Perspectives on Communication Technology Use for Alleviating the Impact of COVID-19 on Hospitalized Patients' Well-Being and Transitions in Care.

BACKGROUND: The COVID-19 pandemic created many challenges for in-patient care including patient isolation and limitations on hospital visitation. Although communication technology, such as video calling or texting, can reduce social isolation, there are challenges for implementation, particularly for older adults. OBJECTIVE/METHODS: This study used a mixed methodology to understand the challenges faced by in-patients and to explore the perspectives of patients, family members, and health care providers (HCPs) regarding the use of communication technology. Surveys and focus groups were used. FINDINGS: Patients who had access to communication technology perceived the COVID-19 pandemic to have more adverse impact on their well-beings but less on hospitalization outcomes, compared to those without. Most HCPs perceived that technology could improve programs offered, connectedness of patients to others, and access to transitions of care supports. Focus groups highlighted challenges with technology infrastructure in hospitals. DISCUSSION: Our study findings may assist efforts in appropriately adopting communication technology to improve the quality of in-patient and transition care.

Population pharmacokinetics of mycophenolic acid and dose optimisation in adult Chinese kidney transplant recipients.

1. This study aimed to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA), quantify the effect of clinical factors and pharmacogenomics of MPA, and optimise the dosage for adult kidney transplant recipients.2. One-hundred and four adult renal transplant patients were enrolled. The PPK model was established using the Phoenix® NMLE software and the stepwise methods were filtered for significant covariates. Monte Carlo simulations were performed to optimise the dosage regimen.3. A two-compartment model with first-order absorption and elimination (including lag time) provided a more accurate description of MPA pharmacokinetics. Serum albumin (ALB) significantly affected the central apparent clearance (CL/F), whereas post-transplant time and creatinine clearance were associated with a central apparent volume of distribution (V/F). The estimated population values obtained by the final model were 17.5 L/h and 93.97 L for CL/F and V/F, respectively. Simulation results revealed that larger mycophenolate mofetil doses are required as the ALB concentration decreases. This study established a PPK model of MPA and validated it using various methods. ALB significantly affected CL/F and recommended optimal dose strategies were given based on the final model. These results provide a reference for the personalised therapy of MPA for kidney transplant patients.

Cardiovascular toxicities following the use of tyrosine kinase inhibitors in hepatocellular cancer patients: a retrospective, pharmacovigilance study.

BACKGROUND: Cardiac adverse events (AEs) are common in tyrosine kinase inhibitors(TKIs). This study explored the cardiac AEs of TKIs through the Food and Drug Administration's Adverse Event Reporting System (FAERS). METHODS: Disproportionality analysis and Bayesian analysis were utilized for data mining of the suspected cardiac AEs of TKIs, based on FAERS data from January 2004 to December 2021. RESULTS: A total of 4708 cardiac AEs reports of sorafenib, regorafenib, lenvatinib, and cabozantinib were identified. Hypertension accounts for the most reported cardiac AE. Lenvatinib appears to induce cardiac failure with the highest signals strength [ROR = 7.7 (3.46,17.17)]. Acute myocardial infarction was detected in lenvatinib [ROR = 7.91 (5.64,11.09)] and sorafenib [ROR = 2.22 (1.74, 2.84)]. Acute coronary syndrome was detected in lenvatinib [ROR = 11.57 (6.84, 19.58)] and sorafenib [ROR = 2.81 (1.87,4.24)]. Atrial fibrillation was detected in sorafenib [ROR = 1.82 (1.55,2.14)] and regorafenib [ROR = 1.36 (1.03,1.81)]. Meanwhile, aortic dissections were detected in sorafenib [ROR = 5.08 (3.31,7.8)] and regorafenib [ROR = 3.39 (1.52,7.56)]. Most patients developed hypertension and cardiac failure within 30 days of initiating TKI treatments. Patients taking lenvatinib had an increased incidence of developing acute coronary syndrome after 180 days of treatment. CONCLUSION: Analysis of FAERS data provides a precise profile on the characteristics of cardiac AEs associated with different TKI regimens. Distinct monitoring and appropriate management are needed in the care of TKI recipients.

Gene polymorphisms affect postoperative imatinib plasma levels and edema in adults with gastrointestinal stromal tumor.

Aim: To assess the role of genetic polymorphisms in postoperative imatinib concentrations and edema in patients with gastrointestinal stromal tumor. Methods: The relationships between genetic polymorphisms, imatinib concentrations and edema were explored. Results: Carriers of the rs683369 G-allele and rs2231142 T-allele had significantly higher imatinib concentrations. Grade ≥2 periorbital edemas were related to the carriership of two C-alleles in rs2072454 with an adjusted odds ratio of 2.85, two T-alleles in rs1867351 with an adjusted odds ratio of 3.42 and two A-alleles in rs11636419 with an adjusted odds ratio of 3.15. Conclusion: rs683369 and rs2231142 affect the metabolism of imatinib; rs2072454, rs1867351 and rs11636419 are related to grade ≥2 periorbital edemas.

Personalized Dose of Adjuvant Imatinib in Patients with Gastrointestinal Stromal Tumors: Results from a Population Pharmacokinetic Analysis.

Purpose: Imatinib is the first-line treatment for patients with gastrointestinal stromal tumors (GIST) after surgery. However, its pharmacokinetic profile varies remarkably between individuals and has not been well characterized in postoperative Chinese patients with GIST. Therefore, this study aimed to develop a population pharmacokinetic (PPK) model and recommend appropriate doses for different patients to achieve the target trough concentration in such a population. Patients and Methods: A total of 110 surgically treated GIST patients were enrolled, of which 85 were applied to conduct a PPK analysis with a nonlinear mixed-effect model and 25 for external validation of the model. Demographic and biomedical covariates, as well as six single nucleotide polymorphisms were tested to explore the sources of variation in pharmacokinetic parameters of imatinib. Monte Carlo simulations were performed to establish the initial dosing regimens. Results: A one-compartment model was established in postoperative GIST patients. The red blood cell count (RBC) and ABCG2 rs2231142 were observed to have a significant effect on the clearance of imatinib. The typical values estimated by the final model were 9.72 L/h for clearance (CL/F) and 229 L for volume of distribution (V/F). Different from the fixed dose regimen of 400 mg each day, patients carrying rs2231142 heterozygous type and with a lower level of RBC (2.9 × 1012/L), 300 mg imatinib daily is enough to achieve the target trough concentration. When RBC rises to 4.9 × 1012/L, 500 mg daily is recommended. For patients with rs2231142 GG genotype, 500 mg a day is required at RBCs of 3.9 × 1012/L and 4.9 × 1012/L. Conclusion: RBC and rs2231142 contribute to the pharmacokinetic variation of imatinib and personalized dose recommendations based on patient characteristics may be necessary.

Cephalic electroacupuncture restores learning and memory in rats with induced ischemic stroke via inhibition of NF-κB nuclear translocation.

Inflammatory responses in the brain contribute to cognitive deficits. Nuclear factor-κB (NF-κB), a critical transcription factor in inflammatory responses, is activated in post-stroke cognitive deficit. Baihui (DU20) and Shenting (DU24) acupoints, the main acupoints of Du Meridian, are widely used to improve cognitive deficits in Chinese patients with stroke. It has been reported that post-stroke cognitive deficits can be treated by electroacupuncture (EA) but the underlying mechanisms of these effects are unclear. Using the rat middle cerebral artery occlusion cerebral ischemia-reperfusion injury model, we found that EA at these 2 acupoints improved neurological function, decreased cerebral infarct lesion volumes, and ameliorated the inflammatory response in the hippocampal CA1 region. The treatment also ameliorated memory and learning deficits by inhibiting the NF-κB signaling pathway in the ischemic hippocampal CA 1 region. This coincided with downregulation of interleukin-1ß, interleukin-6, CD45, and tumor necrosis factor-α. We conclude that EA at these 2 acupoints ameliorates memory and learning deficits following experimental cerebral infarction by inhibiting NF-κB-mediated inflammatory injury in the hippocampal CA1 region.

Effects of miR-107 on Breast Cancer Cell Growth and Death via Regulation of the PTEN/AKT Signaling Pathway.

Objective: Investigate the influence of miR-107 on breast cancer cell growth and death through the PTEN/AKT signaling pathway. Method: As study subjects, the human breast cancer cell line MCF-7 and the normal breast cell line Hs 578Bst were chosen, and MCF-7 cells were, respectively, transfected with control miRNA and miR-107 inhibitor. CCK-8, flow cytometry, scratch assay, and Transwell assay were used to analyze the proliferation, apoptosis, and invasion, and in order to identify the proteins associated with apoptosis in each of the three categories, we used western blot analysis. Bcl-2, cleaved caspase-3, and cleaved caspase-9 expression, as well as PTEN/AKT signaling pathway-associated protein expression, are correlated. Result: The expression of miR-107 in MCF-7 cells was significantly greater than that in Hs 578Bst cells, with a P < 0.05 difference; compared to the blank and miRNA control groups, the miR-107 inhibitor group had a P < 0.05 difference. P < 0.05 showed a decrease in proliferation (42.52) but no difference in proliferation between the blank and miRNA control groups (P > 0.05); the miR-107 inhibitor group had higher apoptosis (38.96) with P < 0.05 than the blank group (4.85) and the miRNA control group (5.89); there was no difference in apoptosis between the blank and miRNA groups (P > 0.05). There was no significant difference between the blank group and the miRNA control group with P > 0.05; compared with the blank group, the miR-107 inhibitor group had a lower expression of Bcl-2 protein (0.18), in addition to the degraded paradigms (0.73) and caspase-9 protein concentrations (0.79), respectively. Conclusion: The PTEN/AKT signaling pathway may be regulated by miR-107 to limit breast cancer cell growth and increase apoptosis, which suggests that miR-107 may be exploited as a tumor marker for therapeutic therapy.

Effects of Freezing and Rewarming Methods on RNA Quality of Blood Samples.

Background: RNA extracted from human blood has been widely applied to biological, medical, and clinical research of numerous diseases. Previous studies have demonstrated that high-quality RNA is indispensable to guarantee the reliability of downstream assays. In this study, we investigated the effects of freezing procedures, rewarming methods, and blood components on RNA quality of blood samples. Methods: Rabbit blood samples were divided into two groups: (1) whole blood (WB) and (2) blood cell components (BCC) with plasma removed. Samples were frozen using four representative freezing procedures (snap freezing in liquid nitrogen, snap freezing at -80°C, traditional slow freezing, and programmable controlled rate freezing) and rewarmed by placing at 4°C or by vortexing. RNA was extracted using the phenol-chloroform RNA extraction method and measured by an Agilent bioanalyzer. Then, human blood was used to verify the best protocol obtained from the rabbit blood experiment. Results: For the four freezing procedures, there were no differences in RNA integrity. For different rewarming methods, RNA integrity number (RIN) values of RNA extracted from frozen WB and BCC samples in the vortex group were above 9, while RNA obtained from WB showed worse quality compared with BCC in the 4°C group. For verification using human blood, RIN values of frozen human WB rewarmed by vortexing ranged from 8.0 to 9.1. Conclusions: Blood components and rewarming methods could affect the RNA quality of blood samples. For scenarios where WB samples have already been cryopreserved, the vortex rewarming method is optimal for high-quality RNA. Otherwise, we would recommend centrifuging fresh WB and cryopreserving it in the form of BCC, which showed a tendency to obtain high-quality RNA by either of the two rewarming methods.

Data mining and safety analysis of BTK inhibitors: A pharmacovigilance investigation based on the FAERS database.

Objective: The introduction of Bruton's tyrosine kinase (BTK) inhibitors was a milestone in the treatment of B-cell malignancies in recent years owing to its desired efficacy against chronic lymphocytic leukaemia and small cell lymphocytic lymphoma. However, safety issues have hindered its application in clinical practice. The current study aimed to explore the safety warning signals of BTK inhibitors in a real-world setting using the FDA Adverse Event Reporting System (FAERS) to provide reference for clinical rational drug use. Methods: Owing to the short marketing time of other drugs (zanbrutinib and orelabrutinib), we only analysed ibrutinib and acalabrutinib in this study. All data were obtained from the FAERS database from January 2004 to December 2021. Disproportionality analysis and Bayesian analysis were utilised to detect and assess the adverse event (AE) signals of BTK inhibitors. Results: In total, 43,429 reports of ibrutinib were extracted and 1527 AEs were identified, whereas 1742 reports of acalabrutinib were extracted and 220 AEs were identified by disproportionality analysis and Bayesian analysis. Among reports, males were more prone to develop AEs (58.2% for males vs. 35.6% for females treated with ibrutinib, and 55.9% vs. 31.9%, respectively, for acalabrutinib), and more than 30% of patients that suffered from AEs were over 65 years of age. Subsequently, we investigated the top 20 preferred terms (PTs) associated with the signal strength of ibrutinib and acalabrutinib, and our results identified 25 (13 vs. 12, respectively) novel risk signals. Among the top 20 PTs related to death reports, the terms infectious, pneumonia, pleural effusion, fall, asthenia, diarrhoea, and fatigue were all ranked high for these two BTK inhibitors. Further, cardiac disorders were also an important cause of death with ibrutinib. Conclusion: Patients treated with ibrutinib were more prone to develop AEs than those treated with acalabrutinib. Importantly, infection-related adverse reactions, such as pneumonia and pleural effusion, were the most common risk signals related to high mortality associated with both BTK inhibitors, especially in elderly patients. Moreover, cardiovascular-related adverse reactions, such as atrial fibrillation and cardiac failure, were fatal AEs associated with ibrutinib. Our results provide a rationale for physicians to choose suitable BTK inhibitors for different patients and provide appropriate monitoring to achieve safer therapy and longer survival.

Academic Map and Hotspot Analysis of China's Legal Construction Research since the Eighteenth National Congress of the Communist Party of China: Visual Analysis Based on CiteSpace.

Since the 18th National Congress of the Communist Party of China, the research on the construction of the rule of law in China has received keen attention from scholars. In this study, CSSCI literature published from 2012 to 2022 included in CNKI, Beijing Wanfang, and Chongqing VIP Chinese databases were used as data templates. NoteExpress software was used to deduplicate and organize, and 4,603 literature related to the construction of the rule of law in China were obtained. The citespace5.8 software has carried out a visual analysis, and the results show that: (1) The research on the "rule of law China" as the overall concept in the academic circle first appeared in 2013, and the overall stability was stable, and the local volatility increased. (2) The relationship between researchers and research institutions in this field is relatively loose, and the high-yield author group has not yet been formed. (3) Through the visualization of keyword co-occurrence map and keyword clustering map and the analysis of high-frequency words and centrality, four academic maps and research hotspots are mainly proposed: core cognition of the construction of the rule of law in China, internal theory, external Practice orientation and construction path. (4) Future research on the construction of the rule of law in China strengthens the legal response to scientific and technological information, pays attention to the research on foreign-related fields of the construction of the rule of law in China, and insists on promoting the combination of "domestic rule of law" and "foreign rule of law."

The Role of Long Non-Coding RNAs in Epithelial-Mesenchymal Transition-Related Signaling Pathways in Prostate Cancer.

Prostate cancer (PCa) is one of the most common male malignancies with frequent remote invasion and metastasis, leading to high mortality. Epithelial-mesenchymal transition (EMT) is a fundamental process in embryonic development and plays a key role in tumor proliferation, invasion and metastasis. Numerous long non-coding RNAs (lncRNAs) could regulate the occurrence and development of EMT through various complex molecular mechanisms involving multiple signaling pathways in PCa. Given the importance of EMT and lncRNAs in the progression of tumor metastasis, we recapitulate the research progress of EMT-related signaling pathways regulated by lncRNAs in PCa, including AR signaling, STAT3 signaling, Wnt/ß-catenin signaling, PTEN/PI3K/AKT signaling, TGF-ß/Smad and NF-κB signaling pathways. Furthermore, we summarize four modes of how lncRNAs participate in the EMT process of PCa via regulating relevant signaling pathways.

Hematologic toxicities of sunitinib in patients with gastrointestinal stromal tumors: a systematic review and meta-analysis.

PURPOSE: Sunitinib offers a significant survival benefit to patients with imatinib-resistant gastrointestinal stromal tumors (GIST). However, the incidence and risk of sunitinib-induced hematologic toxicities in such a population are often overlooked and have not been well characterized. This meta-analysis was performed to assess the summary incidence and risk of hematologic toxicities secondary to sunitinib in patients with GIST. METHODS: Searches were performed in PubMed, Embase, Cochrane Library, and Web of Science as well as ClinicalTrials.gov to identify relevant studies up to April 2022. Studies with adequate safety profile, including anemia, neutropenia, and thrombocytopenia, were included to calculate the pooled incidence, relative risk (RR), and corresponding 95% confidence intervals (CIs). This study was registered with PROSPERO under number CRD42022328202. RESULTS: A total of 2593 patients from 13 studies were included in the present meta-analysis. For patients with GIST assigned to sunitinib, the overall incidences of all-grade anemia, neutropenia, and thrombocytopenia were 26.2% (95% CI, 14.9-39.4%), 41.8% (95% CI, 29.0-55.1%), and 36.4% (95% CI, 22.8-51.1%), respectively. Regarding high-grade (grades 3 and 4) events, there were 4.7% (95% CI, 3.8-5.6%) for anemia, 9.3% (95% CI, 5.6-13.7%) for neutropenia and 5.0% (95% CI, 2.9-7.3%) for thrombocytopenia. Compared to placebo arms, sunitinib was related to an increased risk of high-grade neutropenia with an RR of 10.39 (95% CI, 1.53-70.72; p = 0.017). CONCLUSIONS: Sunitinib carries a relatively high incidence of hematologic toxicities and a substantial increased risk of high-grade neutropenia in patients with GIST. Appropriate prevention and management seem to be inevitable.

Formation of Iridium(III) and Rhodium(III) Amine, Imine, and Amido Complexes Based on Pyridine-Amine Ligands: Structural Diversity Arising from Reaction Conditions, Substituent Variation, and Metal Centers.

Herein, we present the different coordination modes of half-sandwich iridium(III) and rhodium(III) complexes based on pyridine-amine ligands. The pyridyl-amine iridium(III) and rhodium(III) complexes, the corresponding oxidation pyridyl-imine products, and 16-electron pyridyl-amido complexes can be obtained through the change in reaction conditions (nitrogen/adventitious oxygen atmosphere, reaction time, and solvents) and structural variations in the metal and ligand. Overall, the reaction of pyridine-amine ligands with [(η5-C5(CH3)5)MCl2]2 (M = Ir or Rh) in the presence of adventitious oxygen afforded the oxidized pyridyl-imine complexes. The possible mechanism for the oxidation of iridium(III) and rhodium(III) amine complexes was confirmed by the detection of the byproduct hydrogen peroxide. Moreover, the formation of pyridyl-amine complexes was favored when nonpolar solvent CH2Cl2 was used instead of CH3OH. The rarely reported complex with [(η5-Cp*)IrCl3] anions can also be obtained without the addition of NH4PF6. The introduction of the sterically bulky i-Bu group on the bridge carbon of the ligand led to the formation of stable 16-electron pyridyl-amido complexes. The pyridyl-amine iridium(III) and rhodium(III) complexes were also synthesized under a N2 atmosphere, and no H2O2 was detected in the whole process. In particular, the aqueous solution stability and in vitro cytotoxicity toward A549 and HeLa human cancer cells of these complexes were also evaluated. No obvious selectivity was observed for cancer cells versus normal cells with these complexes. Notably, the represented complex 5a can promote an increase in the reactive oxygen species level and induce cell death via apoptosis.

3' untranslated region variants in DEFA5 gene associated with susceptibility to IgA nephropathy in the Chinese Han population.

Aim: To evaluate the association between single-nucleotide polymorphisms in the 3' untranslated region of the DEFA5 gene and IgA nephropathy (IgAN) risk, the authors performed an association study in the Chinese Han population. Materials & methods: The authors recruited 426 IgAN patients and 498 controls. The MassARRAY platform (Agena Bioscience, Inc., CA, USA) was used to genotype single-nucleotide polymorphisms in DEFA5. Odds ratios and 95% CIs were calculated through logistic regression analysis. Results: The authors observed that rs12716641 significantly reduced IgAN risk in the allele (odds ratio: 0.77; p = 0.026) and genotype (odds ratio: 0.75; p = 0.039) models. Stratification analysis revealed that several genotypes of rs12716641 played a protective role against IgAN. Conclusion: The authors' results revealed that single-nucleotide polymorphisms in the 3' untranslated region of DEFA5 were associated with IgAN risk.

Machine learning-based method for tacrolimus dose predictions in Chinese kidney transplant perioperative patients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC), a first-line immunosuppressant in solid-organ transplant, has a narrow therapeutic window and large inter-individual variability, which affects its use in clinical practice. Successful predictions using machine learning algorithms have been reported in several fields. However, a comparison of 10 machine learning model-based TAC pharmacogenetic and pharmacokinetic dosing algorithms for kidney transplant perioperative patients of Chinese descent has not been reported. The objective of this study was to screen and establish an appropriate machine learning method to predict the individualized dosages of TAC for perioperative kidney transplant patients. METHODS: The records of 2551 patients were collected from three transplant centres, 80% of which were randomly selected as a 'derivation cohort' to develop the dose prediction algorithm, while the remaining 20% constituted a 'validation cohort' to validate the final algorithm selected. Important features were screened according to our previously established population pharmacokinetic model of tacrolimus. The performances of the algorithms were evaluated and compared using R-squared and the mean percentage in the remaining 20% of patients. RESULTS AND DISCUSSION: This study identified several factors influencing TAC dosage, including CYP3A5 rs776746, CYP3A4 rs4646437, haematocrit, Wuzhi capsules, TAC daily dose, age, height, weight, post-operative time, nifedipine and the medication history of the patient. According to our results, among the 10 machine learning models, the extra trees regressor (ETR) algorithm showed the best performance in the training set (R-squared: 1, mean percentage within 20%: 100%) and test set (R-squared: 0.85, mean percentage within 20%: 92.77%) of the derivation cohort. The ETR model successfully predicted the ideal TAC dosage in 97.73% of patients, especially in the intermediate dosage range (>5 mg/day to <8 mg/day), whereby the ideal TAC dosage could be successfully predicted in 99% of the patients. WHAT IS NEW AND CONCLUSION: The results indicated that the ETR algorithm, which was chosen to establish the dose prediction model, performed better than the other nine machine learning models. This study is the first to establish ETR algorithms to predict TAC dosage. This study will further promote the individualized medication of TAC in kidney transplant patients in the future, which has great significance in ensuring the safety and effectiveness of drug use.

Epidemiology of hospitalizations due to pesticide intoxication-associated acute kidney injury in China.

BACKGROUND: There is a paucity of epidemiological data regarding pesticide intoxication-associated acute kidney injury (AKI). Therefore, the aim of this study was to identify the epidemiological features, risk factors, and adverse outcomes of AKI in this population. METHODS: The data used in this multi-center, hospitalized population-based, retrospective study were retrieved from electronic medical records. AKI was defined as an acute increase in serum creatinine according to the criteria of Kidney Disease: Improving Global Outcomes. The Charlson Comorbidity Index was used to evaluate the burden of in-hospital mortality. RESULTS: Of 3,371 adult patients in 11 hospitals, 398 (11.8%) were diagnosed with AKI (grade 1, 218 [6.5%]; grade 2, 89 [2.6%]; grade 3, 91 [2.7%]). Herbicide intoxication was associated with the highest incidence of AKI (53.5%) and higher grades of AKI. After multivariable adjustment, pesticide categories and moderate or severe renal disease were independently associated with AKI. As compared with the referred category, insecticide and herbicide intoxications were associated with a 1.3-fold (95% CI 1.688-3.245) and 3.8-fold (95% CI 3.537-6.586) greater risk of AKI. Regardless of the pesticide category, AKI was independently associated with in-hospital mortality, with odds ratios of 3.433 (95% CI 1.436-8.203) for insecticides, 2.153 (95% CI 1.377-3.367) for herbicides, and 4.524 (95% CI 1.230-16.632) for unclassified or other pesticides. CONCLUSION: AKI is common in pesticide intoxication and associated with an increased in-hospital mortality. Herbicides pose the greatest risks of AKI and death.

COVID-19 and gastroenteric manifestations.

Coronavirus disease 2019 (COVID-19), caused by the infection of a novel coronavirus [severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)], has become a pandemic. The infection has resulted in about one hundred million COVID-19 cases and millions of deaths. Although SARS-CoV-2 mainly spreads through the air and impairs the function of the respiratory system, it also attacks the gastrointestinal epithelial cells through the same receptor, angiotensin converting enzyme 2 receptor, which results in gastroenteric symptoms and potential fecal-oral transmission. Besides the infection of SARS-CoV-2, the treatments of COVID-19 also contribute to the gastroenteric manifestations due to the adverse drug reactions of anti-COVID-19 drugs. In this review, we update the clinical features, basic studies, and clinical practices of COVID-19-associated gastroenteric manifestations.

Population pharmacokinetic analysis and dosing guidelines for tacrolimus co-administration with Wuzhi capsule in Chinese renal transplant recipients.

WHAT IS KNOWN AND OBJECTIVES: Tacrolimus (TAC) is a first-line immunosuppressant which is used to prevent transplant rejection after solid organ transplantation (SOT). However, it has a narrow therapeutic index and high individual variability in pharmacokinetics (PK) and pharmacogenomics (PG). It has been reported that the metabolism of TAC can be affected by genetic factors, leading to different rates of metabolism in different subjects. Wuzhi Capsule (WZC) is a commonly used TAC-sparing agent in Chinese SOT to reduce TAC dosing due to its inhibitory effect on TAC metabolism by enzymes of the CYP3A subfamily. The aims of this study were to assess the effect of TAC+WZC co-administration and genetic polymorphism on the pharmacokinetics of TAC, by using a population pharmacokinetic (PPK) model. A dosing guideline for individualized TAC dosing is proposed based on the PPK study. METHODS: The medical records of 165 adult patients with kidney transplant and their 824 TAC concentrations from two kidney transplantation centres were reviewed. The genotypes of four single-nucleotide polymorphisms (SNPs) in CYP3A5*3 and ABCB1 (rs1128503, rs2032582 and rs1045642) were tested by MASSARRAY. A PPK model was constructed by nonlinear mixed effect model (NONMEM® , Version 7.3). Finally, Monte Carlo simulations were employed to design initial dosing regimens based on the final model. RESULTS AND DISCUSSION: The one-compartmental PPK model with first-order absorption and elimination of TAC was established in kidney transplant recipients (KTRs). CYP3A5*3 had significant impact on the PPK model. The haematocrit (HCT), postoperative time (POD) and CYP3A5*3 genotypes had a significant influence on TAC clearance when combined with WZC. The model was expressed as 23.4 × (HCT/0.3)-0.729  × 0.837 (combination with WZC) × e-0.0875(POD/12.6) ×1.18 (CYP3A5 expressors). For patients carrying the CYP3A5*3/*3 allele and with 30% HCT, the required TAC dose to achieve target trough concentrations of 10-15 ng/ml was 4 mg twice daily (q12h). For patients with the CYP3A5*3/*3 allele, the required dose was 3 mg TAC q12h when combined with WZC, and for patients with the CYP3A5*1/*1 or *1/*3 allele, the required dose was 4 mg of TAC q12h when co-administered with WZC. WHAT IS NEW AND CONCLUSION: Wuzhi Capsule co-administration and CYP3A5 variants affect the PK of TAC Dosing guidelines are made based on the PPK model to allow individualized administration of TAC, especially when co-administered with WZC.