Comparative Efficacy and Safety of Different Stent Types for Pancreatic Fluid Collections: A Systematic Review and Network Meta-Analysis.

BACKGROUND AND AIMS: Drainage of pancreatic fluid collections (PFCs) is required in select cases including infected or symptomatic collections. In this network meta-analysis, we have compared lumen-apposing metal stents (LAMS), fully covered self-expandable metal stents (FCSEMS), and double-pigtail stents (DPS) to identify the most useful stent type in the management of PFCs. METHODS: We reviewed several databases to identify studies that compared DPS or FCSEMS with LAMS and the ones which compared DPS with FCSEMS for the treatment of PFCs. Our outcomes of interest were clinical success, adverse events, technical success, recurrence of PFCs, and procedure duration. Random effects model and frequentist approach were used for statistical analysis. RESULTS: We included 28 studies with 2974 patients. Rate of clinical success was significantly lower with DPS compared to LAMS, OR (95% CI): 0.43 (0.32, 0.59). Rate of recurrence was higher with DPS compared to LAMS, OR (95% CI): 2.06 (1.19, 3.57). We found no significant difference in rate of adverse events between groups. Rate of technical success was higher for FCSEMS compared to LAMS. Procedure duration was significantly shorter for LAMS compared to DPS and FCSEMS. Based on frequentist approach, LAMS was found to be superior to DPS and FCSEMS in achieving higher clinical success, lower rate of adverse events and recurrence, and shorter procedure time. CONCLUSIONS: This network meta-analysis demonstrates the superiority of LAMS over DPS and FCSEMS in the management of PFCs in achieving a higher clinical success, shorter procedure time, and lower rate of recurrence. Some of the analyses are not adequately powered to make firm conclusions, and future large multicenter RCTs are required to further evaluate this issue.

Basic Principles and Role of Endoscopic Ultrasound in Diagnosis and Differentiation of Pancreatic Cancer from Other Pancreatic Lesions: A Comprehensive Review of Endoscopic Ultrasound for Pancreatic Cancer.

Pancreatic cancer is one of the leading causes of cancer-related deaths worldwide. Pancreatic lesions consist of both neoplastic and non-neoplastic lesions and often pose a diagnostic and therapeutic challenge due to similar clinical and radiological features. In recent years, pancreatic lesions have been discovered more frequently as incidental findings due to the increased utilization and widespread availability of abdominal cross-sectional imaging. Therefore, it becomes imperative to establish an early and appropriate diagnosis with meticulous differentiation in an attempt to balance unnecessary treatment of benign pancreatic lesions and missing the opportunity for early intervention in malignant lesions. Endoscopic ultrasound (EUS) has become an important diagnostic modality for the identification and risk stratification of pancreatic lesions due to its ability to provide detailed imaging and acquisition of tissue samples for analysis with the help of fine-needle aspiration/biopsy. The recent development of EUS-based technology, including contrast-enhanced endoscopic ultrasound, real-time elastography-endoscopic ultrasound, miniature probe ultrasound, confocal laser endomicroscopy, and the application of artificial intelligence has significantly augmented the diagnostic accuracy of EUS as it enables better evaluation of the number, location, dimension, wall thickness, and contents of these lesions. This article provides a comprehensive overview of the role of the different types of EUS available for the diagnosis and differentiation of pancreatic cancer from other pancreatic lesions while discussing their key strengths and important limitations.

Rates of Recurrent Intestinal Metaplasia and Dysplasia After Successful Endoscopic Therapy of Barrett's Neoplasia by Endoscopic Mucosal Resection vs Endoscopic Submucosal Dissection and Ablation: A Large North American Multicenter Cohort.

INTRODUCTION: Endoscopic eradication therapy (EET) combining endoscopic resection (ER) with endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD) followed by ablation is the standard of care for the treatment of dysplastic Barrett's esophagus (BE). We have previously shown comparable rates of complete remission of intestinal metaplasia (CRIM) with both approaches. However, data comparing recurrence after CRIM are lacking. We compared rates of recurrence after CRIM with both techniques in a multicenter cohort. METHODS: Patients undergoing EET achieving CRIM at 3 academic institutions were included. Demographic and clinical data were abstracted. Outcomes included rates and predictors of any BE and dysplastic BE recurrence in the 2 groups. Cox-proportional hazards models and inverse probability treatment weighting (IPTW) analysis were used for analysis. RESULTS: A total of 621 patients (514 EMR and 107 ESD) achieving CRIM were included in the recurrence analysis. The incidence of any BE (15.7, 5.7 per 100 patient-years) and dysplastic BE recurrence (7.3, 5.3 per 100 patient-years) were comparable in the EMR and ESD groups, respectively. On multivariable analyses, the chances of BE recurrence were not influenced by ER technique (hazard ratio 0.87; 95% confidence interval 0.51-1.49; P = 0.62), which was also confirmed by IPTW analysis (ESD vs EMR: hazard ratio 0.98; 95% confidence interval 0.56-1.73; P = 0.94). BE length, lesion size, and history of cigarette smoking were independent predictors of BE recurrence. DISCUSSION: Patients with BE dysplasia/neoplasia achieving CRIM, initially treated with EMR/ablation, had comparable recurrence rates to ESD/ablation. Randomized trials are needed to confirm these outcomes between the 2 ER techniques.

Adjuvant Radiofrequency Ablation Along With Stenting Versus Stenting Alone for Biliary Tree Drainage in Patients With Malignant Biliary Strictures: A Systemic Review and Meta-analysis.

OBJECTIVE: This metanalysis aims to assess the efficacy and safety of biliary stenting along with radiofrequency ablation compared with stents alone to treat malignant biliary obstruction (MBO) due to extrahepatic biliary strictures secondary to cholangiocarcinoma, pancreatic cancer, and metastatic cancer. METHODS: A systemic search of major databases through April 2022 was done. All original studies were included comparing radiofrequency ablation with stenting versus stenting alone for treating malignant biliary strictures. The primary outcomes of interest were the difference in the mean stent patency and overall survival (OS) days between the 2 groups. The secondary outcome was to compare the adverse events of the 2 groups. The mean difference in the stent patency and OS days was pooled by using a random-effect model. We calculated the odds ratio to compare the adverse events between the 2 groups. RESULTS: A total of 13 studies with 1339 patients were identified. The pooled weighted mean difference in stent patency was 43.50 days (95% CI, 25.60-61.41), favoring the RFA plus stenting. Moreover, the pooled weighted mean difference in OS was 90.53 days (95% CI, 49.00-132.07), showing improved survival in the RFA group. Our analysis showed no statistically significant difference in adverse events between the 2 groups OR 1.13 (95% CI, 0.90-1.42). CONCLUSION: Our analysis showed that RFA, along with stent, is safe and is associated with improved stent patency and overall patient survival in malignant biliary strictures. More robust prospective studies should assess this association further.

Safety and adverse events of EUS-guided gallbladder drainage using lumen-apposing metal stents and percutaneous cholecystostomy tubes: a systematic review and meta-analysis.

BACKGROUND AND AIMS: EUS-guided gallbladder drainage using lumen-apposing metal stents (EUS-GBD-LAMSs) and percutaneous cholecystostomy for gallbladder drainage (PTGBD) are the alternative treatment modalities in high-risk surgical patients with acute cholecystitis (AC). The aim of this study was to compare the safety of these procedures for AC in surgically suboptimal candidates. METHODS: Six studies compared the 2 groups' early, delayed, and overall adverse events; they also compared length of hospital stay, re-interventions, and re-admissions rate. A random effect model calculated odds ratios (ORs) with a 95% confidence interval (CI). RESULTS: The 2 groups had similar early adverse events; however, EUS-GBD-LAMS was associated with a lower rate of delayed (OR, .21; 95% CI, .07-.61; P ≤ .01) and overall (OR, .43; 95% CI, .30-.61; P ≤ .01) adverse events. Patients with EUS-GBD-LAMSs had a shorter hospital stay than PTGBD. CONCLUSIONS: EUS-GBD-LAMS is a safer option than PTGBD and is associated with a shorter hospital stay in nonsurgical candidates with AC.

Comparing EUS-directed Transgastric ERCP (EDGE) Versus Laparoscopic-Assisted ERCP Versus Enteroscopic ERCP: A Network Meta-analysis.

BACKGROUND: Management of choledocholithiasis in patients with Roux-en-Y gastric bypass surgery is challenging. This study aims to compare technical success rates, adverse events, and procedural time between 3 current approaches: endoscopic ultrasound-directed transgastric Endoscopic retrograde cholangiopancreatography (ERCP) (EDGE), enteroscopy-assisted ERCP (E-ERCP), and laparoscopic-assisted ERCP (LA-ERCP). METHODS: A systematic search of 5 databases was conducted. Direct and network meta-analyses were performed to compare interventions using the random effects model. A significance threshold of P < 0.05 was applied. RESULTS: Sixteen studies were included. On direct meta-analysis, technical success rates were comparable between EDGE and LA-ERCP (odds ratio: 0.768, CI: 0.196-3.006, P = 0.704, I2 = 14.13%). However, EDGE and LA-ERCP showed significantly higher success rates than E-ERCP. No significant differences in adverse events were found between EDGE versus LA-ERCP, EDGE versus E-ERCP, and LA-ERCP versus E-ERCP on direct meta-analysis. In terms of procedural time, EDGE was significantly shorter than E-ERCP [mean difference (MD): -31 minutes, 95% CI: -40.748 to -21.217, P < 0.001, I2 = 19.89%), and E-ERCP was shorter than LA-ERCP (MD: -44.567 minutes, 95% CI: -76.018 to -13.116, P = 0.005, I2 = 0%). EDGE also demonstrated a significant time advantage over LA-ERCP (MD: -78.145 minutes, 95% CI: -104.882 to -51.407, P < 0.001, I2 = 0%). All findings were consistent with network meta-analysis on random effects model. The heterogeneity of the model was low. CONCLUSIONS: EDGE and LA-ERCP showed superior technical success rates compared with E-ERCP. Adverse events did not significantly differ among the three approaches. Furthermore, EDGE demonstrated the shortest procedural duration. We recommend considering EDGE as a first-choice procedure.

Transesophageal echocardiography-associated gastrointestinal injuries: systematic review and pooled rates of gastrointestinal injuries.

Upper gastrointestinal (GI) injuries are associated with transesophageal echocardiography (TEE) complications. We reviewed rates and various types of complications with GI injuries. A comprehensive literature search using five databases was conducted. Pooled rates were calculated for overall injuries, pooled GI complications, lacerations, and perforations with a 95% confidence interval (CI). A total of 26 studies involving 55,319 patients met inclusion criteria. The overall rate of adverse events was 0.51% (95% CI 0.3% to 0.7%). Bleeding was the most commonly reported adverse event, followed by dysphagia and lacerations. The highest rate of adverse events was observed in liver transplant patients (1.35%), followed by critically ill patients in the intensive care unit (1.1%), hospitalized patients (1.1%), patients undergoing intraoperative TEE (0.7%), and those undergoing cardiac procedures (0.67%). The pooled complication rate for bleeding was 0.17% (95% CI 0.1% to 0.3%), while odynophagia/dysphagia had a rate of 0.27% (95% CI -0.1% to 0.5%) and lacerations had a rate of 0.12% (95% CI -0.1% to 0.5%). A subgroup analysis comparing variceal and nonvariceal cohorts from three studies showed no significant difference in bleeding rates. Our study findings showed a low risk of esophageal injury in patients undergoing TEE.

Temporal trends in mortality location in patients with anal cancer in the USA: an analysis of the National Center for Health Statistics mortality data.

OBJECTIVES: Investigate trends in where patients died of anal cancer in the USA. METHODS: Retrospective cohort study using the US National Center for Health Statistics Wide-Ranging ONline Data for Epidemiologic Research platform from 2003 to 2020; all patients with death certificates listing anal cancer as the underlying cause of death in the USA. Main outcome measure of location of patient death: inpatient facility, home, hospice, nursing home/long-term care facility and other. RESULTS: There were a total of 16 296 deaths with anal cancer as the underlying diagnosis during the study period. The crude rate increased from 0.191 per 100 000 deaths in 2003 to 0.453 per 100 000 deaths in 2020. Over the study period, 22.4% of patient deaths occurred in inpatient facilities, 44.9% at home, 12.2% at hospice facilities and 13.1% at nursing homes/long-term care facilities. The percentage of deaths occurring in hospice facilities increased from 1.0% to 13.3% during the study period. Deaths at home also increased from 42.7% in 2003 to 55.8% in 2020. Meanwhile, inpatient deaths decreased from 33.5% in 2003 to 14.4% in 2020. CONCLUSIONS: There has been a significant increase in the proportion of patients with anal cancer dying at home or hospice from 2003 to 2020.

Genome Editing and Fatty Liver.

Fatty liver disease is characterized as nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). Fatty liver disease is one of the most common causes of chronic liver disease worldwide among adults and children. It is characterized by excessive fat accumulation in the liver cells. It has a genetically heterogenous background with complex pathogenesis and progressions and is accompanied by significant morbidity, mortality, and healthcare costs. NAFLD's risk factors include metabolic syndrome, abdominal obesity, type 2 diabetes, and atherogenic dyslipidemia. ALD is associated with the excessive consumption of alcohol. Here, we describe the functions of various proteins encoded by gene variants contributing to the pathogenesis of nonalcoholic fatty liver disease and alcoholic fatty liver disease. Advancements in genome engineering technology have generated various in vivo and in vitro fatty liver disease models reflecting the genetic abnormalities contributing toward fatty liver disease. We will discuss currently developed different ALD and NAFLD models using the clustered regularly interspaced short palindromic repeats (CRISPR/Cas9) genome editing tool.Furthermore, we will also discuss the salient features of CRISPR/Cas9 editing technology and Cas9 variants such as prime and base editors to replicate genetic topographies linked specifically to ALD and NAFLD. The advantages and limitations of currently available genome delivery methods necessary for optimal gene editing will also be discussed in this review. This review will provide the essential guidance for appropriate genome editing tool selection and proper gene delivery approaches for the effective development of ALD and NAFLD models, leading to the development of clinical therapeutics for fatty liver disease.

Impact of second-generation transoral incisionless fundoplication on atypical GERD symptoms: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Transoral incisionless fundoplication (TIF) using the EsophyX device (EndoGastric Solutions, Inc, Redmond, Wash, USA) is a minimally invasive endoscopic fundoplication technique. Our study aimed to assess the efficacy of TIF for atypical GERD symptoms in patients with chronic or refractory GERD. METHODS: A systematic search of 4 major databases was performed. All original studies assessing atypical GERD using a validated symptom questionnaire (the reflux symptom index [RSI]) were included. The RSI score was assessed before and after TIF at a 6- and 12-month follow-up. Data on technical success rate, adverse events, proton pump inhibitor (PPI) use, and patient satisfaction were also collected. Only TIF procedures currently in practice using the EsophyX device (ie, TIF 2.0) and TIF with concomitant hiatal hernia repair were included in the review. RESULTS: Ten studies (564 patients) were included. At the 6- and 12- month follow-up, there was a mean reduction of 15.72 (95% confidence interval, 12.15-19.29) and 14.73 (95% confidence interval, 11.74-17.72) points, respectively, in the RSI score post-TIF, with a technical success rate of 99.5% and a pooled adverse event rate of 1%. At both time intervals, more than two-thirds of the patients were satisfied with their health condition and roughly three-fourths of the patients were off daily PPIs. CONCLUSIONS: Our study shows that TIF using the EsophyX device is safe and effective in reducing atypical GERD symptoms at 6 and 12 months of follow-up. It improves patient-centered outcomes and can be a minimally invasive therapeutic option for patients suffering from atypical GERD symptoms on chronic medical therapy.

A Consensus Diagnosis Utilizing Surface KI-67 Expression as an Ancillary Marker in Low-Grade Dysplasia Helps Identify Patients at High Risk of Progression to High-Grade Dysplasia and Esophaegal Adenocarcinoma.

Esophageal adenocarcinoma (EAC) develops in a step-wise manner, from low-grade dysplasia (LGD) to high-grade dysplasia (HGD), and ultimately to invasive EAC. However, there remains diagnostic uncertainty about LGD and its risk of progression to HGD/EAC. The aim is to investigate the role of Ki-67, immune-histochemical marker of proliferation, surface expression in patients with confirmed LGD, and risk stratify progression to HGD/EAC. A retrospective cohort study was conducted. Patients with confirmed LGD and indefinite for dysplasia (IND), with a mean follow-up of ≥1 year, were included. Pathology specimens were stained for Ki-67 and analyzed for evidence of surface expression. Our results reveal that 29% of patients with confirmed LGD who stained positive with Ki-67 progressed to HGD/EAC as opposed to none (0%) of the patients who stained negative, a statistically significant result (P = 0.003). Similarly, specimens from patients with IND were stained and analyzed revealing a nonsignificant trend toward a higher rate of progression for Ki-67 positive cases versus Ki-67 negative, 30% versus 21%, respectively. Ki-67 expression by itself can identify patients with LGD at a high risk of progression.

H63D Homozygous Mutation: An Unusual Cause of Deranged Liver Function Test in an Elderly Patient.

Hereditary hemochromatosis is an autosomal recessive disorder characterized by dysregulated iron homeostasis resulting in body iron overload. Hemochromatosis leads to excessive iron deposition in the parenchymal cells of different body organs, resulting in the compromise of their normal functioning in genetically predisposed patients. It presents in genetically predisposed male patients aged between 40 and 70 years. Various mutations have been described in hemochromatosis, C282Y is the most prevalent and is commonly associated with iron overload. Other mutations such as H63D and S65C rarely lead to iron overload in patients. We present an unusual case of an 84-year-old male who was referred for comprehensive evaluation. He was found to have mildly elevated liver function tests (LFTs). Further workup revealed raised ferritin levels, and on a detailed investigation, it was found to be homozygous for the H63D mutation for hemochromatosis. The patient was seen by hematology and was treated with therapeutic phlebotomy, which led to the normalization of the LFTs and improvement in ferritin levels and clinical symptoms.

Correlation of Hypothyroidism With Disease Activity Score-28 in Patients of Rheumatoid Arthritis.

Introduction Rheumatoid arthritis (RA) is a chronic autoimmune disorder with variable disease course including periods of flares and remissions. High disease activity in terms of disease activity score-28 (DAS-28) results in significant morbidity. Hypothyroidism is found to be associated with higher DAS-28 scores in RA. This study is planned to determine overt and subclinical hypothyroidism and its correlation with the DAS-28 score in patients with RA. Methodology This study was conducted from June 2021 to March 2022 at the department of rheumatology and immunology at Shaikh Zayed Hospital, Lahore, Pakistan. Inclusion criteria were any male and female patients aged between 18 and 70 years. The blood samples of diagnosed patients with RA were sent for thyroid function tests (thyroxine [FT4], thyroid-stimulating hormone [TSH]), and erythrocyte sedimentation rate (ESR), and the patients were categorized as overt hypothyroidism, subclinical hypothyroidism, and non-hypothyroid. The collected data were analyzed on Statistical Package for the Social Sciences (SPSS) version 24.0 (IBM Corp., Armonk, NY). Results The mean age of patients was 38.18 ± 9.78 years. The mean duration of symptoms was 14.65 ± 1.04 months. There were 182 (91%) females and 18 (9%) males. The mean number of swollen joints was 2.26 ± 2.8, and the mean number of tender joints was 4.16 ± 5.11. Sixty patients (30%) had high disease activity, i.e., DAS-28 score > 5.1. Fifty-seven patients (28.5%) with RA had subclinical hypothyroidism, and 19 patients (9.5%) had overt hypothyroidism. Pain visual analog scale (VAS) and DAS-28 were significantly higher in hypothyroid patients. Conclusion It was concluded that patients of RA with concomitant hypothyroidism had increased disease activity with increased tender joints. Thyroid function tests should be included in the clinical evaluation of RA patients. The evaluation of thyroid functional status must be done during screening in RA patients. This will detect thyroid disorders earlier, with early treatment initiation and possibly a better prognosis.

The Association of Metabolic-Associated Fatty Liver Disease with Clinical Outcomes of COVID-19: A Systematic Review and Meta-Analysis.

Introduction: Metabolic-associated fatty liver disease (MAFLD) is a hepatic manifestation of metabolic syndrome (MS). MAFLD patients have a higher prevalence of COVID-19. MAFLD also is associated with worse clinical outcomes of COVID-19, such as disease severity, intensive care unit (ICU) admission rate, and higher mortality rates. However, this evidence has not been well characterized in the literature. This meta-analysis aimed to determine the clinical outcomes of COVID-19 among MAFLD patients compared to the non-MAFLD group. Methods: A comprehensive search was conducted in the Cumulative Index of Nursing and Allied Health (CINAHL), PubMed/Medline, and Embase for studies reporting MAFLD prevalence among COVID-19 patients and comparing clinical outcomes such as severity, ICU admission, and mortality among patients with and without MAFLD. The pooled prevalence of MAFLD among COVID-19 patients and the pooled odds ratios (OR) with 95% confidence intervals (CI) for clinical outcomes of COVID-19 were calculated. Results: Sixteen observational studies met inclusion criteria involving a total of 11,484 overall study participants, including 1,746 MAFLD patients. The prevalence of COVID-19 among MAFLD patients was 0.29 (95% CI: 0.19-0.40). MAFLD was associated with the COVID-19 disease severity OR 3.07 (95% CI: 2.30-4.09). Similarly, MAFLD was associated with an increased risk of ICU admission compared to the non-MAFLD group OR 1.46 (95% CI: 1.12-1.91). Lastly, the association between MAFLD and COVID-19 mortality was not statistically significant OR 1.45 (95% CI: 0.74-2.84). Conclusions: In this study, a high percentage of COVID-19 patients had MAFLD. Moreover, MAFLD patients had an increased risk of COVID-19 disease severity and ICU admission rate.

A Novel Image Encryption Scheme Based on Elliptic Curves over Finite Rings.

Image encryption based on elliptic curves (ECs) is emerging as a new trend in cryptography because it provides high security with a relatively smaller key size when compared with well-known cryptosystems. Recently, it has been shown that the cryptosystems based on ECs over finite rings may provide better security because they require the computational cost for solving the factorization problem and the discrete logarithm problem. Motivated by this fact, we proposed a novel image encryption scheme based on ECs over finite rings. There are three main steps in our scheme, where, in the first step, we mask the plain image using points of an EC over a finite ring. In step two, we create diffusion in the masked image with a mapping from the EC over the finite ring to the EC over the finite field. To create high confusion in the plain text, we generated a substitution box (S-box) based on the ordered EC, which is then used to permute the pixels of the diffused image to obtain a cipher image. With computational experiments, we showed that the proposed cryptosystem has higher security against linear, differential, and statistical attacks than the existing cryptosystems. Furthermore, the average encryption time for color images is lower than other existing schemes.

A time series forecasting analysis of overall and sector-based natural gas demand: a developing South Asian economy case.

Pakistan is developing South Asian country which is currently considering alternative energy sources including coal, solar, compressed natural gas, and wind energy to cope with the worst energy crisis in its history. Moreover, the policy promotion of compressed natural gas especially in the transport sector has raised concerns about the demand management of natural gas to avoid future shortages and ensure sustainable use of this precious non-renewable source of energy. Against this background, this study aimed to forecast natural gas demand in Pakistan for the 2016-2030 period by applying relevant univariate time series econometric methods. Apart from forecasting the overall natural gas demand, the forecasting analysis is also conducted for natural gas demand in Pakistan's total natural gas consumption and also for natural gas consumption across the household, industrial, commercial, transport, fertilizer production, power generation, and cement production sectors. Overall, the findings revealed that ARIMA is the appropriate model for forecasting gas consumption in Pakistan. Further, the growth of increase in the level of compressed natural gas consumption in the household sector is more as compared to all other sectors of the economy up to the year 2030. The key findings show that (a) natural gas consumption is likely to grow with time, (b) mixed projection trends are observed for the overall natural gas consumption and other sector-based natural gas consumption trends, and (c) the difference between natural gas consumption and production in Pakistan is likely to grow leading to 2030. As part of the policy recommendation in line with the findings, policymakers in Pakistan should increase the availability of natural gas, particularly in sectors where its consumption is likely to be declining. In addition, more proactive measures should be undertaken to explore the existing natural gas reserves in the long run while also importing natural gas from the neighboring nations in the short run. Furthermore, the government of Pakistan should seriously consider strategizing the development of the nation's compressed natural gas sector.

Feasibility and safety of targeting mitochondria for cancer therapy - preclinical characterization of gamitrinib, a first-in-class, mitochondriaL-targeted small molecule Hsp90 inhibitor.

Mitochondria are key tumor drivers, but their suitability as a therapeutic target is unknown. Here, we report on the preclinical characterization of Gamitrinib (GA mitochondrial matrix inhibitor), a first-in-class anticancer agent that couples the Heat Shock Protein-90 (Hsp90) inhibitor 17-allylamino-geldanamycin (17-AAG) to the mitochondrial-targeting moiety, triphenylphosphonium. Formulated as a stable (≥24 weeks at -20°C) injectable suspension produced by microfluidization (<200 nm particle size), Gamitrinib (>99.5% purity) is heavily bound to plasma proteins (>99%), has intrinsic clearance from liver microsomes of 3.30 mL/min/g and minimally penetrates a Caco-2 intestinal monolayer. Compared to 17-AAG, Gamitrinib has slower clearance (85.6 ± 5.8 mL/min/kg), longer t1/2 (12.2 ± 1.55 h), mean AUC0-t of 783.1 ± 71.3 h∙ng/mL, and unique metabolism without generation of 17-AG. Concentrations of Gamitrinib that trigger tumor cell killing (IC50 ~1-4 µM) do not affect cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2B6, CYP2C8 or ion channel conductance (Nav1.5, Kv4.3/KChIP2, Cav1.2, Kv1.5, KCNQ1/mink, HCN4, Kir2). Twice weekly IV administration of Gamitrinib to Sprague-Dawley rats or beagle dogs for up to 36 d is feasible. At dose levels of up to 5 (rats)- and 12 (dogs)-fold higher than therapeutically effective doses in mice (10 mg/kg), Gamitrinib treatment is unremarkable in dogs with no alterations in clinical-chemistry parameters, heart function, or tissue histology, and causes occasional inflammation at the infusion site and mild elevation of serum urea nitrogen in rats (≥10 mg/kg/dose). Therefore, targeting mitochondria for cancer therapy is feasible and well tolerated. A publicly funded, first-in-human phase I clinical trial of Gamitrinib in patients with advanced cancer is ongoing (ClinicalTrials.gov NCT04827810).

EUS-guided versus percutaneous transhepatic cholangiography biliary drainage for obstructed distal malignant biliary strictures in patients who have failed endoscopic retrograde cholangiopancreatography: A systematic review and meta-analysis.

EUS-guided biliary drainage (EUS-BD) and percutaneous transhepatic cholangiography biliary drainage (PTC) are the two alternate methods for biliary decompression in cases where ERCP fails. We conducted a systematic review and meta-analysis of studies to compare the efficacy and safety of endoscopic and percutaneous biliary drainage for malignant biliary obstruction in patients with failed ERCP. A total of ten studies were included, fulfilling the inclusion criteria, including four retrospective studies and six randomized controlled trials. We compared the technical and clinical success rates and the acute, delayed, and total adverse events of EUS-BD with PTC. The odds ratios (ORs) and confidence intervals (CIs) were calculated. There was no difference between technical (OR: 0.47 [95% CI: 0.20-1.07]; P = 0.27) and clinical (OR: 2.24 [95% CI: 1.10-4.55]; P = 0.51) success rates between EUS-PD and PTC groups. Procedural adverse events (OR: 0.17 [95% CI: 0.09-0.31]; P = 0.03) and total adverse events (OR: 0.09 [95% CI: 0.02-0.38]; P < 0.01) were significantly different between the two groups; however, delayed adverse events were nonsignificantly different (OR: 0.73 [95% CI: 0.34-1.57]; P = 0.97). This meta-analysis indicates that endoscopic biliary drainage (EUS-BD) is equally effective but safer in terms of acute and total adverse events than percutaneous transhepatic biliary drainage (PTC) for biliary decompression in patients with malignant biliary strictures who have failed an ERCP.

Application of Rikkli and Regazzoni three-column theory in distal radius intraarticular fractures and its functional and radiological assessment.

Objectives: To determent the effectiveness of Rikli and Regazzoni three-column theory in treating intra-articular fractures of the distal radius with T-plate and K-wire in terms of functional outcome and fracture union. METHODS: The cross-sectional study was conducted at the Department of Orthopaedic Surgery and Traumatology, King Edward University, Mayo Hospital, Lahore, Pakistan, from June 2013 to March 2017, and comprised patients aged 15-60 years having closed intraarticular fracture of the distal radius <1 month older. The subjects were divided into two group A, managed by percutaneous K-wire fixation, and group B, managed with open reduction and internal fixation using T-plates. Wound infection, supination and pronation, flexion and extension at the wrist joint, bone union and functionality were observed. All patients were followed up with intervals for 12 months in the out-patient department, and wound infection and supination and pronation of the forearm were observed clinically. Union was observed using the standard criterion, and function was evaluated using the Disabilities of Arm, Shoulder and Hand score. Data was analysed using SPSS 20. RESULTS: Of the 60 patients, there were 30(50%) with mean age 48.83±11.11 years in group A, and 30(50%) with mean age 49.87±13.45 years in group B. Overall, there were 49(81.7%) males and 11(18.3%) females. There were 33(55%) cases with right side involvement, and 27(45%) had the left side involved. Functionality imprived significantly in both groups (p<0.05). Union was observed in all cases in both groups, while the mean duration in group A was 9.21±1.74 weeks, and in group B it was 9.87±2.14 weeks. Conclusion: Restoration of the three columns of distal radius could either be fixed with T-plates and K-wires because there was no significant difference between the two groups.