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Background: Alcoholic Liver Disease (ALD) poses a significant global health threat, contributing to millions of deaths each year. Despite the well-established link between chronic alcohol consumption and liver damage, treatment options remain limited, emphasizing the need for innovative approaches. Methods: An open-label, randomized controlled trial was conducted in India, involving 68 adult ALD patients over a 12-week period. The patients were randomized into two groups: one receiving standard therapy and the other receiving standard therapy along with BoozLiv™ syrup. Liver function tests, Model for End-Stage Liver Disease (MELD) scores, and safety parameters were assessed at various intervals. Results: The study demonstrated that BoozLiv™ syrup, as an add-on therapy, significantly reduced total bilirubin, direct bilirubin, SGOT, SGPT, ALP, and GGT levels compared to standard therapy alone (p ​

Abstract Triple-negative breast cancer (TNBC) is a metastatic disease and a formidable treatment challenge as it does not respond to existing therapies. Epigenetic regulators play a crucial role in the progression and metastasis by modulating the expression of anti-apoptotic, pro-apoptotic markers and related miRNAs in TNBC cells. We have investigated the anti-TNBC potential of dietary flavonoid ‘Apigenin’ and its combination with Vorinostat on MDA-MB-231 cells. At Apigenin generated ROS, inhibited cell migration, arrested the cell cycle at subG0/G1 phases, and induced apoptotic-mediated cell death. Apigenin reduced the expression of the class-I HDACs at the transcriptomic and proteomic levels. In the immunoblotting study, Apigenin has upregulated pro-apoptotic markers and downregulated anti-apoptotic proteins. Apigenin inhibited the enzymatic activity of HDAC/DNMT and increased HAT activity. Apigenin has manifested its effect on miRNA expression by upregulating the tumor-suppressor miR-200b and downregulation oncomiR-21. Combination study reduced the growth of TNBC cells synergistically by modulating the expression of epigenetic and apoptotic regulators. Molecular docking and MD simulations explored the mechanism of catalytic inhibition of HDAC1 and HDAC3 and supported the in-vitro studies. The overall studies demonstrated an anti-TNBC potential of Apigenin and may help to design an effective strategy to treat metastatic phenotype of TNBC.

Background: Traditional medicines remain integral to healthcare worldwide especially in developing countries. Our prior studies highlighted the anti-melanoma potential of Prosopis juliflora leave methanolic extract (PJLME), leading us to further isolate and characterize bioactive compounds from PJLME and evaluate their efficacy against melanoma. In this context, we identified alkaloid fractions derived from PJLME (PJLME-AF) as key agents in PJLME's cytotoxic effect against melanoma cells. Purpose: The purpose of this research was to evaluate the anti-cancer effects and mechanisms of PJLME-AF on melanoma cell lines. Methods: Chemical Profiling of PJLME-AF was conducted by using LC-ESI-MS/MS. Cell viability and anti-migratory effects of PJLME-AF were assessed through MTT, wound healing and transwell assays. Mechanistic study of PJLME-AF was explored using ROS generation assay, apoptosis assays (Annexin V) assay, western blot (apoptotic protein, EMT markers, stem cell markers and signalling pathways), qPCR. In-vitro spheroid assay was performed to explored the PJLME-AF cytotoxic effects on tumour spheroid forming ability of melanoma cells. Additionally, the anti-tumor efficacy of PJLME-AF was tested in an in-vivo C57BL/6 mouse model. Results: PJLME-AF demonstrated potent anti-proliferative, anti-migratory and anti-invasive effects on melanoma cells. Mechanistic study indicates that PJLME-AF strongly induce ROS generation and subsequent apoptotic cell death in melanoma cells. Furthermore, PJLME-AF downregulated epithelial-to-mesenchymal transition (EMT) proteins, stem cell markers and Akt/Erk cell survival proteins providing insights into its molecular mechanisms. Notably, PJLME-AF inhibited spheroid formation and reduced PD-L1 expression. Finally, anti-tumor activity of PJLME-AF was further confirmed in a in-vivo mice model. Additionally, PJLME-AF combined with dacarbazine, exhibited enhanced cytotoxicity on melanoma compared to the drug alone. Conclusion: PJLME-AF exhibit promising natural anti-cancer agents for metastatic melanoma treatment. This research contributes to the development of novel, safe, and cost-effective agents for metastatic melanoma treatment and as a potential candidate for further cancer research.

Metastasis is an intricate and formidable pathophysiological process encompassing the dissemination of cancer cells from the primary tumour body to distant organs. It stands as a profound and devastating phenomenon that constitutes the primary driver of cancer-related mortality. Despite great strides of advancements in cancer research and treatment, tailored anti-metastasis therapies are either lacking or have shown limited success, necessitating a deeper understanding of the intrinsic elements driving cancer invasiveness. This comprehensive review presents a contemporary elucidation of pivotal facets within the realm of cancer metastasis, commencing with the intricate processes of homing and invasion. The process of angiogenesis, which supports tumour growth and metastasis, is addressed, along with the pre-metastatic niche, wherein the primary tumour prepares for a favorable microenvironment at distant sites for subsequent metastatic colonization. The landscape of metastasis-related genetic and epigenetic mechanisms, involvement of metastasis genes and metastasis suppressor genes, and microRNAs (miRNA) are also discussed. Furthermore, immune modulators' impact on metastasis and their potential as therapeutic targets are addressed. The interplay between cancer cells and the immune system, including immune evasion mechanisms employed by metastatic cells, is discussed, highlighting the importance of targeting immune modulation in arresting metastatic progression. Finally, this review presents promising treatment opportunities derived from the insights gained into the mechanisms of metastasis. Identifying novel therapeutic targets and developing innovative strategies to disrupt the metastatic cascade holds excellent potential for improving patient outcomes and ultimately reducing cancer-related mortality.

Magnetic resonance imaging (MRI) is a powerful medical imaging technique widely used for diagnosing various conditions because it provides detailed images of internal structures within the body. However, like any imaging modality, MRI images can be susceptible to artifacts that may arise from various sources, including hardware imperfections, patient motion, and image acquisition techniques. Detecting and mitigating these artifacts are crucial steps in ensuring MRI scans’ reliability and clinical utility. In this paper, we present algorithms specifically designed to address the challenges of undersampling and motion artifacts in MR images. Our approach involves leveraging advanced image processing techniques, including line detection algorithms for undersampling detection and blur parameter estimation for motion artifact analysis. By accurately identifying and quantifying these artifacts, our algorithms aim to improve MRI data’s overall quality and completeness, ultimately enhancing diagnostic accuracy and patient care.

Introduction: Type 1 Diabetes Mellitus (T1DM) is one of the most common paediatric endocrine illnesses. It is a chronic condition that involves regular administration of insulin, meal planning, strict adherence to physical activity and home-based sugar monitoring. Regular follow-up is essential to prevent short-term and long-term complications. Telemedicine has been extensively used in the management of multiple chronic conditions in adults. However, there are limited studies showing the impact of telemedicine in T1DM paediatric patients in the Indian population. Aim: To compare the glycaemic control in paediatric T1DM patients, before and after the use of telephonic reinforcement. Materials and Methods: A prospective, interventional study was conducted at Shree Krishna Hospital, Karamsad, Gujarat, India with no sub-specialty clinic. The duration of the study was one year and five months, from November 2017 to April 2019. Paediatric patients upto the age of 18 years, diagnosed with T1DM (by paediatricians/physicians) were included in the study. The records of 64 patients were traced, 27 were enrolled prospectively for the study (who could be contacted and consented to the present study). The baseline weight, height, age, duration of T1DM, insulin dosage and baseline Glycosylated Haemoglobin (HbA1c) were recorded. Majority of the patients 24 (89.4%) from rural area belonged to lower socioeconomic class, belonging to lower socioeconomic class. After receiving due consent, the patients/parents were provided telephonic reinforcement by a paediatrician to ensure regular sugar monitoring, solve queries of parents and to ensure regular follow-up. The clinical profile and parameters were repeated at three monthly intervals and compared. A paired t-test was used with a p-value=0.05 as a cut-off to compare data before and after intervention. Results: The mean and median ages of the study participants at diagnosis were found to be 8.9 years and 10.5 years, respectively. Average duration of T1DM was four years. On telephone, three things were reinforced: 1) To take insulin regularly as advised; 2) To come for follow-up regularly and 3) If any difficulties faced by them while taking insulin or coming for follow-up then to contact us. The patients were followed-up as per routine, diabetic care protocol every three months and value of HbA1c was reduced significantly during follow-up. The (p-value

Brain tumor detection in clinical applications is a complex and challenging task due to the intricate structures of the human brain. Magnetic Resonance (MR) imaging is widely preferred for this purpose because of its ability to provide detailed images of soft brain tissues, including brain tissue, cerebrospinal fluid, and blood vessels. However, accurately detecting brain tumors from MR images remains an open problem for researchers due to the variations in tumor characteristics such as intensity, texture, size, shape, and location. To address these issues, we propose a method that combines multi-level thresholding and Convolutional Neural Networks (CNN). Initially, we enhance the contrast of brain MR images using intensity transformations, which highlight the infected regions in the images. Then, we use the suggested CNN architecture to classify the enhanced MR images into normal and abnormal categories. Finally, we employ multi-level thresholding based on Tsallis entropy (TE) and differential evolution (DE) to detect tumor region(s) from the abnormal images. To refine the results, we apply morphological operations to minimize distortions caused by thresholding. The proposed method is evaluated using the widely used Harvard Medical School (HMS) dataset, and the results demonstrate promising performance with 99.5% classification accuracy and 92.84% dice similarity coefficient. Our approach outperforms existing state-of-the-art methods in brain tumor detection and automated disease diagnosis from MR images.

Abstract Modifications in the epigenetic landscape have been considered a hallmark of cancer. Histone deacetylation is one of the crucial epigenetic modulations associated with the aggressive progression of various cancer subtypes. Herein, we have repurposed the neprilysin inhibitor sacubitrilat as a potent anticancer agent using in-silico protein–ligand interaction profiler (PLIP) analysis, molecular docking, and in vitro studies. The screening of PLIP profiles between vorinostat/panobinostat and HDACs/LTA4H followed by molecular docking resulted in five (Sacubitrilat, B65, BDS, BIR, and NPV) FDA-approved, experimental and investigational drugs. Sacubitrilat has demonstrated promising anticancer activity against colorectal cancer (SW-480) and triple-negative breast cancer (MDA-MB-231) cells, with IC50 values of 14.07 μg/mL and 23.02 μg/mL, respectively. FACS analysis revealed that sacubitrilat arrests the cell cycle at the G0/G1 phase and induces apoptotic-mediated cell death in SW-480 cells. In addition, sacubitrilat inhibited HDAC isoforms at the transcriptomic level by 0.7–0.9 fold and at the proteomic level by 0.5–0.6 fold as compared to the control. Sacubitrilat increased the protein expression of tumor-suppressor (p53) and pro-apoptotic makers (Bax and Bid) by 0.2–2.5 fold while decreasing the expression of anti-apoptotic Bcl2 and Nrf2 proteins by 0.2–0.5 fold with respect to control. The observed cleaved PARP product indicates that sacubitrilat induces apoptotic-mediated cell death. This study may pave the way to identify the anticancer potential of sacubitrilat and can be explored in human clinical trials.

Prostate cancer, one of the most frequently occurring cancers in men, is a heterogeneous disease involving multiple cell types within tumors. This tumor heterogeneity at least partly results from genomic instability leading to sub-clonal cellular differentiation. The differentiated cell populations originate from a small subset of cells with tumor-initiating and stem-like properties. These cells, termed prostate cancer stem cells (PCSCs), play crucial roles in disease progression, drug resistance, and relapse. This review discusses the origin, hierarchy, and plasticity of PCSCs; methods for isolation and enrichment of PCSCs; and various cellular and metabolic signaling pathways involved in PCSC induction and maintenance, as well as therapeutic targeting.

HIV-associated neurocognitive disorders (HAND) are highly prevalent in those ageing with HIV. High-income country data suggest that vascular risk factors (VRFs) may be stronger predictors of HAND than HIV-disease severity, but data from sub-Saharan Africa are lacking. We evaluated relationships of VRFs, vascular end-organ damage and HAND in individuals aged ≥ 50 in Tanzania. c-ART-treated individuals were assessed for HAND using consensus criteria. The prevalence of VRFs and end organ damage markers were measured. The independent associations of VRFs, end organ damage and HAND were examined using multivariable logistic regression. Data were available for 153 individuals (median age 56, 67.3% female). HAND was highly prevalent (66.7%, 25.5% symptomatic) despite well-managed HIV (70.5% virally suppressed). Vascular risk factors included hypertension (34%), obesity (10.5%), hypercholesterolemia (33.3%), diabetes (5.3%) and current smoking (4.6%). End organ damage prevalence ranged from 1.3% (prior myocardial infarction) to 12.5% (left ventricular hypertrophy). Measured VRFs and end organ damage were not independently associated with HAND. The only significant association was lower diastolic BP (p 0.030, OR 0.969 (0.943–0.997). Our results suggest that vascular risk factors are not major drivers of HAND in this setting. Further studies should explore alternative aetiologies such as chronic inflammation.

Non-small cell lung cancer (NSCLC) is one of the most devastating cancers with a high incidence and mortality rates of all cancers. Locally advanced or metastatic NSCLC patients can benefit from platinum-based chemotherapy and targeted therapy drugs. Nevertheless, primary or acquired drug resistance will result in ineffective treatment, leading to tumor progression. The detailed mechanism underlying drug resistance to NSCLC are complicated and result from various factor. Among them, long noncoding RNAs (lncRNAs) have been found to be critically involved in NSCLC development and play a vital role in mediating therapy resistance. In this review, we attempt to systematically summarize the mechanisms underlying the lncRNA-mediated resistance to chemotherapy agents and targeted therapy drugs against lung cancer.

Aims: The aim of the study was to reveal the variability in soil properties influencing pigeonpea (Cajanus cajana L.) seed yield under semi-arid rainfed condition. Methods: Soils were initially classified into series level and further these series were divided into soil-phase units. For two site years viz., 2018-19 and 2019-20, surface soil samples from each soil-phase unit were collected before sowing of pigeonpea and subsequently crop growth parameters at critical stages were recorded. Results: The principal component analysis with varimax rotation resulted in seven components for both the site years, having eigenvalues greater than one, explained more than 80% of the variability. The step wise linear regression analysis showed that the pigeonpea seed yield was linearly correlated with PC3 (p

Abstract The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Mammary carcinoma was induced by subcutaneously inoculating 4T1 cells into the mammary fat pad of the animals. Intraperitoneal administration of Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen was carried out once a week for three weeks. Treatment of Mulmina began one week before chemotherapy and continued till the end of the chemotherapy cycle. After three cycles of chemotherapy, cognitive decline was assessed by Morris water maze task followed by assessment of locomotor activity by open-field test. Tumor progression was evaluated by measurement of tumor volume. Oxidative and neuroinflammatory markers were also evaluated from the isolated brain samples. CMF treatment resulted in a considerable reduction in tumour volume. We found chemotherapy negatively affected behavioral and biochemical parameters in animals and Mulmina treatment ameliorated these cognitive impairments by restoring antioxidant and maintaining cytokine levels. The combination of phytochemicals in Mulmina proved its possible ability to alleviate CICI without affecting chemotherapeutic efficiency and could pave the way for identifying treatment strategies to combat chemobrain.

Abstract Introduction QTc prolongation is key in diagnosing long QT syndrome (LQTS), however 25%–50% with congenital LQTS (cLQTS) demonstrate a normal resting QTc. T wave morphology (TWM) can distinguish cLQTS subtypes but its role in acquired LQTS (aLQTS) is unclear. Methods Electronic databases were searched using the terms “LQTS,” “long QT syndrome,” “QTc prolongation,” “prolonged QT,” and “T wave,” “T wave morphology,” “T wave pattern,” “T wave biomarkers.” Whole text articles assessing TWM, independent of QTc, were included. Results Seventeen studies met criteria. TWM measurements included T‐wave amplitude, duration, magnitude, Tpeak‐Tend, QTpeak, left and right slope, center of gravity (COG), sigmoidal and polynomial classifiers, repolarizing integral, morphology combination score (MCS) and principal component analysis (PCA); and vectorcardiographic biomarkers. cLQTS were distinguished from controls by sigmoidal and polynomial classifiers, MCS, QTpeak, Tpeak‐Tend, left slope; and COG x axis. MCS detected aLQTS more significantly than QTc. Flatness, asymmetry and notching, J‐Tpeak; and Tpeak‐Tend correlated with QTc in aLQTS. Multichannel block in aLQTS was identified by early repolarization (ERD30%) and late repolarization (LRD30%), with ERD reflecting hERG‐specific blockade. Cardiac events were predicted in cLQTS by T wave flatness, notching, and inversion in leads II and V5, left slope in lead V6; and COG last 25% in lead I. T wave right slope in lead I and T‐roundness achieved this in aLQTS. Conclusion Numerous TWM biomarkers which supplement QTc assessment were identified. Their diagnostic capabilities include differentiation of genotypes, identification of concealed LQTS, differentiating aLQTS from cLQTS; and determining multichannel versus hERG channel blockade.

Summary: The hybrid renewable energy system (HRES) can overcome the problem of the mismatch of supply of variable renewable energies and demand. The optimal sizing of the HRES methodology is implemented by employing the generalized reduced gradient (GRG) method. A case study of HRES with solar, bio, and hydro sources for tribal areas in a hilly region of India is demonstrated. Both the grid-connected scenario and the standalone scenario in island mode are simulated. The optimal LCOE of 0.106–0.053 $/kWh is achieved in standalone mode for 100%–70% reliability. The grid-connected scenario is simulated with two different rates of payment for the electric energy delivered to the grid and a range of grid purchase prices. The LCOE results to around 0.06 $/kWh for the prospective grid-connected mode cases. The sensitivity analysis and validation of the work are also performed.

Abstract Background Natural products with targeted bioactivity have gained major attention in the field of cancer research owing to emerging anti‐cancer drug resistance and off target toxicities. Chloroxylon swietenia (Roxb.) DC is recognized as a folklore medicinal plant and has numerous therapeutic benefits in the folklore medicine system, however the anti‐cancer potential of this plant and its mechanism of action is poorly understood. Aims The aim of the study was to investigate the anti‐breast cancer efficacy of C. swietenia leaves methanol extract (CSLME) against MCF‐7 hormone dependent human breast cancer cell line with possible mechanism of action. Methods and results The anti‐breast cancer activity of CSLME against MCF‐7 cells was assessed by evaluating its efficacy toward cytotoxicity, cell migration, colony formation, DNA fragmentation, apoptosis, cytoskeleton, angiogenesis, cell cycle regulation, and animal toxicity. The preliminary screening of CSLME against MCF‐7 cells revealed the cytotoxicity (IC50 20 μg/ml), inhibited cell migration, colony formation, and angiogenesis. It was observed that CSLME induces apoptosis by nuclear fragmentation and disruption of cytoskeleton by actin derangement. The results of Annexin V‐FITC assay and cell cycle analysis by flow cytometry clearly pointed out the sizable fraction of apoptotic cells, and arrested the cells at G2/M phase of cell cycle. The results of the immunoblotting experiments showed that CSLME activates intrinsic pathway of apoptosis with down regulation of anti‐apoptotic marker like Bcl2, up regulation of pro‐apoptotic markers like Bax & Bad, along with successful cleavage of Caspase‐9 and PARP‐1. Further, western blot analysis revealed the possible down regulation of NF‐κB pathway by CSLME, which may be responsible for anti‐cancer activity in MCF‐7 cells. In vivo animal model studies using NOD‐SCID mice demonstrated impressive anti‐tumor activity with significant reduction in tumor volume of MCF‐7 tumor xenograft. Of note, in‐vivo acute oral toxicity study as per Organization for Economic Cooperation and Development 423 revealed the nontoxic nature of CSLME. Conclusion The in vitro and in vivo findings clearly outline the potential of CSLME as inhibitor of growth and proliferation of MCF‐7 cells. Mechanistically, CSLME seems to activate intrinsic pathway of apoptosis, arrest cell cycle, target actin cytoskeleton, inhibit growth, colony formation, migration, and angiogenesis, with down regulation of NF‐κB pathway leading to cell death.

Abstract Background As right colon polyps are challenging to detect, a retroflexed view of right colon (RV) may be useful. However, cecal retroflexion (CR) without a RV to the hepatic flexure (HF) is inadequate. We aimed to determine the frequency of CR and quality of the RV in routine practice. Methods This prospective observational study performed at an academic medical center assessed colonoscopy inspection technique of endoscopists who had performed ≥ 100 annual screening colonoscopies. We video recorded ≥ 28 screening/surveillance colonoscopies per endoscopist and randomly evaluated 7 videos per endoscopist. Six gastroenterologists blindly reviewed the videos to determine if CR was performed and HF withdrawal time (cecum to HF time, excluding ileal/polypectomy time). Results Reviewers assessed 119 colonoscopies performed by 17 endoscopists. The median HF withdrawal time was 3 min and 46 s. CR was performed in 31% of colonoscopies. CR frequency varied between endoscopists with 9 never performing CR and 2 performing CR in all colonoscopies. When performed, nearly half (43%) of RVs did not extend to the HF with median RV duration of 16 s (IQR 9–30 s). Three polyps were identified in the RV (polyp detection rate of 8.1%), all identified prior to a forward view. Conclusions CR is performed infrequently in routine practice. When CR is performed, the RV is of low quality with a very short inspection duration and insufficient ascending colon examination. Further education is required to educate endoscopists in optimal technique to improve overall colonoscopy quality.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Traumatic brain injury, stroke, and neurodegenerative diseases represent a major cause of morbidity and mortality in Africa, as in the rest of the world. Traumatic brain and spinal cord injuries specifically represent a leading cause of disability in the younger population. Stroke and neurodegenerative disorders predominantly target the elderly and are a major concern in Africa, since their rate of increase among the ageing is the fastest in the world. Neuroimmunology is usually not associated with non-communicable neurological disorders, as the role of neuroinflammation is not often considered when evaluating their cause and pathogenesis. However, substantial evidence indicates that neuroinflammation is extremely relevant in determining the consequences of non-communicable neurological disorders, both for its protective abilities as well as for its destructive capacity. We review here current knowledge on the contribution of neuroinflammation and neuroimmunology to the pathogenesis of traumatic injuries, stroke and neurodegenerative diseases, with a particular focus on problems that are already a major issue in Africa, like traumatic brain injury, and on emerging disorders such as dementias.

Background: India has reported more than 70,000 cases and 2000 deaths. Pune is the second city in the Maharashtra state after Mumbai to breach the 1000 cases. Total deaths reported from Pune were 158 with a mortality of 5.7%. To plan health services, it is important to learn lessons from early stage of the outbreak on course of the disease in a hospital setting. Objectives: To describe the epidemiological characteristics of the outbreak of COVID-19 in India from a tertiary care hospital. Methods: This was a hospital-based cross-sectional study which included all admitted laboratory confirmed COVID19 cases from March 31, to April 24, 2020. The information was collected in a predesigned pro forma which included sociodemographic data, duration of stay, family background, outcome, etc., by trained staff after ethics approval. Epi Info7 was used for data analysis. Results: Out of the total 197 cases, majority cases were between the ages of 31–60 years with slight male preponderance. Majority of these cases were from the slums. Breathlessness was the main presenting symptom followed by fever and cough. More than 1/5th of patients were asymptomatic from exposure to admission. The case fatality rate among the admitted cases was 29.4%. Comorbidity was one of the significant risk factors for the progression of disease and death (odds ratio [OR] = 16.8, 95% confidence interval [CI] = 7.0 − 40.1, P < 0.0001). Conclusion: Mortality was higher than the national average of 3.2%; comorbidity was associated with bad prognosis.

Background and study aims Colonoscopy inspection quality (CIQ) assesses skills (fold examination, cleaning, and luminal distension) during inspection for polyps and correlates with adenoma detection rate (ADR) and serrated detection rate (SDR). We aimed to determine whether providing individualized CIQ feedback with instructional videos improves quality metrics performance. Methods We prospectively studied 16 colonoscopists who already received semiannual benchmarked reports of quality metrics (ADR, SDR, and withdrawal time [WT]). We randomly selected seven colonoscopies/colonoscopist for evaluation. Six gastroenterologists graded CIQ using an established scale. We created instructional videos demonstrating optimal and poor inspection techniques. Colonoscopists received the instructional videos and benchmarked CIQ performance. We compared ADR, SDR, and WT in the 12 months preceding (“baseline”) and following CIQ feedback. Colonoscopists were stratified by baseline ADR into lower (≤ 34 %) and higher-performing (> 34 %) groups. Results Baseline ADR was 38.5 % (range 26.8 %–53.8 %) and SDR was 11.2 % (2.8 %–24.3 %). The proportion of colonoscopies performed by lower-performing colonoscopists was unchanged from baseline to post-CIQ feedback. All colonoscopists reviewed their CIQ report cards. Post-feedback, ADR (40.1 % vs 38.5 %, P = 0.1) and SDR (12.2 % vs. 11.2 %, P = 0.1) did not significantly improve; WT significantly increased (11.4 vs 12.4 min, P

IntroductionGenomic research and neurobiobanking are expanding globally. Empirical evidence on the level of awareness and willingness to donate/share biological samples towards the expansion of neurobiobanking in sub-Saharan Africa is lacking.AimsTo ascertain the awareness, perspectives and predictors regarding biological sample donation, sharing and informed consent preferences among community members in Ghana and Nigeria.MethodsA questionnaire cross-sectional survey was conducted among randomly selected community members from seven communities in Ghana and Nigeria.ResultsOf the 1015 respondents with mean age 39.3 years (SD 19.5), about a third had heard of blood donation (37.2%, M: 42.4%, F: 32.0%, p = 0.001) and a quarter were aware of blood sample storage for research (24.5%; M: 29.7%, F: 19.4%, p = 0.151). Two out of ten were willing to donate brain after death (18.8%, M: 22.6%, F: 15.0%, pConclusionThere is a greater need for research attention in the area of brain banking and informed consent. Improved context-sensitive public education on neurobiobanking and informed consent, in line with the sociocultural diversities, is recommended within the African sub region.

Large vessel disease and carotid stenosis are key mechanisms contributing to vascular cognitive impairment (VCI) and dementia. Our previous work, and that of others, using rodent models, demonstrated that bilateral common carotid stenosis (BCAS) leads to cognitive impairment via gradual deterioration of the neuro-glial-vascular unit and accumulation of amyloid-β (Aβ) protein. Since brain-wide drainage pathways (glymphatic) for waste clearance, including Aβ removal, have been implicated in the pathophysiology of VCI via glial mechanisms, we hypothesized that glymphatic function would be impaired in a BCAS model and exacerbated in the presence of Aβ. Male wild-type and Tg-SwDI (model of microvascular amyloid) mice were subjected to BCAS or sham surgery which led to a reduction in cerebral perfusion and impaired spatial learning acquisition and cognitive flexibility. After 3 months survival, glymphatic function was evaluated by cerebrospinal fluid (CSF) fluorescent tracer influx. We demonstrated that BCAS caused a marked regional reduction of CSF tracer influx in the dorsolateral cortex and CA1-DG molecular layer. In parallel to these changes increased reactive astrogliosis was observed post-BCAS. To further investigate the mechanisms that may lead to these changes, we measured the pulsation of cortical vessels. BCAS impaired vascular pulsation in pial arteries in WT and Tg-SwDI mice. Our findings show that BCAS influences VCI and that this is paralleled by impaired glymphatic drainage and reduced vascular pulsation. We propose that these additional targets need to be considered when treating VCI.

Background and study aims Practicing endoscopists have variable polypectomy skills during colonoscopy and limited training opportunities for improvement. Simulation-based training enhances procedural skill, but its impact on polypectomy is unclear. We developed a simulation-based polypectomy intervention to improve polypectomy competency. Methods All faculty endoscopists at our tertiary care center who perform colonoscopy with polypectomy were recruited for a simulation-based intervention assessing sessile and stalked polypectomy. Endoscopists removed five polyps in a simulation environment at pretest followed by a training intervention including a video, practice, and one-on-one feedback. Within 1–4 weeks, endoscopists removed five new simulated polyps at post-test. We used the Direct Observation of Polypectomy Skills (DOPyS) checklist for assessment, evaluating individual polypectomy skills, and global competency (scale: 1–4). Competency was defined as an average global competency score of ≥ 3. Results 83 % (29/35) of eligible endoscopists participated and 95 % (276/290) of planned polypectomies were completed. Only 17 % (5/29) of endoscopists had average global competency scores that were competent at pretest compared with 52 % (15/29) at post-test (P = 0.01). Of all completed polypectomies, the competent polypectomy rate significantly improved from pretest to post-test (55 % vs. 71 %; P

The robustness of 3D-printed mini-tablets as a platform to administer milligram dosages, intended for age-specific therapy, without the need of tablet splitting while maintaining similar release profiles, was investigated. Griseofulvin, as a model poorly water-soluble drug, and hydroxypropyl cellulose along with Kollicoat Protect as polymers were used to prepare filaments at 1–20% drug concentrations via hot-melt extrusion (HME). Higher drug concentrations served for testing the feasibility of a reduced number of mini-tablets to be administered. A reliable dose titration in the range 0.19–3.91 mg at a high accuracy (R2 of 0.999) was achieved through composite unit (multi-unit) mini-tablets. All mini-tablets produced had excellent content uniformity and their label claim values were within the acceptable range, proving that HME processing followed by 3D printing promotes content uniformity even for mini-tablets containing low drug doses (0.19 mg). Remarkably, the proposed approach allowed achieving similar drug release profiles via composite unit mini-tablets as well as single mini-tablets at high drug concentrations. In contrast, split tablets demonstrated different release behaviors, attributed to their size and shape differences. Overall, the distinct advantages of mini-tablets to provide dose flexibility while maintaining similar release profiles was demonstrated.

Abstract Background: Snake venoms are composed of pharmacologically active proteins that are evolutionarily diverse, stable and specific to targets. Hence, venoms have been explored as a source of bioactive molecules in treating numerous diseases. Recent evidences suggest that snake venom proteins may affect the formation of new blood vessels. Excessive angiogenesis has been implicated in several pathologies including tumours, diabetic retinopathy, arthritis, inter alia. In the present study, we have examined the effects of P-I metalloproteinases isolated from Bothrops moojeni (BmMP-1) and Bothrops atrox (BaMP-1) and L-amino acid oxidases (LAAO) isolated from B. moojeni (BmLAAO) and B. atrox (BaLAAO) on biochemical and functional aspects of angiogenesis. Methods: P-I metalloproteinases and LAAO were purified from venom by molecular size exclusion and ion-exchange chromatography and subsequently confirmed using mass spectrometry. The P-I metalloproteinases were characterized by azocaseinolytic, fibrinogenolytic and gelatinase activity and LAAO activity was assessed by enzyme activity on L-amino acids. Influence of these proteins on apoptosis and cell cycle in endothelial cells was analysed by flow cytometry. The angiogenic activity was determined by in vitro 3D spheroid assay, Matrigel tube forming assay, and in vivo agarose plug transformation in mice. Results: P-I metalloproteinases exhibited azocaseinolytic activity, cleaved α and partially β chain of fibrinogen, and displayed catalytic activity on gelatin. LAAO showed differential activity on L-amino acids. Flow cytometry analysis indicated that both P-I metalloproteinases and LAAO arrested the cells in G0/G1 phase and further induced both necrosis and apoptosis in endothelial cells. In vitro, P-I metalloproteinases and LAAO exhibited significant anti-angiogenic properties in 3D spheroid and Matrigel models by reducing sprout outgrowth and tube formation. Using agarose plug transplants in mice harbouring P-I metalloproteinases and LAAO we demonstrated a marked disruption of vasculature at the periphery. Conclusion: Our research suggests that P-I metalloproteinases and LAAO exhibit anti-angiogenic properties in vitro and in vivo.

Background and study aims Storage of full-length endoscopic procedures is becoming increasingly popular. To facilitate large-scale machine learning (ML) focused on clinical outcomes, these videos must be merged with the patient-level data in the electronic health record (EHR). Our aim was to present a method of accurately linking patient-level EHR data with cloud stored colonoscopy videos. Methods This study was conducted at a single academic medical center. Most procedure videos are automatically uploaded to the cloud server but are identified only by procedure time and procedure room. We developed and then tested an algorithm to match recorded videos with corresponding exams in the EHR based upon procedure time and room and subsequently extract frames of interest. Results Among 28,611 total colonoscopies performed over the study period, 21,170 colonoscopy videos in 20,420 unique patients (54.2 % male, median age 58) were matched to EHR data. Of 100 randomly sampled videos, appropriate matching was manually confirmed in all. In total, these videos represented 489,721 minutes of colonoscopy performed by 50 endoscopists (median 214 colonoscopies per endoscopist). The most common procedure indications were polyp screening (47.3 %), surveillance (28.9 %) and inflammatory bowel disease (9.4 %). From these videos, we extracted procedure highlights (identified by image capture; mean 8.5 per colonoscopy) and surrounding frames. Conclusions We report the successful merging of a large database of endoscopy videos stored with limited identifiers to rich patient-level data in a highly accurate manner. This technique facilitates the development of ML algorithms based upon relevant patient outcomes.

Background and study aims The quality of screening-related colonoscopy depends on several physician- and patient-related factors. Adenoma detection rate (ADR) varies considerably between endoscopists. Educational interventions aim to improve endoscopists’ ADRs, but their overall impact is uncertain. We aimed to assess whether there is an association between educational interventions and colonoscopy quality indicators. Methods A comprehensive search was performed through August 2019 for studies reporting any associations between educational interventions and any colonoscopy quality indicators. Our primary outcome of interest was ADR. Two authors assessed eligibility criteria and extracted data independently. Risk of bias was also assessed for included studies. Pooled rate ratios (RR) with 95 % confidence intervals (CI) were reported using DerSimonian and Laird random effects models. Results From 2,253 initial studies, eight were included in the meta-analysis for ADR, representing 86,008 colonoscopies. Educational interventions were associated with improvements in overall ADR (RR 1.29, 95 % CI 1.25 to 1.42, 95 % prediction interval 1.09 to 1.53) and proximal ADR (RR 1.39, 95 % CI 1.29 to 1.48), with borderline increases in withdrawal time, ([WT], mean difference 0.29 minutes, 95 % CI – 0.12 to 0.70 minutes). Educational interventions did not affect cecal intubation rate ([CIR], RR 1.01, 95 % CI 1.00 to 1.01). Heterogeneity was considerable across many of the analyses. Conclusions Educational interventions are associated with significant improvements in ADR, in particular, proximal ADR, and are not associated with improvements in WT or CIR. Educational interventions should be considered an important option in quality improvement programs aiming to optimize the performance of screening-related colonoscopy.

Background and study aims Critically ill patients may require endoscopic retrograde cholangiopancreatography (ERCP) but performing ERCP in the intensive care unit (ICU) poses logistic and technical challenges. There are no data on ICU patients undergoing ERCP in the endoscopy suite. The primary aim of this study was to report outcomes, including safety, when ERCP in critically ill patients is performed in the endoscopy suite. Patients and methods We queried our institutional endoscopy database to identify all ICU patients who underwent ERCP at a single academic medical center from 04/01/2010 to 11/30/2017. Only patients admitted to an ICU prior to ERCP were included. Results Of 7,218 ERCPs performed during the study period, 260 ERCPs (3.6 %) were performed in 231 ICU patients (mean age 61y; 53 % male); nearly all ICU patient ERCPs (n = 258; 99 %) occurred in the endoscopy suite. ERCP indications included cholangitis (50 %), post-liver transplant cholestasis (15 %), and bile leak (10 %). All ERCPs were performed with anesthesiology, most with general anesthesia (60 %) and in the prone position (60 %). Most patients (73 %) had sepsis. Prior to ERCP, 17 % of patients required vasopressors; vasopressors were begun during ERCP in 4 %.The cannulation success rate was 95 % (94 % in native papillae). Adverse events occurred in 9 % (n = 23) of cases with post-ERCP pancreatitis most common. No patients died during or within 24 hours of ERCP. Mortality at 30 days was 16 %, all attributed to underlying disease. Conclusions When advanced ventilatory and hemodynamic support is available, critically ill patients can safely and effectively undergo ERCP in the endoscopy suite.

The ethical, legal, and social implications (ELSI) of emerging neurobiobanks and data resources are unclear in an African scientific landscape with unique cultural, linguistic, and belief systems. The overarching goal of the African Neurobiobank for Precision Stroke Medicine–—ELSI Project is to identify, examine, and develop novel approaches to address ELSI issues of biobanking and stroke genomic research in sub-Saharan Africa (SSA). To accomplish the goal we will (1) explore knowledge, attitude, perceptions, barriers, and facilitators influencing ELSI issues related to biobanking and stroke genomic research; (2) use information obtained to craft a community intervention program focused on ELSI issues; and (3) build capacity and careers related to genomics and biobanking for effective client/community engagement while enhancing regulatory, governance, and implementation competences in biobanking science in SSA. A community-based participatory research and mixed-methodological approach, focused on various levels of the social ecological model, will be used to identify and examine relevant ELSI issues. Contextual intervention tools, platforms, and practices will be developed to enhance community understanding and participation in stroke biobanking and genomics research activities while facilitating enduring trust, and equitable and fair utilization of biobanking resources for genetic and trans-omics research. A concurrent capacity building program related to genetic counseling and biobanking will be implemented for early career researchers. The huge potential for neurobiobanking and genomics research in Africa to advance precision medicine applicable to stroke and other neurological disorders requires addressing ELSI challenges while building sustainable research, career, and regulatory capacities in trans-omics and biobanking science.

Background and study aims Non-adherence to scheduled colonoscopy burdens endoscopic practices and innovative approaches to improve adherence are needed. We aimed to assess the effect of an educational video emphasizing colonoscopy importance delivered through the electronic health record patient portal upon “no-show” and late cancellation rates (non-adherence) in patients scheduled for first-time screening colonoscopy. Patients and methods We conducted a single center randomized controlled trial among patients scheduled for their first screening colonoscopy. Patients were randomized to routine care (“control”) or video education (“video”). Control patients received a portal message 14 days prior to colonoscopy date; video patients additionally received a link to the educational video. Results In total, 830 patients (59 % female, median age 55 years) were randomized (“control”: 406; “video”: 424). Nearly all (88 %) opened the message; in the video arm, most (72 %) watched a majority of the video. Overall, 80 % attended their scheduled colonoscopy appointment (late cancel: 18 %, “no show”: 1 %) and 90 % underwent colonoscopy within 3 months of appointment. Adherence rates did not differ between video and control arms for the scheduled appointment (OR 1.2, CI 0.9–1.8) or for colonoscopy within 3 months of scheduled appointment (OR 1.3, CI 0.8–2.1). Bowel preparation quality did not differ between the groups. Conclusion Most patients scheduled for colonoscopy will open a patient portal message and, when delivered, watch an educational video. However, delivery of an educational video two weeks prior to screening colonoscopy appointment did not improve adherence.

The aim of this paper is to introduce and study upper and lower ω-continuous functions. Some characterizations and several properties concerning upper (resp. lower) ω-continuous functions are obtained.

Abstract Background The optimal approach to the drainage of malignant obstruction at the liver hilum remains uncertain. We aim to compare percutaneous transhepatic biliary drainage (PTBD) to endoscopic retrograde cholangiography (ERC) as the first intervention in patients with cholestasis due to suspected malignant hilar obstruction (MHO). Methods The INTERCPT trial is a multi-center, comparative effectiveness, randomized, superiority trial of PTBD vs. ERC for decompression of suspected MHO. One hundred and eighty-four eligible patients across medical centers in the United States, who provide informed consent, will be randomly assigned in 1:1 fashion via a web-based electronic randomization system to either ERC or PTBD as the initial drainage and, if indicated, diagnostic procedure. All subsequent clinical interventions, including crossover to the alternative procedure, will be dictated by treating physicians per usual clinical care. Enrolled subjects will be assessed for successful biliary drainage (primary outcome measure), adequate tissue diagnosis, adverse events, the need for additional procedures, hospitalizations, and oncological outcomes over a 6-month follow-up period. Subjects, treating clinicians and outcome assessors will not be blinded. Discussion The INTERCPT trial is designed to determine whether PTBD or ERC is the better initial approach when managing a patient with suspected MHO, a common clinical dilemma that has never been investigated in a randomized trial. Trial registration ClinicalTrials.gov, Identifier: NCT03172832. Registered on 1 June 2017.

Filaments loaded with griseofulvin (GF), a model poorly water-soluble drug, were prepared and used for 3D printing via fused deposition modeling (FDM). GF was selected due to its high melting temperature, enabling lower temperature hot-melt extrusion (HME) keeping GF largely crystalline in the filaments, which could help mitigate the disadvantages of high HME processing temperatures such as filament quality, important for printability and the adverse effects of GF recrystallization on tablet properties. Novel aspects include single-step fusion-assisted ASDs generation during FDM 3D printing and examining the impact of tablet surface areas (SA) through printing multi-mini and square-pattern perforated tablets to further enhance drug supersaturation during dissolution. Kollicoat protect and hydroxypropyl cellulose were selected due to their low miscibility with GF, necessary to produce crystalline filaments. The drug solid-state was assessed via XRPD, DSC and FT-IR. At 165 °C HME processing temperature, the filaments containing ~80% crystalline GF were printable. Fusion-assisted 3D printing led to GF supersaturation of ~153% for cylindrical tablets and ~293% with the square-pattern perforated tablets, indicating strong monotonous impact of tablet SA. Dissolution kinetics of drug release profiles indicated Fickian transport for tablets with higher SA, demonstrating greater SA-induced drug supersaturation for well-designed 3D printed tablets.

A key question that has remained unanswered is how pathogenic fungi switch from vegetative growth to infection-related morphogenesis during a disease cycle. Here, we identify a fungal oxylipin analogous to the phytohormone jasmonic acid (JA), as the principal regulator of such a developmental switch to isotropic growth and pathogenicity in the rice-blast fungus Magnaporthe oryzae. Using specific inhibitors and mutant analyses, we determined the molecular function of intrinsic jasmonates during M. oryzae pathogenesis. Loss of 12-Oxo-phytodienoic Acid (OPDA) Reductase and/or consequent reduction of jasmonate biosynthesis, prolonged germ tube growth and caused delayed initiation and improper development of infection structures in M. oryzae, reminiscent of phenotypic defects upon impaired cyclic AMP (cAMP) signaling. Chemical- or genetic-complementation completely restored proper vegetative growth and appressoria in opr1Δ. Mass spectrometry-based quantification revealed increased OPDA accumulation and significantly decreased jasmonate levels in opr1Δ. Most interestingly, exogenous jasmonate restored proper appressorium formation in pth11Δ that lacks G protein/cAMP signaling; but failed to do so in the Mitogen-activated protein (MAP) kinase mutants. Epistasis analysis placed jasmonate upstream of the cAMP pathway in rice blast. Mechanistically, intrinsic jasmonate orchestrates timely cessation of the vegetative phase and induces pathogenic development via a complex regulatory interaction with the cAMP-PKA cascade and redox signaling in rice blast.

Erdal Ekici has introduced and studied nearly continuous multifunctions in [5]. The purpose of the present paper is to introduce and study upper and lower nearly ω-continuous multifunctions as a weaker form of upper and lower nearly continuous multifunctions. Basic characterizations, several properties of upper and lower nearly ω-continuous multifunctions are investigated.

Abstract Background Lateral flap numbness is a known side-effect of midline skin incision in total knee arthroplasty (TKA) and a cause of patient dissatisfaction. Anterolateral incision is an alternative approach which preserves the infrapatellar branches of the saphenous nerve and avoids numbness. Studies have compared both incisions, but in different patients. However, different patients may assess the same sensory deficit dissimilarly, because of individual variations in anatomy and healing responses. We compared the two incisions in the same patient at the same time, using an anterolateral incision on one knee and a midline incision on the other knee in simultaneous bilateral TKA. Other surgical steps including medial arthrotomy were idential. We also correlated subjective and objective findings. Materials and methods Twenty patients were prospectively randomized. Sensory loss and skin healing were assessed at 6, 12 and 52 weeks. Subjective preference for the knee with less numbness was charted on Wald’s Sequential Probability Ratio Test. Sensation scores for touch, vibration, static and moving two-point discrimination were measured. Scar healing was evaluated using the Patient and Observer Scar Assessment Scale (POSAS). Functional scores were measured. Results A statistically significant difference favoring knees with anterolateral incision was observed in patient preference at all assessment points and this correlated with sensation scores. A statistically significant difference was observed in POSAS score favoring knees with anterolateral incision at 6 and 12 weeks which became statistically insignificant at 1 year. Functional scores remained comparable. Conclusion We recommend anterolateral incision as a safe and effective method to circumvent the problem of lateral flap numbness with midline incision. Level of evidence I.

The impact of mixer type and critical process parameters (CPPs) on critical quality attributes (CQAs), including the drug content uniformity (CU) of slurry-cast polymer films loaded with micro-sized poorly water-soluble drugs were investigated. Previously untested hypothesis was that the best mixer at suitable CPPs promotes uniform drug dispersion within film precursors leading to acceptable dried-film CU at low, ~0.6 wt% drug concentrations. Taguchi design was utilized to select the best of three mixers; low-shear impeller, high-shear planetary, and high-intensity vibrational, for dried-film drug concentration of ~23 wt%. As-received fenofibrate, a model poorly water-soluble drug (~6 µm) was directly mixed with the hydroxypropyl methylcellulose (HPMC) and glycerin aqueous solution. Impeller and planetary mixers yielded desirable film relative standard deviation (RSD), while vibrational mixer could not. For the lowest dried-film drug concentration of ~0.6 wt%, only planetary mixer yielded RSD