Polymers of functionalized diaminopropionic acid are efficient mediators of active exogenous enzyme delivery into cells.

Delivery of active protein especially enzyme is one of the major therapeutic challenge. Replacing or substituted invalid/improper acting protein offer fast and effective treatment of disease. Herein, we describe the synthesis and properties of biotinylated peptidomimetics consisting of oxoacid-modified 2,3, L-diaminopropionic acid residues with guanidine groups on its side chains. Electrophoretic analysis showed that the obtained compounds interact with FITC-labeled streptavidin or a streptavidin-ß-galactosidase hybrid in an efficient manner. Complexes formed by the abovementioned molecules are able to cross the cell membranes of cancer or healthy cells and show promising compatibility with live cells. Analysis of ß-galactosidase activity inside the cells revealed surprisingly high levels of active enzyme in complex-treated cells compared to controls. This observation was confirmed by immunochemical studies in which the presence of ß-galactosidase was detected in the membrane and vesicles of the cells.

Nutritional Ergogenic Aids in Cycling: A Systematic Review.

This systematic review aimed to evaluate the effectiveness of the independent or combined use of nutritional ergogenic aids belonging to Group A of the ABCD classification by the Australian Institute of Sport (AIS) in the context of cycling (caffeine, creatine, sodium bicarbonate, beta-alanine, nitrates, and glycerol). A comprehensive search was carried out using three databases: PubMed, Scopus, and Web of Science. All the databases were searched for Randomized Controlled Trials or crossover design studies assessing the effects of supplementation on cycling performance in comparison with placebos in healthy adults. The methodological quality of each study was evaluated using the Physiotherapy Evidence Database scale. Thirty-six articles involving 701 participants were included in this review, examining supplementation with caffeine (n = 5), creatine (n = 2), sodium bicarbonate (n = 6), beta-alanine (n = 3), and nitrates (n = 8). Additionally, supplemental combinations of caffeine and creatine (n = 3), caffeine and sodium bicarbonate (n = 3), caffeine and nitrates (n = 1), creatine and sodium bicarbonate (n = 1), and sodium bicarbonate and beta-alanine (n = 4) were analyzed. A benefit for cyclists' athletic performnce was found when consuming a caffeine supplement, and a potential positive effect was noted after the consumption of sodium bicarbonate, as well as after the combination of caffeine and creatine. However, no statistically significant effects were identified for the remaining supplements, whether administered individually or in combination.

A new green approach to L-histidine and ß-alanine analysis in dietary supplements using rapid and simple contactless conductivity detection integrated with high-resolution glass-microchip electrophoresis.

The analysis of dietary supplements is far less regulated than pharmaceuticals, leading to potential quality issues. Considering their positive effect, many athletes consume supplements containing L-histidine and ß-alanine. A new microfluidic method for the determination of L-histidine and ß-alanine in dietary supplement formulations has been developed. For the first time, capacitively coupled contactless conductivity detection was employed for the microchip electrophoresis of amino acids in real samples. A linear relationship between detector response and concentration was observed in the range of 10-100 µmol L-1 for L-histidine (R2 = 0.9968) and ß-alanine (R2 = 0.9954), while achieved limits of detection (3 × S/N ratio) were 4.2 µmol L-1 and 5.2 µmol L-1, respectively. The accuracy of the method was confirmed using recovery experiments as well as CE-UV-VIS and HPLC-UV-VIS techniques. The developed method allows unambiguous identification of amino acids in native form without chemical derivatization and with the possibility of simultaneous analysis of amino acids with metal cations.

Efficacy of amino acids in sports nutrition- review of clinical evidences.

The efficacy of amino acids as popular sports supplements has triggered debates, with their impact on athletic performance varying across sports disciplines due to diversity and heterogeneity in clinical trials. This review evaluates the ergogenic potential of amino acids, by critical appraisal of results of clinical trials of Branched chain amino acids (BCAAs), arginine, glutamine, citrulline, ß-alanine, and taurine, performed on elite sportsmen from various land and water sports. Clinical trials reviewed here confirm notable physiological benefits thereby supporting the claim that BCAA, citrulline and arginine in various doses can have positive effects on endurance and overall performance in sportsperson. Furthermore, results of clinical trials and metabolomic studies indicate that in future it would be more beneficial to design precise formulations to target the requirement of specific sports. For instance, some combinations of amino acids may be more suitable for long term endurance and some others may be suitable for short burst of excessive energy. The most important insights from this review are the identification of three key areas where research is urgently needed: a) Biomarkers that can identify the physiological end points and to distinguish the specific role of amino acid as anti-fatigue or reducing muscle soreness or enhancing energy b) In-depth sports-wise clinical trials on elite sportsperson to understand the ergogenic needs for the particular sports c) Design of precision formula for similar types of sports instead of common supplements.

The ROCK inhibitor netarsudil in the treatment of corneal endothelial decompensation caused by corneal endotheliitis: A case report and literature review.

Proper hydration and the clarity of the cornea are maintained through the crucial function of the corneal endothelium. Inflammation of the corneal endothelium, known as endotheliitis, can disrupt endothelial function, resulting in alterations to vision. Corneal endotheliitis is characterised by corneal oedema, the presence of keratic precipitates, inflammation within the anterior chamber, and occasionally, limbal injection, neovascularisation, and the concurrent or overlapping presence of uveitis. The aetiology of this condition is diverse, predominantly viral, but it may also be drug-induced, result from bacterial or fungal infections, be associated with systemic diseases and procedures, or remain idiopathic with no identifiable cause. To date, no standardised protocol for the treatment of this ocular disease exists, and in severe cases, corneal transplantation may be required. A 31-year-old male was transferred to our hospital for the management of corneal endothelial decompensation resulting from corneal endotheliitis. Hormonal therapy and antiviral medications proved ineffective, rendering the patient a candidate for corneal transplantation. As a final measure, treatment with the ROCK inhibitor netarsudil was initiated. The patient demonstrated significant improvement in symptoms, and the inflammation was successfully managed after nine months. In this study, a novel approach employing ROCK inhibitor therapy was utilised for the treatment of corneal endotheliitis, leading to marked recovery during patient follow-up. This case report represents the inaugural application of the ROCK inhibitor netarsudil in managing corneal endothelial decompensation attributed to corneal endotheliitis. These findings suggest that this method warrants consideration as a potential novel treatment option for similar conditions.

Comprehensive characterization of ß-alanine metabolism-related genes in HCC identified a novel prognostic signature related to clinical outcomes.

Hepatocellular carcinoma (HCC) stands out as the most prevalent type of liver cancer and a significant contributor to cancer-related fatalities globally. Metabolic reprogramming, particularly in glucose, lipid, and amino acid metabolism, plays a crucial role in HCC progression. However, the functions of ß-alanine metabolism-related genes (ßAMRGs) in HCC remain understudied. Therefore, a comprehensive evaluation of ßAMRGs is required, specifically in HCC. Initially, we explored the pan-cancer landscape of ßAMRGs, integrating expression profiles, prognostic values, mutations, and methylation levels. Subsequently, scRNA sequencing results indicated that hepatocytes had the highest scores of ß-alanine metabolism. In the process of hepatocyte carcinogenesis, metabolic pathways were further activated. Using ßAMRGs scores and expression profiles, we classified HCC patients into three subtypes and examined their prognosis and immune microenvironments. Cluster 3, characterized by the highest ßAMRGs scores, displayed the best prognosis, reinforcing ß-alanine's significant contribution to HCC pathophysiology. Notably, immune microenvironment, metabolism, and cell death modes significantly varied among the ß-alanine subtypes. We developed and validated a novel prognostic panel based on ßAMRGs and constructed a nomogram incorporating risk degree and clinicopathological characteristics. Among the model genes, EHHADH has been identified as a protective protein in HCC. Its expression was notably downregulated in tumors and exhibited a close correlation with factors such as tumor staging, grading, and prognosis. Immunohistochemical experiments, conducted using HCC tissue microarrays, substantiated the validation of its expression levels. In conclusion, this study uncovers ß-alanine's significant role in HCC for the first time, suggesting new research targets and directions for diagnosis and treatment.

Neurotoxic non-protein amino acids in commercially harvested Lobsters (Homarus americanus H. Milne-Edwards).

Cyanobacteria produce neurotoxic non-protein amino acids (NPAAs) that accumulate in ecosystems and food webs. American lobsters (Homarus americanus H. Milne-Edwards) are one of the most valuable seafood industries in Canada with exports valued at > $2 billion. Two previous studies have assessed the occurrence of ß-N-methylamino-L-alanine (BMAA) in a small number of lobster tissues but a complete study has not previously been undertaken. We measured NPAAs in eyeballs, brain, legs, claws, tails, and eggs of 4 lobsters per year for the 2021 and 2022 harvests. Our study included 4 male and 4 female lobsters. We detected BMAA and its isomers, N-(2-aminoethyl)glycine (AEG), 2,4-diaminobutyric acid (DAB) and ß-aminomethyl-L-alanine (BAMA) by a fully validated reverse phase chromatography-tandem mass spectrometry method. We quantified BMAA, DAB, AEG and BAMA in all of the lobster tissues. Our quantification data varied by individual lobster, sex and collection year. Significantly more BMAA was quantified in lobsters harvested in 2021 than 2022. Interestingly, more BAMA was quantified in lobsters harvested in 2022 than 2021. Monitoring of lobster harvests for cyanobacterial neurotoxins when harmful algal bloom events occur could mitigate risks to human health.

Topical netarsudil for the treatment of primary corneal endothelial degeneration in dogs.

This study evaluated the tolerability and efficacy of the topical rho-kinase inhibitor netarsudil for canine primary corneal endothelial degeneration (PCED). Twenty-six eyes of 21 client-owned dogs with PCED were enrolled in a prospective, randomized, vehicle control clinical trial and received topical netarsudil 0.02% (Rhopressa®) or vehicle control twice daily (BID) for the first 4 months. Then, all patients received netarsudil for the next 4 or 8 months. Complete ophthalmic examination, ultrasonic pachymetry, Fourier-domain optical coherence tomography, and in vivo confocal microscopy were performed at baseline and 1, 2, 4, 6, 8 and 12 months. Effect of netarsudil on central corneal thickness (CCT), percentage of cornea with edema, and endothelial cell density (ECD) were evaluated by repeated measures ANOVA. Kaplan-Meier curves and log-rank test were used to compare corneal edema and clinical progression of eyes in netarsudil versus vehicle control groups. All dogs developed conjunctival hyperemia in at least one eye while receiving netarsudil. Unilateral transient reticulated intraepithelial bullae and stromal hemorrhage were observed respectively in 2 dogs in the netarsudil group. Two dogs showed persistently decreased tear production while receiving netarsudil, requiring topical immunomodulatory treatment. No significant differences in CCT, ECD, corneal edema or clinical progression were observed between netarsudil or vehicle treated eyes. When comparing efficacy of topical netarsudil BID and topical ripasudil 0.4% administered four times daily from our previous study, dogs receiving ripasudil had significantly less progression than those receiving netarsudil.

Control of three-carbon amino acid homeostasis by promiscuous importers and exporters in Bacillus subtilis: role of the "sleeping beauty" amino acid exporters.

The Gram-positive model bacterium Bacillus subtilis can acquire amino acids by import, de novo biosynthesis, or degradation of proteins and peptides. The accumulation of several amino acids inhibits the growth of B. subtilis, probably due to misincorporation into cellular macromolecules such as proteins or peptidoglycan or due to interference with other amino acid biosynthetic pathways. Here, we studied the adaptation of B. subtilis to toxic concentrations of the three-carbon amino acids L-alanine, ß-alanine, and 2,3-diaminopropionic acid, as well as the two-carbon amino acid glycine. Resistance to the non-proteinogenic amino acid ß-alanine, which is a precursor for coenzyme A biosynthesis, is achieved by mutations that either activate a cryptic amino acid exporter, AexA (previously YdeD), or inactivate the amino acid importers AimA, AimB (previously YbxG), and BcaP. The aexA gene is very poorly expressed under most conditions studied. However, mutations affecting the transcription factor AerA (previously YdeC) can result in strong constitutive aexA expression. AexA is the first characterized member of a group of amino acid exporters in B. subtilis, which are all very poorly expressed. Therefore, we suggest to call this group "sleeping beauty amino acid exporters." 2,3-Diaminopropionic acid can also be exported by AexA, and this amino acid also seems to be a natural substrate of AerA/AexA, as it can cause a slight but significant induction of aexA expression, and AexA also provides some natural resistance toward 2,3-diaminopropionic acid. Moreover, our work shows how low-specificity amino acid transporters contribute to amino acid homeostasis in B. subtilis.IMPORTANCEEven though Bacillus subtilis is one of the most-studied bacteria, amino acid homeostasis in this organism is not fully understood. We have identified import and export systems for the C2 and C3 amino acids. Our work demonstrates that the responsible amino acid permeases contribute in a rather promiscuitive way to amino acid uptake. In addition, we have discovered AexA, the first member of a group of very poorly expressed amino acid exporters in B. subtilis that we call "sleeping beauty amino acid exporters." The expression of these transporters is typically triggered by mutations in corresponding regulator genes that are acquired upon exposure to toxic amino acids. These exporters are ubiquitous in all domains of life. It is tempting to speculate that many of them are not expressed until the cells experience selective pressure by toxic compounds, and they protect the cells from rare but potentially dangerous encounters with such compounds.

Maternal separation regulates sensitivity of stress-induced depression in mice by affecting hippocampal metabolism.

Depression is a serious mental illness. Previous studies found that early life stress (ELS) plays a vital role in the onset and progression of depression. However, relevant studies have not yet been able to explain the specific effects of early stress on stress-induced depression sensitivity and individual behavior during growth. Therefore, we constructed a maternal separation (MS) model and administered chronic social frustration stress at different stages of their growth while conducting metabolomics analysis on the hippocampus of mice. Our results showed that the immobility time of mice in the forced swimming test was significantly reduced at the end of MS. Meanwhile, mice with MS experience significantly decreased total movement distance in the open field test and sucrose preference ratio in the sucrose preference test when subjected to chronic social defeat stress (CSDS) during adolescence. In adulthood, the results were the opposite. In addition, we found that level changes in metabolites such as Beta-alanine, l-aspartic acid, 2-aminoadipic acid, and Glycine are closely related to behavioral changes. These metabolites are mainly enriched in Pantothenate, CoA biosynthesis, and Beta Alanine metabolism pathways. Our experiment revealed that the effects of ELS vary across different age groups. It will increase an individual's sensitivity to depression when facing CSDS in adolescence, but it will reduce their sensitivity to depression when facing CSDS in adulthood. This may be achieved by regulating the hippocampus's Pantothenate and CoA biosynthesis and Beta Alanine metabolism pathways represented by Beta-alanine, l-Aspartic acid, 2-aminoadipic acid, and Glycine metabolites.

Integrative proteomics and metabolomics data analysis exploring the mechanism of brain injury after cardiac surgery in chronic stress rats.

OBJECTIVE: Preoperative chronic stress (CS) is associated with postoperative brain injury in patients undergoing open heart cardiac surgery. This research is to explore the potential molecular biological mechanisms of brain damage following cardiac surgery in preoperative CS rats by the analyses combining proteomics and metabolomics. METHODS: We constructed the chronic unpredictable stress (CUS) and cardiac surgery models in adult rats. We proved the brain injury in CUS cardiac surgery rats by Hematoxylin-Eosin (H&E) staining, followed by separating the hippocampal tissue and investigating the potential mechanisms of brain injury by the methods of data-independent acquisition proteomics and untargeted metabolomics. RESULTS: The signaling pathways of glycoproteins and metabolism of amino acids were the main possible mechanisms of brain injury in CUS rats following cardiac surgery according to the proteomics and metabolomics. In addition, the pathways of animo acids metabolism such as the pathways of lysine degradation and ß-alanine metabolism may be the main mechanism of cardiac surgery related brain injury in preoperative CUS rats. CONCLUSIONS: The pathways of animo acids metabolism such as lysine degradation and ß-alanine metabolism may be the potential mechanisms of brain injury in CUS rats following cardiac surgery. We should focus on the varieties of bioproteins and metabolites in these pathways, and related changes in other signaling pathways induced by the two pathways.

Treatment of acute pulmonary embolism after catheter-directed thrombolysis with dabigatran vs warfarin: Results of a multicenter randomized RE-SPIRE trial.

BACKGROUND: Thrombolytic therapy is effective method in the high-risk acute pulmonary embolism (PE) treatment. Reduced-dose thrombolysis (RDT) plus oral anticoagulation therapy is effective and safe method in the moderate and severe PE treatment. It is leading to good early and intermediate-term outcomes. In the RE-COVER and RE-COVER II studies, dabigatran showed similar effectiveness as warfarin in the treatment of acute PE. Dabigatran leads to fewer hemorrhagic complications and is not inferior in efficacy to warfarin in the prevention of PE after mechanical fragmentation and RDT (catheter-directed treatment [CDT]+RDT) in patients with high and intermediate to high PE risk. We sought to evaluate the efficacy and safety (incidence of clinically significant recurrence of venous thromboembolic complications and deaths) during a 6-month course of treatment with dabigatran or warfarin in patients with high and intermediate to high acute PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT). METHODS: The RE-SPIRE is a prospective, multicenter randomized double-arm study. Over a 5-year period, 66 consecutive patients with symptomatic high and intermediate to high PE risk after endovascular mechanical thrombus fragmentation procedure with RDT (CDT+RDT) were randomized into two groups within the next 48 hours. The first group continued treatment with dabigatran 150 mg twice a day for 6 months; the second group continued treatment with warfarin under the control of international normalized ratio (2.0-3.0) for 6 months. Both groups received low molecular weight heparins for 2 days after surgery. Then, group 1 continued to receive low molecular-weight-heparin for 5 to 7 days, followed by a switch to dabigatran at a dosage of 150 mg two times a day. Group 2 received both low-molecular-weight heparin and warfarin up to an international normalized ratio of >2.0, followed by heparin withdrawal. The follow-up period was 6 months. RESULTS: There were 63 patients who completed the study (32 in the dabigatran group and 31 in the warfarin group). In both groups, there was a statistically significant decrease in the mean pulmonary artery pressure. The mean pulmonary artery pressure at the 6-month follow-up after surgery was 24 mm Hg (interquartile range, 20.3-29.25 mm Hg) in the dabigatran group and 23 mm Hg (interquartile range, 20.0-26.3 mm Hg) in the warfarin group. The groups did not differ statistically in the deep vein thrombosis dynamics. Partial recanalization occurred in 52.0% vs 73.1% in the dabigatran and warfarin groups, respectively (P = .15). Complete recanalization occurred in 28.0% vs 19.2% in the dabigatran and warfarin groups, respectively (P = .56). The groups did not differ in the frequency of major bleeding events according to the International Society for Thrombosis and Hemostasis (0% vs 3.2% in the dabigatran and warfarin groups, respectively; P = 1.00). However, there were more nonmajor bleeding events in the warfarin group than in the dabigatran group (16.1% vs 0%, respectively; P = .02). CONCLUSIONS: The results of the study show that dabigatran is comparable in effectiveness to warfarin. Dabigatran has greater safety in comparison with warfarin in the occurrence of all cases of bleeding in the postoperative and long-term periods. Thus, dabigatran may be recommended for the treatment and prevention of PE after CDT with RDT in patients with high and intermediate to high PE risk.

Molecular properties of linear amino acids in water.

Four linear amino acids of increased separation of the carboxyl and amino groups, namely glycine (aminoacetic acid), ß-alanine (3-aminopropanoic acid), GABA (4-aminobutanoic acid) and DAVA (5-aminopentanoic acid), have been studied by quantum chemical ab initio and DFT methods including the solvent effect in order to get electronic structure and molecular descriptors, such as ionisation energy, electron affinity, molecular electronegativity, chemical hardness, electrophilicity index, dipole moment, quadrupole moment and dipole polarizability. Thermodynamic functions (zero-point energy, inner energy, enthalpy, entropy, and the Gibbs energy) were evaluated after the complete vibrational analysis at the true energy minimum provided by the full geometry optimization. Reaction Gibbs energy allows evaluating the absolute redox potentials on reduction and/or oxidation. The non-local non-additive molecular descriptors were compared along the series showing which of them behave as extensive, varying in match with the molar mass and/or separation of the carboxyl and amino groups. Amino acidic forms and zwitterionic forms of the substances were studied in parallel in order to compare their relative stability and redox properties. In total, 24 species were investigated by B3LYP/def2-TZVPD method (M1) including neutral molecules, molecular cations and molecular anions. For comparison, MP2/def2-TZVPD method (M2) with full geometry optimization and vibrational analysis in water has been applied for 12 species; analogously, for 24 substances, DLPNO-CCSD(T)/aug-cc-pVTZ method (M3) has been applied in the geometry obtained by MP2 and/or B3LYP. It was found that the absolute oxidation potential correlates with the adiabatic ionisation energy; the absolute reduction potential correlates with the adiabatic electron affinity and the electrophilicity index. In order to validate the used methodology with experimental vertical ionisation energies and vibrational spectrum obtained in gas phase, calculations were done also in vacuo.

The Role of Rho Kinase Inhibitors in Corneal Diseases.

The cornea, as the outermost layer of the eye, plays a crucial role in vision by focusing light onto the retina. Various diseases and injuries can compromise its clarity, leading to impaired vision. This review aims to provide a thorough overview of the pharmacological properties, therapeutic potential and associated risks of Rho-associated protein kinase (ROCK) inhibitors in the management of corneal diseases. The article focuses on four key ROCK inhibitors: Y-27632, fasudil, ripasudil, and netarsudil, providing a comparative examination. Studies supporting the use of ROCK inhibitors highlight their efficacy across diverse corneal conditions. In Fuchs' endothelial corneal dystrophy, studies on the application of Y-27632, ripasudil, and netarsudil demonstrated noteworthy enhancements in corneal clarity, endothelial cell density, and visual acuity. In pseudophakic bullous keratopathy, the injection of Y-27632 together with cultured corneal endothelial cells into the anterior chamber lead to enhanced corneal endothelial cell density and improved visual acuity. Animal models simulating chemical injury to the cornea showed a reduction of neovascularization and epithelial defects after application of fasudil and in a case of iridocorneal endothelial syndrome netarsudil improved corneal edema. Addressing safety considerations, netarsudil and ripasudil, both clinically approved, exhibit adverse events such as conjunctival hyperemia, conjunctival hemorrhage, cornea verticillata, conjunctivitis, and blepharitis. Monitoring patients during treatment becomes crucial to balancing the potential therapeutic benefits with these associated risks. In conclusion, ROCK inhibitors, particularly netarsudil and ripasudil, offer promise in managing corneal diseases. The comparative analysis of their pharmacological properties and studies supporting their efficacy underscore their potential therapeutic significance. However, ongoing research is paramount to comprehensively understand their safety profiles and long-term outcomes in diverse corneal conditions, guiding their optimal application in clinical practice.

Effect of amino acid enriched diets on hemolymph amino acid composition in honey bees.

Amino acids (AAs) are an abundant class of nectar solutes, and they are involved in the nectar attractiveness to flower visitors. Among the various AAs, proline is the most abundant proteogenic AA, and γ-amino butyric acid (GABA) and ß-alanine are the two most abundant non-proteogenic AAs. These three AAs are known to affect insect physiology, being involved in flight metabolism and neurotransmission. The aim of this study was to investigate the effects of artificial diets enriched with either ß-alanine, GABA, or proline on consumption, survival, and hemolymph composition in honey bees belonging to two different ages and with different metabolism (i.e., newly emerged and foragers). Differences in feed intake among diets were not observed, while a diet enriched with ß-alanine improved the survival rate of newly emerged honey bees compared to the control group. Variations in the hemolymph AA concentrations occurred only in newly emerged honey bees, according to the diet and the time of hemolymph sampling. A greater susceptibility of young honey bees to enriched diets than older honey bees was observed. The variations in the concentrations of hemolymph AAs reflect either the accumulation of dietary AAs or the existence of metabolic pathways that may lead to the conversion of dietary AAs into different ones. This investigation could be an initial contribution to studying the complex dynamics that regulate hemolymph AA composition and its effect on honey bee physiology.

Trimethylamine N-oxide, ß-alanine, tryptophan index, and vitamin B6-related dietary patterns in association with stroke risk.

BACKGROUND AND AIMS: The aim of this study was to examine the associations of dietary patterns derived by reduced-rank regression (RRR) model reflecting variation in novel biomarkers (trimethylamine N-oxide, ß-alanine, tryptophan index, and vitamin B6) with stroke risk. METHODS AND RESULTS: We performed analyses based on a community-based cohort study "the Prospective Follow-up Study on Cardiovascular Morbidity and Mortality in China (PFS-CMMC)". Factor loadings were calculated by RRR using 11 food groups collected via a validated food frequency questionnaire and the four response variables based on its nested case-control data (393 cases of stroke vs. 393 matched controls). Dietary pattern scores were derived by applying the factor loadings to the food groups in the entire cohort (n = 15,518). The associations of dietary pattern with the stroke risk were assessed using Cox proportional hazards models. The dietary pattern characterized with higher intakes of red meat and poultry but lower intakes of fresh vegetables, fresh fruits, and fish/seafoods were identified for further analyses. The hazard ratios (HR) for the highest vs. lowest quartile was 1.55 [95 % confidence interval (CI): 1.18-2.03, P trend = 0.001] for total stroke, 2.96 [95 % CI: 1.53-5.71, P trend <0.001] for non-ischemic stroke, after adjustment for sex, age, educational attainment, current smoking, current drinking, body mass index, total energy intake, family history of stroke, hypertension, diabetes, hyperlipidemia, and estimated glomerular filtration rate. CONCLUSION: Our findings highlight the importance of limited meat intake and increased intakes of fresh vegetables, fruits, and fish/seafoods in the prevention of stroke among Chinese adults.

MERCURY-3: a randomized comparison of netarsudil/latanoprost and bimatoprost/timolol in open-angle glaucoma and ocular hypertension.

PURPOSE   : To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: MERCURY-3 was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. RESULTS: Overall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). CONCLUSIONS: Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

Assessment of breast cancer chemotherapy dose reduction in an integrated healthcare delivery system.

PURPOSE: Most cytotoxic drugs are dosed using body surface area (BSA), yet not all cancer patients receive the full BSA-determined dose. Prior work suggests that breast cancer patients who are obese are more likely to experience dose reduction than normal weight patients. However, the factors driving dose reduction remain unclear. METHODS: In 452 women diagnosed with stage I-IIIA primary breast cancer at Kaiser Permanente Northern California, we evaluated the association between obesity and dose reduction, and further explored other factors in relation to dose reduction, including various sociodemographic characteristics, tumor characteristics, and comorbidities. Study participants were a part of the Pathways Study, diagnosed between 2006 and 2013 and treated with cyclophosphamide + doxorubicin, followed by paclitaxel (ACT). Dose reduction was assessed using first cycle dose proportion (FCDP) and average relative dose intensity (ARDI), a metric of dose intensity over the course of chemotherapy. RESULTS: Overall, 8% of participants received a FCDP < 90% and 21.2% had an ARDI < 90%, with dose reduction increasing with body mass index. In adjusted logistic regression models, obese women had 4.1-fold higher odds of receiving an ARDI < 90% than normal weight women (95% CI: 1.9-8.9; p-trend = 0.0006). Increasing age was positively associated with an ADRI < 90%, as was the presence of comorbidity. Dose reduction was less common in later calendar years. CONCLUSION: Results offer insight on factors associated with chemotherapy dosing for a common breast cancer regimen. Larger studies are required to evaluate relevance to other regimens, and further work will be needed to determine whether dose reductions impact outcomes in obese women.

Integrative Placental Multi-Omics Analysis Reveals Perturbed Pathways and Potential Prognostic Biomarkers in Gestational Hypertension.

BACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood. OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups. RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and ß-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, ß-alanine, and histidine) with potential to distinguish GH and HP. CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.

Comparison of safety and efficacy of Netarsudil 0.02% and Bimatoprost 0.01% monotherapy and combination therapy in primary open-angle glaucoma and ocular hypertension.

PURPOSE: To study and compare the efficacy and safety profile of Rho-kinase inhibitor (netarsudil 0.02%) and prostaglandin analog (bimatoprost 0.01%) both as monotherapy and in combination. DESIGN: Prospective, randomized, monocentric, open-label clinical trial. METHODS: Patients ≥20 years of age with primary open-angle glaucoma or ocular hypertension (IOP >21 mmHg) were recruited and randomized to receive either netarsudil 0.02%, netarsudil 0.02% + bimatoprost 0.01%, or bimatoprost 0.01% once daily for a period of 12 weeks. IOP and side effects were documented at 4, 8, and 12 weeks. RESULTS: The mean treated IOP ranged 17.51-18.57 mmHg for netarsudil, 15.80-16.46 mmHg for bimatoprost, and 14.00-14.87 mmHg for the combination therapy group. The mean IOP reduction from baseline at 4, 8, and 12 weeks was found to be statistically significant ( P < 0.001) in all three groups. The safety profile of netarsudil/bimatoprost combination was consistent with each constituent individually. The only frequently observed ocular adverse event was conjunctival hyperemia, which was seen mostly in netarsudil and netarsudil + bimatoprost groups ( P < 0.001). CONCLUSION: The IOP-lowering effect of netarsudil 0.02% once daily is non-inferior to bimatoprost 0.01% in patients with POAG and ocular hypertension with acceptable ocular safety, and the combination therapy achieved a higher IOP-lowering effect. This group of medications can be a useful adjunct in patients on maximal therapy.