Is tirzepatide 15 mg the preferred treatment strategy for type 2 diabetes? A meta-analysis and trial-sequence-analysis.

OBJECTIVE: The study aims to evaluate tirzepatide's efficacy and safety in treating type 2 diabetes by meta-analysis and trial-sequential-analysis (TSA). MATERIALS AND METHODS: Eight databases were searched for clinical trials on tirzepatide for type 2 diabetes with a time limit of November 2022. Revman5.3 and TSA 0.9.5.10 Beta were selected for meta-analysis and TSA. RESULTS: Compared with placebo, the meta-analysis demonstrated that tirzepatide 15 mg reduced hemoglobin-type-A1C (HbA1c) (p<0.00001), fasting-serum-glucose (FSG) (p<0.00001), and weight (p<0.00001). Compared with insulin, tirzepatide 15 mg reduced HbA1c (p<0.00001), FSG (p<0.00007), and weight (p<0.00001). Compared with glucagon-like-peptide-1 receptor-agonist (GLP-1 RA), tirzepatide 15 mg reduced HbA1c (p=0.00004), FSG (p=0.001), and weight (p<0.00001). In safety endpoints, the meta-analysis revealed that adverse events (AEs) of placebo, insulin and GLP-1 RA were comparable to tirzepatide 15 mg. The total AEs (p=0.02) and gastrointestinal (GI) AEs (p=0.03) were higher in tirzepatide 15 mg than in the placebo, while hypoglycemia (<54 mg/dl) was comparable. The major adverse cardiovascular events-4 (MACE-4) (p=0.03) and hypoglycemia (<54 mg/dl) (p<0.00001) of tirzepatide 15 mg were lower when compared to insulin, while total AEs (p=0.03) were increased. Compared with GLP-1 RA, tirzepatide 15 mg was comparable in safety endpoints in total AEs and GI AEs, while hypoglycemia (<54 mg/dl) (p=0.04) was higher. TSA indicated that HgA1c, FSG, and weight benefits were conclusive. In safety endpoints, only MACE-4 and hypoglycemia (<54 mg/dl) of Tirzepatide 15 mg vs. Insulin were conclusive. Harbord regression of AEs suggested no evident publication bias (p=0.618). CONCLUSIONS: Tirzepatide 15 mg reduced HbA1c and weight more effectively than placebo, insulin, and GLP-1 RA. Total AEs were higher than placebo and insulin but comparable to GLP-1 RA. Tirzepatide 15 mg is a kind of optimal strategy to treat type 2 diabetes. However, there is a need to focus on GI AEs.

[Feasibility and safety of new simplified left bundle branch area pacing via nine-partition method].

Objective: To investigate the efficacy and safety of left bundle branch area pacing (LBBaP) with the new simplified approach (nine-partition method). Methods: A total of 118 patients with clinical indications and received pacemaker implantation from December 1, 2018 to December 31, 2019 in Beijing Anzhen Hospital were enrolled. LBBaP was performed with the nine-partition method (in the right anterior oblique 30° position, the ventriculogram was divided into nine partitions and the initial implant sites were located in the lower base 1/3 partitions). In X-ray image, the 3830 lead is located in the left bundle branch area, the unipolar pacing QRS wave is in the form of right bundle branch block, and the peak time from stimulation to left ventricular activation<90 ms is defined as successful operation. The clinical characters, such as the methods of venipuncture, electrode parameters, operation duration, fluoroscopy duration, the peak time from stimulation to left ventricular, pacemaker types, surgical success rate, complications, and immediate postoperative ECG parameters were collected. The patients were followed up after the operation, and the electrode parameters and postoperative complications were recorded. Results: This study is a retrospective study. There were 62 (52.5%) male patients in this cohort, the average age was (65.9±13.4) years old,and there were 49(41.5%) sick sinus syndrome, 6(5.1%) abnormal sinus node and atrioventricular node simultaneously, 63(53.4%) atrioventricular block, 26(22.0%) atrial fibrillation, 20(16.9%) cardiomyopathy; the baseline duration of QRS was (109.21±39.03) ms. Successful LBBaP was achieved in 109 patients with"nine-partition method"and the success rate was 92.4%; 104 patients (95.5%) were axillary vein puncture, 5 (4.6%) were subclavian vein puncture; the operation duration was (80.3±23.0) min, the fluoroscopy duration was (12.29±5.13) min; the QRS duration after LBBaP was (116.36±18.11) ms. The threshold of the left bundle branch (LBB) lead was (0.92±0.63) V, the R wave amplitude was (10.60±5.04) mV and the impedance was (798.71±194.90) Ω. In 1 V pacing, the peak time from stimulation to left ventricular activation was (67.91±12.15) ms, and in 5 V pacing was (67.52±12.45) ms; 1 case (0.9%) with a single-chamber pacemaker implanted, 106 cases (97.3%) with dual-chamber pacemaker and 2 cases (1.8%) with three-chamber pacemakers. There were no hematomas, pneumothorax, hemothorax, electrode dislocation, infection, and capsular hemorrhage and other serious surgery-related complications during the operation. A total of 97 patients (89.0%) were followed up for (6.21±2.90) months. The electrode parameters of all patients were stable and no complications observed. Conclusions: The LBBaP with nine-partition method is a simple, safe and effective physiological pacing approach. However, its long-term effect still needs to be further verified.

Screening of adjunct cultures and their application in ester formation in Camembert-type cheese.

The ethanol content and esterase and alcohol acyltransferase activities are the limiting factors in the synthesis of ethyl esters in Camembert-type cheeses. This study aimed to investigate the effects of alcohol, esterase and alcohol acyltransferase activities on ethyl ester formation in Camembert-type cheeses. Five experimental cheeses were prepared with three adjunct cultures with different enzyme activities and two levels of ethanol content (400 or 800 µg/g). The cheeses were aged for 4 weeks and analysed weekly for basic physicochemical, textural, volatile and sensory properties. The results showed that both the enzyme activity and ethanol content were limiting factors in the synthesis of ethyl esters in the Camembert-type cheeses. Variation in the esterase synthesis activity was observed among lactic acid bacteria, and the starter culture Lactococcus lactis MA 14 LYO distinguished itself through its high acidifying and esterase hydrolysis abilities. The addition of CCFM 12, a lactic acid bacteria strain with high esterase and alcohol acyltransferase activity, along with 400 or 800 µg/g of ethanol, notably enhanced the generation of ethyl esters and the corresponding fruity flavour, without causing dramatic changes in the basic physicochemical indices and microbial profile. In addition, cohesiveness was influenced by the addition of 400 and 800 µg/g of ethanol, and more resilience with 800 µg/g of ethanol had been found. The results showed that the addition of CCFM12 with 400 and 800 µg/g of ethanol may be applied in the production of Camembert cheese to enhance its fruity flavour.

Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal-maternal interface.

Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor ß (TGF-ß), VDR and 1-α-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-ß were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA.

Venom Peptides and Toxins - A Prospective Spearhead in Cancer Treatment.

BACKGROUND & AIM: Cancer is a condition of genetically or environmentally mutated, uncontrollable cell growth that directly affects human morbidity and mortality. Many treatments have been adopted to reduce cancer cell proliferation; however, new mutated developments of some cancer cells have started to show resistance towards current therapies and treatments that cause some drugs to lose their efficacy. Additionally, deleterious side-effects of some hard application methods like radiation therapy, chemotherapy, and surgery are less favorable. Accumulative research effort has revealed that peptides and toxins identified from underutilized natural sources including venomous reptiles, amphibians, insects, arachnids, marine organisms and plants are increasingly being employed in cancer treatment. This demands more peptides / toxins to be identified from underutilized natural sources as an alternative therapeutic approach. METHOD & RESULTS: Accumulative research effort has revealed that peptides and toxins identified from underutilized natural sources including venomous reptiles, amphibians, insects, arachnids, marine organisms and plants are increasingly being employed in cancer treatment. Secondary structures / pharmacophore modifications have proven to be an important criterion for raising the efficacy level and anticancer effects. Structure specificity and structural-related cytotoxicity have successfully allowed these peptides to target and cause sufficient damage to malignant cells with minimal cytotoxicity effects towards healthy cells. On top of that, some these pure peptides had adopted multiple anticancer mechanisms and demonstrated collective anticancer effects within a single application. CONCLUSION: Our review exclusively selected peptides and toxins found identified from various natural sources in combating malignant cells, their selectivity towards specific anticancer mechanisms, and the prospective of conjugated peptide as a single entity for a new therapeutic strategy.

Women with recurrent spontaneous abortion have decreased 25(OH) vitamin D and VDR at the fetal-maternal interface

Immunological mechanisms have been proposed to underlie the pathogenesis of recurrent spontaneous abortion (RSA). Vitamin D has a potent immunomodulatory effect, which may affect pregnancy outcome. The objective of this study was to investigate 25-hydroxyvitamin D [25(OH) D] concentration and vitamin D receptor (VDR) expression in the decidual tissues of RSA patients. Thirty women with RSA (RSA group) and thirty women undergoing elective abortion (control group) were recruited during 2016 from gynecology outpatient clinics. We measured 25(OH) D, interleukin (IL)-17, IL-23, transforming growth factor β (TGF-β), VDR and 1-α-hydroxylase (CYP27B1) in decidual tissues collected during the abortion procedure. In the RSA group, 25(OH) D and TGF-β were significantly decreased while IL-17 and IL-23 were significantly increased compared with the control group. VDR expression was significantly decreased in the RSA group compared with the control group. Logistic regression analysis showed a significant negative correlation between 25(OH) D in decidual tissues and RSA. These results indicated that vitamin D concentrations in the decidua are associated with inflammatory cytokine production, suggesting that vitamin D and VDR may play a role in the etiology of RSA.

Iodinated tracers for imaging amyloid plaques in the brain.

Excessive amounts of protein deposits, beta-amyloid (Abeta) plaques, are commonly detected in the postmortem brains of Alzheimer's disease (AD) patients. These Abeta plaques are believed to play an important role in the pathogenesis of the disease. Development of Abeta plaque-specific imaging agents for detecting and monitoring the changes of Abeta plaque deposition in living brains are reported. These agents, if successfully developed, may serve as potential biomarkers for the disease. Several iodinated derivatives based on variety of core structures are labeled with radioiodine as single photon emission computed tomography (SPECT) imaging agents. Thioflavin (or benzothiazole) derivatives displayed excellent in vitro characteristics with high binding affinities for Abeta aggregates (in subnanomolar to nanomolar range) and excellent plaque labeling of AD brain sections. However, the in vivo kinetic properties appeared unfavorable for further development. A novel series of imidazo-pyridine derivative, such as 2-(4'-dimethylaminophenyl)-6-iodo-imidazo[1,2-a]pyridine (IMPY), exhibited highly desirable in vivo properties. Additional structural modification resulting in stilbene derivatives displayed good binding affinities for Abeta aggregates. In addition, fluorene compounds with a rigid tricyclic structure showed in vitro and in vivo characteristics as potential SPECT imaging agents. Criteria for selection of radioiodinated tracers with suitable in vivo properties to detect amyloid plaques are discussed.