .05 using the multiple regression analysis. A multivariate time series ARDL regression analysis model was used to analyze the data. Results: The study ARDL model concluded that Real exchange rate depreciation led to a notable decrease in domestic tax revenue performance, with β = -0.223945 and p = 0.000 < 0.05. This effect is intensified when considering the lagged impact, where a one-period lagged depreciation results in an even greater reduction in tax revenue performance, β = -1.927412 and p = 0.0004 < 0.05. Conclusion: The study recommended that government of Kenya should stabilize the exchange rate and prevent excessive depreciation by fostering a favorable trade balance and maintaining investor confidence. Additionally, future research could focus on the effects of fiscal Policy Changes on domestic tax revenue performance. Also, future studies could examine Impact of Global Economic Shocks on Domestic Tax Revenue.

A randomized controlled clinical trial of a Wim Hof Method intervention in women with high depressive symptoms

ObjectiveStress is a driver of depression, and people with depression often struggle to cope with stress and anxiety. This study directly compares the mental health effects of a Wim Hof Method intervention to an active control condition (slow breathing) in women with high stress and high depressive symptoms. MethodsWe randomized 84 healthy midlife women with high stress and high depressive symptoms to either: 1) the hormetic stress condition based on the Wim Hof Method (WHM) involving a breathing technique designed to induce intermittent hypoxia and cold showers (n = 41) or 2) an active comparison condition involving slow-paced breathing and warm showers (n = 43). We provided participants with daily audio instructions (15 min) for three weeks during the COVID-19 pandemic (2020–2021). Our primary outcomes were depressive symptoms, anxiety symptoms, and perceived stress collected at pre-intervention, post-intervention, and 3 months later. We also assessed daily stress rumination and affect with daily diary during the intervention, and participants completed a laboratory stressor, the Trier Social Stress Test, before and after the intervention, and provided samples for salivary cortisol reactivity. ResultsParticipants in the active control condition perceived the intervention to be more credible and expected greater mental wellbeing benefits compared to those in the Wim Hof Method condition. Differential attrition was observed with six participants (7 %) dropping out -- all from WHM condition. Among the participants who completed the intervention, both groups improved on mental health outcomes immediately after the intervention with a 24 % reduction in depressive symptoms, a 27 % reduction in anxiety symptoms, and 20 % reduction in perceived stress. Improvements were maintained at the 3-month follow-up with 46 % of the sample reporting mild or no depressive symptoms. Participants in the WHM condition had significant reductions in rumination after daily stressful events compared to those in the active control group. Both conditions had reduced daily negative affect across the intervention and lower peak cortisol reactivity to the lab stressor post-intervention. ConclusionsCounter to the preregistered predictions, and despite participants’ differing expectations, the interventions led to equivalent reductions in depressive symptoms, anxiety symptoms, and perceived stress, which were sustained at three months. They also produced comparable reductions in cortisol reactivity and daily negative affect. However, the WHM condition was associated with greater reduction in reported rumination after daily stressful events than the active control, a finding that needs replication with larger and more diverse samples.

Early adoption of triamcinolone acetonide suprachoroidal injection for uveitic macular edema: a physician survey

ObjectiveTo obtain physicians’ “real-world” perspectives on early experiences with triamcinolone acetonide suprachoroidal injection (SCS-TA) for treatment of patients with uveitic macular edema (UME).ResultsTwelve retina/uveitis specialists in the United States were surveyed about SCS-TA injection procedure and patient outcomes. Survey participants administered ≥ 291 SCS-TA injections to 243 patients with UME with various disease characteristics (etiologies, chronicity, and anatomical subtypes). Commonly reported reasons for SCS-TA adoption included potential for lowering the risk of steroid-associated intraocular pressure elevations versus intravitreal injections or implants (100%), potential for longer duration of action versus intravitreal steroid injections or implants (92%), and desire to use a new delivery modality (83%). Nearly all participants (92%) found injection procedure relatively easy post-training, with most (75%) procedurally comfortable after completing 2–5 injections. 58% of participants indicated that their patients gained 2–3 lines of vision by first follow-up visit, and 92% reported having patients who experienced 100–150 μm or greater reduction in central subfield thickness. Overall, 92% of participants were satisfied with SCS-TA treatment outcomes. Findings from this survey of early adopters of SCS-TA indicate that the suprachoroidal injection technique was easy to learn and resulted in favorable patient outcomes consistent with clinical trial data.

Characterizing body composition modifying effects of a glucagon-like peptide 1 receptor-based agonist: A meta-analysis.

Diabetes is an independent risk factor for muscle mass loss, with possible mechanisms including impaired insulin signalling and chronic inflammation. The use of a glucagon-like peptide 1 (GLP-1) receptor-based agonist could lead to weight reduction, which might result from the loss of both fat and skeletal muscle. However, the body composition-modifying effects of GLP-1 receptor-based agonists have not been systematically characterized. PubMed, EMBASE, the Cochrane Center Register of Controlled Trials for Studies and Clinicaltrial.gov were searched from inception to October 2023. Randomized controlled trials of GLP-1 receptor agonist or glucose-dependent insulinotropic polypeptide/GLP-1 receptor dual agonist, which reported the changes of body composition, were included. The results were computed as weighted mean differences (WMDs) and 95% confidence intervals (CIs) in a random-effects model. In all, 19 randomized controlled trials were included. When compared with controls, substantial reductions in fat body mass were observed in patients using GLP-1 receptor-based agonist treatment (WMD = -2.25 kg, 95% CI -3.40 to -1.10 kg), with decrease in areas of both subcutaneous fat (WMD = -38.35 cm2, 95% CI, -54.75 to -21.95 cm2) and visceral fat (WMD = -14.61 cm2, 95% CI, -23.77 to -5.44 cm2). Moreover, greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users compared with non-users (WMD = -1.02 kg, 95% CI, -1.46 to -0.57 kg), while the changes in lean mass percentage were comparable between GLP-1 receptor-based agonist users and non-users. Compared with the controls, GLP-1 receptor-based agonist users experienced greater reductions in fat body mass, with body shaping effects in terms of both subcutaneous fat mass and visceral fat mass. Although greater reductions in lean body mass were also observed in GLP-1 receptor-based agonist users, the changes in lean mass percentage were comparable between the users and non-users.

Three vs 6 Cycles of Chemotherapy for High-Risk Retinoblastoma

Adjuvant therapy is an important and effective treatment for retinoblastoma. However, there is a lack of head-to-head clinical trials comparing 3 vs 6 cycles of CEV chemotherapy (carboplatin, etoposide, and vincristine) for enucleated unilateral retinoblastoma with high-risk pathological features. To assess whether 3 cycles of CEV chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features. This double-center, randomized, open-label, noninferiority trial was conducted at 2 premier eye centers in China and included 187 patients who had undergone enucleation for unilateral retinoblastoma with high-risk pathological features (massive choroidal infiltration, retrolaminar optic nerve invasion, or scleral infiltration) between August 2013 and March 2024. The final date of follow-up was March 21, 2024. Patients were randomly assigned to receive either 3 (n = 94) or 6 (n = 93) cycles of CEV chemotherapy regimen after enucleation. The primary end point was disease-free survival, with a noninferiority margin of 12%. Secondary end points encompassed overall survival, safety, economic burden, and the quality of life of children. All 187 patients (median [IQR] age, 25.0 [20.0-37.0] months; 83 [44.4%] female) completed the trial. Median (IQR) follow-up was 79.0 (65.5-102.5) months. Five-year disease-free survival was 90.4% for the 3-cycle group vs 89.2% for the 6-cycle group (difference, 1.2% [95% CI, -7.5% to 9.8%]), which met the noninferiority criterion (P = .003 for noninferiority). The 6-cycle group experienced a higher frequency of adverse events, greater reduction in quality of life scores, and increased costs compared with the 3-cycle group. Among patients with unilateral pathologic high-risk retinoblastoma, 3 cycles of CEV chemotherapy resulted in 5-year disease-free survival that was noninferior to 6 cycles of CEV chemotherapy. ClinicalTrials.gov Identifier: NCT01906814.

Curcumin-encapsulated glucan nanoparticles as an oxidative stress modulator against human hepatic cancer cells

In Hepatitis B patients, the virus targets liver cells, leading to inflammation and liver damage, which can result in severe complications such as liver failure, cirrhosis, and liver cancer. Therapeutic options for liver disease are currently limited. Curcumin, a polyphenol with potential protective effects against chronic diseases like cancer, suffers from poor water solubility, restricting its pharmacological applications. This study explores the encapsulation of curcumin in glucan nanoparticles (NPs) and its impact on oxidative stress in liver cancer cells. Two sizes of curcumin-loaded glucan NPs, GC111 (111 nm) and GC398 (398 nm), were produced with nearly 100 % encapsulation efficiency. Cytotoxicity studies revealed that particle size influences the extent of observed effects, with GC111 NPs causing a greater reduction in cell viability. Additionally, the smaller GC111 NPs demonstrated a higher capacity to induce oxidative stress in cancer cells by stimulating the production of ROS, NO, and the chemokine RANTES in a concentration-dependent manner. These findings suggest that the smaller GC111 NPs are promising candidates for future studies aimed at evaluating oxidative stress-induced tumor cell death mechanisms.

Effectiveness and safety of the modified multiple mode procedures versus traditional multiple mode procedures on treating facial atrophic acne scars: a propensity score matching retrospective cohort study.

Multiple mode procedures (MMP) of fractional CO2 laser provide higher efficacy and shorter downtime in treating acne scars, compared to traditional fractional CO2 laser therapy. This study aims to evaluate the effectiveness and safety of modified MMP integrated with fractional microneedle radiofrequency (FMR), ultra-pulse CO2 laser and fractional CO2 laser in treating acne scars. A retrospective analysis of 162 acne scar patients treated with MMP or modified MMP was conducted. Acne scars were evaluated using the Echelle d'Evaluation Clinique des Cicatrices d'Acné (ECCA) grading scale, modified Manchester Scar Scale (mMSS), and Global Assessment Scale (GAS). Baseline variables were balanced with propensity score matching (PSM) to improve the comparability of treatment effectiveness and safety between groups. Among 162 patients with facial acne scars, 68 were treated with modified MMP and 94 with traditional MMP. After PSM, both groups had 55 patients with comparable baseline characteristics (P > 0.05). The ECCA score decreased more significantly in the modified MMP group (60%±11%) than in the MMP group (45%±16.6%, P < 0.001). The modified MMP group also had higher mMSS color score (2.6 ± 0.7 vs. 2.1 ± 0.9, P = 0.005), greater reduction in pore size and skin laxity (P < 0.001), shorter postoperative erythema duration (22.2 ± 4.0 vs. 31.3 ± 3.7 days, P < 0.001), but higher pain scores (Visual Analogue Scale, VAS: 6.7 ± 1.6 vs. 3.8 ± 0.8, P < 0.001). Modified MMP is more effective than traditional MMP in treating acne scars, especially for patients with large pores and skin laxity.

Efficacy and safety of levosimendan in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: The LEVOCEST trial.

Primary angioplasty is the standard procedure for patients with ST-segment elevation myocardial infarction (STEMI). However, myocardial reperfusion results in additional cell damage. Levosimendan, due to its pleiotropic effects, may be a therapeutic alternative to prevent this damage. The objective of this study was to evaluate whether this drug can reduce infarct size in patients with STEMI. Patients were randomized to receive a 24-h infusion of either levosimendan (0.1 μg/kg/min) or placebo after the primary angioplasty. The main objective was to assess the size of the infarct by cardiac resonance at 30 days and 6 months after the event. Other variables such as left ventricular ejection fraction (LVEF) and adverse ventricular remodeling (AVR) were assessed by speckle-tracking echocardiography and magnetic resonance. Major adverse cardiovascular events (MACE) were also collected. 157 patients were analysed (levosimendan, n = 79; placebo, n = 78). We found that after 6 months, patients treated with levosimendan had a greater reduction in infarct size (13.19% ± 9.5% vs.11.79% ± 9%, p = 0.001), compared with those in the placebo group (13.35% ± 7.1% vs. 13.43% ± 7.8%, p = 0.38). There were no significant differences in MACE between both groups. Levosimendan is a safe and effective therapeutic option for reducing infarct size in patients with STEMI.

Intraocular Pressure Fluctuation as Assessed by Water Drinking Test Following iStent inject Implantation in Open Angle Glaucoma Patients.

Introduction This study investigated the intraocular pressure (IOP) fluctuation as assessed by the water drinking test (WDT) in open-angle glaucoma (OAG) patients after combined cataract surgery with iStent implantation. Methods This was a prospective non-randomized comparative study. Eyes with OAG and cataracts that were planned for either combined phacoemulsification and iStent implantation (iStent+CS) or phacoemulsification alone (CS) were recruited. The iStent inject (Model G2-M-IS) or iStent injectW (Model G2-W) trabecular micro-bypass stent (Glaukos Corporation, San Clemente, CA, USA) was implanted in the iStent+CS group. Water drinking test (WDT) was performed before and 3 months after surgery. WDT-IOP parameters including peak IOP, IOP fluctuation, and area under curve (AUC) were compared between the two groups. Results There were 20 eyes in the iStent+CS group and 16 eyes in the CS group. Both groups had similar pre-operative baseline IOP (15.6 ± 3.7 mmHg vs 15.8 ± 1.8 mmHg in the iStent+CS and CS group, respectively, p = 0.883). The iStent+CS group experienced greater numerical reduction in peak IOP (2.6 ± 1.9 mmHg vs 1.9 ± 2.4 mmHg; p = 0.355), IOP fluctuation (1.7 ± 2.2 mmHg vs 0.8 ± 2.5 mmHg; p = 0.289), and AUC (54.8 ± 103.6 mmHg x minute vs 25.3 ± 79.0 mmHg x minute; p = 0.355) than the CS group. There was more reduction in the number of anti-glaucoma medications in the iStent+CS group (1.4 ± 1.2) than the CS group (0.3 ± 0.9; p = 0.005). Conclusion Both combined phacoemulsification with iStent inject implantation and phacoemulsification alone reduced peak IOP, IOP fluctuation, and AUC, and none of these parameters showed statistically significant difference. Greater reduction in anti-glaucoma medications was seen in the combined group.

Long-Term Efficacy and Tolerability of an Emollient Containing Glycerol and Paraffin for Moderate-to-Severe Uremic Xerosis: A Randomized Phase3 Study.

There is an unmet need for effective topical therapies for patients with uremic xerosis and chronic kidney disease-associated pruritus (CKD-aP). The long-term efficacy and tolerability of an emollient containing glycerol 15% and paraffin 10% (V0034CR) was evaluated in a phase3 study. In this randomized, double-blind, two-parallel group, vehicle-controlled study, patients with moderate-to-severe uremic xerosis were randomized to once-daily application of V0034CR or vehicle control for 28days (periodI). This was followed by a treatment-free period of ≤ 21days (periodII), then all patients received open-label treatment with V0034CR for ≥ 84days (periodIII). Outcomes included treatment response at the end of periodI (El Gammal's xerosis severity score), instrumental measures of scaling (D-Squame technique), time to relapse during periodII, rate of recurrence during periodIII, pruritus severity over time, patient acceptability, and adverse events (AEs). The intent-to-treat population comprised 235 patients randomized to V0034CR (n = 118) or vehicle control (n = 117) during periodI. Treatment response at the end of periodI was achieved by 71 patients (60.2%) in the V0034CR group versus 48 (41.0%) with vehicle control (p = 0.0041). This coincided with greater reductions in the total surface area of squames (p = 0.001 vs vehicle control). Xerosis relapsed progressively without treatment in periodII; however, remission was durable under maintenance therapy in periodIII. Improvements in pruritus severity were comparable between V0034CR and vehicle control, suggesting that the antipruritic effect of V0034CR was mainly exerted by its oil-in-water emulsion base. V0034CR had high patient acceptability and was well tolerated; the most common treatment-related AEs were irritation or erythema (2.1%), exacerbated pruritus (1.3%), and vesicles at the application site (0.9%). These data support the use of V0034CR, with its hydrating and occlusive properties, for the long-term management of patients with moderate-to-severe uremic xerosis and CKD-aP. ClinicalTrials.gov identifier NCT01084148; EudraCT number 2006-002201-31.