Dual Combination Research Articles

O90 EFFICACY AND SAFETY OF DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS AS FIRST-LINE THERAPY: A SYSTEMATIC REVIEW AND META-ANALYSIS OF RANDOMIZED CONTROLLED TRIALS

Background: Hypertension remains the primary cause of mortality worldwide, resulting in about 11 million deaths annually. Despite recent hypertension guidelines advocating for dual combination of antihypertensive drugs as the first-line therapy for most patients, many patients do not receive this therapy. Objective: To assess, among adults with hypertension, dual combinations of AHTDs compared to monotherapy as first-line treatment for blood pressure (BP)-lowering efficacy and safety. Methods: We systematically searched multiple electronic databases until December 2022 to identify relevant randomized, double-blind trials. We included trials involving adults with hypertension who were either treatment naive or untreated for at least 2 weeks, compared dual combinations of drugs with monotherapy from 5 major classes of AHTDs (angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, beta blockers, and diuretics), for a duration of at least 4 weeks and reported data on BP reduction. AHTDs and their combinations were categorized based on standard daily doses. Outcomes were reduction in BP, treatment related adverse events (TRAE) and withdrawals from the treatment due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: We included 98 trials (636 comparisons and 25892 participants). Overall, baseline mean BP was 159/102 mmHg. Overall BP reduction with dual combination compared to monotherapy was 4.4 (CI: 3.8-5.1)/3.5 (CI:3.2-3.9) mmHg. Compared with standard-dose monotherapy, dual combinations of <1 + <1, 1 + <1 and 1 + 1 (i.e. low-to-standard dose), showed a dose-response relationship in reducing BP by 1.4 (CI: 0.01-2.7)/2.3 (CI: 1.4-3.1), 4.4 (CI: 3.6-5.2)/ 3.3 (CI: 2.9-3.8) and 7.8 (CI: 6.2-8.9)/5.2 (CI: 4.4-5.9) mmHg, respectively. TRAEs [4.8% vs 4.9%; RR 0.92 (0.80 to 1.06)] and WDAEs [0.8% vs 0.9%; RR 1.8 (1.5 to 2.1)] were uncommon with low-to-standard dose dual combinations, with no significant difference compared with standard-dose monotherapy. Conclusion: First-line treatment with low-to-standard dose dual combination therapy is more efficacious and equally safe compared to monotherapy to reduce BP.

P103 EFFICACY AND SAFETY OF TRIPLE VERSUS DUAL COMBINATIONS OF ANTIHYPERTENSIVE DRUGS: A SYSTEMATIC REVIEW AND META-ANALYSIS OF DOUBLE-BLIND RANDOMIZED CLINICAL TRIALS

Background: Some patients taking two blood pressure (BP) lowering drugs do not achieve and maintain BP <140/90mmHg on two drugs and substantially more do not reach <130/80 mmHg targets that are increasingly recommended by guidelines. Objective: To evaluate, among adults with hypertension, triple combination of antihypertensive drugs (AHTDs) compared to dual combinations of AHTDs for BP-lowering efficacy and safety. Methods: We searched multiple databases and the USFDA website until December 2023 for randomized, double-blind trials involving adults with hypertension, that compared triple versus dual combinations of AHTDs from five major classes (angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, calcium channel blockers, beta-blockers, and diuretics) over a minimum of 4 weeks. Drugs and doses were categorized by standard daily doses based on WHO daily defined dose. Primary outcomes were reduction in BP and treatment withdrawals due to adverse events (WDAE). Meta-analyses were conducted using random-effects model. Results: Twenty-four trials (15,533 participants) were included. Overall, triple compared with dual combination reduced BP by 5.1/3.7 mmHg (95% CI 4.3-5.9/3.0-4.4, p<0.001 for both), improved BP control by 69% versus 54% (relative risk [RR] 1.35 [95% CI: 1.25%-1.45%], p=<0.001). Incidence of WDAE was 4.2% versus 2.9% (RR 1.9 [95% CI: 1.3-2.4], P=0.004). Addition of a third drug to dual combinations at 0.5, 1, 1.5 and 2 standard doses resulted in additional SBP reduction of 3.4 (95% CI: 2.2-4.6), 6.1 (95% CI: 4.8-7.0), 4.5 (95% CI: 1.7-7.6) and 7.5 (95% CI: 6.2-8.8) mmHg, respectively with no significant difference in incidence of WDAEs [RR 1.63 (95% CI: 0.84-3.18) vs 1.58 (95% CI: 1.14-2.19) vs 0.94 (95% CI: 0.44-1.98)]. Conclusion: Triple combinations of AHTDs reduce BP significantly, compared to dual combinations. Adding a third AHTD to dual combination, at 0.5 or 1 standard dose appear to produce most BP reduction and can avoid dose-related adverse effects.

P110 INITIAL TREATMENT WITH A SINGLE CAPSULE CONTAINING HALF-DOSE QUADRUPLE THERAPY VS STANDARD-DOSE DUAL THERAPY IN HYPERTENSIVE PATIENTS (QUADUAL): A RANDOMIZED, BLINDED, CROSSOVER TRIAL

Background and Objective: Guidelines recognized the dual combination in initial antihypertensive therapy. Studies demonstrated low-dose quadruple combination antihypertensive was superior to monotherapy. However, whether low-dose quadruple therapy is better than dual combination is unknown. Methods: A randomized blinded crossover trial was conducted to compare the efficacy and safety of low-dose quadruple antihypertensives (irbesartan 75 mg + metoprolol 23·75 mg + amlodipine 2·5 mg + indapamide 1·25 mg) with standard-dose dual antihypertensives (irbesartan 150 mg + amlodipine 5 mg) in the initial treatment of patients with mild to moderate hypertension. Patients were randomly assigned in a 1:1 ratio to two crossover sequences. Each sequence received four-weeks of either half-dose quadruple antihypertensives or standard-dose dual antihypertensives, followed by a two-week washout and crossover for four-weeks. Participants and researchers were blinded, except for randomization and drug coding. The primary outcome was the reduction of mean 24-hour systolic blood pressure in ambulatory blood pressure monitoring. Safety outcomes were adverse events and changes in biochemistry after treatment. Analyses were per intention to treat. This trial was prospectively registered on www.clinicaltrials.gov (NCT05377203), and is now complete. Results: A total of 90 eligible participants were randomized between July 13, 2022, and April 20, 2023. The mean age of the population was 43.88 years, and 25.6% were women. The mean baseline 24-h blood pressure was 145.59/93.84 mm Hg. Half-dose quadruple treatment compared with standard-dose dual treatment further reduced mean 24-hour blood pressure by 4.72/4.17 mm Hg (P < 0.001 for both systolic and diastolic blood pressure). Except for fasting blood glucose (P = 0.029) and blood uric acid increased significantly (P < 0.001) in half-dose quadruple group, other adverse events and changes in laboratory values between the two treatments were not statistical different. Conclusions: Initiating treatment with half-dose quadruple combination therapy was more effective in lowering blood pressure than standard-dose dual therapy. The safety of half-dose quadruple therapy was comparable.

1478P Dual single-nucleotide polymorphism biomarker combination to select opioid for cancer pain management

1478P Dual single-nucleotide polymorphism biomarker combination to select opioid for cancer pain management

O92 EFFICACY AND SAFETY OF LOW-DOSE ANTIHYPERTENSIVE COMBINATION DRUGS INCLUDING AMLODIPINE, TELMISARTAN, AND CHLORTHALIDONE: A MULTICENTER, RANDOMIZED, DOUBLE-BLINDED, PARALLEL, PHASE II CLINICAL TRIAL

Background and Objective: Although single pill high-dose triple antihypertensive combinations are already available on South Korea, there are no reports evaluating the efficacy and safety of the low-dose combination of amlodipine, telmisartan, and chlorthalidone. The aim of this clinical trial was to assess the efficacy and safety of low-dose combination drug containing telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (6.25 mg). Methods: This study was a randomized, double-blinded, parallel, multicenter, phase II clinical trial. In total, 221 subjects from 21 clinical trial sites in South Korea were randomly assigned to groups 1 (AD-209; telmisartan 20 mg/amlodipine 2.5 mg/chlorthalidone 6.25 mg), 2 (AD-209-1A; telmisartan 20 mg/amlodipine 2.5 mg), 3 (AD-209-1B; amlodipine 2.5 mg/chlorthalidone 6.25 mg), and 4 (AD-209-1C; telmisartan 20 mg/chlorthalidone 6.25 mg) in a 1:1:1:1 ratio, and the treatments lasted 8 weeks. After the initial drug administration, the subjects visited the clinical trial sites at weeks 4 and 8 to evaluate drug efficacy and safety. Results: In patients with mild-moderate hypertension, the mean change in MSSBP from baseline to week 8 between group 1 and groups 2, 3, and 4 was -5.93, -8.69, and -1.51 mmHg, respectively. The blood pressure of the subjects in group 1 was significantly lower than that of those in groups 2 and 3. It was also lower than that of subjects in group 4 although this difference was not significant. Among the 221 subjects enrolled, 20 (9.05%) experienced 25 treatment-emergent adverse events (TEAEs); of these, 14 (6.33%) experienced 17 adverse drug reactions (ADRs). No significant differences in the TEAE or ADR incidence rates were found between group 1 and groups 2, 3, and 4. Conclusions: AD-209 (telmisartan 20 mg/amlodipine 2.5 mg/chlorthalidone 6.25 mg), a low-dose triple combination drug, demonstrated a higher blood pressure lowering effect than the corresponding a low-dose dual combination drugs in patients with essential hypertension. Its safety was similar to that of the dual-combination drugs.

Характеристика факторів серцево-судинного ризику в пацієнтів з артеріальною гіпертензією, які приймають подвійну комбінацію антигіпертензивних препаратів: результати дослідження ФАКТОР-дуо

The aim – to study the characteristics of cardiovascular risk factors, the structure and effectiveness of treatment in hypertensive patients (pts) on the background of a dual combination of antihypertensive drugs, to evaluate the efficacy and tolerability of calcium channel blockers (CCB) (amlodipine and lercanidipine) when added to the combination of renin-angiotensin-aldosterone system (RAAS) inhibitor with a diuretic.Materials and methods. A multicenter study with 1616 hypertensive pts who received dual combination antihypertensive therapy. Cardiovascular risk factors were studied (smoking status, alcohol consumption, physical activity, family history of cardiovascular disease), concomitant cardiovascular diseases, carbohydrate metabolism disorders, and body mass index were determined, and current antihypertensive therapy and its effectiveness were evaluated based on office blood pressure (BP) measurements. Amlodipine 5-10 mg/day or lercanidipine 10–20 mg/day was added to the combination of RAAS blocker with a diuretic in the case of office BP ≥ 140/90 mm Hg. 1198 hypertensive pts received triple combined therapy. The effectiveness and tolerability of the treatment were evaluated after 4 weeks according to data from office BP measurements and home BP monitoring (HBPM). Lercanidipine was taken by 76 % of pts and amlodipine was taken by 24 % of pts.Results and discussion. Hypertensive pts were characterized by a significant prevalence of obesity (38.6 %), smoking (27.9 %), and insufficient physical activity (31.2 %). A significantly higher percentage of smoking and alcohol consumption was registered among men, while a lower level of physical activity was registered among women. Concomitant type 2 diabetes was present in almost a quarter of pts, stroke/TIA in 8.7 %, and myocardial infarction/revascularization in 8.3 %. At the same time, 53.2 % of the pts received statin therapy, and 64.7 % received antiplatelet drugs.Conclusions. The addition of CCB contributed to office BP target achievement in 69.1 % of pts, and optimal BP according to HBPM data in 54.3 % of pts. Lercanidipine and amlodipine have demonstrated comparable antihypertensive efficacy. Lercanidipine demonstrated a better tolerability profile compared to amlodipine: the incidence of side effects was significantly lower, respectively, 3.6 vs. 12.3 %; edema of the lower legs occurred in 6.5 times more often under amlodipine treatment than lercanidipine.

In vivo analysis of hybrid hydrogels containing dual growth factor combinations, and skeletal stem cells under mechanical stimulation for bone repair

Bone tissue engineering requires a combination of materials, cells, growth factors and mechanical cues to recapitulate bone formation. In this study we evaluated hybrid hydrogels for minimally invasive bone formation by combining biomaterials with skeletal stem cells and staged release of growth factors together with mechanotransduction. Hybrid hydrogels consisting of alginate and decellularized, demineralised bone extracellular matrix (ALG/ECM) were seeded with Stro-1+ human bone marrow stromal cells (HBMSCs). Dual combinations of growth factors within staged-release polylactic-co-glycolic acid (PLGA) microparticles were added to hydrogels to mimic, in part, the signalling events in bone regeneration: VEGF, TGF-β3, PTHrP (fast release), or BMP-2, vitamin D3 (slow release). Mechanotransduction was initiated using magnetic fields to remotely actuate superparamagnetic nanoparticles (MNP) targeted to TREK1 ion channels. Hybrid hydrogels were implanted subcutaneously within mice for 28 days, and evaluated for bone formation using micro-CT and histology. Control hydrogels lacking HBMSCs, growth factors, or MNP became mineralised, and neither growth factors, HBMSCs, nor mechanotransduction increased bone formation. However, structural differences in the newly-formed bone were influenced by growth factors. Slow release of BMP-2 induced thick bone trabeculae and PTHrP or VitD3 increased bone formation. However, fast-release of TGF-β3 and VEGF resulted in thin trabeculae. Mechanotransduction reversed the trabecular thinning and increased collagen deposition with PTHrP and VitD3. Our findings demonstrate the potential of hybrid ALG/ECM hydrogel–cell–growth factor constructs to repair bone in combination with mechanotransduction for fine-tuning bone structure. This approach may form a minimally invasive reparative strategy for bone tissue engineering applications.

PVP-assisted synthesis of NiSnO3 firmly anchored on graphene as a high-performance lithium battery: A combination of theoretical and experimental study.

Tiny NiSnO3 nanoparticles with the assistance of polyvinylpyrrolidone (PVP) are prepared to uniformly and stably "bond" on the surface of graphene to form a stable NiSnO3/RGO-PVP structure. At the same time, the excellent performance of lithium-ion batteries (LIBs) with the use of NiSnO3/RGO-PVP structure is verified through a dual combination of experiment and theory. The resulting NiSnO3/RGO-PVP structure enhanced the performance of LIBs with high cycling stability and better rate capability; even after undergoing rate performance tests at different high current densities, the NiSnO3/RGO-PVP electrode can still reach a capacity of 624 mA h g-1 at 200 mA g-1 after 400 cycles. The superior electrochemical performance of NiSnO3/RGO-PVP nanocomposites can be attributed to the synergistic effects between tiny NiSnO3 nanoparticles synthesized with the assistance of PVP and RGO, which can be verified through first-principles calculations based on DFT. The charge transfer between NiSnO3 and RGO through an electron density difference indicates a strong interaction between the two. Meanwhile, the low adsorption energies (-3.914, -0.77, and -0.65eV), low diffusion barriers (0.025, 0.49, and 0.141eV), and high diffusion coefficients (1.79 × 10-3, 5.38 × 10-11, and 2.97 × 10-5cm2s-1) of lithium ions at three different positions indicate the excellent rate performance of the NiSnO3/RGO-PVP heterostructure, which is consistent with experimental results. This work analyzes the excellent electrochemical performance of NiSnO3/RGO-PVP from the experimental results and supports the reliability of the experimental results through theoretical calculations.

A systematic review and meta-analysis of comparative clinical studies on antibiotic treatment of brucellosis

Brucellosis is a difficult to treat infection that requires antibiotic combinations administered over several weeks for clearance of infection and relapse prevention. This systematic review summarizes current evidence for antibiotic treatment of human brucellosis. PubMed, EMBASE, Scopus, CINAHL, Web of Science, and China Academic Journal databases were searched for prospective studies that had compared different antibiotic regimens for treating human brucellosis in the last 25 years. Thirty-four studies recruiting 4182 participants were eligible. Standard dual therapy with doxycycline + rifampicin had a higher risk of treatment failure compared to triple therapy which added streptomycin (RR: 1.98, 95% CI 1.17–3.35, p = 0.01) or levofloxacin (RR: 2.98, 95% CI 1.67–5.32, p = 0.0002), but a similar or lower risk compared to alternative dual antibiotic combinations (p > 0.05). The same combination had a higher risk of relapses compared to triple therapy which added streptomycin (RR: 22.12, 95% CI 3.48–140.52, p = 0.001), or levofloxacin (RR: 4.61, 95% CI 2.20–9.66, p < 0.0001), but a similar or lower risk compared to other dual antibiotic combinations (p > 0.05). Triple antibiotic therapy is more effective than standard dual therapy with rifampicin and doxycycline. However, the latter is also efficacious and suitable for uncomplicated disease.

Dual combination of resveratrol and pterostilbene aqueous core nanocapsules for integrated prostate cancer targeting.

Aim: Development and evaluation of aqueous core nanocapsules (ACNs) of BCS-II-class drug like resveratrol (RSV) and pterostilbene (PTE)for prostate cancer.Materials & methods: Identify synergistic effects of molar ratios of RSV and PTE against PC-3 cell. Selected ratio of drugs was added to ACNs by double-emulsification-method using Box-Behnken design. Further, assessed for physicochemical characterization, release kinetics, compatibility, invitro cytotoxicity, in vivo pharmacokinetic and biodistribution studies.Results: Selected 1:1 ratio of RSV and PTE had greatest synergy potential have smaller particle-size (128.1±3.21nm), zeta-potential (-22.12±0.2mV), 0.53PDI, improved encapsulation (87% for RSV, 72% for PTE), stable, no systemic toxicity, high biodistributed/accumulated in prostate cells.Conclusion: ACNs exhibited high t1/2 (12.42±1.92hs) and 8.20±8.21hs Mean Residence Time and lower clearance, proving the high effectiveness for prostate cancer.

Comparative analysis of dual immune checkpoint inhibitor combination therapy versus immune checkpoint inhibitor plus tyrosine kinase inhibitor combination therapy for renal cell carcinoma with inferior vena cava tumor thrombosis.

Whether immune checkpoint inhibitor (ICI) plus ICI combination therapy or ICI plus tyrosine kinase inhibitor (TKI) combination therapy is useful for renal cell carcinoma (RCC) with inferior vena cava tumor thrombosis (IVCTT) remains unclear. We retrospectively evaluated the therapeutic effects and incidence of treatment-related adverse events (TRAEs) associated with ICI-based combination therapy in 36 patients with advanced RCC with IVCTT. The median age at initiation of treatment was 71years; the IVCTT stages were cT3b in 22 patients and cT3c in 14. The ICI-ICI and ICI-TKI groups comprised 15 and 21 patients, respectively. Median tumor shrinkage at the best response showed that the primary tumor diameter decreased by 1.8cm (22%), and the IVCTT height decreased by 1.5cm (26%). A higher proportion of patients in the ICI-TKI group experienced tumor shrinkage than those in the ICI-ICI group (primary tumor, p = 0.0325; IVCTT, p = 0.0112). Approximately 27% of patients experienced an increase in the IVCTT height with ICI-ICI combination therapy. No significant difference was observed in the relative tumor shrinkage of IVCTT, primary or level-down staging of IVCTT, other treatment effects, incidence of TRAEs, surgical outcomes, or prognosis between the groups. ICI-based combination therapy is effective against IVCTT and primary RCC. Although ICI-ICI is associated with a higher probability of tumor growth compared with ICI-TKI in the frequency of tumor regression, both therapies may be almost equally effective against primary RCC with IVCTT.

Dual and triple gene combinations of KRT5, KRT17, and S100A2 identify basal-like subtype of pancreatic ductal adenocarcinoma and correlate with survival outcome.

There is a significant difference in prognosis and response to chemotherapy between basal and classical subtypes of pancreatic ductal adenocarcinoma (PDAC). Further biomarkers are required to identify subtypes of PDAC. We selected candidate biomarkers via review articles. Correlations between these candidate markers and the PDAC molecular subtype gene sets were analyzed using bioinformatics, confirming the biomarkers for identifying classical and basal subtypes. Subsequently, 298 PDAC patients were included, and their tumor tissues were immunohistochemically stratified using these biomarkers. Survival data underwent analysis, including Cox proportional hazards modeling. Our results indicate that the pairwise and triple combinations of KRT5/KRT17/S100A2 exhibit a higher correlation coefficient with the basal-like subtype gene set, whereas the corresponding combinations of GATA6/HNF4A/TFF1 show a higher correlation with the classical subtype gene set. Whether analyzing unmatched or propensity-matched data, the overall survival time was significantly shorter for the basal subtype compared with the classical subtype (p < .001), with basal subtype patients also facing a higher risk of mortality (HR = 4.017, 95% CI 2.675-6.032, p < .001). In conclusion, the combined expression of KRT5, KRT17, and S100A2, in both pairwise and triple combinations, independently predicts shorter overall survival in PDAC patients and likely identifies the basal subtype. Similarly, the combined expression of GATA6, HNF4A, and TFF1, in the same manner, may indicate the classical subtype. In our study, the combined application of established biomarkers offers valuable insights for the prognostic evaluation of PDAC patients.

Management of Hypertension in Patients with Type 2 Diabetes Mellitus: Indian Guideline 2024 by Association of Physicians of India and Indian College of Physicians.

In India and the Southeast Asian population, hypertension and type 2 diabetes mellitus (T2DM) are the leading lifestyle-related diseases, responsible for a majority burden of morbidity and mortality. Multiple population-spanning studies have revealed the staggering prevalence of both diseases in India, and the prevalence of both will only increase further due to factors such as an aging population, rapid urbanization, increased obesity, and sedentary lifestyles. More than 50 percent of hypertensive patients in India are also diagnosed with T2DM, and a detailed management protocol for the same is required, especially when a major portion of the disease is managed at the primary care level. The Association of Physicians of India (API) guidelines for the management of hypertension in patients with T2DM have been formulated based on consultation with leading physicians, cardiologists, diabetologists, and endocrinologists of India and Southeast Asia, keeping in mind the challenges faced by the patients in these countries and the appropriate management protocols that will be beneficial. While standard office-based blood pressure (BP) measurement forms the cornerstone of hypertension diagnosis and demands a uniform methodology to be followed, home blood pressure monitoring (HBPM) is recommended for long-term follow-up with validated devices. Ambulatory blood pressure monitoring (ABPM) offers comprehensive insights crucial for cardiovascular (CV) risk stratification. The complications of diabetic hypertension can span from increased CV risk, heart failure (HF), and renal dysfunction, and nonpharmacological and pharmacological management should be aimed toward not only control of the BP values but also protecting the end organs. While nonpharmacological measures include a focus on nutrition and diet, they also focus on approaches to weight loss, including a novel section covering the benefits of yoga. The guideline also focuses on a novel section of factors influencing CV risk, especially in the Indian population. For the pharmacological management, the guidelines address each of the categories of antihypertensive drugs, emphasizing the significance of combination therapies in the management of diabetic hypertension. In line with leading global guidelines for the management of hypertension in T2DM, for diabetic patients who often struggle with BP management and carry a high CV risk, the recommended dual combination antihypertensive therapy is particularly crucial and should be considered as first-line management therapy. While angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) play a highly beneficial role in the management of diabetic hypertension, a combination of ACEi or ARB with dihydropyridine calcium channel blockers (DHP-CCBs) is recommended to reduce the risk of complications and enhance patient adherence. To achieve the target of effective BP control and end-organ protection, it is beneficial and recommended to include newer CCBs (e.g., cilnidipine) in the management protocol in combination with ACEi/ARBs. Combination therapy including ARBs and DHP-CCBs should be preferred over β-blockers and thiazides. Among the CCBs, cilnidipine, a novel molecule, is a more effective and safer option for diabetic hypertensive patients in India. β-blockers should be used if there is a history of myocardial infarction (MI), HF, coronary artery disease (CAD), or stable angina along with the initial hypertensive regimen. The guideline also focuses on the novel reno- and cardioprotective molecules such as finerenone and sodium-glucose cotransporter 2 inhibitors (SGLT2i) and their benefits in the management of diabetic hypertension.

Qualitative and quantitative differentiation efficiency of dual-tracer PET/CT with 18F-fluorodeoxyglucose and 11C-acetate for primary hepatocellular carcinoma: a systematic review and meta-analysis.

Primary hepatocellular carcinoma (HCC) represents a substantial global health challenge. Early diagnosis of HCC is crucial for improved patient outcomes. The aim of this study was to assess qualitative and quantitative diagnostic performance of PET/CT using 11C-acetate and [18F]-fluorodeoxyglucose (FDG) in detection of primary HCC and to determine if 11C-acetate added to [18F]-FDG alleviates the low sensitivity rate mentioned in guidelines. Protocol was pre-registered at https://osf.io/2vcb9 . We searched PubMed, Web of Science, Embase, and the Cochrane Library for included studies. Quality Assessment of Diagnostic Accuracy Studies 2 was used to assess the risk of bias. Possible sources of statistical heterogeneity were explored. Additionally, mentioned three PET/CT tests were evaluated for their diagnostic performance in differentiating HCC from its differential diagnoses. Grades of Recommendation, Assessment, Development, and Evaluation was used to assess quality of generated evidence. Twenty-four studies were analyzed. Qualitative dual-tracer PET/CT demonstrated 92.0% per-lesion sensitivity, and a significantly higher direct sensitivity difference of 30% to conventional CT, 44.7% to [18F]-FDG, and 12.0% to 11C-acetate. Regarding differentiation rate, [18F]-FDG was superior to 11C-acetate in poorly differentiated lesions while 11C-acetate was superior in well-differentiated lesions. Regarding size, dual tracer combination solved the high missing rate of HCC lesions in 1-2cm and 2-5cm groups but could not help in size < 1cm. Dual-tracer PET/CT utilizing 11C-acetate and [18F]-FDG represents a sensitive method for detecting primary HCC. By concurrently quantifying or qualifying the uptake of 11C-acetate and [18F]-FDG, this multimodal approach enables precise localization of intrahepatic lesions.

Phytophthora pseudocryptogea Is Associated with Root and Crown Rot of Nursery-Grown Common Sage in Hungary.

In October 2009, necrotic bark lesions at the root collar and lower stem associated with root rot, reduced growth, and wilting were observed on container-grown 2-year-old common sage (Salvia officinalis L. 'Icterina') in two ornamental nurseries in Somogy and Zala counties in Hungary. The disease occurred at a frequency of 15-20% (100 to 150 symptomatic plants in each nursery). A P. cryptogea-like species was isolated consistently from necrotic root collars of many plants on carrot (CA) PARPB agar. Six isolates from the nursery in Zala county and three isolates from the nursery in Somogy county were deposited in the culture collection of Plant Protection Institute (Budapest, Hungary). All developed slightly petaloid colonies on CA agar. Chlamydospores and gametangia were not present in single and dual culture combinations of isolates. Radial colony growth was the fastest at 25°C (6.8 to 7.4 mm/day) and no growth occurred above 34°C. On mycelial discs floating in nonsterile stream water, persistent, nonpapillate, mostly ovoid to obpyriform sporangia (37.4±3.5 to 47.8±4.6 μm long and 22.3±2.6 to 29.2±3.7 μm wide) and hyphal swellings were produced abundantly. Pathogenicity of one selected isolate from each nursery was tested on 3-month-old seedlings of S. officinalis 'Icterina' in 2010. Isolates were grown for 4 weeks at 20°C on autoclaved millet grains moistened with CA broth. Infested and uninfested grains were mixed with autoclaved soil (30 cm3 grain/liter), and the mixes were used as potting media for transplanting five treated and five control plants per isolate, respectively. Plants were kept in a growth room (20-25°C, 16/8 h dark/light). Pots were flooded for 24 hours on the 1st day and every 2 weeks. All and only treated plants showed symptoms of wilt associated with basal stem and root necrosis within three weeks. The trial was repeated with the same result. The pathogen could be reisolated only from the treated plants. Identity of isolates from nurseries and inoculated plants was confirmed recently by amplification and sequence analysis of the rDNA internal transcribed spacers (ITS) and gene regions of cytochrome c oxidase subunit I (coxI) and β-tubulin (tub) according to Jung et al. (2017). BLASTn searches showed 100% identity and only 97.3-99.0% similarity to the corresponding sequences of authenthic P. pseudocryptogea and P. cryptogea strains, respectively (e.g., GenBank accession nos. KP288336-KP288342, KP288370-KP288372, KP288386-KP288392, MN872725, MN872776). Sequences of the 9 field isolates were deposited in GenBank under accession nos. OR771701-OR771709 (ITS), OR787508-OR787516 (coxI) and OR787517-OR787525 (tub). P. pseudocryptogea was delineated from P. cryptogea sensu lato (Safaiefarahani et al. 2015), which has been reported from S. officinalis in the United States (Koike 1997), and S. leucantha (Cacciola et al. 2002) and S. officinalis (Garibaldi et al. 2015) in Italy. The known natural hosts of P. pseudocryptogea includes plant species in families other than Lamiaceae (cf. Aloi et al. 2023), but it was pathogenic on the lamiaceous Plectranthus scutellarioides in artificial inoculations (Christova 2020). The pathogen is present in European nurseries (Antonelli et al. 2023). This is the first report of P. pseudocryptogea on S. officinalis in Hungary. The causal agent threatens the production of sages and other ornamentals, and its spread in Hungary should be prevented by proper disease management and phytosanitary actions.

Research on GNSS-IR soil moisture retrieval based on random forest algorithm

Abstract Soil moisture (SM) retrieval is of great significance in climate, agriculture, ecology, hydrology, and natural disaster monitoring, and it is one of the essential hydrometeorological parameters studied in the world at present. With the continuous development of the GNSS, a technique called GNSS-IR became widely used in ground SM inversion. Therefore, based on the frequency, amplitude and phase of signal-to-noise ratio residuals (δSNR), this study takes P037 and P043 stations set by UNAVCO in the United States as examples and develops the research of SM inversion from Random Forest Regression (RFR) prediction. The experimental results show that the retrieval accuracy of SM under different practical schemes can be in descending order: L1 + L2 dual frequency combination &gt; L2 single frequency &gt; L1 single frequency. It is confirmed that the experimental scheme based on the L1+L2 dual-frequency combination is beneficial to the inversion of SM. In the L1+L2 dual-frequency combination, the prediction set accuracy of the P037 station is as follows: R is 0.796, RMSE is 0.032 cm3cm-3, ME is 0.002 cm3cm-3. The prediction accuracy of the P043 station is as follows: R is 0.858, RMSE is 0.039 cm3cm-3, ME is -0.009 cm3cm-3. Among them, the RMSE of the L1+L2 dual-frequency combination of the two stations has an improvement effect of 13%-37% compared with their single-frequency, which has a noticeable improvement effect. The difference between the SM retrieved by GNSS-IR and the reference value of PBO-H2O is concentrated around 0, further showing the accuracy of SM retrieved by GNSS-IR technology. To sum up, this study considers that SM retrieval based on the RFR model has good reliability and accuracy, which makes GNSS-IR technology an efficient means for SM retrieval. With the continuous improvement of the GNSS system and technology, the application of GNSS-IR technology in SM will become broader.

Estimated impact of guidelines-based initiation of dual antihypertensive therapy on long-term cardiovascular outcomes in 1.1 million individuals.

Guidelines recommend initiation of dual combination antihypertensive therapy, preferably single-pill combination (SPC), in most patients with hypertension. Evidence on narrowing gaps in clinical practice relative to guidelines is limited. Monte Carlo simulation was applied to 1.1 million patients qualifying for dual combination therapy from a previously conducted retrospective analysis of clinical practice, hospital statistics, and national statistics in the UK. We provide 10-year Kaplan-Meier event rates for the primary endpoint representing a composite of nonfatal myocardial infarction, nonfatal stroke (ischemic or hemorrhagic), nonfatal heart failure hospitalization or cardiovascular death. Cox model results from a previously conducted study were utilized to estimate baseline risk, together with evidence on risk reduction from the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC) meta-analysis and published evidence on BP-lowering efficacy of antihypertensive therapies. In the overall population, estimated 10-year event rates for the primary endpoint in patients with 100% persistence in monotherapy were 17.0% for irbesartan (I) and 17.6% for ramipril (R). These rates were only modestly better than that observed in clinical practice (17.8%). In patients with 100% persistence in dual therapy, estimated event rates were 13.6% for combinations of Irbesartan+Amlodipine (ARR=8.7% compared to untreated) and 14.3% for Ramipril+Amlodipine (ARR=8.0% compared to untreated). The absolute risk of the primary endpoint was reduced by 15.9% in patients with ASCVD and 6.6% in those without ASCVD. Similarly, the absolute risk was reduced by 11.7% in diabetics and 7.8% in those without diabetes. This study represents the first to investigate guidelines-based treatment in hypertensive patients and demonstrates the opportunity for considerable risk reduction by ensuring recommended dual therapy in clinical practice, particularly in the form of SPC with high persistence, relative to no treatment or monotherapy.

Effectiveness of dual combination therapy of acarbose plus metformin and acarbose plus myo-inositol in ameliorating the metabolic and endocrinologic complications of polycystic ovary syndrome – A randomized controlled trial

IntroductionPCOS, beyond being characterized by reproductive disturbances, is a complicated rapid expanding metabolic and endocrinologic disorder of the recent times. Nearly 70% PCOS women show resistance to insulin. AIM: The aim of the study is to determine and compare the effectiveness of acarbose plus metformin and acarbose plus myo-inositol combination therapy in alleviating the metabolic and endocrinologic complications of PCOS. Materials and methodsAn open labelled RCT was conducted on 168 PCOS women attending the gynaecology clinic at SRM MCH & RC, Chengalpattu and the trial was registered in CTRI (No. CTRI/2022/04/041877). Group A (n = 56) received metformin 500 mg/TID alone; group B (n = 54) received (acarbose 25 mg/TID for 4 weeks then 50 mg/TID for other 20 weeks) along with metformin 500 mg/TID and group C (n = 54) received (acarbose 25 mg/TID for 4 weeks then 50 mg/TID for other 20 weeks) along with myoinositol 1000 mg/BD. All parameters were measured at baseline and at the end of 6 months. ResultsSignificant reduction of LH, LH: FSH, TT, HOMA-IR was observed in all the groups. FSH increased only in metformin group. Increase in serum progesterone and reduction in FI, TGL, LDL were significant only in acarbose plus myo-inositol group. SHBG and HDL increased significantly only in acarbose plus metformin group. No changes in BMI, TC and VLDL were observed in any group. ConclusionTherefore, decrease in FI, HOMA-IR, TGL, LDL seen in acarbose plus myo-inositol group indirectly contributes to cardio-metabolic safety in PCOS. Similarly, a significant increase in SHBG levels with acarbose plus metformin group shows correction of the excess androgen and restoration of ovulation.

CDK4/6 inhibition to resensitize BRAF/EGFR inhibitor in patient-derived BRAF/PTEN-mutant colon cancer cells.

In v-raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant colorectal cancer (CRC), encorafenib-cetuximab has been established as standard second-line therapy, but not all patients respond and the duration of response is relatively short. Overcoming intrinsic or acquired resistance to BRAF/EGFR inhibitors is crucial for enhancing treatment outcomes in metastatic BRAF-mutated CRC. The aim of the study is to investigate the resistance mechanisms in BRAF-mutant CRC patient refractory to BRAF/EGFR targeted therapy. We established patient-derived cells (PDCs) from a patient with BRAF/PTEN-mutant metastatic colon cancer who progressed rapidly on encorafenib plus cetuximab. To explore potential treatment options for inherent resistance caused by simultaneous PTEN mutation in BRAF-mutated CRC, we conducted cell viability assays using PDCs treated with encorafenib-cetuximab in combination with a cyclin-dependent kinase-4 and 6 (CDK4/6) inhibitor. The patient's tumor had concurrent PTEN loss-of-function alteration at diagnosis and PDCs were generated from ascites after resistance to the BRAF/EGFR inhibitor. The PDCs were resistant to the encorafenib-cetuximab combination even at a high concentration of cetuximab (up to 500 µg/mL). Adding the CDK4/6 inhibitor, ribociclib, to encorafenib-cetuximab showed a synergistic effect in a proliferation assay. Ribociclib plus encorafenib-cetuximab represented a significantly lower expression of Ki-67 compared to the dual combination alone. An MTS assay showed that triplet therapy with ribociclib, encorafenib, and cetuximab suppressed cell viability more efficiently than the two-drug combinations. Investigating the combined effect of triplet therapy using the calculated combination index (CI) showed that ribociclib had a synergistic effect with encorafenib-cetuximab when applied to PDCs with a concurrent BRAF/PTEN mutation. Our results suggest that combining the CDK4/6 inhibitor with the BRAF/EGFR inhibitormight be a novel treatment strategy for concomitant BRAF and PTEN-mutant CRC.

Effectiveness of Lianhua Qingwen Granule and Jingyin Gubiao Prescription in Omicron BA.2 Infection and Hospitalization: A Real-World Study of 56,244 Cases in Shanghai, China.

To examine the effectiveness of Chinese medicine (CM) Lianhua Qingwen Granule (LHQW) and Jingyin Gubiao Prescription (JYGB) in asymptomatic or mild patients with Omicron infection in the shelter hospital. This single-center retrospective cohort study was conducted in the largest shelter hospital in Shanghai, China, from April 10, 2022 to May 30, 2022. A total of 56,244 asymptomatic and mild Omicron cases were included and divided into 4 groups, i.e., non-administration group (23,702 cases), LHQW group (11,576 cases), JYGB group (12,112 cases), and dual combination of LHQW and JYGB group (8,854 cases). The length of stay (LOS) in the hospital was used to assess the effectiveness of LHQW and JYGB treatment on Omicron infection. Patients aged 41-60 years, with nadir threshold cycle (CT) value of N gene <25, or those fully vaccinated preferred to receive CM therapy. Before or after propensity score matching (PSM), the multiple linear regression showed that LHQW and JYGB treatment were independent influence factors of LOS (both P<0.001). After PSM, there were significant differences in LOS between the LHQW/JYGB combination and the other groups (P<0.01). The results of factorial design ANOVA proved that the LHQW/JYGB combination therapy synergistically shortened LOS (P=0.032). Patients with a nadir CT value <25 were more likely to accept CM. The LHQW/JYGB combination therapy could shorten the LOS of Omicron-infected individuals in an isolated environment.