-
BMC Medical Research Methodology Jun 2024Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Baseline imbalances have been identified in randomized trials of evolocumab and alirocumab. Our aim was to quantitatively assess (1) the presence of systematic baseline differences, and (2) the relationship of baseline differences with effects on low-density lipoprotein-cholesterol (LDL-c) and clinical outcomes in the trials.
METHODS
We performed a meta-epidemiological study. PubMed, Embase, regulatory reports, ClinicalTrials.gov and company websites were searched for trials. Seven baseline characteristics (mean age, LDL-c, BMI, percentage males, diabetics, smokers, and hypertensives) and five outcomes (LDL-c, major adverse cardiac events, serious adverse events, any adverse events, all-cause mortality) were extracted. We calculated (1) range and distribution of baseline imbalances (sign-test), (2) pooled baseline differences and heterogeneity (meta-analysis), (3) differences in SDs around continuous variables (sign-test and pooling), and (4) the relationship of baseline differences with outcomes (meta-regression). The comparisons of PCSK9-inhibitor groups with either placebo or ezetimibe were analysed separately and combined.
RESULTS
We identified 43 trials with 63,193 participants. Baseline characteristics were frequently missing. Many trials showed small baseline imbalances, but some large imbalances. Only baseline BMI showed a statistically significant lower pooled mean for the drug versus placebo groups (MD -0.16; 95% CI -0.24 to -0.09). Heterogeneity in baseline imbalances was present in six placebo- and five ezetimibe-comparisons. Heterogeneity was statistically significant for BMI, males, diabetics and hypertensives in the combined comparisons. There was a statistically significant preponderance for larger SDs in the PCSK9-inhibitor versus control groups (sign-test age 0.014; LDL-c 0.014; BMI 0.049). Meta-regression showed clinically relevant relationships of baseline imbalances in age, BMI and diabetics with the risk of any adverse events and the risk of mortality. Two relationships were statistically significant: A higher mean BMI in the drug versus control group with a decreased risk of mortality (beta - 0.56; 95% CI -1.10 to -0.02), and a higher proportion of diabetics with an increased risk of any adverse events (beta 0.02; 95% 0.01 to 0.04).
CONCLUSIONS
Heterogeneous baseline imbalances and systematically different SDs were present in evolocumab and alirocumab trials, so study groups cannot be assumed to be comparable. These findings raise concerns about the design and conduct of the randomization procedures.
Topics: Humans; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Cholesterol, LDL; Male; Anticholesteremic Agents; Randomized Controlled Trials as Topic; Female; Treatment Outcome; Middle Aged; Hypercholesterolemia; PCSK9 Inhibitors; Aged; Proprotein Convertase 9
PubMed: 38909176
DOI: 10.1186/s12874-024-02260-z -
Scientific Reports Jun 2024The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants... (Observational Study)
Observational Study
The number of patients with atrial fibrillation is increasing, and frailty prevalence increases with age, posing challenges for physicians in prescribing anticoagulants to such patients because of possible harm. The effects of frailty on anticoagulant therapy in older Japanese patients with nonvalvular atrial fibrillation (NVAF) are unclear. Herein, we prescribed rivaroxaban to Japanese patients with NVAF and monitored for a mean of 2.0 years. The primary endpoint was stroke or systemic embolism. The secondary endpoints were all-cause or cardiovascular death, composite endpoint, and major or non-major bleeding. Frailty was assessed using the Japanese long-term care insurance system. A multiple imputation technique was used for missing data. The propensity score (PS) was obtained to estimate the treatment effect of frailty and was used to create two PS-matched groups. Overall, 5717 older patients had NVAF (mean age: 73.9 years), 485 (8.5%) were classified as frail. After PS matching, background characteristics were well-balanced between the groups. Rivaroxaban dosages were 10 and 15 mg/day for approximately 80% and the remaining patients, respectively. Frailty was not associated with the primary endpoint or secondary endpoints. In conclusion, frailty does not affect the effectiveness or safety of rivaroxaban anticoagulant therapy in older Japanese patients with NVAF.Trial registration: UMIN000019135, NCT02633982.
Topics: Humans; Atrial Fibrillation; Aged; Male; Female; Frailty; Rivaroxaban; Aged, 80 and over; Anticoagulants; Japan; Stroke; Frail Elderly; Hemorrhage; Factor Xa Inhibitors; East Asian People
PubMed: 38909144
DOI: 10.1038/s41598-024-65237-4 -
Ecotoxicology and Environmental Safety Jun 2024Paraquat (PQ) is a widely used herbicide that poisons human by accident or intentional ingestion. PQ poisoning causes systemic inflammatory response syndrome (SIRS)...
BACKGROUND
Paraquat (PQ) is a widely used herbicide that poisons human by accident or intentional ingestion. PQ poisoning causes systemic inflammatory response syndrome (SIRS) resulting in acute lung injury (ALI) with an extremely high mortality rate. Blood trematode Schistosoma japonicum-produced cystatin (Sj-Cys) is a strong immunomodulatory protein that has been experimentally used to treat inflammation related diseases. In this study, Sj-Cys recombinant protein (rSj-Cys) was used to treat PQ-induced lung injury and the immunological mechanism underlying the therapeutic effect was investigated.
METHODS
PQ-induced acute lung injury mouse model was established by intraperitoneally injection of 20 mg/kg of paraquat. The poisoned mice were treated with rSj-Cys and the survival rate was observed up to 7 days compared with the group without treatment. The pathological changes of PQ-induced lung injury were observed by examining the histochemical sections of affected lung tissue and the wet to dry ratio of lung as a parameter for inflammation and edema. The levels of the inflammation related cytokines IL-6 and TNF-α and regulatory cytokines IL-10 and TGF-β were measured in sera and in affected lung tissue using ELISA and their mRNA levels in lung tissue using RT-PCR. The macrophages expressing iNOS were determined as M1 and those expressing Arg-1 as M2 macrophages. The effect of rSj-Cys on the transformation of inflammatory M1 to regulatory M2 macrophages was measured in affected lung tissue in vivo (EKISA and RT-PCR) and in MH-S cell line in vitro (flow cytometry). The expression levels of TLR2 and MyD88 in affected lung tissue were also measured to determine their role in the therapy of rSj-Cys on PQ-induced lung injury.
RESULT
We identified that treatment with rSj-Cys significantly improved the survival rate of mice with PQ-induced lung injury from 30 % (untreated) to 80 %, reduced the pathological damage of poisoning lung tissue, associated with significantly reduced levels of proinflammatory cytokines (IL-6 from 1490 to 590 pg/ml, TNF-α from 260 to 150 pg/ml) and increased regulatory cytokines (IL-10 from360 to 550 pg/ml, and TGF-β from 220 to 410 pg/ml) in both sera (proteins) and affected lung tissue (proteins and mRNAs). The polarization of macrophages from M1to M2 type was found to be involved in the therapeutic effect of rSj-Cys on the PQ-induced acute lung injury, possibly through inhibiting TLR2/MyD88 signaling pathway.
CONCLUSIONS
Our study demonstrated the therapeutic effect of rSj-Cys on PQ poisoning caused acute lung injury by inducing M2 macrophage polarization through inhibiting TLR2/MyD88 signaling pathway. The finding in this study provides an alternative approach for the treatment of PQ poisoning and other inflammatory diseases.
PubMed: 38905933
DOI: 10.1016/j.ecoenv.2024.116615 -
Polish Journal of Microbiology Jun 2024Chikungunya virus (CHIKV) causes a debilitating fever and joint pain, with no specific antiviral treatment available. Halogenated secondary metabolites from plants are a...
Chikungunya virus (CHIKV) causes a debilitating fever and joint pain, with no specific antiviral treatment available. Halogenated secondary metabolites from plants are a promising new class of drug candidates against chikungunya, with unique properties that make them effective against the virus. Plants produce these compounds to defend themselves against pests and pathogens, and they are effective against a wide range of viruses, including chikungunya. This study investigated the interactions of halogenated secondary metabolites with nsP2pro, a therapeutic target for CHIKV. A library of sixty-six halogenated plant metabolites screened previously for ADME properties was used. Metabolites without violation of Lipinski's rule were docked with nsP2pro using AutoDock Vina. To find the stability of the pipoxide chlorohydrin-nsP2pro complex, the GROMACS suite was used for MD simulation. The binding free energy of the ligand-protein complex was computed using MMPBSA. Molecular docking studies revealed that halogenated metabolites interact with nsP2pro, suggesting they are possible inhibitors. Pipoxide chlorohydrin showed the greatest affinity to the target. This was further confirmed by the MD simulations, surface accessible area, and MMPBSA studies. Pipoxide chlorohydrin, a halogenated metabolite, was the most potent against nsP2pro in the survey.
Topics: Chikungunya virus; Molecular Docking Simulation; Antiviral Agents; Chikungunya Fever; Secondary Metabolism; Molecular Dynamics Simulation; Halogenation; Plants; Computer Simulation; Viral Nonstructural Proteins
PubMed: 38905281
DOI: 10.33073/pjm-2024-020 -
PloS One 2024The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models...
The battle against viral drug resistance highlights the need for innovative approaches to replace time-consuming and costly traditional methods. Deep generative models offer automation potential, especially in the fight against Human immunodeficiency virus (HIV), as they can synthesize diverse molecules effectively. In this paper, an application of an LSTM-based deep generative model named "LSTM-ProGen" is proposed to be tailored explicitly for the de novo design of drug candidate molecules that interact with a specific target protein (HIV-1 protease). LSTM-ProGen distinguishes itself by employing a long-short-term memory (LSTM) architecture, to generate novel molecules target specificity against the HIV-1 protease. Following a thorough training process involves fine-tuning LSTM-ProGen on a diverse range of compounds sourced from the ChEMBL database. The model was optimized to meet specific requirements, with multiple iterations to enhance its predictive capabilities and ensure it generates molecules that exhibit favorable target interactions. The training process encompasses an array of performance evaluation metrics, such as drug-likeness properties. Our evaluation includes extensive silico analysis using molecular docking and PCA-based visualization to explore the chemical space that the new molecules cover compared to those in the training set. These evaluations reveal that a subset of 12 de novo molecules generated by LSTM-ProGen exhibit a striking ability to interact with the target protein, rivaling or even surpassing the efficacy of native ligands. Extended versions with further refinement of LSTM-ProGen hold promise as versatile tools for designing efficacious and customized drug candidates tailored to specific targets, thus accelerating drug development and facilitating the discovery of new therapies for various diseases.
Topics: HIV Protease Inhibitors; Drug Design; Humans; HIV Protease; HIV-1; Acquired Immunodeficiency Syndrome; Molecular Docking Simulation
PubMed: 38905197
DOI: 10.1371/journal.pone.0303597 -
Frontiers in Public Health 2024To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences...
To comprehensively investigate the molecular transmission patterns of HIV-1 genotypes among men who have sex with men (MSM) in Chongqing, we employed 392 pol sequences of MSM to construct a phylogenetic tree and gene transmission network. Among the viral subtypes, CRF07_BC accounted for 73.2% (287/392) and CRF01_AE accounted for 20.7% (81/392), emerging as the predominant subtypes in this investigation. Additionally, we observed the presence of CRF55_01B, subtype B, CRF08_BC and other circulating recombinant forms. The HIV-1 molecular network was constructed with a gene distance threshold of 1.5%, resulting in an entry rate of 61.4% (241/392). Within the network, we identified a total of 23 molecular clusters, with the largest cluster being the CRF07_BC molecular cluster comprising 148 node values. Transmitted drug-resistance (TDR) mutations were found in 4.34% of the cases, with 1.79% associated with protease inhibitors (PIs), 0.51% with nucleoside reverse transcriptase inhibitors (NRTIs), and 2.55% with non-nucleoside reverse transcriptase inhibitors (NNRTIs). Statistical analysis indicated a higher enrollment rate in the HIV-1 molecular network among infected individuals with the CRF07_BC subtype, those identifying with same-sex sexual roles as "vers," and individuals with higher education levels. This suggests the need for strengthened investigation and intervention in this population to prevent the formation of larger transmission clusters. Furthermore, continuous monitoring of the HIV-1 molecular dynamics network is necessary to promptly and accurately track changes in molecular epidemic characteristics.
Topics: Humans; Male; China; Homosexuality, Male; HIV-1; Drug Resistance, Viral; Adult; Phylogeny; HIV Infections; Genotype; Acquired Immunodeficiency Syndrome; Middle Aged; Mutation
PubMed: 38903589
DOI: 10.3389/fpubh.2024.1308784 -
Ugeskrift For Laeger Jun 2024In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to...
In this case report, a 31-year-old woman with heterozygous familial hypercholesterolaemia (FH) underwent treatment with statins and PCSK9 inhibitor but had to discontinue due to elevated creatine kinase levels and neurological and muscular side effects. In 2021, the patient received inclisiran therapy, the first known instance of its application in Denmark. No side effects were reported, and LDL cholesterol levels were significantly reduced. This case report highlights the potential of inclisiran as an effective and well-tolerated treatment for individuals with heterozygous FH.
Topics: Humans; Female; Adult; Hyperlipoproteinemia Type II; PCSK9 Inhibitors; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cholesterol, LDL; Anticholesteremic Agents
PubMed: 38903035
DOI: 10.61409/V12230767 -
The Journal of International Medical... Jun 2024The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left...
The gold standard therapy for end-stage heart failure is cardiac transplantation. However, in the face of a donor shortage, a mechanical assist device such as the left ventricular assist device HeartMate 3 (Abbott Laboratories, Abbott Park, IL, USA) serves as bridging therapy to transplantation and/or destination therapy. Current guidelines recommend anticoagulation with a vitamin K antagonist in combination with low-dose aspirin. We herein report a challenging anticoagulation regimen in a patient with a HeartMate 3 in whom systemic anticoagulation with warfarin was not feasible for 4 years because of low compatibility and a rare X-factor deficiency. This is a rare hematological disorder, estimated to affect approximately 1 in every 500,000 to 1,000,000 people in the general population. The patient finally received a modified anticoagulation regimen involving the combination of rivaroxaban and clopidogrel without warfarin. Under this regimen, the patient remained free of thromboembolic complications for 4 years with placement of the left ventricular assist device. This case illustrates that under specific circumstances, long-term absence of warfarin therapy is feasible in patients with a HeartMate 3.
Topics: Humans; Heart-Assist Devices; Warfarin; Thromboembolism; Anticoagulants; Male; Heart Failure; Middle Aged; Clopidogrel; Rivaroxaban; Withholding Treatment
PubMed: 38901839
DOI: 10.1177/03000605241258474 -
Journal of Cellular and Molecular... Jun 2024Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD... (Review)
Review
Parkinson disease (PD) is one of the most common neurodegenerative diseases of the brain. Of note, brain renin-angiotensin system (RAS) is intricate in the PD neuropathology through modulation of oxidative stress, mitochondrial dysfunction and neuroinflammation. Therefore, modulation of brain RAS by angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may be effective in reducing the risk and PD neuropathology. It has been shown that all components including the peptides and enzymes of the RAS are present in the different brain areas. Brain RAS plays a critical role in the regulation of memory and cognitive function, and in the controlling of central blood pressure. However, exaggerated brain RAS is implicated in the pathogenesis of different neurodegenerative diseases including PD. Two well-known pathways of brain RAS are recognized including; the classical pathway which is mainly mediated by AngII/AT1R has detrimental effects. Conversely, the non-classical pathway which is mostly mediated by ACE2/Ang1-7/MASR and AngII/AT2R has beneficial effects against PD neuropathology. Exaggerated brain RAS affects the viability of dopaminergic neurons. However, the fundamental mechanism of brain RAS in PD neuropathology was not fully elucidated. Consequently, the purpose of this review is to disclose the mechanistic role of RAS in in the pathogenesis of PD. In addition, we try to revise how the ACEIs and ARBs can be developed for therapeutics in PD.
Topics: Renin-Angiotensin System; Humans; Parkinson Disease; Brain; Animals; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors
PubMed: 38899551
DOI: 10.1111/jcmm.18495 -
Journal of Insect Physiology Jun 2024Like other lepidopteran insects, males of the tobacco cutworm moth, Spodoptera litura produce two kinds of spermatozoa, eupyrene (nucleate) and apyrene (anucleate)...
A sperm-activating trypsin-like protease from the male reproductive tract of Spodoptera litura: Proteomic identification, sequence characterization, gene expression profile, RNAi and the effects of ionizing radiation.
Like other lepidopteran insects, males of the tobacco cutworm moth, Spodoptera litura produce two kinds of spermatozoa, eupyrene (nucleate) and apyrene (anucleate) sperm. Formed in the testis, both kinds of sperm are released into the male reproductive tract in an immature form and are stored in the duplex region of the tract. Neither type of sperm is motile at this stage. When stored apyrene sperm from the duplex are treated in vitro with an extract of the prostatic region of the male tract, or with mammalian trypsin, they become motile; activation is greater and achieved more rapidly with increasing concentration of extract or enzyme. The activating effect of prostatic extract is blocked by soybean trypsin inhibitor (SBTI), also in a dose-dependent way. These results suggest that the normal sperm-activating process is due to an endogenous trypsin-like protease produced in the prostatic region. Proteomic analysis of S. litura prostatic extracts revealed a Trypsin-Like Serine Protease, TLSP, molecular weight 27 kDa, whose 199-residue amino acid sequence is identical to that of a predicted protein from the S. litura genome and is highly similar to predicted proteins encoded by genes in the genomes of several other noctuid moth species. Surprisingly, TLSP is only distantly related to Serine Protease 2 (initiatorin) of the silkmoth, Bombyx mori, the only identified lepidopteran protein so far shown to activate sperm. TLSP has features typical of secreted proteins, probably being synthesized as an inactive precursor zymogen, which is later activated by proteolytic cleavage. cDNA was synthesized from total RNA extracted from the prostatic region and was used to examine TLSP expression using qPCR. tlsp mRNA was expressed in both the prostatic region and the accessory glands of the male tract. Injection of TLSP-specific dsRNA into adult males caused a significant reduction after 24 h in tlsp mRNA levels in both locations. The number of eggs laid by females mated to adult males that were given TLSP dsRNA in 10 % honey solution, and the fertility (% hatched) of the eggs were reduced. Injecting pupae with TLSP dsRNA caused the later activation of apyrene sperm motility by adult male prostatic extracts to be significantly reduced compared to controls. Exposure of S. litura pupae to ionizing radiation significantly reduced expression of tlsp mRNA in the prostatic part and accessory gland of irradiated males in both the irradiated generation and also in their (unirradiated) F1 progeny. The implications of these findings for the use of the inherited sterility technique for the control of S. litura and other pest Lepidoptera are discussed.
PubMed: 38897288
DOI: 10.1016/j.jinsphys.2024.104664