Evaluating the impact of Sacubitril/valsartan on diastolic function in patients with heart failure: A systematic review and meta-analysis.

BACKGROUND: Heart failure is a common and severe condition, often complicated by diastolic dysfunction. Current standard therapies such as ACEIs and ARBs have limited efficacy in managing diastolic function. Sacubitril/Valsartan, an emerging therapy, warrants rigorous investigation to elucidate its impact on diastolic function in heart failure patients. METHODS: This systematic review and meta-analysis were conducted adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and utilized the PICO schema. Searches were performed on 4 databases-PubMed, Embase, Web of Science, and Cochrane Library-without temporal restrictions. Inclusion and exclusion criteria were strictly defined, and quality assessments were conducted using the Cochrane Collaboration Risk of Bias tool. Both fixed-effects and random-effects models were used for statistical analysis, depending on inter-study heterogeneity assessed by I2 statistics and Chi-square tests. RESULTS: Out of 1129 identified publications, 8 studies met the criteria and were included in the meta-analysis. These studies consisted of both randomized controlled trials and cohort studies and featured diverse global populations. Significant reductions were found in the echocardiographic parameter E/e' ratio and LAVi upon treatment with Sacubitril/Valsartan compared to standard therapies, with mean differences of -1.38 and -4.62, respectively, both with P values < .01. CONCLUSIONS: This meta-analysis demonstrates that Sacubitril/Valsartan significantly improves diastolic function parameters in heart failure patients compared to standard treatments. These findings underscore the potential benefits of Sacubitril/Valsartan in the management of heart failure, particularly for patients with diastolic dysfunction.

Sacubitril-valsartan vs ACE/ARB in pediatric heart failure: A retrospective cohort study.

BACKGROUND: The first angiotensin receptor/neprilysin inhibitor on the market, sacubitril-valsartan, has shown marked improvements in death and hospitalization for heart failure among adults, and is now approved for use in pediatric heart failure. While the ongoing PANORAMA-HF trial is evaluating the effectiveness of sacubitril-valsartan for pediatric patients with a failing systemic left ventricle, the enrollment criteria do not include the majority of pediatric heart failure patients. Additional studies are needed. METHODS: Using the TriNetX database, we performed a propensity score matched, retrospective cohort study to assess the incidence of a composite of all-cause mortality or heart transplant within 1 year. The 519 patients who received sacubitril-valsartan were compared to 519 matched controls who received an angiotensin converting enzyme inhibitor (ACE) or angiotensin II receptor blocker (ARB). RESULTS: There was no significant difference in the incidence of the composite outcome with sacubitril-valsartan over an ACE/ARB (13.3% vs 13.2%, p = 0.95), or among the components of mortality (5.0% vs 5.8%, p = 0.58) or heart transplantation (8.7% vs 7.5%, p = 0.50). Patients who were receiving full goal-directed medical therapy (14.4% vs 16.0%, p = 0.55) also showed no difference in the composite outcome. We observed a significantly increased incidence of hypotension (10% vs 5.2%, p = 0.006) and a trend toward reduced number of hospitalizations per year (mean (SD) 1.3 (4.4) vs 2.0 (9.1), p = 0.09). CONCLUSIONS: Sacubitril-valsartan is not associated with a decrease in the composite of all-cause mortality or heart transplantation within 1 year. Future studies should evaluate the possible reduction in hospitalizations and optimal dosing to minimize hypotension.

Evaluating prescription of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in patients with diabetes and albuminuria.

AIM: Although guidelines recommend the use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) in patients with diabetes, hypertension, and albuminuria, their use remains suboptimal in several developed countries. Limited data are available on ACEi/ARB use in developing countries. Here, we assessed the use of ACEi/ARB and identified factors contributing to their underutilization at Hatyai Hospital, Thailand. MATERIALS AND METHODS: This retrospective cross-sectional study was conducted using data from the Hatyai Hospital database. Adult patients with diabetes, hypertension, and albuminuria were included. Clinical data and laboratory results were extracted. Furthermore, this study recorded pre-specified conditions that influenced physicians' decisions regarding the prescription of ACEi/ARBs in patients who did not adhere to guidelines. RESULTS: Of 4,655 eligible patients, 500 patients were selected. The average age of the patients was 66.3 years, and 59.6% were female. The adherence rate was 72.4%. Multivariate logistic regression analysis found a significant association between non-adherence and chronic kidney disease (CKD) stage (OR = 1.29, 95% CI: 1.04 - 1.60, p = 0.019). The most common pre-specified condition contributing to non-adherence was "no condition identified" (69.8%). Among the cases of non-adherence, 21.7% were due to ACEi/ARB discontinuation after acute kidney injury, followed by hyperkalemia (5.1%) and a moderate increase in serum creatinine (4.3%). CONCLUSION: ACEi/ARB therapy was suboptimal in patients with diabetes, hypertension, and albuminuria. Non-adherence was associated with CKD stage, possibly because of concerns about adverse events and healthcare-related factors.

Renin-Angiotensin-Aldosterone System: From History to Practice of a Secular Topic.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are standard care in patients with hypertension, heart failure or chronic kidney disease (CKD). Although we have studied the RAAS for decades, there are still circumstances that remain unclear. In this review, we describe the evolution of the RAAS and pose the question of whether this survival trait is still necessary to humankind in the present age. We elucidate the benefits on cardiovascular health and kidney disease of RAAS inhibition and present promising novel medications. Furthermore, we address why more studies are needed to establish a new standard of care away from generally prescribing ACEi or ARB toward an improved approach to combine drugs tailored to the needs of individual patients.

Impact of Insurance Status and Region on Angiotensin Receptor-Neprilysin Inhibitor Prescription During Heart Failure Hospitalizations.

BACKGROUND: An angiotensin receptor-neprilysin inhibitor (ARNI) is the preferred renin-angiotensin system (RAS) inhibitor for heart failure with reduced ejection fraction (HFrEF). Among eligible patients, insurance status and prescriber concern regarding out-of-pocket costs may constrain early initiation of ARNI and other new therapies. OBJECTIVES: In this study, the authors sought to evaluate the association of insurance and other social determinants of health with ARNI initiation at discharge from HFrEF hospitalization. METHODS: The authors analyzed ARNI initiation from January 2017 to June 2020 among patients with HFrEF eligible to receive RAS inhibitor at discharge from hospitals in the Get With The Guidelines-Heart Failure registry. The primary outcome was the proportion of ARNI prescription at discharge among those prescribed RAS inhibitor who were not on ARNI on admission. A logistic regression model was used to determine the association of insurance status, U.S. region, and their interaction, as well as self-reported race, with ARNI initiation at discharge. RESULTS: From 42,766 admissions, 24,904 were excluded for absolute or relative contraindications to RAS inhibitors. RAS inhibitors were prescribed for 16,817 (94.2%) of remaining discharges, for which ARNI was prescribed in 1,640 (9.8%). Self-reported Black patients were less likely to be initiated on ARNI compared to self-reported White patients (OR: 0.64; 95% CI: 0.50-0.81). Compared to Medicare beneficiaries, patients with third-party insurance, Medicaid, or no insurance were less likely to be initiated on ARNI (OR: 0.47 [95% CI: 0.31-0.72], OR: 0.41 [95% CI: 0.25-0.67], and OR: 0.20 [95% CI: 0.08-0.47], respectively). ARNI therapy varied by hospital region, with lowest utilization in the Mountain region. An interaction was demonstrated between the impact of insurance disparities and hospital region. CONCLUSIONS: Among patients hospitalized between 2017 and 2020 for HFrEF who were prescribed RAS inhibitor therapy at discharge, insurance status, geographic region, and self-reported race were associated with ARNI initiation.

Treatment Patterns, Outcomes, and Persistence to Newly Started Heart Failure Medications in Patients with Worsening Heart Failure: A Cohort Study from the United States and Germany.

BACKGROUND: Data are limited regarding guideline-directed medical therapy (GDMT) treatment patterns in patients with worsening heart failure (HF). METHODS: We used administrative claims databases in Germany and the USA to conduct a retrospective cohort study of patients with worsening HF. Two cohorts of patients with prevalent HF and a HF hospitalization (HFH) from 2016 to 2019, alive at discharge (N = 75,140 USA; N = 47,003 Germany) were identified. Index date was the first HFH during the study period. One-year HF rehospitalization and mortality rates were calculated and a composite endpoint of both outcomes assessed using Kaplan-Meier estimation. We evaluated HF medication patterns in the 6 months before and after the index date. New users of a HF medication (at discharge/after index HFH) were followed for 1 year to evaluate persistence (no treatment gaps > 2 months) RESULTS: One-year HF rehospitalization rates were 36.2% (USA) and 47.7% (Germany). One year mortality rates were 30.0% (USA) and 23.0% (Germany), and the composite endpoint (mortality/HF rehospitalization) was reached in 55.1 % (USA) and 56.6% (Germany). Kaplan-Meier plots showed the risk for the composite endpoint was high in the early post discharge period. Comparison of patterns pre- and postindex HFH showed some increase in use of mineralocorticoid receptor antagonists (MRAs), angiotensin receptor-neprilysin inhibitor (ARNI), and triple therapy; use of angiotensin-converting enzyme (ACE) inhibitor/ angiotensin receptor blocker (ARB) plus beta-blockers remained constant/slightly declined; < 20% patients received triple therapy (ACE inhibitor/ARB plus beta-blocker plus MRA). A third of patients were new users; 1 year persistence rates were often low. CONCLUSIONS: Morbidity, mortality, and rehospitalization risk is high among patients with worsening HF; uptake and continuation of GDMT is suboptimal.

Angiotensin-converting-enzyme inhibitors and angiotensin receptor blockers for preventing the progression of diabetic kidney disease.

BACKGROUND: Guidelines suggest that adults with diabetes and kidney disease receive treatment with angiotensin-converting-enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB). This is an update of a Cochrane review published in 2006. OBJECTIVES: We compared the efficacy and safety of ACEi and ARB therapy (either as monotherapy or in combination) on cardiovascular and kidney outcomes in adults with diabetes and kidney disease. SEARCH METHODS: We searched the Cochrane Kidney and Transplants Register of Studies to 17 March 2024 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Registry Platform (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included studies evaluating ACEi or ARB alone or in combination, compared to each other, placebo or no treatment in people with diabetes and kidney disease. DATA COLLECTION AND ANALYSIS: Two authors independently assessed the risk of bias and extracted data. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios (RR) and their 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) or standardised mean difference (SMD) and 95% CI for continuous outcomes. Confidence in the evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS: One hundred and nine studies (28,341 randomised participants) were eligible for inclusion. Overall, the risk of bias was high. Compared to placebo or no treatment, ACEi may make little or no difference to all-cause death (24 studies, 7413 participants: RR 0.91, 95% CI 0.73 to 1.15; I2 = 23%; low certainty) and with similar withdrawals from treatment (7 studies, 5306 participants: RR 1.03, 95% CI 0.90 to 1.19; I2 = 0%; low certainty). ACEi may prevent kidney failure (8 studies, 6643 participants: RR 0.61, 95% CI 0.39 to 0.94; I2 = 0%; low certainty). Compared to placebo or no treatment, ARB may make little or no difference to all-cause death (11 studies, 4260 participants: RR 0.99, 95% CI 0.85 to 1.16; I2 = 0%; low certainty). ARB have uncertain effects on withdrawal from treatment (3 studies, 721 participants: RR 0.85, 95% CI 0.58 to 1.26; I2 = 2%; low certainty) and cardiovascular death (6 studies, 878 participants: RR 3.36, 95% CI 0.93 to 12.07; low certainty). ARB may prevent kidney failure (3 studies, 3227 participants: RR 0.82, 95% CI 0.72 to 0.94; I2 = 0%; low certainty), doubling of serum creatinine (SCr) (4 studies, 3280 participants: RR 0.84, 95% CI 0.72 to 0.97; I2 = 32%; low certainty), and the progression from microalbuminuria to microalbuminuria (5 studies, 815 participants: RR 0.44, 95% CI 0.23 to 0.85; I2 = 74%; low certainty). Compared to ACEi, ARB had uncertain effects on all-cause death (15 studies, 1739 participants: RR 1.13, 95% CI 0.68 to 1.88; I2 = 0%; low certainty), withdrawal from treatment (6 studies, 612 participants: RR 0.91, 95% CI 0.65 to 1.28; I2 = 0%; low certainty), cardiovascular death (13 studies, 1606 participants: RR 1.15, 95% CI 0.45 to 2.98; I2 = 0%; low certainty), kidney failure (3 studies, 837 participants: RR 0.56, 95% CI 0.29 to 1.07; I2 = 0%; low certainty), and doubling of SCr (2 studies, 767 participants: RR 0.88, 95% CI 0.52 to 1.48; I2 = 0%; low certainty). Compared to ACEi plus ARB, ACEi alone has uncertain effects on all-cause death (6 studies, 1166 participants: RR 1.08, 95% CI 0.49 to 2.40; I2 = 20%; low certainty), withdrawal from treatment (2 studies, 172 participants: RR 0.78, 95% CI 0.33 to 1.86; I2 = 0%; low certainty), cardiovascular death (4 studies, 994 participants: RR 3.02, 95% CI 0.61 to 14.85; low certainty), kidney failure (3 studies, 880 participants: RR 1.36, 95% CI 0.79 to 2.32; I2 = 0%; low certainty), and doubling of SCr (2 studies, 813 participants: RR 1.14, 95% CI 0.70 to 1.85; I2 = 0%; low certainty). Compared to ACEi plus ARB, ARB alone has uncertain effects on all-cause death (7 studies, 2607 participants: RR 1.02, 95% CI 0.76 to 1.37; I2 = 0%; low certainty), withdrawn from treatment (3 studies, 1615 participants: RR 0.81, 95% CI 0.53 to 1.24; I2 = 0%; low certainty), cardiovascular death (4 studies, 992 participants: RR 3.03, 95% CI 0.62 to 14.93; low certainty), kidney failure (4 studies, 2321 participants: RR 1.15, 95% CI 0.67 to 1.95; I2 = 29%; low certainty), and doubling of SCr (3 studies, 2252 participants: RR 1.18, 95% CI 0.85 to 1.64; I2 = 0%; low certainty). Comparative effects of different ACEi or ARB and low-dose versus high-dose ARB were rarely evaluated. No study compared different doses of ACEi. Adverse events of ACEi and ARB were rarely reported. AUTHORS' CONCLUSIONS: ACEi or ARB may make little or no difference to all-cause and cardiovascular death compared to placebo or no treatment in people with diabetes and kidney disease but may prevent kidney failure. ARB may prevent the doubling of SCr and the progression from microalbuminuria to macroalbuminuria compared with a placebo or no treatment. Despite the international guidelines suggesting not combining ACEi and ARB treatment, the effects of ACEi or ARB monotherapy compared to dual therapy have not been adequately assessed. The limited data availability and the low quality of the included studies prevented the assessment of the benefits and harms of ACEi or ARB in people with diabetes and kidney disease. Low and very low certainty evidence indicates that it is possible that further studies might provide different results.

Role and molecular mechanism of Salvia miltiorrhiza associated with chemical compounds in the treatment of diabetes mellitus and its complications: A review.

Diabetes mellitus (DM) is one of the most prevalent diseases worldwide, greatly impacting patients' quality of life. This article reviews the progress in Salvia miltiorrhiza, an ancient Chinese plant, for the treatment of DM and its associated complications. Extensive studies have been conducted on the chemical composition and pharmacological effects of S miltiorrhiza, including its anti-inflammatory and antioxidant activities. It has demonstrated potential in preventing and treating diabetes and its consequences by improving peripheral nerve function and increasing retinal thickness in diabetic individuals. Moreover, S miltiorrhiza has shown effectiveness when used in conjunction with angiotensin-converting enzyme inhibitors, angiotensin receptor blockers (ARBs), and statins. The safety and tolerability of S miltiorrhiza have also been thoroughly investigated. Despite the established benefits of managing DM and its complications, further research is needed to determine appropriate usage, dosage, long-term health benefits, and safety.

Initiation and continuation of pharmacological therapies in patients hospitalized for heart failure in Japan.

Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective cohort study evaluating the changes in HF drug utilization patterns in 6 months before and after hospitalizations for HF. The adherence to newly initiated HF medications was evaluated based on the proportion of days covered (PDC) and persistence as continuous treatment episodes among new users. The study included 9091 patients hospitalized for HF between January 2016 and September 2019, including 2735 (30.1%) patients who were newly prescribed at least one HF medication after hospitalization. Despite increases in the use of foundational HF therapy (beta-blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists), 35.6% and 7.6% of patients were treated with the HF foundational monotherapy or diuretics alone after hospitalization, respectively. The mean PDC of newly initiated HF medications ranged from 0.57 for thiazide diuretics to 0.77 for sodium-glucose cotransporter-2 inhibitors. Continuous use of HF medications during the first year after initiation was observed in 30-60% of patients. The mean PDC and one-year continuous HF medication use were consistently lower in patients aged ≥ 75 years and in patients with a history of HF hospitalization for all HF medication classes except for tolvaptan and digoxin. Despite the guideline recommendations of HF pharmacotherapy, both treatment and adherence were suboptimal after HF hospitalization, especially in vulnerable populations such as older patients and those with prior HF hospitalizations.

The role of the brain renin-angiotensin system in Parkinson´s disease.

The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.

Characteristics, Risk Factors, and Outcomes in Acute Kidney Injury Patients: A Retrospective Cross-Sectional Study, Palestine.

Background: Acute kidney injury (AKI) is a major medical problem affecting patients' quality of life and healthcare costs. Objectives: This study evaluated the severity, risk factors, and outcomes of patients diagnosed with acute kidney injury (AKI), including community-acquired AKI (CA-AKI) and hospital-acquired AKI (HA-AKI), who were admitted to tertiary institutions in Palestine. Methods: This retrospective cross-sectional study was conducted at multiple tertiary care hospitals in Palestine by reviewing patient charts from January 2020 to March 2023. The study included all patients aged ≥18 years who were admitted to the hospital and diagnosed with AKI at admission (CA-AKI) or who developed AKI 48 hours after admission (HA-AKI). Patients with incomplete medical records and those with no reported creatinine levels during their stay, pregnant women, kidney transplant patients, and end-stage renal disease patients were excluded. Data were analyzed using SPSS v22.0. The incidence of AKI in each group was compared using the chi-squared test. Results: This study included 259 participants. HA-AKI was present in 27.3% of the patients, while CA-AKI was 72.7%. The most common stage among patients was stage 3 (55.7%, HA-AKI) (42.9%, CA-AKI), and the most common comorbidity contributing to AKI was CKD. NSAIDs, ACE-I/ARBs, and DIURETICs were the most nephrotoxic drugs contributing to AKI. Patients with hyperphosphatemia, hyperkalemia, severe metabolic acidosis, or stage 3 AKI require renal replacement therapy. In addition, our findings revealed a significant association among AKI mortality, age, and heart disease. Conclusion: CA-AKI was more prevalent than HA-AKI in Palestinian patients admitted for AKI. Risk factors for AKI included diabetes, CKD, and medications (antibiotics, NSAID, diuretics, and ACE-I/ARB). Preventive measures, medication management, and disease state management are necessary to minimize AKI during hospital admission or in the community.

Enteropathy and intestinal malabsorption in patients treated with antihypertensive drugs. A retrospective cohort study.

OBJECTIVES: To investigate differences in the incidence of enteropathy or intestinal malabsorption in patients taking angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme inhibitor (ACEI), calcium channel blocker (CCB), and beta blockers (BBs) at a single center in Korea. METHODS: In this retrospective study, we utilized data from the Yangsan electronic medical records to identify 129,169 patients. These individuals were prescribed olmesartan, other ARBs, ACEI, CCB, and BBs between November 2008 and February 2021. RESULTS: Of the 44,775 patients, 51 (0.11%) were observed to have enteropathy or intestinal malabsorption. Compared with the ACEI group, the adjusted odds ratios (ORs) for enteropathy and intestinal malabsorption were OR=1.313 (95% confidence interval [CI]: [0.188-6.798], p=0.893) for olmesartan, OR=0.915 (95% CI: [0.525-1.595], p=0.754) for the other ARBs, OR=0.928 (95% CI: [0.200-4.307]; p=0.924) for the CCB, and OR=0.663 (95% CI: [0.151-2.906]; p=0.586) for the BBs group. These findings were adjusted for factors such as age, gender, duration of antihypertensive medication, and comorbidities. CONCLUSION: In a retrospective cohort study of patients on antihypertensive medications, no significant difference was found in the incidence of enteropathy or intestinal malabsorption when ACEI was compared to olmesartan, other ARBs, CCB, and BBs.

ACE inhibitors and angiotensin receptor blockers differentially alter the response to angiotensin II treatment in vasodilatory shock.

BACKGROUND: Angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blockers (ARB) medications are widely prescribed. We sought to assess how pre-admission use of these medications might impact the response to angiotensin-II treatment during vasodilatory shock. METHODS: In a post-hoc subgroup analysis of the randomized, placebo-controlled, Angiotensin Therapy for High Output Shock (ATHOS-3) trial, we compared patients with chronic angiotensin-converting enzyme inhibitor (ACEi) use, and patients with angiotensin receptor blocker (ARB) use, to patients without exposure to either ACEi or ARB. The primary outcome was mean arterial pressure after 1-h of treatment. Additional clinical outcomes included mean arterial pressure and norepinephrine equivalent dose requirements over time, and study-drug dose over time. Biological outcomes included baseline RAS biomarkers (renin, angiotensin-I, angiotensin-II, and angiotensin-I/angiotensin-II ratio), and the change in renin from 0 to 3 h. RESULTS: We included n = 321 patients, of whom, 270 were ACEi and ARB-unexposed, 29 were ACEi-exposed and 22 ARB-exposed. In ACEi/ARB-unexposed patients, angiotensin-treated patients, compared to placebo, had higher hour-1 mean arterial pressure (9.1 mmHg [95% CI 7.6-10.1], p < 0.0001), lower norepinephrine equivalent dose over 48-h (p = 0.0037), and lower study-drug dose over 48-h (p < 0.0001). ACEi-exposed patients treated with angiotensin-II showed similarly higher hour-1 mean arterial pressure compared to ACEi/ARB-unexposed (difference in treatment-effect: - 2.2 mmHg [95% CI - 7.0-2.6], pinteraction = 0.38), but a greater reduction in norepinephrine equivalent dose (pinteraction = 0.0031) and study-drug dose (pinteraction < 0.0001) over 48-h. In contrast, ARB-exposed patients showed an attenuated effect of angiotensin-II on hour-1 mean arterial pressure versus ACEi/ARB-unexposed (difference in treatment-effect: - 6.0 mmHg [95% CI - 11.5 to - 0.6], pinteraction = 0.0299), norepinephrine equivalent dose (pinteraction < 0.0001), and study-drug dose (pinteraction = 0.0008). Baseline renin levels and angiotensin-I/angiotensin-II ratios were highest in ACEi-exposed patients. Finally, angiotensin-II treatment reduced hour-3 renin in ACEi/ARB-unexposed and ACEi-exposed patients but not in ARB-exposed patients. CONCLUSIONS: In vasodilatory shock patients, the cardiovascular and biological RAS response to angiotensin-II differed based upon prior exposure to ACEi and ARB medications. ACEi-exposure was associated with increased angiotensin II responsiveness, whereas ARB-exposure was associated with decreased responsiveness. These findings have clinical implications for patient selection and dosage of angiotensin II in vasodilatory shock. Trial Registration ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Predicting Antibiotic Resistance and Assessing the Risk Burden from Antibiotics: A Holistic Modeling Framework in a Tropical Reservoir.

Predicting the hotspots of antimicrobial resistance (AMR) in aquatics is crucial for managing associated risks. We developed an integrated modeling framework toward predicting the spatiotemporal abundance of antibiotics, indicator bacteria, and their corresponding antibiotic-resistant bacteria (ARB), as well as assessing the potential AMR risks to the aquatic ecosystem in a tropical reservoir. Our focus was on two antibiotics, sulfamethoxazole (SMX) and trimethoprim (TMP), and on Escherichia coli (E. coli) and its variant resistant to sulfamethoxazole-trimethoprim (EC_SXT). We validated the predictive model using withheld data, with all Nash-Sutcliffe efficiency (NSE) values above 0.79, absolute relative difference (ARD) less than 25%, and coefficient of determination (R2) greater than 0.800 for the modeled targets. Predictions indicated concentrations of 1-15 ng/L for SMX, 0.5-5 ng/L for TMP, and 0 to 5 (log10 MPN/100 mL) for E. coli and -1.1 to 3.5 (log10 CFU/100 mL) for EC_SXT. Risk assessment suggested that the predicted TMP could pose a higher risk of AMR development than SMX, but SMX could possess a higher ecological risk. The study lays down a hybrid modeling framework for integrating a statistic model with a process-based model to predict AMR in a holistic manner, thus facilitating the development of a better risk management framework.

Heart failure management with ß-blockers: can we do better?

Heart failure (HF) is associated with disabling symptoms, poor quality of life, and a poor prognosis with substantial excess mortality in the years following diagnosis. Overactivation of the sympathetic nervous system is a key feature of the pathophysiology of HF and is an important driver of the process of adverse remodelling of the left ventricular wall that contributes to cardiac failure. Drugs which suppress the activity of the renin-angiotensin-aldosterone system, including ß-blockers, are foundation therapies for the management of heart failure with reduced ejection fraction (HFrEF) and despite a lack of specific outcomes trials, are also widely used by cardiologist in patients with HF with preserved ejection fraction (HFpEF). Today, expert opinion has moved away from recommending that treatment for HF should be guided solely by the LVEF and interventions should rather address signs and symptoms of HF (e.g. oedema and tachycardia), the severity of HF, and concomitant conditions. ß-blockers improve HF symptoms and functional status in HF and these agents have demonstrated improved survival, as well as a reduced risk of other important clinical outcomes such as hospitalisation for heart failure, in randomised, placebo-controlled outcomes trials. In HFpEF, ß-blockers are anti-ischemic and lower blood pressure and heart rate. Moreover, ß-blockers also reduce mortality in the setting of HF occurring alongside common comorbid conditions, such as diabetes, CKD (of any severity), and COPD. Higher doses of ß-blockers are associated with better clinical outcomes in populations with HF, so that ensuring adequate titration of therapy to their maximal (or maximally tolerated) doses is important for ensuring optimal outcomes for people with HF. In principle, a patient with HF could have combined treatment with a ß-blocker, renin-angiotensin-aldosterone system inhibitor/neprilysin inhibitor, mineralocorticoid receptor antagonist, and a SGLT2 inhibitor, according to tolerability.

Development of Telmisartan Nanocrystal-Based Dissolving Microneedle for Brain Targeting via Trigeminal Pathway: A Potentially Promising Treatment for Alzheimer's with an Improved Pharmacokinetic Profile.

Telmisartan (TMN), an angiotensin receptor blocker (ARB) drug, is being considered as an alternative therapy for Alzheimer's disease (ALZ). However, when taken orally, its low water solubility leads to a low bioavailability and brain concentration. To overcome this problem, TMN was formulated as nanocrystals (NC), then incorporated into dissolving microneedles (DMN) to enhance drug delivery to the brain via the trigeminal route on the face. TMN-NC was formulated with 1% PVA using the top-down method and stirred for 12 h, producing the smallest particle size of 132 ± 11 nm and showing a better release profile, reaching 89.51 ± 7.52% (2 times greater than pure TMN). TMN-NC-DMN with a combination of 15% PVA and 25% PVP showed optimal mechanical strength and penetration ability; they could dissolve completely within 15 min, and their surface pH was safe for the skin. The permeation test of TMN-NC-DMN showed the highest concentration, reaching 285.80 ± 32.12 µg/mL, compared to TMN-DMN and patch control, which only reached 87.17 ± 11.24 and 94.00 ± 11.09 µg/mL, respectively. The TMN-NC-DMN combination showed better bioavailability and was found to be well-delivered to the brain without any irritation to the skin. Pharmacokinetic parameters had a significant difference (p > 0.05) compared to other preparations, making it a promising treatment for ALZ.

Predicting Response to Immunotargeted Therapy in Endometrial Cancer via Tumor Immune Microenvironment: A Multicenter, Observational Study.

Only one-third of patients with advanced MSS/pMMR endometrial cancer exhibit a lasting response to the combination treatment of Pembrolizumab and Lenvatinib. The combined administration of these two drugs is based on Lenvatinib's ability to modulate the tumor microenvironment, enabling Pembrolizumab to exert its effect. These findings underscore the importance of exploring tumor microenvironment parameters to identify markers that can accurately select candidates for this type of therapy. An open non-randomized observational association study was conducted at six clinical centers, involving a total of 28 patients with advanced MSS/pMMR endometrial cancer who received Pembrolizumab and Lenvatinib therapy. Using TSA-associated multiplex immunofluorescence, we analyzed the proportion of CD8+ T lymphocytes, CD20+ B lymphocytes, FoxP3+ T regulatory lymphocytes, and CD163+ macrophages in tumor samples prior to immunotargeted therapy. The percentage of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio was significantly higher in patients who responded to treatment compared to non-responders (responders vs. non-responders: 0.24 (0.1-1.24)% vs. 0.08 (0.00-0.15)%, p = 0.0114; 1.44 (0.58-2.70) arb. unit vs. 19.00 (3.80-34.78) arb. unit, p = 0.0031). The sensitivity and specificity of these biomarkers were 85.71% and 70.59%, and 85.71% and 85.71%, respectively. The proportion of CD20+ B lymphocytes and the CD8-to-CD20 lymphocytes ratio in the stroma of endometrial cancer serves as both a prognostic marker of response to immunotargeted therapy and a prognostic factor for progression-free survival in patients.

Telmisartan-Induced Myotoxicity in Patients with Essential Hypertension.

Drug-related muscular adverse effects are relatively common among certain groups of drugs, such as statins and steroids. However, these adverse effects are less well-known for angiotensin receptor blockers (ARBs). It is proposed that telmisartan and irbesartan may cause myotoxicity via increased Peroxisome Proliferator-Activated Receptor gamma (PPAR-gamma) activity. Herein, we present two hypertensive patients in whom telmisartan-induced myotoxicity was observed. Therefore, physicians should be aware that telmisartan, along with some other ARBs, can also cause myopathy. Possible drug-drug interactions should be considered in cases of concomitant prescription of these agents with other myopathic drugs.

Detection of Novel BEST1 Variations in Autosomal Recessive Bestrophinopathy Using Third-generation Sequencing.

OBJECTIVE: Autosomal recessive bestrophinopathy (ARB), a retinal degenerative disease, is characterized by central visual loss, yellowish multifocal diffuse subretinal deposits, and a dramatic decrease in the light peak on electrooculogram. The potential pathogenic mechanism involves mutations in the BEST1 gene, which encodes Ca2+-activated Cl- channels in the retinal pigment epithelium (RPE), resulting in degeneration of RPE and photoreceptor. In this study, the complete clinical characteristics of two Chinese ARB families were summarized. METHODS: Pacific Biosciences (PacBio) single-molecule real-time (SMRT) sequencing was performed on the probands to screen for disease-causing gene mutations, and Sanger sequencing was applied to validate variants in the patients and their family members. RESULTS: Two novel mutations, c.202T>C (chr11:61722628, p.Y68H) and c.867+97G>A, in the BEST1 gene were identified in the two Chinese ARB families. The novel missense mutation BEST1 c.202T>C (p.Y68H) resulted in the substitution of tyrosine with histidine in the N-terminal region of transmembrane domain 2 of bestrophin-1. Another novel variant, BEST1 c.867+97G>A (chr11:61725867), located in intron 7, might be considered a regulatory variant that changes allele-specific binding affinity based on motifs of important transcriptional regulators. CONCLUSION: Our findings represent the first use of third-generation sequencing (TGS) to identify novel BEST1 mutations in patients with ARB, indicating that TGS can be a more accurate and efficient tool for identifying mutations in specific genes. The novel variants identified further broaden the mutation spectrum of BEST1 in the Chinese population.