Co-Design, Development, and Evaluation of a Mobile Solution to Improve Medication Adherence in Cancer: Design Science Research Approach.

BACKGROUND: Medication nonadherence negatively impacts the health outcomes of people with cancer as well as health care costs. Digital technologies present opportunities to address this health issue. However, there is limited evidence on how to develop digital interventions that meet the needs of people with cancer, are perceived as useful, and are potentially effective in improving medication adherence. OBJECTIVE: The objective of this study was to co-design, develop, and preliminarily evaluate an innovative mobile health solution called Safety and Adherence to Medication and Self-Care Advice in Oncology (SAMSON) to improve medication adherence among people with cancer. METHODS: Using the 4 cycles and 6 processes of design science research methodology, we co-designed and developed a medication adherence solution for people with cancer. First, we conducted a literature review on medication adherence in cancer and a systematic review of current interventions to address this issue. Behavioral science research was used to conceptualize the design features of SAMSON. Second, we conducted 2 design phases: prototype design and final feature design. Last, we conducted a mixed methods study on patients with hematological cancer over 6 weeks to evaluate the mobile solution. RESULTS: The developed mobile solution, consisting of a mobile app, a web portal, and a cloud-based database, includes 5 modules: medication reminder and acknowledgment, symptom assessment and management, reinforcement, patient profile, and reporting. The quantitative study (n=30) showed that SAMSON was easy to use (21/27, 78%). The app was engaging (18/27, 67%), informative, increased user interactions, and well organized (19/27, 70%). Most of the participants (21/27, 78%) commented that SAMSON's activities could help to improve their adherence to cancer treatments, and more than half of them (17/27, 63%) would recommend the app to their peers. The qualitative study (n=25) revealed that SAMSON was perceived as helpful in terms of reminding, supporting, and informing patients. Possible barriers to using SAMSON include the app glitches and users' technical inexperience. Further needs to refine the solution were also identified. Technical improvements and design enhancements will be incorporated into the subsequent iteration. CONCLUSIONS: This study demonstrates the successful application of behavioral science research and design science research methodology to design and develop a mobile solution for patients with cancer to be more adherent. The study also highlights the importance of applying rigorous methodologies in developing effective and patient-centered digital intervention solutions.

Development of a person-centred digital platform for the long-term support of people living with an adult-onset genetic disease predisposition: a mixed-methods study protocol.

INTRODUCTION: Individuals at an inherited high-risk of developing adult-onset disease, such as breast cancer, are rare in the population. These individuals require lifelong clinical, psychological and reproductive assistance. After a positive germline test result, clinical genetic services provide support and care coordination. However, ongoing systematic clinical follow-up programmes are uncommon. Digital health solutions offer efficient and sustainable ways to deliver affordable and equitable care. This paper outlines the codesign and development of a digital health platform to facilitate long-term clinical and psychological care, and foster self-efficacy in individuals with a genetic disease predisposition. METHODS AND ANALYSIS: We adopt a mixed-methods approach for data gathering and analysis. Data collection is in two phases. In phase 1, 300 individuals with a high-risk genetic predisposition to adult disease will undertake an online survey to assess their use of digital health applications (apps). In phase 2, we will conduct focus groups with 40 individuals with a genetic predisposition to cardiac or cancer syndromes, and 30 clinicians from diverse specialities involved in their care. These focus groups will inform the platform's content, functionality and user interface design, as well as identify the barriers and enablers to the adoption and retention of the platform by all endusers. The focus groups will be audiorecorded and transcribed, and thematic and content data analysis will be undertaken by adopting the Unified Theory of Acceptance and Use of Technology. Descriptive statistics will be calculated from the survey data. Phase 3 will identify the core skillsets for a novel digital health coordinator role. Outcomes from phases 1 and 2 will inform development of the digital platform, which will be user-tested and optimised in phase 4. ETHICS AND DISSEMINATION: This study was approved by the Peter MacCallum Human Research Ethics Committee (HREC/88892/PMCC). Results will be disseminated in academic forums, peer-reviewed publications and used to optimise clinical care.

Weed Detection Using Deep Learning: A Systematic Literature Review.

Weeds are one of the most harmful agricultural pests that have a significant impact on crops. Weeds are responsible for higher production costs due to crop waste and have a significant impact on the global agricultural economy. The importance of this problem has promoted the research community in exploring the use of technology to support farmers in the early detection of weeds. Artificial intelligence (AI) driven image analysis for weed detection and, in particular, machine learning (ML) and deep learning (DL) using images from crop fields have been widely used in the literature for detecting various types of weeds that grow alongside crops. In this paper, we present a systematic literature review (SLR) on current state-of-the-art DL techniques for weed detection. Our SLR identified a rapid growth in research related to weed detection using DL since 2015 and filtered 52 application papers and 8 survey papers for further analysis. The pooled results from these papers yielded 34 unique weed types detection, 16 image processing techniques, and 11 DL algorithms with 19 different variants of CNNs. Moreover, we include a literature survey on popular vanilla ML techniques (e.g., SVM, random forest) that have been widely used prior to the dominance of DL. Our study presents a detailed thematic analysis of ML/DL algorithms used for detecting the weed/crop and provides a unique contribution to the analysis and assessment of the performance of these ML/DL techniques. Our study also details the use of crops associated with weeds, such as sugar beet, which was one of the most commonly used crops in most papers for detecting various types of weeds. It also discusses the modality where RGB was most frequently used. Crop images were frequently captured using robots, drones, and cell phones. It also discusses algorithm accuracy, such as how SVM outperformed all machine learning algorithms in many cases, with the highest accuracy of 99 percent, and how CNN with its variants also performed well with the highest accuracy of 99 percent, with only VGGNet providing the lowest accuracy of 84 percent. Finally, the study will serve as a starting point for researchers who wish to undertake further research in this area.

Inhibition of the hERG potassium ion channel by different non-nucleoside human cytomegalovirus polymerase antiviral inhibitor series and the exploration of variations on a pyrroloquinoline core to reduce cardiotoxicity potential.

Many non-nucleoside human cytomegalovirus (HCMV) inhibitors have been reported in patent and scientific literature, however, none have reached commercialization despite the urgent need for new HCMV treatments. Herein we report select compounds from different templates that all had low micromolar human ether-à-go-go (hERG) ion channel IC50 values. We also describe a series of pyrroloquinoline derivatives that were designed and synthesized to understand the effect of various substitution on human cytomegalovirus (HCMV) polymerase activity, antiviral activity, and hERG inhibition. These results demonstrated that hERG inhibition can be significantly altered based on the substitution on this template. An HCMV inhibitor with low hERG inhibition and reduced cytotoxicity is also described. The results suggest substitution can be fine tuned for the non-nucleoside polymerase inhibitors to reduce hERG inhibition and maintain HCMV antiviral potency.

Bioactive properties and organosulfur compounds profiling of newly developed garlic varieties of Bangladesh.

Studies are being carried out on achieving the maximum quality of garlic through various approaches. In Bangladesh, new garlic varieties (BARI 1-4, BAU-1, BAU-2, BAU-5) have been recently developed by artificial selection to enhance their quality. The present study aimed to evaluate their potency in terms of bioactive properties and organosulfur compounds content using different bioassay and GC-MS techniques while comparing them with other accessible varieties (Chinese, Indian, Local). The new variety, BARI-3 showed the highest antioxidant activity and total phenolic content. It was also found with the highest level of a potent blood pressure-lowering agent, 2-vinyl-4H-1,3-dithiine (78.15 %), which is never reported in any garlic at this percentage. However, the local variety exhibited greater inhibitory properties against the tested organisms including multidrug-resistant pathogens compared to other varieties. This study primarily shows the potential of these two kinds of garlic for their further utilization and development.

Scientific Insights for Drug Development Based on Normal Habitat of Tribal Population of Manipur: An Observational Study Regarding the Implication of "Houttuynia cordata".

The development of new and novel drugs starts following a path of targeting possible candidate drug, elucidation their mechanism of action, animal studies, and finally after the completion of phases I/II and III clinical trials. The fundamental raw materials of drugs may be synthetic substances or plants. Many plants are habitually used in many countries as food or for the remedy of diseases. We found that a tribal population of Bangladesh use an herbal plant regularly and this plant has been shown to have potential positive effect for management of coronavirus disease-2019 (COVID-19). The present observation assessed the incidence and fatality of this community inhabitants due to COVID-19. Although a conclusion cannot be reached due to small sample size, this approach and theological concept may be helpful for the development, discovery, and innovation of new drugs for different pathological conditions. How to cite this article: Rahim MA, Singha SK, Foez SA, et al. Scientific Insights for Drug Development Based on Normal Habitat of Tribal Population of Manipur: An Observational Study Regarding the Implication of "Houttuynia cordata". Euroasian J Hepato-Gastroenterol 2023;13(2):142-144.

Treatment of Nonalcoholic Steatohepatitis by Obeticholic Acid: Current Status.

Nonalcoholic fatty liver disease (NAFLD) is one of the major and prevalent liver diseases from the national and global perspectives. It appears that considerable numbers of the general population have been suffering from NAFLD. When a patient with NAFLD also exhibits inflammation of the liver, the condition is regarded as nonalcoholic steatohepatitis (NASH). Nonalcoholic steatohepatitis is a pathological entity that may progress to cirrhosis of the liver (LC) and hepatocellular carcinoma (HCC). It is acceptable by all that the health burden of NAFLD and NASH is tremendous. Due to the increased prevalence of these pathologies, extensive research has been conducted regarding pathogenesis, diagnostic tools, and staging of the diseases. However, adequate and approved pharmacotherapy for these pathologies is lacking. The farnesoid receptor (FXR) is a bile acid-activated receptor. It regulates lipid, glucose, bile acid metabolism. Farnesoid receptor is also endowed with anti-inflammatory and anti-fibrotic properties on the liver. Obeticholic acid (OCA), a potent and selective FXR ligand, may become a promising molecule to combat NASH and advanced fibrosis. The present review briefly discusses the current recommendation of NASH management with available pharmacological treatments. The scope of OCA with a focus on recent data of major randomized controlled trials (RCTs) is discussed. On the basis of current data and recent interim analysis, OCA seems to improve insulin resistance, steatohepatitis, levels of alanine transaminase (ALT) and fibrosis in NASH. Dose-related adverse effects like pruritus and dyslipidemia may limit its usage. Also, its usage may be restricted in patients with NASH cirrhosis. More adequately powered RCTs that would contain NASH patients with different and heterogeneous properties would be required to develop consensus about these issues. The safety profile of different doses of OCA needs to be established in these patients as well as there remain considerable queries about these. How to cite this article: Roy PP, Mahtab MA, Rahim MA, et al. Treatment of Nonalcoholic Steatohepatitis by Obeticholic Acid: Current Status. Euroasian J Hepato-Gastroenterol 2022;12(Suppl 1):S46-S50.

A Nudge-Inspired AI-Driven Health Platform for Self-Management of Diabetes.

Diabetes mellitus is a serious chronic disease that affects the blood sugar levels in individuals, with current predictions estimating that nearly 578 million people will be affected by diabetes by 2030. Patients with type II diabetes usually follow a self-management regime as directed by a clinician to help regulate their blood glucose levels. Today, various technology solutions exist to support self-management; however, these solutions tend to be independently built, with little to no research or clinical grounding, which has resulted in poor uptake. In this paper, we propose, develop, and implement a nudge-inspired artificial intelligence (AI)-driven health platform for self-management of diabetes. The proposed platform has been co-designed with patients and clinicians, using the adapted 4-cycle design science research methodology (A4C-DSRM) model. The platform includes (a) a cross-platform mobile application for patients that incorporates a macronutrient detection algorithm for meal recognition and nudge-inspired meal logger, and (b) a web-based application for the clinician to support the self-management regime of patients. Further, the platform incorporates behavioral intervention techniques stemming from nudge theory that aim to support and encourage a sustained change in patient lifestyle. Application of the platform has been demonstrated through an illustrative case study via two exemplars. Further, a technical evaluation is conducted to understand the performance of the MDA to meet the personalization requirements of patients with type II diabetes.

Investigation of Intervention Solutions to Enhance Adherence to Oral Anticancer Medicines in Adults: Overview of Reviews.

BACKGROUND: Adherence to anticancer medicines is critical for the success of cancer treatments; however, nonadherence remains challenging, and there is limited evidence of interventions to improve adherence to medicines in patients with cancer. OBJECTIVE: This overview of reviews aimed to identify and summarize available reviews of interventions to improve adherence to oral anticancer medicines in adult cancer survivors. METHODS: A comprehensive search of 7 electronic databases was conducted by 2 reviewers who independently conducted the study selection, quality assessment using the A Measurement Tool to Assess Systematic Reviews 2, and data extraction. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 checklist was adapted to report the results. RESULTS: A total of 29 reviews were included in the narrative synthesis. The overall quality of the systematic reviews was low. The 4 main strategies to promote adherence were focused on education, reminders, behavior and monitoring, and multicomponent approaches. Digital technology-based interventions were reported in most reviews (27/29, 93%). A few interventions applied theories (10/29, 34%), design frameworks (2/29, 7%), or engaged stakeholders (1/29, 3%) in the development processes. The effectiveness of interventions was inconsistent between and within reviews. However, interventions using multiple strategies to promote adherence were more likely to be effective than single-strategy interventions (12/29, 41% reviews). Unidirectional communication (7/29, 24% reviews) and technology alone (11/29, 38% reviews) were not sufficient to demonstrate improvement in adherence outcomes. Nurses and pharmacists played a critical role in promoting patient adherence to oral cancer therapies, especially with the support of digital technologies (7/29, 24% reviews). CONCLUSIONS: Multicomponent interventions are potentially effective in promoting patient adherence to oral anticancer medicines. The seamless integration of digital solutions with direct clinical contacts is likely to be effective in promoting adherence. Future research for developing comprehensive digital adherence interventions should be evidence-based, theory-based, and rigorously evaluated.

Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.

Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

Bile acid-farnesoid X receptor-fibroblast growth factor 19 axis in patients with short bowel syndrome: The randomized, glepaglutide phase 2 trial.

BACKGROUND: The gut-liver axis and enterohepatic circulation have gained increasing attention lately. Patients with short bowel syndrome (SBS) are, in fact, human knock-out models that may assist in the understanding of bile acid synthesis and regulation. We evaluated effect of glepaglutide (a long-acting glucagon-like peptide-2 analog) on bile acid synthesis (the enterohepatic circulation of bile acids and liver biochemistry in patients with SBS). METHOD: In a single-center, double-blinded, dose-finding, crossover phase 2 trial, 18 patients with SBS were randomly assigned to 2 of 3 treatment arms (0.1, 1, and 10 mg) with daily subcutaneous injections of glepaglutide for 3 weeks. The washout period between the 2 treatment periods was 4-8 weeks. Measurements were performed at baseline and at the end of each treatment period and included postprandial plasma samples for fibroblast growth factor 19 (FGF19), 7α-hydroxy-4-cholesten-3-one (C4), total excretion of fecal bile acids, gene expression of farnesoid X receptor (FXR) in intestinal mucosal biopsies, total plasma bile acids, and liver biochemistry. RESULTS: Compared with baseline, the median (interquartile range) postprandial response (area under the curve 0-2h) of FGF19 increased by 150 h × ng/L (41, 195; P = 0.001) and C4 decreased by 82 h × µg/L (-169, -28; p = 0.010) in the 10-mg dose. FXR gene expression did not change in any of the groups. Alkaline phosphatase significantly decreased. CONCLUSION: Glepaglutide may stimulate the bile acid/FXR/FGF19 axis, leading to increased plasma concentrations of FGF19. Thereby, glepaglutide may ameliorate the accelerated de novo bile acid synthesis and play a role in the prevention and/or treatment of intestinal failure-associated liver disease.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with short bowel syndrome and colon in continuity: an open-label pilot study.

OBJECTIVE: Patients with short bowel syndrome (SBS) and colon in continuity have better adaptation potential compared with patients with jejunostomy. Adaptation may involve enhanced postprandial secretion of the enteroendocrine hormones glucagon-like peptide (GLP)-1 and GLP-2 which are normally degraded by dipeptidyl peptidase (DPP)-4. Nevertheless, some patients with SBS with colon in continuity suffer from high-volume faecal excretions and have been shown to benefit from treatment with GLP-2. Therefore, we aimed to evaluate efficacy of sitagliptin, a DPP-4 inhibitor, on reducing faecal excretions in this patient group. DESIGN: In an open-label, case series, proof-of-concept pilot study, 100 mg oral sitagliptin was given two times per day for 8 weeks to patients with SBS with ≥50% colon in continuity with or without the need for parenteral support (PS). To assess intestinal function, metabolic balance studies were done at baseline and following 8 weeks of treatment. RESULTS: Of the 10 patients planned for enrolment, 8 patients were included; 7 patients completed the study. Although postprandial endogenous GLP-2 concentrations increased by 49 hours×pmol/L (39, 105; p=0.018) (median (min, max)), sitagliptin did not significantly reduce median faecal wet weight (-174 g/day (-1510, 675; p=0.176)) or increase intestinal wet weight absorption. However, heterogeneity in the treatment effect was observed: intestinal wet weight absorption increased in all four patients with intestinal failure. One patient achieved a reduction in PS by 500 mL per administration day. CONCLUSION: Following this negative, small pilot study, larger, placebo-controlled, studies are needed to establish the therapeutic potential of DPP-4 inhibition in patients with SBS.

Simulating the Optimization of Carbon Fiber Reinforced Polymer as a Wrapping Structure on Piping System Using SolidWorks.

Carbon Fiber Reinforced Polymer (CFRP) was designed, simulated, and evaluated as a wrapping material on defected pipe using computational approach. This composite material was considered as a unique wrapping material as it may have the combined characteristics of the constituents or have substantially different properties than the individual constituents. Specifically, this research evaluates the capability of CFRP as a wrapper through SolidWorks Simulation using the static analysis, computational fluid dynamics analysis, and data analysis. This approach gives a preliminary consideration and justification on choosing the optimized lamination orientation of CFRP in real cases based on the simulated data. Various orientations were simulated and analyzed throughout this research. Based on all the simulation analysis, the CFRP wrapper with quasi-isotropic lamination with the 8 plies 45∘/90∘/0∘/45∘s orientation was seen most effective in reducing the stress and possess highest minimum safety factor at the fully defected region (100 × 100 × 7.11 mm thru) after the repair. Eventually, this optimized CFRP lamination orientation, proved that it was able to withstand pressures ranging between 0.86 to 19.6 MPa with a layer thickness in between 0.16 up to 3.76 mm. Based on the static analysis, this optimized laminated orientation of CFRP indeed showed that it was able to reduce the stress on an average of 94.10% after the repair was done. Relatively, CFRP was 0.2% higher in reducing the maximum stress at the defected region at the pipe, than the Glass Fiber Reinforced Polymer with the same orientation. Additionally, the flow simulation analysis in SolidWorks showed that fluid flow was undisrupted after the repair was done, and the wrapped region was resistant to any fluid leakages.

Patient clustering using dynamic partitioning on correlated and uncertain biomedical data.

Background and objectivesHealth professionals look for specific patterns by correlating multiple physiological data in the process of deciding treatments to remedy clinical abnormalities. Biomedical data exhibit some common patterns in the event of identical clinical illnesses. The primary interest of this work is automatic discovery of such patterns in vital sign data (e.g. heart rate, blood pressure) using unsupervised learning and utilising them to identify patients with similar clinical conditions. MethodsA patient clustering method is developed that efficiently isolates patients into multiple groups by discovering dynamic patterns in multi-dimensional vital sign data. A dynamic partitioning algorithm and a patient clustering approach is proposed by introducing a measure namely aggregated instance-wise uncertainty (AIU) computed from multi-dimensional physiological time-series data. ResultsThe developed model is evaluated qualitatively using principal component analysis and silhouette value; and quantitatively in terms of its ability of clustering patients associated with different clinical situations. Experiments are conducted using real-world biomedical data of patients having various clinical conditions. Thee observed accuracy was 82.85% and 91.17% on two experimental datasets comprised of 35 and 34 patients data respectively.The comparisons show that the proposed approached outperformed than other methods in state-of-the-art approach. ConclusionsThe experimental outcomes demonstrate the effectiveness of the proposed approach in discovering distinct patterns with predictive significance.

Effect of Glepaglutide, a Long-Acting Glucagon-Like Peptide-2 Analog, on Gastrointestinal Transit Time and Motility in Patients With Short Bowel Syndrome: Findings From a Randomized Trial.

BACKGROUND: Patients with short bowel syndrome (SBS) and distal-bowel resections lack neuroendocrine feedback regulations, potentially resulting in rapid gastrointestinal (GI) transit. The objective was to assess the efficacy of glepaglutide, a long-acting glucagon-like peptide-2 analog, on GI transit in patients with SBS. METHODS: In this single-center, double-blind, dose-finding, phase 2 trial, patients with SBS were randomly assigned to 3 treatments (0.1, 1, and 10 mg) in a 2-period crossover design. Each treatment period included 3 weeks of daily, subcutaneous glepaglutide injections separated by a washout period of 4-8 weeks. Endpoints were changes from baseline and included scintigraphy, wireless motility capsule (WMC, SmartPill Given Imaging, Ltd, Yokneam, Israel), and paracetamol absorption test. RESULTS: A total of 18 patients were randomized. In the 10-mg dose group (n = 9), glepaglutide significantly increased time to 10% gastric emptying (GE) of solids by 27 (4-50) minutes (adjusted mean [95% CI]), time to 50%GE of fluids by 40 (1-80) minutes, and time to 10% small bowel-emptying of solids by 21 (1-41) minutes. The WMC transit did not significantly change in any of the dose groups. The maximum paracetamol concentration significantly increased in the 10-mg dose group; however, the area under the curve remained the same. CONCLUSION: The prolonged GI transit after glepaglutide treatment, along with demonstrated positive effects on intestinal mucosal growth and potential effects on GI hypersecretions, is believed to contribute to the observed beneficial effects on fecal output (primary endpoint) and associated improvement in intestinal absorption.

Antinociceptive Activity of Petroleum Ether Fraction of Clinacanthus nutans Leaves Methanolic Extract: Roles of Nonopioid Pain Modulatory Systems and Potassium Channels.

Methanolic extract of Clinacanthus nutans Lindau leaves (MECN) has been reported to exert antinociceptive activity. The present study aimed to elucidate the possible antinociceptive mechanisms of a lipid-soluble fraction of MECN, which was obtained after sequential extraction in petroleum ether. The petroleum ether fraction of C. nutans (PECN), administered orally to mice, was (i) subjected to capsaicin-, glutamate-, phorbol 12-myristate 13-acetate-, bradykinin-induced nociception model; (ii) prechallenged (intraperitoneal (i.p.)) with 0.15 mg/kg yohimbine, 1 mg/kg pindolol, 3 mg/kg caffeine, 0.2 mg/kg haloperidol, or 10 mg/kg atropine, which were the respective antagonist of α 2-adrenergic, ß-adrenergic, adenosinergic, dopaminergic, or muscarinic receptors; and (iii) prechallenged (i.p.) with 10 mg/kg glibenclamide, 0.04 mg/kg apamin, 0.02 mg/kg charybdotoxin, or 4 mg/kg tetraethylammonium chloride, which were the respective inhibitor of ATP sensitive-, small conductance Ca2+-activated-, large conductance Ca2+-activated-, or nonselective voltage-activated-K+ channel. Results obtained demonstrated that PECN (100, 250, and 500 mg/kg) significantly (P<0.05) inhibited all models of nociception described earlier. The antinociceptive activity of 500 mg/kg PECN was significantly (P<0.05) attenuated when prechallenged with all antagonists or K+ channel blockers. However, only pretreatment with apamin and charybdotoxin caused full inhibition of PECN-induced antinociception. The rest of the K+ channel blockers and all antagonists caused only partial inhibition of PECN antinociception, respectively. Analyses on PECN's phytoconstituents revealed the presence of antinociceptive-bearing bioactive compounds of volatile (i.e., derivatives of γ-tocopherol, α-tocopherol, and lupeol) and nonvolatile (i.e., cinnamic acid) nature. In conclusion, PECN exerts a non-opioid-mediated antinociceptive activity involving mainly activation of adenosinergic and cholinergic receptors or small- and large-conductance Ca2+-activated-K+ channels.

Effects of glepaglutide, a novel long-acting glucagon-like peptide-2 analogue, on markers of liver status in patients with short bowel syndrome: findings from a randomised phase 2 trial.

BACKGROUND: With the introduction of glucagon-like peptide-2 (GLP-2) in the treatment of short bowel syndrome (SBS), there is emerging evidence that GLP-2 may play a role in the restoration of the disturbed homeostatic feedback in the gut-liver axis and may ameliorate SBS-associated liver damage. We have previously presented that daily subcutaneous injections with 1 and 10 mg of glepaglutide improved intestinal function in patients with SBS. As exploratory endpoints, we here assessed the effect of glepaglutide on liver function. METHODS: Liver tests, transient elastography (TE) with controlled attenuation parameter (CAP), indocyanine green (ICG) kinetics, soluble CD163 (sCD163), soluble mannose receptor (sMR), and lipopolysaccharide binding protein (LBP) were assessed in 18 patients with SBS in a randomised, cross-over, dose-finding phase 2 trial before and after three weeks of treatment with glepaglutide. This trial is completed and registered at ClinicalTrials.gov: NCT02690025. FINDINGS: Between Feb 2016 and Jan 2017, 22 patients with SBS were screened. Of these, 18 patients were randomised and treated with glepaglutide; 16 patients completed the trial. Treatment with glepaglutide was associated with increase in TE and ICG-elimination. In the 10 mg dose group, glepaglutide increased sCD163 by 0·44 mg/mL (P = 0·0498), and alkaline phosphatase (ALP) decreased in the 1 mg dose group by 33 U/L (P = 0·032). CAP, sMR, LBP, liver transaminases, and INR were not affected. INTERPRETATION: Glepaglutide may improve hepatic excretory function, but at the same time activate resident liver macrophages and increase liver stiffness. The excretory and the stiffness findings may to some extent relate to increased splanchnic blood flow which would not influence the marker of macrophage activation. Thus, glepaglutide exerted diverse effects on liver status that call for attention in future studies. FUNDING: Zealand Pharma.

Lumbar Ligament Sprain-degeneration and Prolapsed Lumbar Intervertebral Disc: A Frequent Missed Combination.

Low back pain (LBP) is a frequent complaint in the working milieu of pain physicians. Common LBP generators are the lumbar spine, soft tissues around the spine, and intra-abdominal viscera; however, in recent times, lumbar spine ligament (LL) degeneration is increasingly getting more coverage as an important LBP source. Among various LLs, interspinous and supraspinatus ligaments' sprain-degeneration can perpetuate localized central LBP as described in the present case study. Localized LL sprain-degeneration in association with radiating LBP from prolapsed lumbar intervertebral disc (PLID) compressing adjacent nerve roots might further impair a patient's quality of life. In the present report, we describe both LL sprain-degeneration and PLID (a dual source of LBP) in a 26-year-old Bangladeshi woman; physicians often fail to notice this combination in their regular clinical practice.

Antinociceptive activity of petroleum ether fraction obtained from methanolic extract of Clinacanthus nutans leaves involves the activation of opioid receptors and NO-mediated/cGMP-independent pathway.

BACKGROUND: Methanol extract (MECN) of Clinacanthus nutans Lindau leaves (family Acanthaceae) demonstrated peripherally and centrally mediated antinociceptive activity via the modulation of opioid/NO-mediated, but cGMP-independent pathway. In the present study, MECN was sequentially partitioned to obtain petroleum ether extract of C. nutans (PECN), which was subjected to antinociceptive study with aims of establishing its antinociceptive potential and determining the role of opioid receptors and L-arginine/nitric oxide/cyclic-guanosine monophosphate (L-arg/NO/cGMP) pathway in the observed antinociceptive activity. METHODS: The antinociceptive potential of orally administered PECN (100, 250, 500 mg/kg) was studied using the abdominal constriction-, hot plate- and formalin-induced paw licking-test in mice (n = 6). The effect of PECN on locomotor activity was also evaluated using the rota rod assay. The role of opioid receptors was determined by pre-challenging 500 mg/kg PECN (p.o.) with antagonist of opioid receptor subtypes, namely ß-funaltrexamine (ß-FNA; 10 mg/kg; a µ-opioid antagonist), naltrindole (NALT; 1 mg/kg; a δ-opioid antagonist) or nor-binaltorphimine (nor-BNI; 1 mg/kg; a κ-opioid antagonist) followed by subjection to the abdominal constriction test. In addition, the role of L-arg/NO/cGMP pathway was determined by prechallenging 500 mg/kg PECN (p.o.) with L-arg (20 mg/kg; a NO precursor), 1H-[1, 2, 4] oxadiazolo [4,3-a]quinoxalin-1-one (ODQ; 2 mg/kg; a specific soluble guanylyl cyclase inhibitor), or the combinations thereof (L-arg + ODQ) for 5 mins before subjection to the abdominal constriction test. PECN was also subjected to phytoconstituents analyses. RESULTS: PECN significantly (p < 0.05) inhibited nociceptive effect in all models in a dose-dependent manner. The highest dose of PECN (500 mg/kg) also did not significantly (p > 0.05) affect the locomotor activity of treated mice. The antinociceptive activity of PECN was significantly (p < 0.05) inhibited by all antagonists of µ-, δ-, and κ-opioid receptors. In addition, the antinociceptive activity of PECN was significantly (p < 0.05) reversed by L-arg, but insignificantly (p > 0.05) affected by ODQ. HPLC analysis revealed the presence of at least cinnamic acid in PECN. CONCLUSION: PECN exerted antinocicpetive activity at peripheral and central levels possibly via the activation of non-selective opioid receptors and modulation of the NO-mediated/cGMP-independent pathway partly via the synergistic action of phenolic compounds.

First Iranian Experience of the Minimally Invasive Nuss Procedure for Pectus Excavatum Repair: A Case Series and Literature Review.

Pectus excavatum is the most common congenital deformity of the chest wall. The most frequently used techniques include Ravitch (costochondral resection) and Nuss (minimally invasive pectus repair of pectus excavatum [MIRPE]). The Nuss technique includes using temporary metallic bars without costochondral resection to correct the chest wall deformity. Modified MIRPE can be learned easily and performed safely with few complications. There are no reports of successful MIRPE in Iran, although the Ravitch technique is well known. In the present study, we report the first Iranian experience with the modified Nuss procedure in 5 patients with pectus excavatum (age range=13-48 y). All the patients suffered from low self-esteem, and one of them complained of low exercise capacity and occasional chest pain. With single-lung ventilation and sternal elevation, an introducer was entered into the right thoracic cavity and retrosternal tunneling was performed under thoracoscopic vision. The introducer was passed to the left thoracic cavity and exited on the left thoracic wall. A titanium plate bar was implanted and fixed with stabilizers. There were no cases of mortality, and all the patients were discharged in good conditions within 2 weeks. Postoperative complications consisted of 1 case of pneumothorax and 2 cases of fixed bar protrusion. The present case series indicated that a skilled thoracoscopic surgeon is able to do the Nuss procedure in Iranian patients with symmetrical pectus excavatum with few complications. However, mixed or redo cases require more expertise.