Therapy-induced senescent cancer cells exhibit complement activation and increased complement regulatory protein expression.

Therapy-induced senescence (TIS) is a primary response to chemotherapy, contributing to untoward treatment outcomes such as evasion of immunosurveillance. Despite the established role of the complement system in the immune response to cancer, the role of complement in mediating the immune response against senescent tumor cells remains poorly understood. To explore this relationship, we exposed lung adenocarcinoma (A549), breast adenocarcinoma (MCF7) and pancreatic carcinoma (Panc-1) cell lines to sublethal doses of either etoposide or doxorubicin to trigger TIS. Identification of TIS was based on morphological changes, upregulation of the senescence-associated ß-galactosidase, p21Cip1 induction and lamin B1 downregulation. Using immunofluorescence microscopy, quantitative PCR, ELISA of conditioned media and in silico analysis, we investigated complement activation, complement protein expression, C3 levels in the conditioned media of senescent cells and secreted complement proteins as part of the senescence-associated secretory phenotype (SASP), respectively. In cell lines undergoing TIS, complement-related changes included (i) activation of the terminal pathway, evidenced by the deposition of C5b-9 on senescent cells; (ii) an increase in the expression of CD59 and complement factor H and (iii) in A549 cells, an elevation in the expression of C3 with its secretion into the medium. In addition, increased C3 expression was observed in breast cancer samples expressing TIS hallmarks following exposure to neoadjuvant chemotherapy. In conclusion, TIS led to the activation of complement, upregulation of complement regulatory proteins and increased C3 expression. Complement appears to play a role in shaping the cancer microenvironment upon senescence induction.

A potential toxicological risk assessment of heavy metals and pesticides in irrigated rice cultivars near industrial areas of Dhaka, Bangladesh.

Rice intake represents a significant pathway through which humans accumulate heavy metals. This study presents a comprehensive analysis of heavy metal and pesticide contamination in rice cultivars irrigated with industrial wastewater near Dhaka, Bangladesh, a region heavily influenced by industrial activities. This study employed a unique methodology that not only quantified the concentrations of heavy metals and pesticide residues in rice grains but also extended to evaluating the physicochemical properties of rice stems, husks, soil, and irrigation water. The findings revealed alarmingly high levels of heavy metals such as lead, cadmium, chromium, nickel, and mercury in the soil and irrigation water, with concentrations in some cases exceeding the World Health Organization safety thresholds by 2 to 15 times. Notably, the rice grains also exhibited significant contamination, including substantial amounts of diazinon and fenitrothion pesticides, exceeding the established safety limits. The study employed hazard quotients (HQs) and cancer risk (CR) assessments to evaluate the potential health risks associated with the consumption of contaminated rice. The results indicated HQ values were greater than 1 for rice grains across the sampled fields, suggesting a considerable non-carcinogenic health risk, particularly from lead exposure, which was found at levels twice the standard limit in all the sampling fields. Moreover, the CR values for As, Pb, Cd, Co, and Mn highlighted a significant carcinogenic risk in several instances.

Aryl Hydrocarbon Receptor as an Anticancer Target: An Overview of Ten Years Odyssey.

Aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor belonging to the basic helix-loop-helix (bHLH)/per-Arnt-sim (PAS) superfamily, is traditionally known to mediate xenobiotic metabolism. It is activated by structurally diverse agonistic ligands and regulates complicated transcriptional processes through its canonical and non-canonical pathways in normal and malignant cells. Different classes of AhR ligands have been evaluated as anticancer agents in different cancer cells and exhibit efficiency, which has thrust AhR into the limelight as a promising molecular target. There is strong evidence demonstrating the anticancer potential of exogenous AhR agonists including synthetic, pharmaceutical, and natural compounds. In contrast, several reports have indicated inhibition of AhR activity by antagonistic ligands as a potential therapeutic strategy. Interestingly, similar AhR ligands exert variable anticancer or cancer-promoting potential in a cell- and tissue-specific mode of action. Recently, ligand-mediated modulation of AhR signaling pathways and the associated tumor microenvironment is emerging as a potential approach for developing cancer immunotherapeutic drugs. This article reviews advances of AhR in cancer research covering publication from 2012 to early 2023. It summarizes the therapeutic potential of various AhR ligands with an emphasis on exogenous ligands. It also sheds light on recent immunotherapeutic strategies involving AhR.

Evaluation of the efficacy and relapse rates of treatment protocols for moderate acne using isotretinoin based on the global acne grading system: Randomized, controlled, comparative study.

Protocols for treating acne with isotretinoin have varied widely because some factors associated with relapse and treatment duration have not yet been fully determined. This paper evaluates the effectiveness of conventional, low, and intermittent isotretinoin dosage protocols in the treatment of moderate acne and investigates the relationships between GAGS score, treatment duration and relapse rate. The 107 patients with moderate acne were randomly divided into three groups who received isotretinoin for 24 weeks (Group A: 0.5-1 mg/kg/day; Group B: 0.25-0.4 mg/kg/day; Group C: 0.5-0.7 mg/kg/day for 1 week out of every 4 weeks). The results show that both conventional and continuous low doses achieved full clinical effectiveness with minimum relapse rates. However, fewer side effects and better patient satisfaction were reported with the low dose. Significant differences in GAGS scores after 24 weeks were found between groups B and C (p = 0.037) and between groups A and C (p < 0.001), while no significant differences were found between groups A and B (p = 0.153). It was observed that relapse rate increased with initial GAGS score. The average relapse rate was 58.0% for those with initial GAGS scores of 25-30 compared with 5.5% for those with scores of 19-24. It was also noticed that, among the patients who relapsed, the highest percentage (56.3%) were in the age group <20 years. However, GAGS (ß = 0.646, t = 8.323, p < 0.001) was found to be a better predictor of relapse than age (ß = 0.083, t = 1.073, p = 0.286). These results suggest that initial GAGS score is an important factor in determining the treatment protocol for moderate acne. Furthermore, this study recommends that a low-dose treatment is most suitable when GAGS <25, as it can achieve complete clearance of acne with minimal relapses and side effects.

Multiple vas deferens with polyorchidism and many congenital malformations in a symptomatic 11-year-old male patient: a rare case report.

BACKGROUND: Ductus deferens may manifest in a variety of anomalies such as its absence, duplication, ectopy, or diverticulum. Ectopic seminal tract opening has two main types, ectopic ejaculatory duct opening, and ectopic vas deferens opening. Generally, ductus deferens anomalies affect approximately 0.05% of the population. Patients may be asymptomatic or complaining of urinary tract infections and/or epididymitis. Most of these cases are associated with renal dysplasia. To confirm the diagnosis Cystourethroscopy catheterization and retrograde urethrogram should be performed, but the definitive diagnosis is done by vasography. The definitive treatment is complete surgical resection of the pathological urogenital connection. This case is commonly discovered while exploring other findings such as testicular torsion and inguinal hernia. CASE PRESENTATION: We report a rare case of an 11-year-old male who presented with gross hematuria and numerous congenital malformations including a left polydactyly clubfoot, polyorchidism, with several surgical procedures, and left kidney dysgenesis. Surgery was performed for a left inguinal hernia, during which a third undescended testicle was discovered incidentally and was eradicated. A retrograde urethrogram was performed to establish the diagnosis. A fistula- that is connected with the left ureter- was resected. The histopathologic findings confirmed the diagnosis of true duplication of the Vas deferens, with communication between the ureter and the vas deferens. By follow-up, the kidney function tests were within normal limits. CONCLUSIONS: This case report aims to highlight the early diagnosis and management of the duplicated vas deferens and the associated congenital malformations to improve the prognosis and kidney function and to avoid long-term complications.

Thidiazuron suppresses breast cancer via targeting miR-132 and dysregulation of the PI3K-Akt signaling pathway mediated by the miR-202-5p-PTEN axis.

Chemo-resistance and metastasis are the most common causes of breast cancer recurrence and death. Thidiazuron (TDZ) is a plant growth regulator (phytohormone) whose biological effects on humans and animals has not yet been determined. In this study, we investigated the anticancer activity of this phytohormone on the drug resistant-triple negative breast cancer cell line MDA-MB-231. Treatment of the breast cancer cells with TDZ (1-50 µmol/L) caused more stressful environment and induced a significant increase in active caspase-positive cells. In addition, TDZ treatment (5 and 10 µmol/L) significantly attenuated the migration and the invasiveness of these highly metastatic cancer cells. Mechanistically, TDZ reduces cancer progression and invasiveness by targeting miR-202-5p, which stimulates the expression of phosphatase and tensin homolog (PTEN), the tumor suppressor that downregulates the PI3K-Akt signaling pathway. Treatment with TDZ significantly upregulates miRNA-132, the suppressor of breast cancer proliferation, which is also implicated in dysregulation of the TEN-Akt-NFκB signaling pathway. Interestingly, our molecular docking analysis revealed a potential non-covalent interaction between TDZ and Akt, PTEN, and PI3K. These findings suggest that TDZ suppresses breast cancer metastasis by targeting miRNA-132, the miR-202-5p-PTEN axis, and the PI3K-Akt signaling pathway downstream.

Endoscopic transmission of carbapenem-resistant Enterobacteriaceae: implications for U.S. Food and Drug Administration approval and postmarket surveillance of endoscopic devices.

Since the first widely reported case cluster of duodenoscope-associated transmission of carbapenem-resistant Enterobacteriaceae (CRE) in 2013 that affected 38 patients, similar outbreaks have occurred throughout the world. The U.S. Food and Drug Administration (FDA), Centers for Disease Control and Prevention, professional gastroenterology societies, and endoscope manufacturers have taken multiple steps to address this issue. Unlike prior outbreaks attributed to lapses in cleaning and reprocessing, transmission and outbreaks have continued to occur despite compliance with current reprocessing guidelines. A definitive method of duodenoscope reprocessing remains elusive, and the FDA recently recommended transition to new designs with disposable components that do not require reprocessing. The first fully disposable duodenoscope received FDA clearance as a "breakthrough" device in December 2019. Although the human, microbiologic, and endoscopic design factors responsible for infectious transmissions and disinfecting techniques to avoid them have been examined, discussion has not included the critical role of FDA regulation of duodenoscopes through the 510(k) clearance pathway and the mechanisms of postmarket surveillance, including adverse event reporting. We present an overview of the FDA approval of duodenoscopes by analyzing the FDA's 510(k) premarket notification database for data supporting clearance of duodenoscope models implicated in CRE-related outbreaks as well as subsequently required postmarket studies. We address the policy implications of CRE outbreaks on postmarketing surveillance and the need for increased gastroenterologist involvement in the life cycle of duodenoscopes and other medical devices. This includes reporting thorough adverse event data to the FDA and device manufacturers, supporting active surveillance studies to ensure safety and effectiveness, and evaluating implementation of recommendations to reduce adverse events.

Role of routine second-look endoscopy in patients with acute peptic ulcer bleeding: meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Studies evaluating the role of routine second-look endoscopy in patients with acute upper GI bleed because of peptic ulcer disease (PUD) have reported conflicting results. This meta-analysis evaluates the usefulness of routine second-look endoscopy in these patients. METHODS: We reviewed several databases from inception to September 15, 2020 to identify randomized controlled trials (RCTs) that compared routine second-look endoscopy with no planned second-look endoscopy in patients with acute upper GI bleed because of PUD. Our outcomes of interest were recurrent bleeding, mortality, need for surgery, and mean number of units of blood transfused. For categorical variables, we calculated pooled risk ratios (RRs) with 95% confidence intervals (CIs); for continuous variables, we calculated standardized mean difference with 95% CIs. Data were analyzed using a random effects model. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework to ascertain the quality of evidence. RESULTS: We included 9 RTCs comprising 1452 patients; 726 patients underwent planned/routine second-look endoscopy and 726 did not. We found no significant difference in recurrent bleeding (RR, .79; 95% CI, .51-1.23), need for surgery (RR, .58; 95% CI, .29-1.15), mortality (RR, .69; 95% CI, .33-1.45), or mean number of units of blood transfused (standardized mean difference, -.06; 95% CI, -.19 to .07). Quality of evidence ranged from low to moderate based on the GRADE framework. CONCLUSIONS: Single endoscopy with complete endoscopic hemostasis is not inferior to routine second-look endoscopy in reducing the risk of recurrent bleeding, mortality, or need for surgery in patients with acute upper GI bleed because of PUD.

Peroral Endoscopic Myotomy Is a Safe and Feasible Option in Management of Esophageal Diverticula: Systematic Review and Meta-Analysis.

Esophageal diverticula can cause significant symptoms and affect the quality of life. There has been recent interest in the use of peroral endoscopic myotomy in the management of esophageal diverticula (D-POEM). In this meta-analysis, we have evaluated the efficacy and safety of D-POEM in the management of esophageal diverticula. Several databases were reviewed from inception to 6/19/2020 to identify the studies evaluating the feasibility, efficacy and safety of D-POEM in the management of esophageal diverticula. Our outcomes of interest were technical success, adverse events and difference in mean pre- and post-procedure symptom score. We performed subgroup analysis including patients with Zenker's diverticulum who underwent POEM (Z-POEM). Pooled rates with 95% confidence intervals (CI) for all outcomes were calculated using random effect model. We calculated standard mean difference (SMD) with 95% CI to compare mean pre- and post-procedure symptom score. We included 7 studies with 233 patients. For D-POEM, pooled rates (95% CI) for technical success and adverse events were 95% (91%, 97%) and 6% (3%, 10%) respectively. For Z-POEM, pooled rates (95% CI) for technical success and adverse events were 95% (90%, 97%) and 6% (3%, 10%) respectively. Mean post-procedure symptom score for all patients who underwent D-POEM was significantly lower compared to mean pre-procedure symptom score, SMD (95% CI) 2.17 (1.51, 2.83).  This meta-analysis demonstrated that D-POEM is a safe and feasible option for patients with symptomatic esophageal diverticula.

Mangiferin Inhibits Apoptosis in Doxorubicin-Induced Vascular Endothelial Cells via the Nrf2 Signaling Pathway.

Doxorubicin increases endothelial permeability, hence increasing cardiomyocytes' exposure to doxorubicin (DOX) and exposing myocytes to more immediate damage. Reactive oxygen species are major effector molecules of doxorubicin's activity. Mangiferin (MGN) is a xanthone derivative that consists of C-glucosylxanthone with additional antioxidant properties. This particular study assessed the effects of MGN on DOX-induced cytotoxicity in human umbilical vein endothelial cells' (HUVECs') signaling networks. Mechanistically, MGN dramatically elevated Nrf2 expression at both the messenger RNA and protein levels through the upregulation of the PI3K/AKT pathway, leading to an increase in Nrf2-downstream genes. Cell apoptosis was assessed with a caspase-3 activity assay, transferase-mediated dUTP-fluorescein nick end labeling (TUNEL) staining was performed to assess DNA fragmentation, and protein expression was determined by Western blot analysis. DOX markedly increased the generation of reactive oxygen species, PARP, caspase-3, and TUNEL-positive cell numbers, but reduced the expression of Bcl-2 and antioxidants' intracellular concentrations. These were effectively antagonized with MGN (20 µM), which led to HUVECs being protected against DOX-induced apoptosis, partly through the PI3K/AKT-mediated NRF2/HO-1 signaling pathway, which could theoretically protect the vessels from severe DOX toxicity.

Prevalence and significance of potential drug-drug interactions among cancer patients receiving chemotherapy.

BACKGROUND: Cancer patients often receive multiple drugs to maximize their therapeutic benefit, treat co-morbidities and counter the adverse effects of chemotherapy. Concomitant administration of multiple drugs increases the risk of drug interactions leading to compromised therapeutic efficacy or safety of therapy. The purpose of this study was to identify the prevalence, levels and predictors of potential drug-drug interactions (pDDIs) among cancer patients. METHODS: Six hundred and 78 patients receiving chemotherapy from two tertiary care hospitals were included in this cross-sectional study. Patient medication profiles were screened for pDDIs using the Micromedex® database. Logistic regression analysis was performed to identify the predictors of pDDIs. RESULTS: The overall prevalence of pDDIs was 78%, majority of patients had 1-2 pDDIs (39.2%). A total of 1843 pDDIs were detected. Major-pDDIs were most frequent (67.3%) whereas, a significant association of pDDIs was found between > 7 all prescribed drugs (p < 0.001) and ≥ 3 anti-cancer drugs (p < 0.001). Potential adverse outcomes of these interactions include reduced therapeutic effectiveness, QT interval prolongation, tendon rupture, bone marrow suppression and neurotoxicity. CONCLUSIONS: Major finding of this study is the high prevalence of pDDIs signifying the need of strict patient monitoring for pDDIs among cancer patients. Patients at higher risk to pDDIs include those prescribed with > 7 any types of drugs or ≥ 3 anticancer drugs. Moreover, list of most frequently identified major and moderate interactions will aid health care professional in timely identification and prevention of pDDIs.

Potential drug-drug interactions associated with adverse clinical outcomes and abnormal laboratory findings in patients with malaria.

BACKGROUND: Hospitalized patients with malaria often present with comorbidities or associated complications for which a variety of drugs are prescribed. Multiple drug therapy often leads to drug-drug interactions (DDIs). Therefore, the current study investigated the prevalence, levels, risk factors, clinical relevance, and monitoring parameters/management guidelines of potential DDIs (pDDIs) among inpatients with malaria. METHODS: A retrospective cohort study was carried out at two tertiary care hospitals. A total of 398 patients' profiles were evaluated for pDDIs using the Micromedex Drug-Reax®. Odds ratios were calculated to identify the strength of association between presence of DDIs and potential risk factors via logistic regression analysis. Further, the clinical relevance of frequent pDDIs was investigated. RESULTS: Of 398 patients, pDDIs were observed in 37.2% patients, while major-pDDIs in 19.3% patients. A total of 325 interactions were found, of which 45.5% were of major- and 34.5% moderate-severity. Patients with the most common pDDIs were found with signs/symptoms and abnormalities in laboratory findings representing nephrotoxicity, hepatotoxicity, QT interval prolongation, and reduced therapeutic efficacy. The following drug pairs reported the highest frequency of adverse events associated with the interactions; calcium containing products-ceftriaxone, isoniazid-rifampin, pyrazinamide-rifampin, isoniazid-acetaminophen, and ciprofloxacin-metronidazole. The adverse events were more common in patients prescribed with the higher doses of interacting drugs. Multivariate regression analysis showed statistically significant association of pDDIs with 5-6 prescribed medicines (p = 0.01), > 6 prescribed medicines (p < 0.001), > 5 days of hospital stay (p = 0.03), and diabetes mellitus (p = 0.04). CONCLUSIONS: PDDIs are commonly observed in patients with malaria. Healthcare professional's knowledge about the most common pDDIs could help in preventing pDDIs and their associated negative effects. Pertinent clinical parameters, such as laboratory findings and signs/symptoms need to be checked, particularly in patients with polypharmacy, longer hospital stay, and diabetes mellitus.

Prevalence of QTc interval prolongation and its associated risk factors among psychiatric patients: a prospective observational study.

BACKGROUND: QT interval prolongation is a growing concern worldwide, posing psychiatric patients to life-threatening fatal arrhythmias i.e., torsade de pointes. This study aimed to identify the prevalence of QT interval prolongation, its associated risk factors and prescribing patterns of QT prolonging drugs among psychiatric patients. METHOD: A prospective observational study was conducted that included psychiatric patients from a tertiary care hospital and a psychiatry clinic in Peshawar, Khyber Pakhtunkhwa, Pakistan. Electrocardiogram was recorded of those patients who were using psychotropic medications for ≥7 days, aged 18 years or more, and of either gender, male or female. The Fredericia correction formula was used for measuring QTc values (corrected QT). Chi-square test was applied to estimate differences between patients with or without prolonged QTc interval whereas, logistic regression analysis was performed to identify various predictors of QT interval prolongation. RESULTS: Out of 405 patients, the QTc interval was prolonged in 23 (5.7%) patients including 1 (0.2%) patient with highly abnormal prolonged QTc interval (> 500 ms). QT drugs (91.6%), female sex (38.7%) and hypertension (10.6%) were the most common QT prolonging risk factors. Prolonged QTc interval was significantly higher among male patients (p = 0.007). CONCLUSION: In the present study, QT interval prolongation was observed in a considerable number of psychiatric patients. While, the high prevalence of QT prolonging risk factors among these patients warrants the increased risk of fatal arrhythmias. Therefore, risk assessment and electrocardiographic monitoring, and prescription of safer alternatives are highly recommended.

Time for a Changing of Guard: From Minimally Invasive Surgery to Endoscopic Drainage for Management of Pancreatic Walled-off Necrosis.

BACKGROUND AND AIMS: Endoscopic drainage (ED) with or without necrosectomy, and minimally invasive surgical necrosectomy (MISN) have been increasingly utilized for treatment of symptomatic sterile and infected pancreatic walled-off necrosis (WON). We conducted this systematic review to compare the safety of ED with MISN for management of WON. METHODS: We searched several databases from inception through November 9, 2017 to identify comparative studies evaluating the safety of ED versus MISN for management of WON. MISN could be performed using video-assisted retroperitoneal debridement or laparoscopy. We evaluated difference in mortality, major organ failure, adverse events, and length of hospital stay. RESULTS: Six studies (2 randomized controlled trials and 4 observational studies) with 641 patients (326 ED and 315 MISN) were included in this meta-analysis. Rates of mortality for ED and MISN were 8.5% and 14.2%, respectively. Pooled odds ratio (OR) with 95% confidence interval was 0.59 (0.35-0.98), I=0% in favor of ED. On subgroup analysis: no difference in mortality was seen based on randomized controlled trials [OR, 0.65 (0.08-5.11)], while ED had improved survival in observational studies [OR, 0.49 (0.27-0.89)]. Development of new major organ failure rates after interventions were 12% and 54% for ED and MISN, respectively. Pooled OR was 0.12 (0.06-0.31), I=25% in favor of ED. For adverse events, pooled OR was 0.25 (0.10-0.67), I=70% in favor of ED. There was no difference in risk of bleeding [OR, 0.68 (0.44-1.05)], while ED was associated with a significantly lower rate of pancreatic fistula formation [OR, 0.20 (0.11-0.37)], I=0%. Length of stay was also lower with ED, pooled mean difference was -21.07 (-36.97 to -5.18) days. CONCLUSIONS: When expertise is available, ED is the preferred invasive management strategy over MISN for management of WON as it is associated with lower mortality, risk of major organ failure, adverse events, and length of hospital stay.

Tungsten-disulphide-based heterojunction photodetector.

Two-dimensional (2D) materials have realized significant new applications in photonics, electronics, and optoelectronics. Among these materials is tungsten disulphide (WS2), which is a 2D material that shows excellent optoelectronic properties, tunable/sizable bandgap in the visible range, and good absorption. A polycrystalline WS2 thin film is successfully deposited on a substrate using radio frequency magnetron sputtering at room temperature. The x-ray diffraction pattern reveals two hexagonal structured peaks along the (100) and (110) planes. Energy-dispersive x-ray spectroscopy reveals a non-stoichiometric WS2 film with 1.25 ratio of S/W for a 156.3 nm thick film, while Raman shifts are observed at the E2g1 and A1g phonon modes located at 350.70 cm-1 and 415.60 cm-1, respectively. A sandwiched heterojunction photodetector device is successfully fabricated and illuminated within the violet range at 441 nm and 10 V of bias voltage. The maximum photocurrent values are calculated as 0.95 µA, while the responsivity is observed at 169.3 mA W-1 and detectivity 1.48×108 Jones at illuminated power of 0.6124 µm. These results highlight the adaptability of the present technique for large-scale applications as well as the flexibility to promote development of advanced optoelectronic devices.

Prevalence of the risk factors for QT prolongation and associated drug-drug interactions in a cohort of medical inpatients.

BACKGROUND/PURPOSE: Medical inpatients are at increased risk of QT interval prolongation due to multiple risk actors and QT prolonging drugs. This study aimed to identify the prevalence of risk factors for QT prolongation; QT prolonging medications; associated drug-drug interactions (QT-DDIs); their predictors; and TdP (torsades de pointes) risks of drugs. METHODS: This cohort study was carried out in medical wards of two tertiary hospitals in Khyber Pakhtunkhwa, Pakistan. The QT-DDIs were identified using Micromedex DrugReax® and AZCERT (Arizona Center for Education and Research on Therapeutics) QT drugs lists. AZCERT QT drugs lists were used to identify TdP risks. Logistic regression analysis was performed to identify predictors of QT-DDIs. RESULTS: Total 400 patients were included in this study. The most frequent QT prolonging risk factors included use of ≥1 QT prolonging drugs (74.5%), female gender (55%) and diabetes mellitus (36.3%). Total 487 QT prolonging drugs were identified. According to AZCERT classification, 33.8% of the interacting drugs were included in list-1 (known risk of TdP), 0.9% in list-2 (possible risk of TdP) and 58.8% in list-3 (conditional risk of TdP). The occurrence of QT-DDIs was significantly associated with ≥10 prescribed medications (p = 0.01), chronic liver disease (p = 0.05), chronic obstructive pulmonary disease (p = 0.03), gastroenteritis (p = 0.02), antimicrobials (p < 0.001), antiemetics (p < 0.001) and antinausea (p < 0.001). CONCLUSION: A substantial number of patients were exposed to risk factors for QT prolongation; and QT prolonging drugs such as proton pump inhibitors, antimicrobials and diuretics which may lead to serious outcomes.

Aptamers Chemistry: Chemical Modifications and Conjugation Strategies.

Soon after they were first described in 1990, aptamers were largely recognized as a new class of biological ligands that can rival antibodies in various analytical, diagnostic, and therapeutic applications. Aptamers are short single-stranded RNA or DNA oligonucleotides capable of folding into complex 3D structures, enabling them to bind to a large variety of targets ranging from small ions to an entire organism. Their high binding specificity and affinity make them comparable to antibodies, but they are superior regarding a longer shelf life, simple production and chemical modification, in addition to low toxicity and immunogenicity. In the past three decades, aptamers have been used in a plethora of therapeutics and drug delivery systems that involve innovative delivery mechanisms and carrying various types of drug cargos. However, the successful translation of aptamer research from bench to bedside has been challenged by several limitations that slow down the realization of promising aptamer applications as therapeutics at the clinical level. The main limitations include the susceptibility to degradation by nucleases, fast renal clearance, low thermal stability, and the limited functional group diversity. The solution to overcome such limitations lies in the chemistry of aptamers. The current review will focus on the recent arts of aptamer chemistry that have been evolved to refine the pharmacological properties of aptamers. Moreover, this review will analyze the advantages and disadvantages of such chemical modifications and how they impact the pharmacological properties of aptamers. Finally, this review will summarize the conjugation strategies of aptamers to nanocarriers for developing targeted drug delivery systems.

Efficacy and Safety of Lumen-Apposing Metal Stents in Management of Pancreatic Fluid Collections: Are They Better Than Plastic Stents? A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound (EUS)-guided transmural drainage has been increasingly utilized as a first-line therapeutic modality for drainage of pancreatic fluid collections (PFC). Recently, lumen-apposing metal stents (LAMS) have been utilized for management of PFCs. We conducted a systematic review and meta-analysis to evaluate the cumulative efficacy and safety of LAMS in the management of PFC (primary outcome). We also compared the efficacy and safety of LAMS with multiple plastic stents (MPS) in the management of PFC (secondary outcome). METHODS: We searched Medline, Embase and Cochrane databases from inception to November 5, 2016, to identify studies (with ≥ 10 patients) reporting technical success, clinical success, and adverse events (AE) of EUS-guided transmural drainage of PFC using LAMS. Weighted pooled rates (WPR) were calculated for technical success, clinical success and AE. Risk ratios (RR) were calculated and pooled to compare LAMS with MPS in terms of technical success, clinical success, and AE. Pooled mean difference (MD) was calculated to compare the number of endoscopic sessions required by each type of stent to achieve clinical success. All analyses were done using random effects model. RESULTS: Eleven studies with 688 patients were included in this meta-analysis. WPR for technical success of LAMS in PFC management was 98% (96, 99%), (I 2 = 15%). WPR for clinical success was 93% (89, 96%) with moderate heterogeneity (I 2 = 50%). There was no difference in clinical success for pseudocysts (PP) versus walled-off pancreatic necrosis (WON) (P = 0.51). WPR for AE was 13% (9, 20%), (I 2 = 64%). AE were 10% more in WON as compared to PP (P = 0.009). Most common AE requiring intervention was stent migration (4.2%), followed by infection (3.8%), bleeding (2.4%), and stent occlusion (1.9%). Six studies with 504 patients compared the performance of LAMS with MPS. Pooled RR for technical success was 1.71 (0.38, 7.37). Pooled RR for clinical success was 0.37 (0.20, 0.67) in favor of LAMS. Pooled RR for AE was 0.39 (0.18, 0.84), (I 2 = 50%). Pooled MD for number of endoscopic sessions was - 0.84 (- 1.69, 0.01). CONCLUSIONS: LAMS seem to have excellent efficacy and safety in the management of PFCs. They may be preferred over plastic stents as they are associated with better clinical success and lesser adverse events.

Drug-Drug Interactions in Hepatitis Patients: Do these Interactions Matter in Clinical Perspectives?

INTRODUCTION AND AIM: Hepatitis patients usually present with comorbidities and polypharmacy which increases risk of potential drug-drug interactions (pDDIs). We explored frequency, levels, predictors, and clinical relevance of pDDIs in hospitalized hepatitis patients. MATERIAL AND METHODS: Retrospective cohort study was used. Clinical profiles of 413 hepatitis patients were reviewed for pDDIs using Micromedex-DrugReax. Frequency, levels and clinical relevance of pDDIs were reported. Logistic regression analysis was used to calculate odds-ratios for predictors. RESULTS: Of total 413 patients, pDDIs were reported in 55.2%. Major-pDDIs were found in 35% patients. Total 660 pDDIs were identified, of which, 304 (46%) were of major-severity and 299 (45%) of moderateseverity. Patient's profiles of top-10 major-pDDIs were presented with signs/symptoms such as fever, hepatomegaly, anorexia, jaundice, hypertension, tachycardia, bradycardia, & pedal edema; and abnormalities in labs such as electrolytes-level, alanine aminotransferase, blood urea nitrogen, bilirubin-level, & serum creatinine. Significant association was observed for the presence of pDDIs with > 9 prescribed medicines (p < 0.001), hospitalization of > 5 days (p = 0.03), and stroke as comorbidity (p = 0.05). Moreover, odds of exposure to major-pDDIs were significantly higher in patients taking > 9 prescribed medicines (p < 0.001), hospitalization of > 5 days (p = 0.002), and stroke as comorbidity (p = 0.002). CONCLUSION: We observed hepatitis patients presented with a considerable number of clinically relevant pDDIs. Attention should be given to widespread major-pDDIs and their potential adverse outcomes. Clinically relevant parameters, such as labs and signs/symptoms should be monitored particularly in high risk patients having polypharmacy, prolong hospitalization, and stroke as comorbidity.

Potential drug-drug interactions in outpatient department of a tertiary care hospital in Pakistan: a cross-sectional study.

BACKGROUND: Potential drug-drug interactions (pDDIs) are one of the preventable drug related problems having the risk of serious adverse events or therapeutic failure. In developing countries like Pakistan, this issue remains poorly addressed. The objective of this study was to explore prevalence of pDDIs in the Outpatient Department (OPD) of a tertiary care hospital in Pakistan. The secondary aim was to describe the levels of reported pDDIs and develop a list of widespread clinically relevant interactions. METHODS: Prescriptions of 2400 OPD patients were analyzed for pDDIs through Micromedex Drug-Reax®. Prevalence, severity- and documentation-levels and widespread clinically relevant interactions were reported. RESULTS: Of total 2400 prescriptions, pDDIs were present in 22.3%. Whereas, moderate- and major-pDDIs were found in 377 (15.7%) and 225 (9.4%), respectively. PDDIs were more prevalent in Medicine (9.2%) and Cardiology (2.6%) as compared with other OPD specialties. Total 942 pDDIs were identified, of which, the majority were either moderate- (61.9%) or major-pDDIs (32.1%). Some of the most common interactions were ibuprofen + levofloxacin (n = 50), ciprofloxacin + diclofenac (32), aspirin + atenolol (24), and diclofenac + levofloxacin (19). The potential adverse outcomes of widespread interactions were seizures, bleeding, QT-interval prolongation, arrhythmias, tendon rupture, hypoglycemia/hyperglycemia, serotonin syndrome, drug toxicity, and decreased therapeutic response. CONCLUSIONS: OPD patients were at risk to pDDIs, particularly to major- and moderate-pDDIs. Screening of prescriptions for pDDIs and monitoring of pharmacotherapy in terms of response and associated adverse drug events will contribute to patient safety.