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Hepatocellular carcinoma (HCC) continues to have a dismal prognosis, with 5-year survival below 20%. This poor prognosis can be in part attributed to failures along the cancer screening process continuum such as underuse of screening in at risk patients and appropriate treatments for patients with HCC. Better understanding these process failures, and how they compare to those seen in other cancer types, can help inform potential intervention targets and strategies to reduce HCC-related mortality. Herein, we outline a conceptual model with several discrete steps in the HCC screening process continuum including risk assessment, screening initiation, follow-up of screening results, diagnostic evaluation, and treatment evaluation. The conceptual model illustrates how each step in the screening process is prone to delays or failure, resulting in worse outcomes such as late stage diagnosis or poor survival, and how factors at the patient, provider, and health care system levels can contribute to these failures. We compare cancer screening processes for HCC with those employed in breast and colorectal cancer screening to identify opportunities for improvement. The Translational Liver Cancer consortium was recently established by the National Cancer Institute with the goal of improving early detection of HCC. Studies designed to address failures in the HCC screening process continuum will help accomplish this goal.

To study the ameliorative capacity of Syzygium cumini fruit Pulp Extract (SPE) on cryopreserved bovine semen, three ejaculates each of three fertile bulls (total nine samples) were collected. Each ...

PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

Purpose Fear of COVID-19 is one of the pivotal components that have generated higher levels of stress, obsessions and anxiety among the adult population, thus creating numerous mental health issues. The purpose of this study was to evaluate psychological well-being based on COVID-19-related fear, obsessions and anxiety during the pandemic situation. Design/methodology/approach The current study aimed to evaluate the relationship between COVID-19-related fear, obsessions, anxiety, stress and well-being among adult populations. Additionally, the aim was to see the impact of COVID-19-related fear, obsessions, anxiety and stress on well-being. This was a cross-sectional study based on nonclinical sample of (n = 250) adults; data was obtained via online questionnaire survey method and analysis was performed by using the statistical package for social sciences (SPSS-22). Findings The authors’ findings based on descriptive statistics showed that COVID-19-related fear and obsessions were positively associated with COVID anxiety and stress and negatively associated with well-being. COVID anxiety was positively associated with stress and negatively associated with well-being. Moreover, perceived stress is negatively associated with well-being. The results additionally provide the outcome/conclusion that COVID-related anxiety significantly negatively predicted the psychological well-being. Overall the model explained 24% of the variance in psychological well-being. Females scored significantly high in COVID-19-related anxiety and obsessions as compared to males. Research limitations/implications A distinctive feature of this study is the understanding of COVID-19-related fear, obsessions, anxiety, stress and well-being among adult populations, and the findings are highlighting the need for psychological and social interventions for this specific population; therefore, immediate attention is needed by the clinical health professionals dealing with mental health issues. Originality/value There is a vital need to explore and develop psychological interventions aiming at the negative consequences being faced by the adult populations due to the COVID-19 pandemic and the impending second wave that will expose individuals to various mental health issues evolving because of the health crisis.

BACKGROUND: Pregnant women are susceptible to coronavirus infection due to physiological changes in the circulatory and immunological parameters. AIM: The current study aimed to determine the demographic factors, clinical symptoms, and fetal-maternal outcomes and also compare the blood parameters and chest X-ray results among coronavirus disease 2019 (COVID-19) positive and negative pregnant women. MATERIALS AND METHODS: Complete blood count and Chest X-rays were performed as a routine in all pregnant women. Polymerase chain reaction for COVID-19 was performed for all women and the newborn. RESULTS: The blood parameters revealed that a significantly greater proportion of COVID-19 positive pregnant women had abnormal hemoglobin, total leukocyte count, neutrophil count, lymphocyte count, monocyte count, bilirubin, aspartate aminotransferase, alanine aminotransferase, and urea. CONCLUSIONS: The present study provided crucial insights into epidemiological and clinical features during the perinatal period. Chest X-rays and blood routine examination are reliable findings to prevent COVID-19 complications among pregnant women.

Background: Congenital Stationary Night Blindness (CSNB) is a clinically and genetically heterogenous inherited retinal disorder associated with nystagmus, myopia, strabismus, defective dark adaptation, and decreased vision. Pathogenic variants in at least 17 genes have been associated with CSNB, where a hemizygous variant of NYX causing an X-linked form of the disorder is among the commonest causes.Materials and Methods: A retrospective chart review of a single pedigree was performed. Three pediatric patients underwent ophthalmic examinations, visual electrophysiology, and ocular imaging. Molecular genetic testing for CSNB was pursued where clinically indicated.Results: Two male siblings demonstrated clinical and electroretinographic evidence of complete CSNB. Genetic testing identified a NYX pathogenic, in-frame deletion in both children. Targeted variant analysis of the mother failed to identify the variant in two independent samples, most consistent with mosaicism.Conclusions: Clinical and molecular analyses within the described family demonstrate the possibility of maternal mosaicism in NYX-related CSNB. The importance of cascade molecular testing is highlighted. The prospect of somatic or germline mosaicism in NYX-related CSNB informs genetic counseling, genetic testing decisions, and risk assessment in affected families.

Atopic dermatitis (AD) is one of the most common skin diseases of dogs. Defects in the skin barrier and overproduction of inflammatory cytokines may be the pathogenesis of canine AD. Therefore, the present study was aimed to quantify the gene expression of certain skin barrier proteins and inflammatory cytokines in dogs with AD. Eleven dogs with AD and three healthy dogs were included in the present study. The skin barrier proteins, namely Filaggrin (FLG) and Involucrin (IVL), gene expression was quantified by Real-time PCR in the lesional skin tissues of the atopic dogs and normal skin of the healthy dogs. In addition to the skin proteins, the gene expressions of the interleukin (IL)-13, IL-31, and tumour necrosis factor (TNF)-α were also quantified in the peripheral blood mononuclear cells (PBMCs) of these dogs. Compared to the healthy dogs, significantly higher (P ≤ 0.01) FLG gene expression and significantly (P ≤ 0.05) lower expression of the IVL gene were quantified in the skin of atopic dogs. Further, the dogs with AD revealed significantly higher expression of TNF-α (P ≤ 0.01), IL-31 (P ≤ 0.05), and IL-13 (P ≤ 0.05) as compared to the healthy dogs. The findings of our present study evidently suggest significantly increased and decreased expressions of FLG and IVL genes, respectively, which may be responsible for disruption of the skin barrier in dogs with AD. While, the over-expressions of TNF-α, IL-31, and IL-13 genes might be attributed to the clinical pathology and manifestations of AD in dogs. However, further studies are warranted to substantiate our hypothesis about pathogenesis and clinical manifestation of AD in dogs by including a large number of animals.

BACKGROUND AND AIMS Therapeutic, clinical trial entry and stratification decisions for hepatocellular carcinoma (HCC) are made based on prognostic assessments, using clinical staging systems based on small numbers of empirically selected variables that insufficiently account for differences in biological characteristics of individual patients' disease. APPROACH AND RESULTS We propose an approach for constructing risk scores from circulating biomarkers that produce a global biological characterization of individual patient's disease. Plasma samples were collected prospectively from 767 patients with HCC and 200 controls, and 317 proteins were quantified in a Clinical Laboratory Improvement Amendments-certified biomarker testing laboratory. We constructed a circulating biomarker aberration score for each patient, a score between 0 and 1 that measures the degree of aberration of his or her biomarker panel relative to normal, which we call HepatoScore. We used log-rank tests to assess its ability to substratify patients within existing staging systems/prognostic factors. To enhance clinical application, we constructed a single-sample score, HepatoScore-14, which requires only a subset of 14 representative proteins encompassing the global biological effects. Patients with HCC were split into three distinct groups (low, medium, and high HepatoScore) with vastly different prognoses (medial overall survival 38.2/18.3/7.1 months; P

Retinoblastoma-binding proteins 4 and 7 (RBBP4 and RBBP7) are two highly homologous human histone chaperones. They function in epigenetic regulation as subunits of multiple chromatin-related complexes and have been implicated in numerous cancers. Due to their overlapping functions, our understanding of RBBP4 and 7, particularly outside of Opisthokonts, has remained limited. Here, we report that in the ciliate protozoan Tetrahymena thermophila a single orthologue of human RBBP4 and 7 proteins, RebL1, physically interacts with histone H4 and functions in multiple epigenetic regulatory pathways. Functional proteomics identified conserved functional links associated with Tetrahymena RebL1 protein as well as human RBBP4 and 7. We found that putative subunits of multiple chromatin-related complexes including CAF1, Hat1, Rpd3, and MuvB, co-purified with RebL1 during Tetrahymena growth and conjugation. Iterative proteomics analyses revealed that the cell cycle regulatory MuvB-complex in Tetrahymena is composed of at least five subunits including evolutionarily conserved Lin54, Lin9 and RebL1 proteins. Genome-wide analyses indicated that RebL1 and Lin54 (Anqa1) bind within genic and intergenic regions. Moreover, Anqa1 targets primarily promoter regions suggesting a role for Tetrahymena MuvB in transcription regulation. RebL1 depletion decreased cellular viability and altered the expression of selected targets. Consistent with observations in glioblastoma tumors, RebL1 depletion suppressed DNA repair protein Rad51 in Tetrahymena, thus underscoring the evolutionarily conserved functions of RBBP4/7 proteins. Our results suggest the essentiality of RebL1 functions in multiple epigenetic regulatory complexes in which it impacts transcription regulation and cellular viability.

Objective The aim of this study was to investigate automated feature detection, segmentation, and quantification of common findings in periapical radiographs (PRs) by using deep learning (DL)–based computer vision techniques. Study Design Caries, alveolar bone recession, and interradicular radiolucencies were labeled on 206 digital PRs by 3 specialists (2 oral pathologists and 1 endodontist). The PRs were divided into “Training and Validation” and “Test” data sets consisting of 176 and 30 PRs, respectively. Multiple transformations of image data were used as input to deep neural networks during training. Outcomes of existing and purpose-built DL architectures were compared to identify the most suitable architecture for automated analysis. Results The U-Net architecture and its variant significantly outperformed Xnet and SegNet in all metrics. The overall best performing architecture on the validation data set was “U-Net+Densenet121” (mean intersection over union [mIoU] = 0.501; Dice coefficient = 0.569). Performance of all architectures degraded on the “Test” data set; “U-Net” delivered the best performance (mIoU = 0.402; Dice coefficient = 0.453). Interradicular radiolucencies were the most difficult to segment. Conclusions DL has potential for automated analysis of PRs but warrants further research. Among existing off-the-shelf architectures, U-Net and its variants delivered the best performance. Further performance gains can be obtained via purpose-built architectures and a larger multicentric cohort.

Aims and Objective Cervical Consistency Index (CCI) is a new technique to measure the consistency of Cervix (softening) and is expected to show changes before cervical shortening. The aim of this study was 1. To find out the normative values of mid-trimester Cervical Consistency Index in women delivering at term. 2. To compare the discriminative ability of cervical consistency index with cervical length for prediction of spontaneous preterm birth. Method A total of 144 antenatal patients undergoing mid-trimester anomaly scan were subjected to transvaginal cervical length measurement as per Fetal Medicine Foundation criteria. Cervical consistency index was measured as defined by Para et al. The anterior–posterior diameter of cervix was measured before compression (AP) and after compression (AP') in the same sitting. Cervical consistency index (CCI) was calculated by the formula:CCI = APⅹ/AP × 100;The result of CCI was not used in the clinical management of the patient. Women who delivered at 37 weeks and beyond were included to form the normative data. An attempt was made to study the ability of mid-trimester cervical consistency index to predict spontaneous preterm birth as compared to cervical length (CL). Results Range of CCI in our study was 41–100% and that of CL was 2–4 cm.Based on values of CCI and CL an ROC curve was made, AUC measured for CCI was 0.923 and for CL was 0.849. The cut off determined for CCI was 64.5%, above which all women delivered at ≥ 37 weeks. Only Two women who delivered preterm (< 37) weeks had a CCI of less than 64.5% (64 and 47%), but cervical length was greater than 2.5 cms in both of them. The Sensitivity, Specificity, Positive Predictive Value, Negative Predictive Value and accuracy of CCI for predicting term delivery at a cutoff of 64.5% in our study was 83.8%, 100%, 100%, 8% and 93.8% respectively, whereas the corresponding figures for predicting preterm delivery were 100%, 83.8%, 8%, 100% and 93.8%. Discriminative ability of CCI in comparison to CL could not be determined because only two women delivered preterm in our study. Conclusion This was a pilot study to form the normative values of CCI for women delivering at term. At a cutoff value of 64.5% or more all women delivered at term. Two women who delivered preterm had a CCI of less than 64.5%. Further large studies are required before CCI can be incorporated as a routine to assess the antenatal cervix.

Arrhythmia-induced cardiomyopathy secondary to frequent ventricular premature contractions is a well-studied phenomenon; however, there is a paucity of data showing a similar association with frequent atrial premature contractions (APCs). Early recognition and successful APC ablation can reverse left ventricular dysfunction in these patients. (Level of Difficulty: Beginner.), Central Illustration

The natural capacity of plants to endure salt stress is largely regulated by multifaceted structural and physio-biochemical modulations. Salt toxicity endurance mechanism of six ecotypes of Typha domingensis Pers. was evaluated by analyzing photosynthesis, ionic homeostasis, and stomatal physiology under different levels of salinity (0, 100, 200 and 300 mM NaCl). Typha populations were collected across different areas of Punjab, an eastern province in Pakistan. All studied attributes among ecotypes presented differential changes as compared to control. Different salt treatments not only affected gas exchange attributes but also shown significant modifications in stomatal anatomical changes. As compared to control, net photosynthetic rate, transpiration rate, total chlorophyll contents and carotenoids were increased by 111%, 64%, 103% and 171% respectively, in Sahianwala ecotype among all other ecotypes. Similarly, maximum water use efficiency (WUE), sub stomatal CO2 concentration, sodium (Na+) and chloride (Cl−) contents were observed in Sahianwala (191%, 93%, 168%, 158%) and Knotti (162%, 75%, 146%, 182%) respectively, as compared to the others ecotypes. Adaxial and abaxial stomatal areas remained stable in Sahianwala and Knotti. The highest abaxial stomatal density was observed in Gatwala ecotype (42 mm2) and maximum adaxial stomatal density was recorded in Sahianwala ecotype (43 mm2) at 300 mM NaCl salinity. The current study showed that Typha ecotypes responded varyingly to salinity in terms of photosynthesis attributes to avoid damages due to salinity. Overall, differential photosynthetic activity, WUE, and changes in stomatal attributes of Sahianwala and Knotti ecotypes contributed more prominently in tolerating salinity stress. Therefore, Typha domingensis is a potential species to be used to rehabilitate salt affected lands for agriculture and aquatic habitat.

Objective There are an estimated 38 million people with HIV (PWH), with significant economic consequences. We aimed to collate global lifetime costs for managing HIV. Design We conducted a systematic review (PROSPERO: CRD42020184490) using five databases from 1999 to 2019. Methods Studies were included if they reported primary data on lifetime costs for PWH. Two reviewers independently assessed the titles and abstracts, and data were extracted from full texts: lifetime cost, year of currency, country of currency, discount rate, time horizon, perspective, method used to estimate cost and cost items included. Descriptive statistics were used to summarize the discounted lifetime costs [2019 United States dollars (USD)]. Results Of the 505 studies found, 260 full texts were examined and 75 included. Fifty (67%) studies were from high-income, 22 (29%) from middle-income and three (4%) from low-income countries. Of the 65 studies, which reported study perspective, 45 (69%) were healthcare provider and the remainder were societal. The median lifetime costs for managing HIV differed according to: country income level: $5221 [interquartile range (IQR)]: 2978-11 177) for low-income to $377 820 (IQR: 260 176-541 430) for high-income; study perspective: $189 230 (IQR: 14 794-424 069) for healthcare provider, to $508 804 (IQR: 174 781-812 418) for societal; and decision model: $190 255 (IQR: 13 588-429 772) for Markov cohort, to $283 905 (IQR: 10 558-453 779) for microsimulation models. Conclusion Estimating the lifetime costs of managing HIV is useful for budgetary planning and to ensure HIV management is affordable for all. Furthermore, HIV prevention strategies need to be strengthened to avert these high costs of managing HIV.

Brian De,1,* Sweet Ping Ng,1,2,* Amy Y Liu,1 Santiago Avila,1 Randa Tao,3 Emma B Holliday,1 Zachary Brownlee,4 Ahmed Kaseb,5 Sunyoung Lee,3 Kanwal Raghav,5 Jean-Nicolas Vauthey,6 Bruce D Minsky,1 Joseph M Herman,1 Prajnan Das,1 Grace L Smith,1 Cullen M Taniguchi,1 Sunil Krishnan,7 Christopher H Crane,8 Clemens Grassberger,9 Theodore S Hong,9 Steven H Lin,1 Albert C Koong,1 Radhe Mohan,1 Eugene J Koay1 1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 2Department of Radiation Oncology, Austin Health, Melbourne, Victoria, Australia; 3Department of Radiation Oncology, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA; 4Department of Radiation Oncology, Tufts Medical Center, Boston, MA, USA; 5Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 6Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 7Department of Radiation Oncology, Mayo Clinic Jacksonville, Jacksonville, FL, USA; 8Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; 9Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA*These authors contributed equally to this workCorrespondence: Eugene J KoayMD Anderson Cancer Center, Department of Radiation Oncology, 1400 Pressler St. Unit 1422, Houston, TX, 77030, USATel + 1 713-563-2381Fax +1 713-563-2331Email EKoay@mdanderson.orgBackground: The immune system plays a crucial role in cancer surveillance. Previous studies have shown that lymphopenia associated with radiotherapy (RT) portends a poor prognosis. We sought to differentiate the effects of proton and photon RT on changes in absolute lymphocyte count (ALC) for patients with hepatocellular carcinoma (HCC).Patients and Methods: Patients with HCC treated with definitive RT from 2006 to 2016 were studied. Serial ALCs were graded according to CTCAE v4.0. Overall survival (OS), disease-free survival, and distant metastasis-free survival were analyzed using the Kaplan–Meier method. Univariableand multivariable Cox-proportional hazards analyses were used to identify predictors of OS. A cohort analysis matched for treatment volume was performed to investigate differences in ALC dynamics between photon and proton therapy.Results: Of 143 patients identified, the median age was 66 (range, 19– 90) years. The treatment modality was photon in 103 (72%) and proton in 40 (28%). Median follow-up was 17 months (95% confidence interval, 13– 25 months). The median time to ALC nadir after initiation of RT was 17 days with a median relative decrease of 67%. Those who received proton RT had a higher median ALC nadir (0.41 vs 0.32 k/μL, p=0.002) and longer median OS (33 vs 13 months, p=0.002) than those who received photon RT. Matched cohort analyses revealed a larger low-dose liver volume in the photon group, which correlated with lower ALC. On multivariable Cox analysis, Grade 3 or higher lymphopenia prior to or after RT, portal venous tumor thrombus, larger planning target volumes, Child-Pugh (CP) Class B, and increased CP score after RT were associated with a higher risk of death, whereas the use of proton therapy was associated with lower risk.Conclusion: Grade 3 or higherlymphopenia may be associated with poorer outcomes in patients receiving RT for HCC. Protons may mitigate lymphopenia compared with photons, potentially due to reduced dose exposure of sites of lymphopoiesis.Keywords: lymphocyte count, circulating lymphocytes, splenic dose, liver dose, overall survival

The present study was aimed to prepare and characterize new cocrystals of lornoxicam (LORX), a BCS class II drug employing 1,3-dimethyl urea (DMU) as a coformer to improve physicochemical, pharmaceutical, and pharmacokinetic performance.A screening study was conducted by employing three techniques viz. neat grinding, liquid-assisted grinding (LAG), and solvent evaporation (SE) using different drug-coformer molar ratios (1:1, 1:2, and 1:3). Samples were characterized by DSC, PXRD, ATR-FTIR, SEM, intrinsic dissolution rate (IDR) studies, compressional studies, and pharmacokinetic studies.LAG and SE were found successful in ratio 1:3 and IDR showed approximately 28- and 19-fold increase, respectively in 0.1 N HCl (pH 1.2) and buffer (pH 7.4) as compared to pure LORX. The cocrystal exhibited good tabletability and was ∼2.5 times that of LORX at 6000 Psi. Dissolution profiles of tablets of cocrystal increased (56% and 100% at pH 1.2 and 7.4, respectively in contrast to those of physical mixture (PhyMix) (∼35% and ∼10%) and pure LORX (∼17% and ∼7%) within 60 min. TheThe study indicates that cocrystallization with DMU can concomitantly improve tabletability, dissolution rate, and

Investigate imaging follow-up patterns and assessment of malignancy rate of BI-RADS 3 lesions in women younger than 30 years.We retrospectively reviewed consecutive studies between January 1, 2013 and January 1, 2015 with BI-RADS 3 assessment in women30 years. Lesion size, follow-up rate, and biopsy rate were recorded. Completion of 24-month imaging follow-up or biopsy determined the endpoint. Statistical analysis of follow-up rates and biopsy timing was performed.Of 2525 BI-RADS 3 lesions, 278 were identified in 215 women30 years. Fifty-two (24%) women underwent a biopsy which was more frequently done at patient request than for lesion growth [33 (63.4%) versus 19 (36.5%), P.01]. The odds of having biopsy upfront was significantly higher in lesions2 cm in diameter (OR: 4.4 [95% CI 2.1-9.4], P.01). The malignancy rate in our cohort was 0% (95% CI 0-1.7%). Of the 188 women expected for follow-up imaging, 58 (30%) were lost to follow-up, while 103 (55%) had 6-month follow-up, 74 (39%) 12-month follow-up, and 56 (30%) 24-month follow-up.BI-RADS 3 lesions identified in our cohort had high biopsy rates and low compliance with no cancers. Our findings suggest that probable fibroadenomas in young women may only warrant abbreviated short-term follow-up at 6-months.

Sophora alopecuroides L. is a highly medicinal plant. The aim of the current study was to determine the phytochemical screening, pharmacological potentials and application of scanning electron microscope (SEM) of S. alopecuroides (SA) seeds. To achieve this purpose, six different solvents were used to prepare SA seed extracts. Phytochemical and antioxidant activities were determined calorimetrically. To investigate the antidiabetic activity, α-amylase inhibition assay was determined. Brine shrimp assay was used to determine cytotoxicity potential. Anti-leishmanial potential was confirmed using MTT assay. Disc-diffusion method was used to detect protein kinase inhibitory, antibacterial and antifungal activities and showed significant results. SEM analysis was used as an identification tool. Considerable amount of phenolic and flavonoid contents were identified in methanol extract (SASM) (93.76 ± 2.71 GAE/mg) and (77 ± 3.60 QE/mg). Highest DPPH scavenging potential (82%) was reported for SASM. Significant total antioxidant capacity (90.60 ± 1.55 alpha amylase enzyme [AAE]/mg) and total reducing power (94.44 ± 1.38 AAE/mg) were determined for LOSM. Highest α-amylase inhibition was reported in SASM (78.20 ± 1.58%). Highest LD50 of brine shrimp was found for n-hexane extract (SASH) 13.03 μg/ml. All extracts showed strong anti-leishmanial activity except SASH. The seeds of SA were seen to be oblong to obovate, projections, wavy slightly straight, anticlinal wall was raised with apex acuminate. In conclusion, our experimental findings highly support the ethnomedicinal and biological potentials of the SA seeds. Moreover, SA seeds need to be explored for identification and isolation of bioactive compounds. In future, we recommend further in vivo toxicity assays and clinical efficacies to further evaluate its different biomedical properties.

Background Cancer of unknown primary (CUP) presenting as bone‐predominant (BCUP) or lymph node‐only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the “one‐treatment‐fits‐all” approach. Materials and Methods We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non‐BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan‐Meier method was used to estimate overall survival and compared using log‐rank test. Results In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor‐risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor‐risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil‐to‐lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS. Conclusion BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor‐risk Culine group and high neutrophil‐to‐lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long‐term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site‐directed therapy. Implications for Practice Cancer of unknown primary (CUP) rarely presents as bone‐predominant (BCUP) or lymph node‐only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor‐risk group and neutrophil‐to‐lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided., Considering the limited understanding of bone‐predominant or lymph‐node‐only cancers of unknown primary, this article describes the clinical features and outcome data of these two unique conditions.

This study was undertaken to investigate the starter and probiotic potential of lactic acid bacteria isolated from dromedarian camel's milk using both culture-dependent and -independent approaches and metataxonomic analysis. Strains of lactic acid bacteria recovered were examined in vitro for tolerance to gastric acidity, bile, and lysozyme. Bile salt hydrolysis, serum cholesterol-lowering, oxalate degradation, proteolytic activity, exopolysaccharide production, and cell surface characteristics necessary for colonizing intestinal mucosa were also evaluated. A single strain of the species, Lactobacillus fermentum named NPL280, was selected through multivariate analysis as it harbored potential probiotic advantages and fulfilled safety criteria. The strain assimilated cholesterol, degraded oxalate, produced exopolysaccharides, and proved to be a proficient alternate yogurt starter with good viability in stored bio-yogurt. A sensorial analysis of the prepared bio-yogurt was also found to be exemplary. We conclude that the indigenous L. fermentum strain NPL280 has the desired traits of a starter and adjunct probiotic culture for dairy products.

PURPOSE BRAF V600E mutations are rarely associated with objective responses to the BRAF inhibitor vemurafenib in patients with metastatic colorectal cancer (CRC). Blockade of BRAF V600E by vemurafenib causes feedback upregulation of EGFR, whose signaling activities can be impeded by cetuximab. METHODS One hundred six patients with BRAF V600E-mutated metastatic CRC previously treated with one or two regimens were randomly assigned to irinotecan and cetuximab with or without vemurafenib (960 mg PO twice daily). RESULTS Progression-free survival, the primary end point, was improved with the addition of vemurafenib (hazard ratio, 0.50, P = .001). The response rate was 17% versus 4% ( P = .05), with a disease control rate of 65% versus 21% ( P < .001). A decline in circulating tumor DNA BRAF V600E variant allele frequency was seen in 87% versus 0% of patients ( P < .001), with a low incidence of acquired RAS alterations at the time of progression. RNA profiling suggested that treatment benefit did not depend on previously established BRAF subgroups or the consensus molecular subtype. CONCLUSION Simultaneous inhibition of EGFR and BRAF combined with irinotecan is effective in BRAF V600E-mutated CRC.

Biological markers for Metabolic Syndrome, such as serum lipids and Hemoglobin A1c may have genetic variability among African Americans versus their Caucasian American counterparts. Although cases of Type 2 diabetes and its sequela significantly outweigh Caucasian Americans in the US, paradoxically research has found a lower prevalence of Metabolic Syndrome among blacks versus whites despite there being higher rates of Type 2 diabetes among the former population. Research has shown Metabolic Syndrome lipid parameters among African Americans are more favorable despite outstanding Type 2 diabetes incidence. With the emergence of the Human Genome Project and Genome Wide Association Studies, genetic differences in these parameters have been uncovered and genetic variability may play a role in such paradoxical mismatch. It may be reasonable to consider modifying Metabolic Syndrome parameters as given this new biological evidence. Hemoglobin A1c, also a biological marker used to monitor glucose levels over time, shows variability in its measurements with respect to African Americans. Genetic factors may play a role in the discrepancies among African Americans populations when using this parameter to monitor blood glucose. Precision medicine is now at the forefront of a biomedical new age, to find therapies that cater to specific populations based on genetic research. African Americans may not benefit from such a revolutionary paradigm shift in medicine due to evidence of lack of inclusivity in such studies like the Human Genome Project. Consideration should be made to the future of molecular medicine to include more minority populations such as African Americans in order to cater to specific differences rather than generalized standards of care.

There has been rapid implementation of virtual oncology appointments in response to the COVID-19 pandemic, particularly in its first wave. Our objective was to assess patterns and perspectives towards virtual oncology appointments during the pandemic among patients with cancer undergoing active treatment. We conducted an international Internet-based cross-sectional survey. Participants were eligible if they (1) were ≥18 years of age; (2) had been diagnosed with cancer (3) were currently undergoing cancer treatment, and (4) spoke English or French. Between 23 April 2020 and 9 June 2020, 381 individuals accessed the survey, with 212 actively undergoing treatment for cancer, including 27% with colorectal, 21% with breast, 7% with prostate and 7% with lung cancer. A total of 52% of respondents were from Canada and 35% were from the United States. Many participants (129, 62%) indicated having had a virtual oncology appointment during the COVID-19 pandemic and most were satisfied with their experience (83%). We found older participants (≥50 years; adjusted OR 0.22, 95% CI 0.06 to 0.85 compared to 12 months) were less likely to be satisfied with virtual oncology appointments. Virtual health platforms used differed across countries with higher telephone use in Canada (87%) and other countries (86%) as compared to the United States (54%; p-value < 0.05), where there was higher use of video conferencing. Altogether, our findings demonstrate favorable patient perspectives towards virtual oncology appointments experienced during the first wave of the COVID-19 pandemic.

The continuous deterioration of arable lands by metal pollution compels finding suitable strategies to increase plant tolerance under contaminated regimes. Current study was designed to examine the synergistic role of Bacillus subtilis FBL-10 and silicon (Si) with respect to mitigation of lead (Pb) induced phytotoxicity in Solanum melongena L. Lead stress (75 mg kg-1) reduced chlorophyll (Chl) content, photosynthetic rate and gas exchange characteristics of S. melongena plants. The Si and B. subtilis FBL-10 individually upgraded all the above-mentioned growth attributes. However, co-application of Si (50 mg kg-1) and B. subtilis FBL-10 significantly improved biochemical and growth attributes of Pb challenged plants. The abridged levels of oxidative markers including hydrogen peroxide (H2O2), and malondialdehyde (MDA) besides reduced Pb accumulation in foliage tissues, were recorded in Si and microbe assisted plants. Furthermore, plants inoculated with B. subtilis FBL-10 alone or in combination with Si showed increment in total soluble proteins, photosynthetic rate and gas exchange attributes. The inoculated plants treated with Si exhibited higher level of auxins and improved activity of antioxidant enzymes under Pb stress. Present research elucidates interactive role of B. subtilis FBL-10 and Si in reduction of Pb toxicity in S. melongena plants. Alone application of Si or B. subtilis FBL-10 was less effective for attenuation of Pb stress; however, synergism between both phyto-protectants demonstrated fabulous ability for Pb stress assuagement. Consequently, executions of field studies become indispensable to comprehend the efficacy of Si applied alone or in combination with plant growth promoting bacteria (PGPB) like B. subtilis FBL-10. From current research, it is concluded that the interaction of Si and PGPB seems an auspicious technique and eco-friendly approach to enhance metal tolerance in crop plants.

Objective Diabetic peripheral neuropathy (DPN) affects over 40% of diabetic patients. It presents as numbness, pain, or touch sensitivity. Its neuropathic origin and clinical presentation resembles that of burning mouth syndrome (BMS), however the association between the two processes in not well documented. This investigation aimed to explore the association between DPN and BMS-like symptoms. Methods A cross sectional study was conducted in Islamabad. Following implementation of the exclusion criterion, 350 consenting patients were requested to provide information about their demographics, time of onset of diabetes, mode of treatment, HbA1c, diabetic status, presence of DPN and positivity of BMS symptoms. Results One hundred and eighty-nine (54%) presented with BMS-like symptoms, while 161 (46%) did not. Statistically significant relationship was noted between the presence of BMS and age, treatment regimen, time since diagnosis, Hb1AC, diabetic status and DPN of hands and feet and nature of peripheral neuropathy. According to binary logistic regression analysis three predictor variables for BMS were isolated, these included diabetic status, peripheral neuropathy of hands and peripheral neuropathy of feet. Conclusion Uncontrolled diabetes, presence DPN of hands and feet in patients are strong predictors of BMS-like symptoms in patients with type II diabetes mellitus.

Objectives Although racial/ethnic disparities in healthcare have long been recognized, recent discourse around structural racism will hopefully lead to improved transparency surrounding these issues. Despite the disproportionate impact of COVID-19 on racial/ethnic minorities, the extent and reliability of race reporting in COVID research is unclear. Methods COVID-19 research published in three top medical journals during the first wave of the COVID-19 pandemic was reviewed and assessed for race reporting and proportional representation. Results Of the 95 manuscripts that were identified, 56 reporting on 252,262 patients met eligibility. Thirty-five (62.5%) did not report race distribution and 15 (26.7%) did not report ethnicity. There was no difference based on journal (P = 0.87), study sponsor (P = 0.41), whether the study was retrospective or prospective (P = 0.33), or observational vs interventional (P = 0.11). Studies with ≥250 patients were more likely to report on race (OR 4.01, 95% CI: 1.12–14.37, P = 0.027), and North American (USA and Canada) studies were more likely than European studies (OR 7.88, 95% CI: 1.73–37.68, P = 0.006) to report on race. COVID-19 research mirrored USA COVID-19 racial incidence; however, both showed higher distribution of COVID-19 infection among Blacks and a smaller proportion of Whites compared to the USA population. This suggests that research is broadly representing infection rates and that social determinants of health are impacting racial distribution of infection. Conclusions Despite increasing awareness of racial disparities and inequity, COVID-19 research during the first wave of the pandemic lacked appropriate racial/ethnicity reporting. However, research mirrored COVID-19 incidence in the USA, with an increased burden of infection among Black individuals.

The tunable cobalt oxide nanoparticles (CoONPs) are produced due to the phytochemicals present in Rhamnus virgata (RhV) leaf extract which functions as reducing and stabilization agents. The synthesis of CoONPs was confirmed using different analytical techniques: UV-Vis spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), dynamics light scatterings (DLS), Fourier-transform infrared spectroscopy (FTIR), energy dispersive X-ray, and Raman spectroscopy analyses. Furthermore, multiple biological activities were performed. Significant antifungal and antibacterial potentials have been reported. The in vitro cytotoxic assays of CoONPs revealed strong anticancer activity against human hepatoma HUH-7 (IC50 : 33.25 μg/ml) and hepatocellular carcinoma HepG2 (IC50 : 11.62 μg/ml) cancer cells. Dose-dependent cytotoxicity potency was confirmed against Leishmania tropica (KMH23 ); amastigotes (IC50 : 58.63 μg/ml) and promastigotes (IC50 : 32.64 μg/ml). The biocompatibility assay using red blood cells (RBCs; IC50 : 4,636 μg/ml) has confirmed the bio-safe nature of CoONPs. On the whole, results revealed nontoxic nature of RhV-CoONPs with promising biological potentials.

Background & Aims It is unclear whether the model for end-stage liver disease-sodium (MELD-Na) score captures the clinical severity of acute-on-chronic liver failure (ACLF). We compared observed 90-day mortality in patients with ACLF with expected mortality based on the calculated MELD-Na and examined the consequences of underestimating clinical severity. Methods We identified patients with ACLF during hospitalization for cirrhosis in 127 VA hospitals between 01/01/2004 and 12/31/2014. We examined MELD-Na scores by ACLF presence and grade. We used actual and observed 90-day mortality to estimate a standardized mortality ratio (SMR) by ACLF presence and grade. We used transplant center-specific median MELD-Na at transplantation (MMaT) to estimate the proportion likely to receive priority for liver transplantation (LT) based on MELD-Na alone. Results Of 71,894 patients hospitalized for decompensated cirrhosis, 18,979 (26.4%) patients met the criteria for ACLF on admission. The median (P25-P75) MELD-Na on admission was 26 (22–30) for ACLF compared to 15 (12–20) for patients without ACLF; it was 24 (21–27), 27 (23–31), and 32 (26–37) for ACLF-1, 2 and 3, respectively. At 90 days, 40.0% of patients with ACLF died (30.8%, 41.6% and 68.8% with ACLF-1, 2 and 3, respectively) compared to 21.3% of patients without ACLF. Compared to the expected death rate based on MELD-Na, mortality risk was higher for patients with ACLF, SMR (95% CI): 1.52 (1.48–1.52), 1.46 (1.41–1.51), 1.50 (1.44–1.55), 1.66 (1.58–1.74) for overall ACLF, ACLF-1, -2 and -3, respectively. Only 9.1% of patients with ACLF reached the national median MELD-Na of 35 and between 17.3% to 35.1% exceeded the MMaT at any center. During index admission, 589 (0.8%) patients with ACLF were considered for LT evaluation and 16 (0.1%) were listed for LT. Conclusions In a US cohort of hospitalized patients with decompensated cirrhosis, MELD-Na did not capture 90-day mortality risk in patients with ACLF. Patients with ACLF are at a disadvantage in the current MELD-Na-based system. Lay summary Acute-on-chronic liver failure (ACLF) is a condition marked by multiple organ failures in patients with cirrhosis and is associated with a high risk of death. Liver transplantation may be the only curative treatment for these patients. A score called model for end-stage liver disease-sodium (MELD-Na) helps guide donor liver allocation for transplantation in the United States. The higher the MELD-Na score in a patient, the more likely that a patient receives a liver transplant. Our study data showed that MELD-Na score underestimates the risk of dying at 90 days in patients with ACLF. Thus, physicians need to start liver transplant evaluation early instead of waiting for a high MELD-Na number.

Objective: To determine different treatment options in patients of Patent Ductus Arteriosus with pulmonary hypertension beyond neonatal period. Study Design: Descriptive cross sectional study. Place and Duration of Study: This study was carried out in Pediatric Cardiology department of Rawalpindi Institute of Cardiology, from Jan 2017 to Jan 2019. Methodology: Patients having PDA with pulmonary hypertension were included in the study. Treatment options were divided into percutaneous catheter device closure, surgical ligation of patent ductus arteriosus and palliative treatment. Any adverse event during the procedure was documented. Stratification was done in regard to gender and age group. Post stratification chi square test was applied and p-value less than or equal to 0.05 was considered as significant. Results: Total number of patients included in the study were 37. Mean age (years) of patients (Mean ± SD) was 19.21 ± 8.76. Mean ± SD pulmonary artery pressure was 56.43 ± 11.55 mmHg. Percutaneous catheter device closure was successful in 24 (64.9%) patients, in 7 (18.9%) patients primary surgical PDA ligation was done, 3 (8.1%) patients were advised palliative treatment and in 3 (8.1%) patients adverse events occurred during percutaneous device closure and were thus referred for surgical ligation. Patent ductus Arteriosus Occlutech device was used in 18 (48.6%) patients, Occlutech VSD device was used in 7 (18.5%) patients and in 1 (2.7%) patient AGA duct occluder was used. Conclusion: In patients with patent ductus arteriosus and pulmonary artery hypertension, percutaneous catheter device closure is a safe and effective procedure.

Background: A number of non-steroidal anti-inflammatory drugs (NSAIDs) including aspirin, indomethacin, ibuprofen, flufenamic acid, and phenylbutazone are being clinically used to treat inflammatory disorders. These NSAIDs are associated with serious side effects such as gastric ulceration, nephrotoxicity, and bleeding. Therefore, the identification of potent and safe therapy for inflammatory disorders is still of great interest to the medicinal chemist. Methods: A series of varyingly substituted benzoyl, acetyl, alkyl ester, and sulfonate ester substituted coumarins 1-64 were screened for the inhibition of ROS, generated from zymosan activated whole blood phagocytes, using luminol-enhanced chemiluminescence technique. Results: Among all tested compounds, 8 (IC50 = 65.0 ± 3.1 μM), 24 (IC50 = 41.8 ± 1.5 μM), 26 (IC50 = 10.6 ± 2.8 μM), 28 (IC50 = 20.9 ± 1.5 μM), and 41 (IC50 = 4.6 ± 0.3 μM) showed good anti- inflammatory potential as compared to standard antiinflammatory drug ibuprofen (IC50 = 54.3 ± 1.9 μM). Specifically, compounds 24, 26, 28, and 41 showed superior activity than standard antiinflammatory drug. Furthermore, compounds 12 (IC50 = 219.0 ± 1.4 μM), 14 (IC50 = 216.5 ± 6.2 μM), 16 (IC50 = 187.4 ± 2.2 μM), and 20 (IC50 = 196.2 ± 2.0 μM) showed moderate ROS inhibitory activity. Limited SAR study revealed that the hydroxy-substituted compound showed better ROS inhibition potential in case of 3-benzoyl and 3-ethylester coumarin derivatives. Whereas, chloro substitution was found to be important in case of 3-acetyl coumarin derivatives. Similarly, in case of sulfonate ester, chloro, and nitro groups especially at positions -4 and -3 of ring “R” played vital role in ROS inhibition. Furthermore, cytotoxicity of all active compounds was also checked on NIH-3T3 cell line. Compounds 12, 14, and 20 were found to be non-cytotoxic. Whereas, 8, 16, 24, 26, 28, and 41 were found to be very weak cytotoxic as compared to standard cycloheximide (IC50 = 0.13 ± 0.02 μM). Conclusion: Identified ROS inhibitors offer the possibility of additional modifications that could give rise to lead structures for further research in order to obtain more potent, and safer antiinflammatory agent.

Background and Objective: Adverse drug reactions (ADRs) are associated with increased economic burden on the society. Monitoring of ADRs can help in decreasing the incidence of preventable adverse reactions. Methods: Under Pharmacovigilance Program of India, collection and reporting of ADRs has been going on at Dayanand Medical College and Hospital since January 2011. Here, we have analyzed the individual case safety reports (ICSRs) reported and uploaded between January 2017 and June 2019 from our centre. The ADR form provided by PvPI was used for collecting information, and the causality assessment was done according to the WHO-UMC scale. Results: A total of 498 ICSRs were uploaded through Vigiflow software during this period. Highest number of ADRs were recorded in the age group of 31-45 years (29.01%) and the least number of ADRs were recorded in the children less than 15 years of age (6.76%). General Medicine ward reported the highest number of ADRs and the antibiotics were most commonly associated with ADRs (26.21%), followed by antipsychotics (13.83%) and NSAIDs (12.14%). More than 90% of ADRs were non-serious (93.17%) and most of the ADRs were skin and soft tissue related (49.20%). Conclusion: Spontaneous reporting among indoor patients shows highest number of ADRs with use of antibiotics and almost all of the ADRs were non-serious in nature. Almost half of the total ADRs were skin and subcutaneous tissue related. Continuous efforts are required for further strengthening of the pharmacovigilance program of India.

Latcripin-16 (Lp16-PSP) is a gene that was extracted as a result of de novo characterization of the Lentinula edodes strain C91-3 transcriptome. The aim of the present study was to clone, express, and investigate the selective in vitro anticancer potential of Lp16-PSP in human cell lines. Lp16-PSP was analyzed using bioinformatics tools, cloned in a prokaryotic expression vector pET32a (+) and transformed into E. coli Rosetta gami. It was expressed and solubilized under optimized conditions. The differential scanning fluorometry (DSF)-guided refolding method was used with modifications to identify the proper refolding conditions for the Lp16-PSP protein. To determine the selective anticancer potential of Lp16-PSP, a panel of human cancerous and non-cancerous cell lines was used. Lp16-PSP protein was identified as endoribonuclease L-PSP protein and a member of the highly conserved YjgF/YER057c/UK114 protein superfamily. Lp16-PSP was expressed under optimized conditions (37 °C for 4 h following induction with 0.5 mM isopropyl β-d-1-thiogalactopyranoside). Solubilization was achieved with mild solubilization buffer containing 2 M urea using the freeze–thaw method. The DSF guided refolding method identified the proper refolding conditions (50 mM Tris–HCl, 100 mM NaCl, 1 mM EDTA, 400 mM Arginine, 0.2 mM GSH and 2 mM GSSG; pH 8.0) for Lp16-PSP, with a melting transition of ~ 58 °C. A final yield of ~ 16 mg of purified Lp16-PSP from 1 L of culture was obtained following dialysis and concentration by PEG 20,000. A Cell Counting Kit-8 assay revealed the selective cytotoxic effect of Lp16-PSP. The HL-60 cell line was demonstrated to be most sensitive to Lp16-PSP, with an IC50 value of 74.4 ± 1.07 µg/ml. The results of the present study suggest that Lp16-PSP may serve as a potential anticancer agent; however, further investigation is required to characterize this anticancer effect and to elucidate the molecular mechanism underlying the action of Lp16-PSP.

Background Sudoku is a popular cognitively stimulating leisure-time activity. Many studies have been directed toward finding an algorithm to solve Sudoku, but the investigation of the neural substrates involved in Sudoku has been challenging. Methods Sudoku task was divided into two steps to understand the differential function of the prefrontal cortex (PFC) while applying heuristic rules. PFC activity was recorded at 16 optode locations using functional near infrared spectroscopy. Classical two-way analysis of variance as well as general linear model-based approach was used to analyze the data from 28 noise-free recordings obtained from right-handed participants. Results Post hoc analysis showed a significant increase in oxyhemoglobin concentrations and decrease in deoxyhemoglobin concentrations at all 16 optode locations during step 1 (3 × 3 subgrids) and step 2 (easy level 9 × 9 Sudoku) when compared with the rest (p < 0.0001). Contrasting the step 2 – step 1 revealed that medial regions of PFC were preferentially activated. Conclusion Both the medial and lateral regions of PFC are activated during Sudoku task. However, the medial regions of PFC play a differential role, especially when we consider searching and selecting the heuristic rules. Thus, Sudoku may be used for cognitive remediation training in neuropsychiatric disorders involving PFC., Graphical abstract

Background Bioinformatics tools are of great significance and are used in different spheres of life sciences. There are wide variety of tools available to perform primary analysis of DNA and protein but most of them are available on different platforms and many remain undetected. Accessing these tools separately to perform individual task is uneconomical and inefficient. Objective Our aim is to bring different bioinformatics models on a single platform to ameliorate scientific research. Hence, our objective is to make a tool for comprehensive DNA and protein analysis. Methods To develop a reliable, straight-forward and standalone desktop application we used state of the art python packages and libraries. Bioinformatics Mini Toolbox (BMT) is combination of seven tools including FastqTrimmer, Gene Prediction, DNA Analysis, Translation, Protein analysis and Pairwise and Multiple alignment. Results FastqTrimmer assists in quality assurance of NGS data. Gene prediction predicts the genes by homology from novel genome on the basis of reference sequence. Protein analysis and DNA analysis calculates physiochemical properties of nucleotide and protein sequences, respectively. Translation translates the DNA sequence into six open reading frames. Pairwise alignment performs pairwise global and local alignment of DNA and protein sequences on the basis or multiple matrices. Multiple alignment aligns multiple sequences and generates a phylogenetic tree. Conclusion We developed a tool for comprehensive DNA and protein analysis. The link to download BMT is https://github.com/nasiriqbal012/BMT_SETUP.git.

Breast cancer is a major cause of cancer related deaths in women worldwide. Available treatments pose serious limitations such as systemic toxicity, metastasis, tumor recurrence, off-target effects, and drug resistance. In recent years, phytochemicals such as secondary metabolites due to their effective anticancer potential at very low concentration have gained attention. Aim of the study was to evaluate anticancer potential of Citrullus colocynthis and its possible molecular targets on MCF-7, a human breast cancer cell line. Methanolic extract of leaves was prepared and fractionated by solvents (n-hexane, chloroform, ethyl acetate and n-butanol) with increasing polarity. Bioassays and gene expression regulation was conducted to evaluate the anticancer activity, proliferation rate and cell cycle regulation of breast cancer cells treated with extract and its fractions, separately. Results showed a significant anticancer activity of methanolic extract of C. colocynthis and two of its fractions prepared with chloroform and ethyl acetate. Bioassays depicted significant decrease in proliferation and growth potential along with cell cycle arrest of treated cells compared to control untreated cells. Expression regulation of genes further confirmed the cell cycle arrest through significant upregulation of cyclin-CDK inhibitors (p21 and p27) and cell cycle checkpoint regulators (HUS1, RAD1, ATM) followed by downregulation of downstream cell cycle progression genes (Cyclin A, Cyclin E, CDK2). It is concluded that C. colocynthis arrests cell cycle in human breast cancer cells through expression regulation of cyclin-CDK inhibitors and with further research can be proposed for therapeutic interventions.

PURPOSE ERBB2 amplification (human epidermal growth factor receptor 2 positivity [HER2+]) in metastatic colorectal cancer (mCRC) has important therapeutic implications that necessitate the need for accurate diagnostics. The study purpose was to establish and validate harmonized diagnostic criteria for HER2+ mCRC among 3 groups (GI-SCREEN-Japan, NCTN-SWOG-USA, and Korea). PATIENTS AND METHODS We assessed HER2 status by immunohistochemistry (IHC), ERBB2/CEP17 ratio, gene copy number (GCN) by fluorescence in situ hybridization (FISH), and copy number variation (CNV) using two targeted next-generation sequencing (NGS) panels. Tumor samples from 475 and 16 patients with mCRC in exploratory and validation cohorts, respectively, were used for cross-validation of the NGS panels. RESULTS Consensus diagnostic criteria among the 3 groups for HER2+ mCRC were established as follows: IHC 3+ or IHC 2+ and ERBB2/CEP17 ratio by FISH ≥ 2.0, tumor content > 10% for surgically resected specimens, and necessary tumor content not defined for biopsy specimens. The median GCN and CNV for HER2+ patients were 10.9 and 27.7 compared with 2.5 ( P < .0001) and 3.5 ( P < .0001), respectively, in HER2-negative patients. These findings were validated in a validation cohort (GCN, 16.2 v 2.4 [ P = .0002]; CNV, 42.5 v 2.0 [ P = .0003]). GCN correlated with CNV in both cohorts (exploratory, r = 0.90; validation, r = 0.97; P < .0001). CNV in cross-validation of the 2 NGS panels also showed a strong correlation ( r = 0.98; P < .0001). CNV in patients who fulfilled the consensus criteria was > 4.0 in all, which demonstrates the accuracy of the IHC/FISH criteria and cross-validation of NGS panels. CONCLUSION We have established and verified harmonized diagnostic criteria for HER2+ and demonstrated consistency between IHC/FISH and CNV determined by NGS in mCRC.

Background With the global surge in COVID-19 pandemic, it has become inevitable for everyone, inclusive of nuclear medicine personnel, to play their role in combating and containing its transmission. During fall 2019, China encountered a novel coronavirus in Wuhan city which was later on termed as COVID-19. The pneumonia caused by COVID-19 is characterized by dry cough, fever, fatigue, and shortness of breathing (dyspnea). Until now, this virus has spread worldwide and continues to cause exponential causalities. Main body This global catastrophic scenario calls for stringent measures to control COVID-19 infection. Thus herein, the respective authors have endeavored to review precautionary measures for nuclear medicine department, encompassing its personnel as well as the patients so that intradepartmental transmission can be prevented. This requires development and execution of a robust and dynamic plan elaborating the healthcare guidelines. Hence, our review paper covers the arena of nuclear medicine services in particular. Conclusion Nuclear medicine can play its role in mitigating COVID-19 transmission to personnel and patients if provided with ample PPEs and guidelines are strictly followed. With implementing SOPs (standard operating procedures) based on these guidelines, nuclear medicine facilities will be better prepared for impromptu actions in case of any future outbreak while retaining the smooth flow of obligatory healthcare services.

PurposePakistan is a developing country where one of the rapidly growing diseases is diabetes. Well-informed diabetic patients are expected to improve the quality of life, self-care behaviors and better cooperation with the health care team. The present study is designed to investigate the information behavior of diabetic patients, and to investigate the role of one institution that is working for diabetes management, treatment, education and counseling in Pakistan i.e. Diabetic's Institute Pakistan (DIP).Design/methodology/approachThe “Embedded Design” based on the mixed methods research approach was adopted to carry out the current research. The study was mainly based on quantitative research design, quantitative data were collected through an adapted questionnaire, the supportive/supplementary qualitative data was collected through an in-depth interview of the medical director, observation record sheets and analysis of the available relevant documents i.e. prescription (prescription notepad with information), brochure and the website was applied.FindingsDiabetic patients want to know about how to control diabetes and mostly rely on humans particularly health professionals and interpersonal networks. The use of books, journals, seminars, libraries is comparatively low. It is an important finding that health-related information is mostly required in national language by Pakistani patients. Lack of computer literacy and information overload were among the barriers that were reported by diabetic patients.Practical implicationsHealth information seeking channels, formats and language preferences should be considered to design patients' cantered information services. Health information service providers i.e. government, health practitioners, health-related institutions and libraries should work in a liaison for creating health awareness. Identified barriers faced by diabetic patients are important to consider for designing health-related information services.Originality/valueInvestigating health information behavior is crucial particularly of the patients from developing countries. The study is first of its kind that is reported from Pakistan. The results of the study may help libraries, health professionals and diabetes-related organizations to design patient's centered policies and information-based services. These institutions may work together to create awareness and to help patients in managing their disease. The study findings are maybe helpful for other developing countries also.

Due to the high mortality rate and an increase in breast cancer incidence, it has been challenging for researchers to come across an effective chemotherapeutic strategy with minimum side effects. Therefore, the need for the development of effective chemotherapeutic drugs is still on the verge. Consequently, we approached a new mechanism to address this issue. The naturally available peptide named latcripin-7A (LP-7A), extracted from a mushroom called Lentinula edodes, provided us promising results in terms of growth arrest, apoptosis, and autophagy in breast cancer cells (MCF-7 and MDA-MB-231). Expressions of protein markers for apoptosis, autophagy, and cell cycle were confirmed via Western blot analysis. Migration and invasion assays were performed to analyze the anti-migratory and anti-invasive properties of LP-7A, while cell cycle analysis was performed via flow cytometry to evaluate its affect over cell growth. Supportive assays were performed like acridine orange, Hoechst 33258 stain, DNA fragmentation, and mitochondrial membrane potential (MMP) to further confirm the anticancer effect of LP-7A on breast cancer cell lines. It is concluded that LP-7A effectively reduces migration and promotes apoptosis as well as autophagy in MCF-7 and MDA-MB-231 breast cancer cell lines by inducing cell growth arrest at G0/G1 phase and decreasing mitochondrial membrane potential without adverse effects on MCF-10A normal breast cells. • In this study, we have investigated the anti-cancer activity of novel latcripin-7A (LP-7A), a protein extracted as a result of de novo characterization of Lentinula edodes C91–3. • We conclude in our research work that LP-7A can initiate diverse cell death-related events, i.e., apoptosis and autophagy in both triple-positive and triple-negative breast cancer cell lines by interacting with different nodes of cellular signaling that can further be investigated in vivo to gain a better understanding.

Background: Pakistan has a high incidence of breast cancer in Asia, where annually 16,232 deaths are reported. There are many exogenous and endogenous risk factors that affect the tumor suppressor genes and oncogenes. The p53 gene is a tumor suppressor gene and it has a role to protect the whole genome from external and internal stresses, which causes damages to the genome. Objective: The aim of the current study was to investigate the p53 gene expression by using the real-time PCR technique in different grades of breast cancer as compared to the normal tissue. Methods: Fresh Modified Radical Mastectomy (MRM) samples (grade1-grade3) were collected from different hospitals of the Lahore. The project was approved by an ethical review committee of Jinnah Hospital, Lahore. And before sampling an informed consent was obtained from patients and clinicians. RNA from fresh biopsies was extracted by Qiagen extraction kit and cDNA was formed. Real time PCR performed by using SYBR green master mix (ABI) and the data was evaluated by using Livak method. Statistical analysis was done by using Microsoft Excel. Results: There was an abnormal gene expression of p53 in all grades of the breast tumors. Non-significant (p>0.05) differ- ence of down and up regulation of p53 in different grades of breast tumor was found. However, as a whole up-regulation was more than down-regulation with significant difference (p

Background Proportionate female representation in health research is necessary for scientific rigor and health equity. We aimed to assess the representation of women in clinical trials leading to U.S. Food and Drug Administration (FDA) cancer drug approvals. Materials and Methods Trials supporting FDA cancer drug approvals between July 2008 and June 2018 were sourced from PubMed and ClinicalTrials.gov. The ratio of female to male trial enrollment was compared with cancer incidence and mortality in the U.S. using International Agency for Research on Cancer data. Reproductive tract and breast cancers were excluded. Odds ratios (ORs) and 95% confidence intervals (CIs) comparing trial enrollment with population incidence and mortality were calculated. Results A total of 186 trials leading to 170 FDA cancer drug approvals showed slight female underrepresentation compared with overall cancer incidence in the U.S. (OR, 0.97; 95% CI, 0.95–0.98, p < .0001). Female enrollment for drugs approved between 2008–2013 and 2014–2018 was unchanged (OR, 1.02; 95% CI, 0.99–1.05, p = .25). There was slight female underrepresentation in hematological trials (OR, 0.95; 95% CI, 0.91–0.998; p = .040 for leukemia; OR, 0.95; 95% CI, 0.90–0.997; p = .040 for lymphoma) and significant female underrepresentation in colorectal (OR, 0.72; 95% CI, 0.69–0.76; p < .0001), pancreas (OR, 0.85; 95% CI, 0.78–0.93; p = .0004), lung (OR, 0.77; 95% CI, 0.75–0.80; p < .0001), kidney (OR, 0.63; 95% CI, 0.60–0.67; p < .0001), and thyroid cancer trials (OR, 0.26; 95% CI, 0.23–0.28; p < .0001) compared with U.S. incidence. Conclusion Female underrepresentation has persisted within solid organ tumor trials but is less notable in hematologic trials. Additional work is required to identify drivers of such disparity. Implications for Practice Adequate gender representation in clinical trials is a matter of health equity. This study demonstrates that women remain underrepresented in trials across hematological and solid organ trials compared with cancer incidence and mortality in women, with the disparity worse in a number of solid organ tumor types. There are thus still significant improvements to be made regarding adequate representation of women in trials. Studies exploring the reasons for ongoing disparity in gender representation are warranted to help clinicians to rectify this.

BACKGROUND: Systemic diseases have been associated with oral health and gut microbiota. We examined the association between oral health and the community composition and structure of the adherent colonic gut microbiota. METHODS: We obtained 197 snap-frozen colonic biopsies from 62 colonoscopy-confirmed polyp-free individuals. Microbial DNA was sequenced for the 16S rRNA V4 region using the Illumina MiSeq, and the sequences were assigned to the operational taxonomic unit based on SILVA. We used a questionnaire to ascertain tooth loss, gum disease, and lifestyle factors. We compared biodiversity and relative abundance of bacterial taxa based on the amount of tooth loss and the presence of gum disease. The multivariable negative binomial regression model for panel data was used to estimate the association between the bacterial count and oral health. False discovery rate-adjusted P value (q value) < .05 indicated statistical significance. RESULTS: More tooth loss and gum disease were associated with lower bacterial alpha diversity. The relative abundance of Faecalibacterium was lower (q values < .05) with more tooth loss. The association was significant after adjusting for age, ethnicity, obesity, smoking, alcohol use, hypertension, diabetes, and the colon segment. The relative abundance of Bacteroides was higher in those with gum disease. CONCLUSIONS: Oral health was associated with alteration in the community composition and structure of the adherent gut bacteria in the colon. The reduced anti-inflammatory Faecalibacterium in participants with more tooth loss may indicate systemic inflammation. Future studies are warranted to confirm our findings and investigate the systemic role of Faecalibacterium.

Background: Free radicals are the main cause of numerous diseases. Their overproduction needs to be controlled in order to combat several ailments. The current study deals with the discovery of new free radical scavengers. Methods: Substituted N-hydrazinecarbothioamide indazoles 1-18 were evaluated for DPPH and ABTS radical scavenging activities. Results: All synthetic compounds possess good radical DPPH and ABTS scavenging potential in the ranges of IC50 = 2.11 ± 0.17 - 5.3 ± 0.11 μM and IC50 = 2.31 ± 0.06 - 5.5 ± 0.07 μM, respectively, as compared to standard ascorbic acid having IC50 = 2.02 ± 0.11 μM for DPPH and IC50 = 2.1 ± 0.07 μM for ABTS. Conclusion: These compounds could serve as leads for antioxidant activity that have the ability to control free radical generation and ward off free radical-induced disorders.

Purpose: BRAF V600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing. Experimental Design: We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAFV600E testing. Outcomes among IHC-detected BRAFV600E mCRC (BRAFIHC) were compared with patients with next-generation sequencing (NGS)–identified BRAFV600E-mutated mCRC from two institutions (BRAFNGS) with patients spanning from 2004 to 2018. Results: All-stage population prevalence of BRAFV600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAFIHC had worse median overall survival (mOS) than BRAFNGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89–4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAFV600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96–2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line. Conclusions: Patients with BRAFV600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.

The death rate of people is increasing globally during the current outbreak of coronavirus To combat with COVID-19 havoc, the world has adopted lockdown policies, including Pakistan Ironically, the invisible virus is suffocating humans at a fast rate but on the other side, there is a visible monster in the world gobbling up human health, i e , air pollution Therefore, the main rationale of the present research is to visualize the air quality during the ‘Lockdown’ period in Lahore, Pakistan by mapping via online tools and techniques using a geospatial system According to the present findings, the concentrations of air pollutants, such as particulate matters (PM10 and PM2 5), nitrogen oxides as NO and NO2, and sulphur dioxide, are below the maximum permissible levels of the Punjab Environmental Quality standards (PEQs), although ozone exceeds its PEQs So in light of the results, once this COVID-19 crisis is over, the government should speed up measures to lessen air pollution to achieve targets of sustainable development goals (SDGs) Moreover, the present results of air assessment during COVID-19 would serve as a useful reminder for the government of Punjab to cut down air emission levels after the pandemic © 2020, Faculty of Environment and Resource Studies,Mahidol University All rights reserved

Malignant mesothelioma of the peritoneum in women is an uncommon tumor. In this study, we present the clinicopathologic features of 164 such cases seen in our institution over a period of 42 years (1974-2016). Clinical information, pathologic findings, immunohistochemical results, and follow-up were recorded. Hematoxylin and eosin-stained slides were reviewed in all cases. Patients ranged in age from 3 to 85 years, median: 49 years. Most patients presented with abdominal/pelvic pain, although some were asymptomatic, presented with paraneoplastic syndromes or cervical lymphadenopathy. Overall, 9% of patients had a history of direct or indirect exposure to asbestos. In total, 31% and 69% of patients had either a personal or family history of other tumors; most of these tumors are currently recognized as part of a syndrome. Genetic testing information was available in 5 patients: BAP-1 germline mutation (1), type 2 neurofibromatosis (1), Lynch syndrome (1), McCune-Albright syndrome (1), no BAP-1 or TP53 mutation (1). Most cases had gross and microscopic features typical of malignant mesothelioma of the peritoneum in women; however, some had confounding features such as gelatinous appearance, signet ring or clear cells, and well-differentiated papillary mesothelioma-like areas. Calretinin and WT-1 were the markers more frequently expressed, and up to 23% of the cases showed PAX-8 expression. Patients' treatments predominantly included: chemotherapy, cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy. On multivariate analysis, the predominance of deciduoid cells, nuclear grade 3, and the absence of surgical treatment were associated with worse overall survival (OS). For all patients, the 3- and 5-year OS were 74.3% and 57.4%, respectively. The 3- and 5-year OS for patients treated with cytoreductive surgery, and hyperthermic intraperitoneal chemotherapy were 88.9% and 77.8%, respectively.

The risk and determinants of HCC in patients with primary biliary cholangitis (PBC) are unclear. We conducted a systematic review and meta-analysis of the incidence of HCC and risk factors associated with HCC risk among patients with PBC. We searched PubMed, EMBASE, MEDLINE, Cochrane databases and reference lists from relevant articles to identify cohort studies that examined incidence of HCC in patients with PBC from inception through November 2019. A total of 29 studies including 22,615 patients met the eligibility criteria. The median cohort size was 292 patients followed for an average of 76 months. The pooled incidence rate for patients with PBC was 4.17 per 1000 patient-years (95% CI 3.17–5.47). On subgroup analysis, the incidence of HCC in patients with PBC cirrhosis was 15.7 per 1000 patient-years (95% CI 8.73–28.24). The HCC incidence rate was 9.82 per 1000 person-years (95% CI 5.92–16.28) in men and 3.82 per 1000 person-years (95% CI 2.85–5.11) in women. Cirrhosis is the strongest risk factor for HCC in patients with PBC. Male gender was also a risk factor. Our meta-analysis supports current recommendations of HCC surveillance in patients with PBC cirrhosis. Further studies are needed to evaluate risk factors in this population.

Background Community-acquired urinary tract infections are associated with significant morbidity, and uropathogenic Escherichia coli (UPEC) alone causes 90% of urinary tract infections. This bacterium retains a diverse armament of virulence factors including fimbria, hemolysins, and siderophores production. In a post invasion scenario, formation of intracellular communities mimic biofilm-like characteristics and are linked to recurrent urinary tract infections. We investigated the effects of different frontline antibiotics on the formation, inhibition, and eradication of biofilms of virulent UPEC strains. Materials and methods A total of 155 UPEC strains were scrutinized for various virulence factors including gelatinase, cell surface hydrophobicity, hemagglutination, and serum bactericidal activity. Biofilm formation was confirmed by three different methods: Congo red agar, test tube, and tissue culture plate method. Biofilm inhibition and eradication assays were performed according to the standard protocols. Topographical analysis of biofilms was done by scanning electronic microscopy (SEM). Results Out of 155 strains, 113 (73%) were strong biofilm formesr, while 37 (24%) produced biofilms at moderate level. Significant differences were observed between MICs of planktonic cells (MIC-p) and MICs of UPEC biofilms (MIC-b). Among tested frontline antibiotics, levofloxacin successfully inhibited biofilms at a concentration of 32 µg/mL, while trimethoprim eradicated biofilms at higher concentrations (512-1024 µg/mL). Ciprofloxacin treatment at sub-MIC level significantly enhanced biofilm formation (P Conclusion The majority of UPEC strains are strong biofilm formers and show higher tolerance towards frontline antibiotics in biofilm form. We observed significant inhibitory effects of levofloxacin (32 µg/mL) on UPEC biofilms, while treatment with sub-minimal concentrations of ciprofloxacin significantly enhanced biofilm formation. Out of all tested antibiotics, trimethoprim (512-1024 µg/mL) eradicated UPEC biofilms.

Background Co-morbidity of depression with other non-communicable diseases (NCDs) worsens clinical outcomes for both conditions. Low- and middle-income countries need to strengthen mechanisms for detection and management of co-morbid depression within NCDs. The Behavioural Activation for Comorbid Depression in Non-communicable Disease (BEACON) study explored the acceptability and feasibility of integrating a brief depression intervention (behavioural activation, BA) into NCD services in healthcare facilities in Bangladesh and Pakistan. Methods Face-to-face qualitative interviews were conducted with 43 patients and 18 health workers attending or working in NCD centres in four healthcare facilities in Bangladesh and Pakistan, and with three policy makers in each country. The interviews addressed four research questions (1) how NCD care is delivered, (2) how NCD patients experience distress, (3) how depression care is integrated within NCD provision, and (4) the challenges and opportunities for integrating a brief depression intervention into usual NCD care. The data were analysed using framework analysis, organised by capability, opportunity and motivation factors, cross-synthesised across countries and participant groups. Results Patients and health workers described NCD centres as crowded and time pressured, with waiting times as long as five hours, and consultation times as short as five minutes; resulting in some patient frustration. They did not perceive direct links between their distress and their NCD conditions, instead describing worries about family and finance including affordability of NCD services. Health worker and policy maker accounts suggested these NCD centres lacked preparedness for treating depression in the absence of specific guidelines, standard screening tools, recording systems or training. Barriers and drivers to integrating a brief depression intervention reflected capability, opportunity and motivation factors for all participant groups. While generally valuing the purpose, significant challenges included the busy hospital environment, skill deficits and different conceptions of depression. Conclusions Given current resource constraints and priorities, integrating a brief psychological intervention at these NCD centres appears premature. An opportune first step calls for responding to patients’ expressed concerns on service gaps in provisioning steady and affordable NCD care. Acknowledging differences of conceptions of depression and strengthening psychologically informed NCD care will in turn be required before the introduction of a specific psychological intervention such as BA.

Purpose: To evaluate Pegasus optical coherence tomography (OCT), a clinical decision support software for the identification of features of retinal disease from macula OCT scans, across heterogenous populations involving varying patient demographics, device manufacturers, acquisition sites, and operators. Methods: Five thousand five hundred and eighty-eight normal and anomalous macular OCT volumes (162,721 B-scans), acquired at independent centers in five countries, were processed using the software. Results were evaluated against ground truth provided by the data set owners. Results: Pegasus-OCT performed with areas under the curve of the receiver operating characteristic of at least 98% for all data sets in the detection of general macular anomalies. For scans of sufficient quality, the areas under the curve of the receiver operating characteristic for general age-related macular degeneration and diabetic macular edema detection were found to be at least 99% and 98%, respectively. Conclusion: The ability of a clinical decision support system to cater for different populations is key to its adoption. Pegasus-OCT was shown to be able to detect age-related macular degeneration, diabetic macular edema, and general anomalies in OCT volumes acquired across multiple independent sites with high performance. Its use thus offers substantial promise, with the potential to alleviate the burden of growing demand in eye care services caused by retinal disease.