Clinical manifestation, epidemiology, genetic basis, potential molecular targets, and current treatment of polycystic liver disease.

Polycystic liver disease (PLD) is a rare condition observed in three genetic diseases, including autosomal dominant polycystic liver disease (ADPLD), autosomal dominant polycystic kidney disease (ADPKD), and autosomal recessive polycystic kidney disease (ARPKD). PLD usually does not impair liver function, and advanced PLD becomes symptomatic when the enlarged liver compresses adjacent organs or increases intra-abdominal pressure. Currently, the diagnosis of PLD is mainly based on imaging, and genetic testing is not required except for complex cases. Besides, genetic testing may help predict patients' prognosis, classify patients for genetic intervention, and conduct early treatment. Although the underlying genetic causes and mechanisms are not fully understood, previous studies refer to primary ciliopathy or impaired ciliogenesis as the main culprit. Primarily, PLD occurs due to defective ciliogenesis and ineffective endoplasmic reticulum quality control. Specifically, loss of function mutations of genes that are directly involved in ciliogenesis, such as Pkd1, Pkd2, Pkhd1, and Dzip1l, can lead to both hepatic and renal cystogenesis in ADPKD and ARPKD. In addition, loss of function mutations of genes that are involved in endoplasmic reticulum quality control and protein folding, trafficking, and maturation, such as PRKCSH, Sec63, ALG8, ALG9, GANAB, and SEC61B, can impair the production and function of polycystin1 (PC1) and polycystin 2 (PC2) or facilitate their degradation and indirectly promote isolated hepatic cystogenesis or concurrent hepatic and renal cystogenesis. Recently, it was shown that mutations of LRP5, which impairs canonical Wnt signaling, can lead to hepatic cystogenesis. PLD is currently treated by somatostatin analogs, percutaneous intervention, surgical fenestration, resection, and liver transplantation. In addition, based on the underlying molecular mechanisms and signaling pathways, several investigational treatments have been used in preclinical studies, some of which have shown promising results. This review discusses the clinical manifestation, complications, prevalence, genetic basis, and treatment of PLD and explains the investigational methods of treatment and future research direction, which can be beneficial for researchers and clinicians interested in PLD.

Recent progress in the immunotherapy of hepatocellular carcinoma: Non-coding RNA-based immunotherapy may improve the outcome.

Hepatocellular carcinoma (HCC) is the second most lethal cancer and a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) significantly improved the prognosis of HCC; however, the therapeutic response remains unsatisfactory in a substantial proportion of patients or needs to be further improved in responders. Herein, other methods of immunotherapy, including vaccine-based immunotherapy, adoptive cell therapy, cytokine delivery, kynurenine pathway inhibition, and gene delivery, have been adopted in clinical trials. Although the results were not encouraging enough to expedite their marketing. A major proportion of human genome is transcribed into non-coding RNAs (ncRNAs). Preclinical studies have extensively investigated the roles of ncRNAs in different aspects of HCC biology. HCC cells reprogram the expression pattern of numerous ncRNAs to decrease the immunogenicity of HCC, exhaust the cytotoxic and anti-cancer function of CD8 + T cells, natural killer (NK) cells, dendritic cells (DCs), and M1 macrophages, and promote the immunosuppressive function of T Reg cells, M2 macrophages, and myeloid-derived suppressor cells (MDSCs). Mechanistically, cancer cells recruit ncRNAs to interact with immune cells, thereby regulating the expression of immune checkpoints, functional receptors of immune cells, cytotoxic enzymes, and inflammatory and anti-inflammatory cytokines. Interestingly, prediction models based on the tissue expression or even serum levels of ncRNAs could predict response to immunotherapy in HCC. Moreover, ncRNAs markedly potentiated the efficacy of ICIs in murine models of HCC. This review article first discusses recent advances in the immunotherapy of HCC, then dissects the involvement and potential application of ncRNAs in the immunotherapy of HCC.

Metformin and long non-coding RNAs in breast cancer.

Breast cancer (BC) is the second most common cancer and cause of death in women. In recent years many studies investigated the association of long non-coding RNAs (lncRNAs), as novel genetic factors, on BC risk, survival, clinical and pathological features. Recent studies also investigated the roles of metformin treatment as the firstline treatment for type 2 diabetes (T2D) played in lncRNAs expression/regulation or BC incidence, outcome, mortality and survival, separately. This comprehensive study aimed to review lncRNAs associated with BC features and identify metformin-regulated lncRNAs and their mechanisms of action on BC or other types of cancers. Finally, metformin affects BC by regulating five BC-associated lncRNAs including GAS5, HOTAIR, MALAT1, and H19, by several molecular mechanisms have been described in this review. In addition, metformin action on other types of cancers by regulating ten lncRNAs including AC006160.1, Loc100506691, lncRNA-AF085935, SNHG7, HULC, UCA1, H19, MALAT1, AFAP1-AS1, AC026904.1 is described.

Antibiotic use Evaluation in Hospitalized Pediatric Patients with Respiratory Tract Infections: A Retrospective Chart Review Study.

INTRODUCTION: Respiratory tract infections (RTIs) are a common cause of antibiotic usage in hospitalized pediatric patients. Inappropriate use of antibiotics may lead to the emergence of multidrug-resistant microorganisms and increased treatment costs. OBJECTIVE: This study was designed to assess antibiotic usage in hospitalized pediatric patients with RTIs. METHODS: Medical charts of the patients admitted to the pediatric ward (PW) and pediatric intensive care unit (PICU) of a tertiary respiratory center were reviewed. Patients' demographic and clinical data, including gender, age, weight, history of allergy, length of hospital stay, clinical diagnosis, and prescribed antibiotics (indication, dose, and frequency of administration) were collected. The appropriateness of antibiotic usage was evaluated in each patient according to international guidelines. RESULTS: Two hundred seventy-nine hospitalized patients were included in the study. The most common reason for hospitalization was pneumonia (38%), followed by cystic fibrosis (20.1%) and bronchitis (5%). The most commonly used antimicrobial agents were ceftriaxone, azithromycin, and clindamycin which guideline adherence for their usage was 85.3%, 23.3%, and 47%; respectively. Inappropriate dose selection was the main reason for non-adherence to the guidelines. The adherence rate to RTIs' guidelines (considering all parameters for each patient) was 27.6%. Multivariate logistic regression analysis demonstrated CF and prescription of azithromycin are predictors of guideline non-adherence. CONCLUSION: We found relatively low adherence to international guidelines in our center that could be related to restricted definitions of optimal antibiotic therapy. Despite most patients received logical antimicrobial therapy, actions should be taken into account to reach optimal antibiotic usage.

Potential drug-drug interactions in hospitalized pediatric patients with respiratory disorders: a retrospective review of clinically important interactions.

Background Hospitalized pediatric patients are at an increased risk of experiencing potential drug-drug interactions (pDDIs) due to polypharmacy and the unlicensed and off-label administration of drugs. The aim of this study is to characterize clinically significant pDDIs in pediatric patients hospitalized in a tertiary respiratory center. Methods A retrospective analysis of medications prescribed to pediatric patients admitted to the pediatric ward (PW) and pediatric intensive care unit (PICU) of a respiratory referral center was carried out over a six-month period. The pDDIs were identified using the Lexi-Interact database and considered as clinically relevant according to the severity rating as defined in the database. Frequency, drug classes, mechanisms, clinical managements, and risk factors were recorded for these potential interactions. Results Eight hundred and forty-five pDDIs were identified from the analysis of 176 prescriptions. Of the total pDDIs, 10.2% in PW and 14.6% in PICU were classified as clinically significant. Anti-infective agents and central nervous system drugs were the main drug classes involved in clinically significant pDDIs as object and/or precipitant drugs. A higher number of medications [odds ratio (OR): 4.8; 95% confidence interval (CI): 2.0-11.4; p < 0.001] and the existence of a nonrespiratory disease, which led to a respiratory disorder (OR: 3.8; 95% CI: 1.40-10.4; p < 0.05), were the main risk factors associated with an increased incidence of pDDIs. Conclusions A high and similar risk of pDDIs exists in pediatric patients with respiratory disorders hospitalized in PW and PICU. The patients prescribed a higher number of medications and presenting respiratory symptoms induced by a nonrespiratory disease require extra care and monitoring. Pediatricians should be educated about clinically significant DDIs for highly prescribed medications in their settings in order to take preventive measures and safeguard patient safety.

Clinically important drug-drug interactions in patients admitted to hospital with COVID-19: drug pairs, risk factors, and management.

OBJECTIVES: Coronavirus disease 2019 (COVID-19) is an emerging viral infection without any approved treatment. Investigational therapies for COVID-19 may cause clinically important drug-drug interactions (DDIs). We aimed to study potential DDIs (pDDIs) and their risk factors in COVID-19 patients admitted to the hospital. METHODS: We conducted a cross-sectional study in a tertiary respiratory hospital dedicated to COVID-19 patients. The Lexi-Interact database was used to investigate clinically important pDDIs. The database output including interacting drug pairs, risk rating, reliability rating, mechanism, and management was evaluated. Associations between the occurrence of pDDIs and probable risk factors were assessed by logistic regression analysis. RESULTS: Medical charts of 227 patients were reviewed. About 38% of the patients had at least one clinically important pDDI. More than half of the interactions were between protease inhibitors (lopinavir/ritonavir) and regularly prescribed medications for the management of comorbidities or COVID-19 symptoms (e.g., atorvastatin, alprazolam, salmeterol, and tamsulosin). Ischemic heart disease, chronic respiratory diseases, and ICU admission were significantly associated with the occurrence of pDDIs. CONCLUSIONS: We recommend considering the risk factors for the emergence of clinically important DDIs in the pharmacotherapy of COVID-19 patients. Using an alternative medication or dose adjustments may be required in high-risk patients.

Effect of Adding Magnesium Sulphate to Epidural Bupivacaine and Morphine on Post-Thoracotomy Pain Management: A Randomized, Double-Blind, Clinical Trial.

Post-thoracotomy pain is very severe and may cause pulmonary complications. Thoracic epidural analgesia can greatly decrease the pain experience and its consequences. However, finding new methods to decrease the amount of administered opioids is an important issue of research. We aimed to evaluate the effect of adding epidural magnesium sulphate to bupivacaine and morphine on pain control and the amount of opioid consumption after thoracotomy. Eighty patients undergoing thoracotomy at a tertiary cardiothoracic referral centre were enrolled in a randomized, double-blind trial. Patients were randomly allocated to two groups. Bupivacaine (12.5 mg) and morphine (2 mg) were administered epidurally to all patients at the end of operation. Patients in the magnesium (Mg) group received epidural magnesium sulphate (50 mg), and patients in the control (C) group received normal saline as an adjuvant. Visual analogue scale (VAS) score and the amount of morphine consumption were measured during 24 hr post-operation. Thirty-nine patients in the Mg group and 41 patients in the C group completed the study. Patients in the Mg group had significantly less VAS score at recovery time (p < 0.05), 2 hr (p < 0.01) and 4 hr (p < 0.05) after surgery. The patient-controlled analgesia pump was started earlier in the C group than in the Mg group (p < 0.05). The amount of morphine needed in the Mg group was significantly lower than in the C group (5.64 ± 1.69 mg/24 hr versus 8.44 ± 3.98 mg/24 hr; p < 0.001). Pruritus was seen in the C group (9.7%) and absent in the Mg group (p < 0.05). Co-administration of magnesium sulphate with bupivacaine and morphine for thoracic epidural analgesia after thoracotomy leads to a reduction in post-operative pain score and the need for opioid administration.