Exploring Bioactive Compounds of Rauvolfia tetraphylla L. (RT) for 3CLprotease of SARS-CoV2: GC-MS Analysis and In-Silico Studies.

Studies on the bioactive phytochemicals found in traditional medicinal plants are growing. This study focuses on Rauvolfia tetraphylla L. and its unique bioactive chemical composition. Previous research has demonstrated the plant's antimicrobial properties due to this composition. In this study, however, we also aim to investigate the antiviral properties of the plant. Rauvolfia tetraphylla L. has long been used for medicinal purposes. It is primarily located in Mexico, Central America, the West Indies, and northern South America. Along with checking out its in-silico SARS-CoV-2 activity, current work also evaluates the leaf extracts qualitative phytochemical, antioxidant, and cytotoxicity properties. While several conventional procedures were employed in the bio active compounds and phytochemical study that identified multiple phytochemicals, compounds derived from plants will be the most effective substitution with unfavorable side effects. The focus of this work is on in silico analysis, which determines the experimental plants activity against SARS-CoV-2 using molecular docking and pharmacokinetic analysis. We identified 20 phytochemical compounds from the GC-MS data of the plant, out of these 12 compounds failed to meet ADMET properties and the remaining 8 compounds passed TOPKAT Ames Mutagenicity. These compounds were docked against one important protein 3CLpro (PDB ID: 7DPV) that is implicated in the development of SARS-CoV-2. Docking studies have demonstrated binding results with maximum score and three compounds showed promising results. The results of this study highlighted the potential efficacy of (E,E,E,E,E,E)-()-2,6,10,15,19,23-hexamethyltetracosa-1,6,10,14,18,22-hexaen-3-ol, α-Tocospiro A, and α-Tocopherol. Furthermore, a thorough examination of the in-silico data indicates that the leaf has the potential to be a powerful source of medication and an efficient therapy in the future.

Salivary Interleukin-6 as a Non-Invasive Biomarker for Chronic Periodontitis and Tooth Loss in Type 2 Diabetes.

BACKGROUND: Periodontitis and type 2 diabetes are chronic inflammatory diseases that increase inflammatory Interleukin-6 (IL-6) levels that induce the production of advanced glycation end products (AGEs) causing receptor activator of nuclear factor-kappa B ligand (RANKL) expression on osteoclasts, contributing to further alveolar bone destruction. AIM: To assess the role and diagnostic potential of salivary IL-6 (SIL-6) in the detection and evaluation of chronic periodontitis (CP) and tooth loss in type 2 diabetes mellitus (T2DM). MATERIALS AND METHODS: This cross-sectional study comprised 240 subjects aged 30-69 years with minimum of 15 natural teeth. Fasting, unstimulated whole saliva was collected, full-mouth intra-oral examination and periodontal evaluation were performed using PCP-UNC 15 probe and glycaemic (HbA1c) levels were analysed by high-performance liquid chromatography (HPLC) method. Subjects were categorised into four groups of 60 participants each: Group 1 (controls); Group 2 (CP); Group 3 (T2DM with CP); Group 4 (T2DM with CP and tooth loss). Salivary IL-6 levels were quantitatively assessed by enzyme-linked immune sorbent assay method. RESULTS: Average SIL-6 levels were significantly elevated in Group 4 (T2DM with CP and tooth loss) (P = 0.001) and in severe periodontitis (P = 0.001). Karl Pearson Correlation found a significant association between average SIL-6 and average periodontal pocket depth (APPD) (r = 0.180), average clinical attachment loss ≥3 mm (ACAL3) (r = 0.289) and severity of periodontitis (r = 0.3228). The receiver operating characteristic (ROC) curve depicted an overall sensitivity of 53.3%, specificity of 68.6% and accuracy of 60% in the detection and assessment of CP in T2DM with tooth loss. CONCLUSION: IL-6 in saliva is a valuable, non-invasive biomarker in the detection and evaluation of CP in T2DM with tooth loss.

Evolutionary transition of hypervirulent Klebsiella pneumoniae to multidrug-resistant hypervirulent Klebsiella pneumoniae: Indian experience.

An emerging pathotype of Klebsiella pneumoniae, initially identified in Southeast Asian countries, has now spread to multiple countries, including India. These convergent strains, carrying both resistance and virulence determinants, are classified as multidrug-resistant Hypervirulent Klebsiella pneumoniae (MDR-HvKp). Since the initial reports, there has been a concerning surge in infections caused by this pathotype globally. In this context, we aim to shed light on the evolutionary changes that have taken place in this relatively novel pathotype. Understanding these changes is crucial for devising diagnosis and targeted intervention strategies to mitigate the spread of MDR-HvKp infections.

An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors.

Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood-brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options.

A Comparative Study on Survivors Versus Non-Survivors Among Diabetic Patients Having Mucormycosis.

Introduction Mucormycosis is a rare opportunistic fungal infection caused by fungi belonging to the Mucorales order and Mucoraceae family. It ranks as the third most prevalent angioinvasive fungal infection, following aspergillosis and candidiasis. This severe infection typically affects individuals with compromised immune systems, including those with hematological malignancies like leukemia and lymphoma, individuals who have undergone stem cell transplants, and people with diabetes mellitus. Individuals in good health are rarely affected, making immunocompromised individuals particularly vulnerable to this potentially fatal fungal disease. The aim of this study was to perform a comparative analysis of survivors versus non-survivors among diabetes patients admitted with mucormycosis. Methodology This was a descriptive observational study. A total of 338 patients were enrolled in the study. The study variables included demographics, COVID-19 infection, diabetes mellitus history, steroid use, use of oxygen support, and steam inhalation. Results Of the total 338 patients enrolled in the study, 253 (74.9%) were male and 85 (25.01%) were female. The number of survivors were 305 (90.2%) and non-survivors were 33(9.8%). The mean age of survivors was 52.50 ± 11.31 and non-survivors was 54.06 ± 8.54 years. Patients who underwent steam inhalation had a higher chance of survival compared to those who did not undergo steam inhalation and this association was statistically significant (p=0.01). Males showed a higher chance of survival (93.7%) as compared to females (80.0%). The associations between oxygen support, steroid use, and COVID-19 infection with the survival status were statistically non-significant. Conclusion There was a strong association between the history of steam inhalation and the outcome of mucormycosis among diabetes patients admitted with mucormycosis. Female patients demonstrated a higher fatality rate than males indicating a significant gender disparity observed in cases. Our findings may help to better identify and treat patients who are at higher risk for severe forms of mucormycosis.

Leveraging decagonal in-silico strategies for uncovering IL-6 inhibitors with precision.

Interleukin-6 upregulation leads to various acute phase reactions such as local inflammation and systemic inflammation in many diseases like cancer, multiple sclerosis, rheumatoid arthritis, anemia, and Alzheimer's disease stimulating JAK/STAT3, Ras/MAPK, PI3K-PKB/Akt pathogenic pathways. Since no small molecules are available in the market against IL-6 till now, we have designed a class of small bioactive 1,3 - indanedione (IDC) molecules for inhibiting IL-6 using a decagonal approach computational studies. The IL-6 mutations were mapped in the IL-6 protein (PDB ID: 1ALU) from thorough pharmacogenomic and proteomics studies. The protein-drug interaction networking analysis for 2637 FFDA-approved drugs with IL-6 protein using Cytoscape software showed that 14 drugs have prominent interactions with IL-6. Molecular docking studies showed that the designed compound IDC-24 (-11.8 kcal/mol) and methotrexate (-5.20) bound most strongly to the 1ALU south asian population mutated protein. MMGBSA results indicated that IDC-24 (-41.78 kcal/mol) and methotrexate (-36.81 kcal/mol) had the highest binding energy when compared to the standard molecules LMT-28 (-35.87 kcal/mol) and MDL-A (-26.18 kcal/mol). These results we substantiated by the molecular dynamic studies in which the compound IDC-24 and the methotrexate had the highest stability. Further, the MMPBSA computations produced energies of -28 kcal/mol and -14.69 kcal/mol for IDC-24 and LMT-28. KDeep absolute binding affinity computations revealed energies of -5.81 kcal/mol and -4.74 kcal/mol for IDC-24 and LMT-28 respectively. Finally, our decagonal approach established the compound IDC-24 from the designed 1,3-indanedione library and methotrexate from protein drug interaction networking as suitable HITs against IL-6.

NK1 receptor antagonistic effect of 17-trifluoromethyl phenyl trinor prostaglandin F2α on the growth of human breast cancer cell line.

BACKGROUND: A growing number of genetic and cancer biology investigations have found that the tachykinin NK1 Receptor plays an important role in cancer cell proliferation and survival. In this study. The present study was designed to evaluate the inhibition of cell growth by 17-trifluoromethyl phenyl trinor prostaglandin F2α with NK1 receptor in breast cancer cell lines. MATERIALS AND METHODS: MDB-MB-468 and MCF-7 breast cancer cell lines were used in the experiment were blocked with PGF2a. Cell proliferation and apoptosis were analyzed to evaluate the cytotoxic effect. Cell cycle distribution, Caspase-3 enzyme activity, Bad and Bax protein expression through flow cytometry and molecular docking were carried out to analyze the NK1 receptor activity. RESULTS: We found that PGF2a has a high binding affinity towards NK1 Receptor from molecular docking studies. It exerted cytotoxic and antiproliferative effects against MDB-MB-468 and MCF-7 breast cancer cell lines. Our data found that treatment of cells with 17-TPGF2 resulted in cell death and showed that increased expression of Caspase-3, Bad, and Bax protein and further induces G2 cell cycle arrest. CONCLUSION: Overall this study investigates the NK1 receptor antagonistic effect of PGF2 against breast cancer cell lines. However, further studies are needed to better characterize the application of NK1 receptor inhibition in clinical cancer treatment and cytotoxicity effect.

Identification of novel TMPRSS2 inhibitors against SARS-CoV-2 infection: a structure-based virtual screening and molecular dynamics study.

The scientific insights gained from the severe acute respiratory syndrome (SARS) and the middle east respiratory syndrome (MERS) outbreaks are helping scientists to fast-track the antiviral drug discovery process against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Coronaviruses, as well as influenza viruses, depend on host type 2 transmembrane serine protease, TMPRSS2, for entry and propagation in the human cell. Recent studies show that SARS-CoV-2 also uses TMPRSS2 for its cell entry. In the present study, a structure-based virtual screening of 52,337, protease ligands downloaded from the Zinc database was carried out against the homology model of TMPRSS2 protein followed by the molecular dynamics-based simulation to identify potential TMPRSS2 hits. The virtual screening has identified 13 hits with a docking score range of -10.447 to -9.863 and glide energy range of -60.737 to -40.479 kcal/mol. The binding mode analysis shows that the hit molecules form H-bond (Asp180, Gly184 & Gly209), Pi-Pi stacking (His41), and salt bridge (Asp180) type of contacts with the active site residues of TMPRSS2. In the MD simulation of ZINC000013444414, ZINC000137976768, and ZINC000143375720 hits show that these molecules form a stable complex with TMPRSS2. The complex equilibrates well with a minimal RMSD and RMSF fluctuation. All three structures, as predicted in Glide XP docking, show a prominent interaction with the Asp180, Gly184, Gly209, and His41. Further, MD simulation also identifies a notable H-bond interaction with Ser181 for all three hits. Among these hits, ZINC000143375720 shows the most stable binding interaction with TMPRSS2. The present study is successful in identifying TMPRSS2 ligands from zinc data base for a possible application in the treatment of COVID-19.

Preliminary evaluation of anticancer efficacy of pioglitazone combined with celecoxib for the treatment of non-small cell lung cancer.

PURPOSE: Among the lung cancer types, non-small cell lung cancer (NSCLC) is prominent and less responsive to chemotherapy. The current chemotherapeutics for NSCLC are associated with several dose-limiting side effects like bone-marrow suppression, neurotoxicity, nephrotoxicity, and ototoxicity, etc. which are causing non-compliance in patients. Many tumors, including breasts, lung, ovarian, etc. overexpress PPAR-γ receptors and COX-2 enzymes, which play a crucial role in tumor progression, angiogenesis, and metastasis. Lack of PPAR-γ activation and overproduction of prostaglandins, result in uncontrolled activation of Ras/Raf/Mek ultimately, NF-κB mediated tumor proliferation. This study aimed to investigate the anti-cancer potential of PPAR-γ agonist Pioglitazone combined with COX-2 inhibitor Celelcoxib in NSCLC. METHODS: Sixty adult Balb/C male mice were classified into sham control, disease control, and treatment groups. Mice were treated with Nicotine-derived nitrosamine ketone (NNK) (10 mg/kg), pioglitazone (10 & 20 mg/kg) and celecoxib (25 & 50 mg/kg). Weekly body weight, food intake, mean survival time & % increased life span were determined. Tumor weight and histopathological analysis were performed at the end of the study. RESULTS: The significant tumor reducing potential of pioglitazone combined with celecoxib was observed (p < 0.05). The treatment groups (treated with pioglitazone and celecoxib) showed a remarkable decrease in lung tumor weight, improved life span and mean survival time (p < 0.05). Histopathological studies confirm that treatment groups (treated with pioglitazone and celecoxib) reframed the lung architecture compared to disease control. CONCLUSION: Preliminary results revealed that pioglitazone adjunacy with celecoxib may be an effective chemo-preventive agent against NNK induce NSCLC.

DR-5 and DLL-4 mAb Functionalized SLNs of Gamma-Secretase Inhibitors- An Approach for TNBC Treatment.

Triple-negative breast cancer (TNBC) is the most aggressive and heterogeneous cancer subtypes. High rates of metastasis, poor prognosis, and drug resistance are the major problems associated with TNBC. The current chemotherapeutics eliminate only the bulk tumor cells (non-BCSCs) and do not affect breast cancer stem cells (BCSCs). The BCSCs which are left behind after chemotherapy is reported to promote recurrence and metastasis of TNBC. Death receptor-5 (DR-5) is exclusively expressed in TNBCs and mediates the extrinsic pathway of apoptosis. DR-5, therefore, can be exploited for targeted drug delivery and to induce apoptosis. Gamma-secretase mediated Notch signaling in BCSCs regulates its proliferation, differentiation, and metastasis. The endogenous ligand, Delta-like ligand 4 (DLL4), is reported to activate this Notch signaling in TNBC. Blocking this signaling pathway using both gamma-secretase inhibitors (GSIs) and DLL4 monoclonal antibody (mAb) may produce synergistic benefits. Further, the GSIs (DAPT, LY-411575, RO4929097, MK0752, etc.) suffer from poor bioavailability and off-target side effects such as diarrhea, suppression of lymphopoiesis, headache, hypertension, fatigue, and ventricular dysfunctions. In this hypothesis, we discuss Solid lipid nanoparticles (SLNs) based drug delivery systems containing GSIs and surface modified with DR-5 and DLL4 monoclonal antibodies (mAb) to effectivity target and treat TNBC. The delivery system is designed to deliver the drug cargo precisely to TNBCs through its DR-5 receptors and hence expected to reduce the off-target side effects of GSIs. Further, DLL4 mAb and GSIs are expected to act synergistically to block the Notch signal mediated BCSCs proliferation, differentiation, and metastasis.

Tumor microenvironment and nanotherapeutics: intruding the tumor fort.

Over recent years, advancements in nanomedicine have allowed new approaches to diagnose and treat tumors. Nano drug delivery systems exploit the enhanced permeability and retention (EPR) effect and enter the tumor tissue's interstitial space. However, tumor barriers play a crucial role, and cause inefficient EPR or the homing effect. Mounting evidence supports the hypothesis that the components of the tumor microenvironment, such as the extracellular matrix, and cellular and physiological components collectively or cooperatively hinder entry and distribution of drugs, and therefore, limit the theragnostic applications of cancer nanomedicine. This abnormal tumor microenvironment plays a pivotal role in cancer nanomedicine and was recently recognized as a promising target for improving nano-drug delivery and their therapeutic outcomes. Strategies like passive or active targeting, stimuli-triggered nanocarriers, and the modulation of immune components have shown promising results in achieving anticancer efficacy. The present review focuses on the tumor microenvironment and nanoparticle-based strategies (polymeric, inorganic and organic nanoparticles) for intruding the tumor barrier and improving therapeutic effects.

Preliminary evaluation on the beneficial effects of pioglitazone in the treatment of endometrial cancer.

Endometrial cancer (EMC) is one of the complicated gynecological cancers, affecting more than three million women worldwide. Anticancer strategies such as chemotherapy, radiation, and surgery are found to be ineffective and are associated with patient incompliances. The aim of the present study is to repurpose non-oncological drug, i.e., Pioglitazone, a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, in the treatment of endometrial cancer. The study groups consist of 50 female Swiss albino mice, out of which 40 had endometrial cancer induced with N-ethyl-N-nitrosourea (ENU) and estradiol hexadrobenzoate (EHB). The other groups received saline, EHB, paclitaxel, and different test doses of pioglitazones. Different preliminary parameters such as weekly body weight, mean survival time, percentage increase in life span, and uterine tissue weight were analyzed along with histopathological analysis. We observed a significant change in weekly body weight, improvement in percentage life span, and partial restoration of uterine tissue weight to normal compared to a standard drug, paclitaxel. In the present preliminary evaluation, we have identified that pioglitazone exhibited a significant dose-dependent anticancer activity against ENU- and EHB-induced endometrial cancer, compared to the standard paclitaxel.

Purification of Bhallathaka (Semecarpus anacardium L.f.) enhanced anti-cancer activity.

Semecarpus anacardium L. F. commonly known as Bhallathaka, is an important Ayurvedic medicinal plant of the family Anacardiaceae. Mature fruit of this plant is used as an Ayurvedic drug for treating various ailments including cancer. The drug has been reported to cause irritation, blisters, toxicity and contact dermatitis if used in raw form. In Ayurvedic texts, various methods have been described for purification process of Bhallathaka in order to minimize the toxic effects as well as to potentiate the drug. This study was carried out to evaluate chemical profiles and anti-cancer activity of raw and purified samples of Bhallathaka. Chemical characterization was done by Liquid chromatography mass spectroscopic (LC/MS) analysis and anticancer activity was evaluated using Ehrlich Ascites Carcinoma (EAC) model in mice with 5-fluorouracil as standard. The result indicated that purification of Bhallathaka imparted chemical changes to certain active compounds and enhanced its anti-cancer activity when compared to raw sample. The present study concluded that traditional purification process can impact the chemical and pharmacological profile of herbal drugs and thus beneficial in increasing its safety and efficacy.

DR5 antibody conjugated lipid-based nanocarriers of gamma-secretase inhibitor for the treatment of triple negative breast cancer.

In the present study, Death receptor-5 (DR5) antibody conjugated solid lipid nanoparticles (DR5-DAPT-SLNs) has been formulated for effective intracellular of γ-secretase inhibitor, N-[N-(3,5-Difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) to cancer cells. Emulsification-solvent evaporation, followed by EDC cross-linking methods, was employed to prepare DR5 targeted DAPT-SLNs (DR5-DAPT-SLNs). The formulation was characterized by its particle size, shape, and surface charge. The in vitro & in vivo anticancer efficacy was studied in MDA-MB231 triple negative breast cancer (TNBC) cells and DMBA induced breast cancer model in mice, respectively. The results show that thatDR5-DAPT-SLNs is found to be a spherical shape with an average particle size of 187 ± 0.98 nm and having an average surface charge of 23 ± 2.3 mV. DR5-DAPT-SLNs have higher cytotoxicity in MDA-MB231 cells compared to DAPT-SLNs (non-targeted) and the bulk drug. However, in DR5 negative HEK 293 noncancer cells, the formulation shows minimal cytotoxic effects. The above results, therefore, demonstrate DR5 mediated uptake is responsible for improved cytotoxicity of DAPT. In the in vivo anticancer study, DR5-DAPT-SLNs show greater tumor regression when compared to DAPT-SLNs and the bulk drug. In conclusion, the results of the present study demonstrate that the DR5-DAPT-SLNs selectively target cancer cells and potentiate the anticancer efficacy of DAPT against TNBC cells.

1,3,4-Thiadiazolo (3,2-Α) Pyrimidine-6-Carbonitrile Scaffold as PARP1 Inhibitors.

BACKGROUND: 1,3,4-thiadiazolo pyrimidine is a lead molecule that is versatile for a wide variety of biological activities and in continuation of our interest in establishing some novel heterocyclic compounds for antitumor activity. OBJECTIVE: The objective of the study was to synthesize a series of 5-amino-7-(substituted aldehyde)-2[(naphthalene- 2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives and evaluate their possible in vitro and in vivo anticancer activity. METHODS: Herein, we report the synthetic scheme, which was followed for the preparation of a series of title compounds B1- B9 outlined in scheme 1. The intermediate 5-[(naphthalen-2- yloxy)methyl]-1,3,4-thiadiazolo- 2-amine was prepared by heating 2-naphthoxyacetic acid and thiosemicarbazide in the presence of phosphoryl chloride at a temperature of 65-75°C. The obtained compound reacted with malononitrile and an appropriate amount of aromatic and heteroaromatic aldehydes in refluxing ethanol yielded 5-amino-7-(substituted aldehyde)-2[(naphthalene-2-yloxy)methyl] -[1,3,4]thiadiazolo-[3,2-α]-pyrimidine-6- carbonitrile derivatives (B1 - B9). The purity of the synthesized compounds was ensured by various spectral analyses. RESULTS: In in silico molecular docking studies, compounds B3 and B9 show binding affinity like known PARP1 inhibitor olaparib. The cellular evaluation indicates that the anticancer profile of compounds B1, B3, and B9 is significant when compared to the standard drug (olaparib) against MDA-MB-232 cell line and compounds B3, B6, and B7 are the most active against MCF-7 cell lines. The most active compound B3 was subjected to acute oral toxicity studies by OECD 423 guidelines and in vivo anti-cancer studies were carried out using DMBA induced model. CONCLUSION: The in silico docking study of the newly synthesized compounds was performed; the results showed good binding mode in the active site of PARP1 enzyme. In silico ADME properties of synthesized compounds were also studied and showed good drug-like properties.

Phenyl boronic acid-modified lipid nanocarriers of niclosamide for targeting triple-negative breast cancer.

Aim: To study the active targeting efficacy of phenylboronic acid-modified niclosamide solid lipid nanoparticles (PBA-Niclo-SLN) in triple-negative breast cancer (TNBC). Materials & methods: PBA-Niclo-SLNs were formulated by an emulsification-solvent evaporation method using PBA-associated stearylamine (PBSA) as lipid. The drug uptake and the anticancer propensity of PBA-Niclo-SLN were studied in TNBC (MDA-MB231) cells and tumor-bearing mice. Results: PBA-Niclo-SLN formulation resulted in greater antitumor efficacy by inducing G0/G1 cell cycle arrest and apoptosis. Besides, PBA-Niclo-SLN effectively inhibited STAT3, CD44+/CD24- TNBC stem cell subpopulation, epithelial-mesenchymal transition markers. Besides, PBA-Niclo-SLN selectively accumulated at the tumor site with more significant tumor regression and improved the survivability in TNBC tumor-bearing mice. Conclusion: PBA-Niclo-SLN formulation would be an effective strategy to eradicate TNBC cells (breast cancer stem cells and nonbreast cancer stem cells) efficiently.

Sustained colonoscopy quality improvement using a simple intervention bundle.

BACKGROUND: Unacceptable variation in colonoscopy quality exists. The Quality Improvement in Colonoscopy (QIC) study in 2011 improved quality by introducing an evidence-based "bundle" of measures into routine colonoscopy practice. The QIC bundle included: minimal cecal withdrawal time of ≥ 6 minutes; hyoscine butylbromide use; supine patient position for transverse colon examination; rectal retroflexion. Colonoscopy quality was measured by adenoma detection rate (ADR). The current study measured whether these effects led to a sustained change in practice 3 years following implementation. METHODS: This observational study collected data from eight hospital trusts (sites) in the United Kingdom for a 6-month period, 3 years following QIC bundle implementation. Use of the antispasmodic, hyoscine butylbromide, was measured as a marker of bundle uptake. Bundle effectiveness was measured by ADR change. Comparisons were made between data before and immediately after implementation of the bundle. RESULTS: 28 615 colonoscopies by 188 colonoscopists were studied. Hyoscine butylbromide use increased from 15.8 % pre-implementation to 47.4 % in the sustainability phase (P < 0.01) indicating sustained engagement with QIC measures. ADR was higher in the sustainability period compared with pre-intervention, but only reached statistical significance among the poorest-performing colonoscopists. CONCLUSIONS: The introduction of a simple, inexpensive, pragmatic intervention significantly changed practice over a sustained period, improving colonoscopy quality as measured by ADR, particularly in poorer performers. QIC demonstrates that an easy-to-implement quality improvement approach can deliver a sustained change in practice for many years post intervention.