Efficacy and tolerability of sorafenib in desmoid-type fibromatosis: A need to review dose.

BACKGROUND: Sorafenib is currently one of the recommended treatments for symptomatic patients with desmoid-type fibromatosis (DTF). In this study, we aim to assess the clinical efficacy and tolerability of sorafenib in DTF patients. METHODOLOGY: Patients aged>18 years with a histological diagnosis of DTF and who have received sorafenib were enroled in this prospective observational study. Demographic data, clinical profile, the initial dose of sorafenib, treatment-related toxicities, dose modifications, and responses were recorded. The primary objective was to assess the objective response rate (ORR). The secondary objectives were to evaluate progression-free survival (PFS), tolerability, and adverse effects of sorafenib. Response assessment was based on response evaluation criteria in solid tumours 1.1 criteria. Adverse effects were graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 criteria. Time to event was calculated by Kaplan-Meier analysis, and survival was compared by log-rank test. Univariate and multivariable cox regression analysis were used to find independent predictors of relapse. RESULTS: A total of 104 patients were enroled in the study. The median age of the study population was 32 (range, 18-81) years, and 66.35% of patients were females. On response assessment, ORR was 46.1% and stable disease was observed in 31.7% patients. ORR was higher in the appendicular site (51.7%) compared to the abdominal site (27.2%). PFS at 1 and 2 years was 86.6% (79.6-92.7%) and 73.7% (62.4-82.8%), respectively. Two-thirds (66.6%) of patients had already received some form of treatment. At the time of analysis, 70 (67.3%) patients were continuing sorafenib. Only 4.8% stopped sorafenib due to progression, 10.5% due to intolerable adverse effects, and 17.3% due to other reasons. The common treatment-related toxicities were hand-foot skin reaction (HFSR) (89.4%), fatigue (79.8%), alopecia (70.1%), and diarrhoea (48.0%). In the patients with a starting dose of ≥400 mg (48.0% of patients), discontinuation was necessitated in 12% of patients, and further dose reduction was required in 58%, while only about 13% required dose reduction or discontinuation at a starting dose of 200 mg (51.9% of patients). Responses were not compromised due to lower starting doses. CONCLUSIONS: Sorafenib has good activity in DTF, but it is associated with significant toxicity. The adverse effect profile is distinct in Indian patients with higher HFSR and alopecia. Due to the high rate of dose reduction/discontinuation with a starting dose of 400 mg, a starting dose of 200 mg may be recommended in Indian patients.

Challenges in the management of metastatic gastrointestinal stromal tumor in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Neurofibromatosis type 1 is an inherited cancer predisposition syndrome that is caused by a mutation in the NF1 gene that encodes neurofibromin. Patients with neurofibromatosis type 1 have a higher risk of gastrointestinal stromal tumor. This study reports the case of a patient with gastrointestinal stromal tumor who was later diagnosed to have neurofibromatosis type 1 and, unlike usual features, had some uncommon features such as occurrence at an early age and unusual site of origin. CASE: We report the case of a 29-year-old Indian female diagnosed to have gastrointestinal stromal tumor originating from the greater curvature of the stomach. Gastrointestinal stromal tumor was wild type, negative for c-kit and platelet-derived growth factor receptor, and had an aggressive clinical course not responding to oral tyrosine kinase inhibitors. On later evaluation, we found that the patient had germline mutation in NF1. This case has some unusual features compared with gastrointestinal stromal tumor cases reported in neurofibromatosis type 1. Firstly, the age of onset for gastrointestinal stromal tumor in neurofibromatosis type 1 is earlier in our case compared with previous cases reported in literature. Secondly, the site of occurrence is in the stomach, without involving other parts of the intestine. Gastrointestinal stromal tumor in neurofibromatosis type 1 is usually multifocal, and small intestine is the common site of occurrence. When occurring in the stomach, it is usually associated with other lesions in the small intestine. Lastly, the clinical course is aggressive compared with previous case reports and series. CONCLUSION: Our patient had germline NF1 mutation and cutaneous stigmata of neurofibromatosis. Our patient had unicentric gastrointestinal stromal tumor occurring at younger age and involving greater curvature of the stomach, with spindle cell type histology and high-risk features. If gastrointestinal stromal tumor occurs at young age, we should look into neurocutaneous markers.

In silico, in vitro screening of plant extracts for anti-SARS-CoV-2 activity and evaluation of their acute and sub-acute toxicity.

Background: In the absence of a specific drug for COVID 19, treatment with plant extracts could be an option worthy of further investigation and has motivated to evaluate the safety and anti-SARS-CoV-2 activity of plant extracts. Purpose: To screen the phytochemicals for anti-SARS-CoV-2 in silico and evaluate their safety and efficacy in vitro and in vivo. Method: The phytochemicals for anti-SARS-CoV-2 were screened in silico using molecular docking. The hits generated from in silico screening were subjected for extraction, isolation and purification. The anti-SARS-CoV-2 activity of Zanthoxylum piperitum (E1), Withania somnifera (E2), Calophyllum inophyllum (E3), Andrographis paniculata (E4), Centella asiatica (E5) ethanol extracts. The aerial parts were used for E1, E3, E4, E5 and root was used for E2. The in vitro safety and anti-SARS-CoV-2 activity of plant methanol extracts were performed in VeroE6 cells using Remdesivir as positive control. The acute and sub-acute toxicity study was performed in Wistar male and female rats. Results: The percentage of cell viability for E4, E5 and E2 treated VeroE6 cells were remarkably good on the 24th and 48th hour of treatment. The in vitro anti-SARS-CoV-2 activity of E4, E5 and E2 were significant for both E gene and N gene. The percentage of SARS-CoV-2 inhibition for E4 was better than Remdesivir. For E gene and N gene, Remdesivir showed IC50 of 0.15 µM and 0.11 µM respectively, For E gene and N gene, E4 showed IC50 of 1.18 µg and 1.16 µg respectively. Taking the clue from in vitro findings, the E4, E5 and E2 were combined (E 4.5.2) and evaluated for acute and sub-acute toxicity in Wistar male and female rats. No statistically significant difference in haematological, biochemical and histopathological parameters were noticed. Conclusion: The study demonstrated the anti-SARS-CoV-2 activity in vitro and safety of plant extracts in both in vitro and in vivo experimental conditions.

Diagnostic utility of chest computerized tomography in the diagnosis of recurrence among sputum scarce and sputum negative previously treated pulmonary tuberculosis suspects.

Objective: The objective was to study the sensitivity, specificity, and diagnostic accuracy of various computed tomography (CT) chest findings in diagnosing recurrence among pulmonary tuberculosis (PTB) suspects. Materials and Methods: A prospective observational study was conducted in a tertiary care hospital in New Delhi. A total of 130 suspects with a past history of treatment for PTB, who presented with any of the symptoms suggestive of recurrence were included. Sputum-positive, HIV-positive patients, pregnant females, and patients aged <18 years were excluded. Patients underwent CT chest followed by bronchoalveolar lavage (BAL). Results: A total of 62 patients were there in the final analysis. The median age of the patients with recurrent PTB was 27.5 years. Cough was the universal symptom in all these patients (>90%). Hemoptysis was the predominant symptom among patients with chronic pulmonary aspergillosis (66.6%). Necrotic mediastinal lymph nodes had good diagnostic accuracy of 88.71% with area under the curve of 0.806, P < 0.001 in diagnosing recurrent TB. BAL GeneXpert and mycobacteria growth indicator tube had good sensitivity (83.33% and 84.62%, respectively), specificity (100% for both), and excellent diagnostic accuracy (95.16% and 96.36%, respectively) for diagnosing recurrence in sputum negative and sputum scarce patient, (P < 0.001) when compared with composite reference standard. For culture-positive cases, BAL GeneXpert MTB/RIF had 100% sensitivity and 97.73% specificity in diagnosing recurrent PTB patients. Conclusion: The presence of mediastinal necrotic lymph node is the most accurate CT finding that can differentiate recurrent TB from post-TB sequelae. No other single chest CT scan finding had reliable diagnostic accuracy in comparison to microbiological tools in diagnosing recurrence among sputum negative or scarce previously treated PTB suspects.

In silico, In vitro Screening of Plant Extracts for Anti-SARS-CoV-2 Activity and Evaluation of Their Acute and Sub-Acute Toxicity

BackgroundIn the absence of a specific drug for COVID 19, treatment with plant extracts could be an option worthy of further investigation. PurposeTo screen the phytochemicals for Anti-SARS-CoV-2 in silico and evaluate their safety and efficacy in vitro and in vivo. MethodThe phytochemicals for Anti-SARS-CoV-2 were screened in silico using molecular docking. The hits generated from in silico screening were subjected for extraction, isolation and purification. The anti-SARS-CoV-2 activity of plant extracts of Z. piperitum (ATRI-CoV-E1), W. somnifera (ATRI-CoV-E2), C. inophyllum (ATRI-CoV-E3), A. paniculata (ATRI-CoV-E4), and C. Asiatica (ATRI-CoV-E5). The in vitro safety and anti-SARS-CoV-2 activity of plant extracts were performed in VeroE6 cells using Remdesivir as positive control. The acute and sub-acute toxicity study was performed in Wistar male and female rats. ResultsThe percentage of cell viability for ATRI-COV-E4, ATRI-COV-E5 and ATRI-COV-E2 treated VeroE6 cells were remarkably good on the 24th and 48th hour of treatment. The in vitro anti-SARS-CoV-2 activity of ATRI-COV-E4, ATRI-COV-E5 and ATRI-COV-E2 were significant for both E gene and N gene. The percentage of SARS-CoV-2 inhibition for ATRI-COV-E4 was better than Remdesivir. For E gene and N gene, Remdesivir showed IC50 of 0.15 {micro}M and 0.11 {micro}M respectively, For E gene and N gene, ATRI-CoV-E4 showed IC50 of 1.18 {micro}g and 1.16 {micro}g respectively. Taking the clue from in vitro findings, the plant extracts A. paniculata (ATRI-COV-E4), W. somnifera extract (ATRI-COV-E5) and C. asiatica extract (ATRI-COV-E2) were combined (ATRICOV 452) and evaluated for acute and sub-acute toxicity in Wistar male and female rats. No statistically significant difference in haematological, biochemical and histopathological parameters were noticed. ConclusionThe study demonstrated the Anti-SARS-CoV-2 activity in vitro and safety of plant extracts in both in vitro and in vivo experimental conditions.

Effectiveness and Parental Perception of Silver Diamine Fluoride toward Treatment of Dental Caries in Primary Teeth.

AIM: Silver diamine fluoride (SDF) is taken into account as one among the effective measures for caries arrest and prevention in youngsters, due to the fact it proffers marginally invasive but cost-effective alternative to time-commemorated restorative caries control. The study was carried out to appraise the effectiveness of SDF (38%) in arresting active carious lesions and to gauge parental perception toward the treatment of cavities with SDF in the primary teeth. MATERIALS AND METHODS: A total of 36 children in the age range 2-10 years, having active caries lésions, based on ICDAS criteria, in primary teeth were selected following the baseline examination. After four dropouts and refusal by two patients, 30 patients were treated with 1-2 topical applications of SDF (38%). Lesions were reassessed at 1 week and 3 months taking into account to assess the color and amend inconsistency (soft/hard). Parents have been mentioned regarding features of pain or infection and have been surveyed with regard to subjective feelings regarding SDF. RESULTS: Quantitative variables have been subjected to the Chi-square test. All the 30 participants within the present study at baseline were reported to possess active caries lesion. About 80% of carious lesions were found to be arrested at first recall and 93.3% after 3 months. No occurrence of pain or infection was documented. Parental perception for simple application, taste, and esthetics became statistically significant. Conclusion: Study outcomes endorse SDF to be effective in preventing active carious lesions in deciduous dentition in youngsters, and treatment outcomes were affirmative by the parents. CLINICAL SIGNIFICANCE: SDF has been a possible management option for a noninvasive remedy to inhibit active carious lesions in deciduous dentition without causing any psychological trauma to children. HOW TO CITE THIS ARTICLE: Shrivastava U, Barjatya K, AK BB, et al. Effectiveness and Parental Perception of Silver Diamine Fluoride toward Treatment of Dental Caries in Primary Teeth. Int J Clin Pediatr Dent 2021;14(6):790-794.

Selective Activation of ZAK ß Expression by 3-Hydroxy-2-Phenylchromone Inhibits Human Osteosarcoma Cells and Triggers Apoptosis via JNK Activation.

Although various advancements in radical surgery and neoadjuvant chemotherapy have been developed in treating osteosarcoma (OS), their clinical prognosis remains poor. A synthetic chemical compound, 3-hydroxylflavone, that is reported to regulate ROS production is known to inhibit human bone osteosarcoma cells. However, its role and mechanism in human OS cells remains unclear. In this study, we have determined the potential of 3-Hydroxy-2-phenylchromone (3-HF) against OS using human osteosarcoma (HOS) cells. Our previous studies showed that Zipper sterile-alpha-motif kinase (ZAK), a kinase member of the MAP3K family, was involved in various cellular events such as cell proliferation and cell apoptosis, and encoded two transcriptional variants, ZAKα and ß. In this study, we show that 3-HF induces the expression of ZAK and thereby enhances cellular apoptosis. Using gain of function and loss of function studies, we have demonstrated that ZAK activation by 3-HF in OS cells is confined to a ZAKß form that presumably plays a leading role in triggering ZAKα expression, resulting in an aggravated cancer apoptosis. Our results also validate ZAKß as the predominant form of ZAK to drive the anticancer mechanism in HOS cells.

Green-Synthesized FeSO4 Nanoparticles Exhibit Antibacterial and Cytotoxic Activity by DNA Degradation.

OBJECTIVE: The current study reports a green, rapid and one-pot synthesis of FeSO4 nanoparticles using Hibiscus rosasinensis floral extract as a reducing and capping agent. 0.5M of FeSO4 was stirred with the floral extract of H. rosasinensis for around 20 minutes at 37ºC and pH 7. METHODS: The development of pink color was considered as the endpoint of reduction and the nanoparticles were characterized by UV-Vis spectrum, EDAX, DLS, FTIR, FESEM, and XRD. UV-Vis spectral analysis indicated a peak at 530 nm and EDAX measurement revealed the presence of Fe, S, O and C elements in the nanoparticle sample. The FTIR analysis showed amines, alcohol and alkene groups that act as capping agents for the produced nanoparticles. FESEM and XRD determination presented FeSO4 nanoparticles of 40-60 nm in size. The synthesized nanoparticles were found to have antibacterial activity against 6 pathogenic bacteria with MIC and MBC of 40 mg/mL. RESULTS: To determine the toxicity at the eukaryotic level, brine shrimp toxicity assay was conducted and 100% mortality was found at concentrations >0.06 mg/mL. Gel shift assay suggested the mechanism of toxicity of FeSO4 NPs by binding and degradation of DNA molecules. CONCLUSION: From the results, the authors demonstrate the ease of green synthesis of FeSO4 nanoparticles and its bioactivity that may have potential applications as drugs and drug delivery systems against various diseases.

Neutralization of Naja naja venom induced lethality, edema and myonecrosis by ethanolic root extract of Coix lacryma-jobi.

Coix lacryma-jobi, commonly known as job's tear, is a tall grain-bearing tropical plant of the family Poaceae. The ethanolic root extract (ERE) of the plant was investigated for the first time for anti-venom activity against Indian cobra Naja naja venom. In-vitro studies were conducted to determine neutralization of phospholipase A2 (PLA2) activity of the Naja naja venom by the ERE. ERE showed significant inhibition of PLA2 activity, which was further confirmed from effective neutralization of human red blood cells (HRBC) lysis induced by the venom. In addition, venom-induced proteolysis, fibrinogenolysis, DNase activity were also neutralized by the ERE, which contained carbohydrates, glycolides, resins and tannins. Oral administration of ERE at doses levels 100, 200 and 400 mg/kg effectively inhibited Naja naja venom-induced lethality in mice. Myotoxicity induced by Naja naja venom, measured by creatine kinase activity in rats was significantly neutralized by the ERE at a dose of 200 mg/kg. Stigmasterol, as one of the component isolated from the ERE, was found to have venom phospholipase A2 inhibition potential, which was confirmed by molecular docking studies with PLA2. In summary, these studies indicate the ability of ERE of Coix lacryma-jobi to effectively neutralize the toxic effects of the venom is, in part, contributed by the inhibition of PLA2 activity among other venom-derived factors.

Atomic Layer Deposition of Ultrathin Crystalline Epitaxial Films of V2O5.

Ultrathin epitaxial films (10-90 nm thick) of V2O5 have been grown on c-Al2O3 by atomic layer deposition using vanadyl acetylacetonate as the vanadium precursor along with oxygen plasma. Various process parameters have been optimized for the purpose, and excellent crystalline films could be obtained below 200 °C, without the need for post-heat treatment. With a moderate temperature window, the process yields a growth rate of 0.45 Å/cycle. The films have been characterized by electron microscopy, atomic force microscopy, Raman spectroscopy, and other means. The films exhibit a (001) preferred orientation with respect to c-Al2O3 and undergo compressive strain at the initial few monolayer growth to adjust epitaxially with the substrate. Heterojunction diodes based on TiO2(p)-(n)V2O5 as well as a humidity sensor have been fabricated using the V2O5 films.

Splenic Abscess Caused by Salmonella Typhi and Co-Infection with Leptospira.

Splenic abscesses caused by Salmonella typhi are a very rare complication of typhoid fever in this era of use of specific antibiotics. Co-infection with Leptospira in such a patient is even rarer. Clinical diagnosis of splenic abscess caused by Salmonella is difficult owing to its rarity, being insidious in onset and having nonspecific clinical presentation. Splenic abscesses are potentially fatal complication of typhoid fever. In most of these patients, hemoglobinopathies or some other underlying immunocompromised state is usually present. We report a case of splenic abscess, caused by Salmonella typhi, and co-infection with Leptospira in a previously healthy young male.

Longitudinal Analysis of Adherence to First-Line Antiretroviral Therapy: Evidence of Treatment Sustainability from an Indian HIV Cohort.

INTRODUCTION: Given the chronic nature of HIV infection and the need for life-long antiretroviral therapy (ART), maintaining long-term optimal adherence is an important strategy for maximizing treatment success. In order to understand better the dynamic nature of adherence behaviors in India where complex cultural and logistic features prevail, we assessed the patterns, trajectories and time-dependent predictors of adherence levels in relation to virological failure among individuals initiating first-line ART in India. METHODS: Between July 2010 and August 2013, eligible ART-naïve HIV-infected individuals newly initiating first-line ART within the national program at three sites in southern India were enrolled and monitored for two years. ART included zidovudine/stavudine/tenofovir plus lamivudine plus nevirapine/efavirenz. Patients were assessed using clinical, laboratory and adherence parameters. Every three months, medication adherence was measured using pill count, and a structured questionnaire on adherence barriers was administered. Optimal adherence was defined as mean adherence ≥95%. Statistical analysis was performed using a bivariate and a multivariate model of all identified covariates. Adherence trends and determinants were modeled as rate ratios using generalized estimating equation analysis in a Poisson distribution. RESULTS: A total of 599 eligible ART-naïve patients participated in the study, and contributed a total of 921 person-years of observation time. Women constituted 43% and mean CD4 count prior to initiating ART was 192 cells/mm3. Overall mean adherence among all patients was 95.4%. The proportion of patients optimally adherent was 75.6%. Predictors of optimal adherence included older age (≥40 years), high school-level education and beyond, lower drug toxicity-related ART interruption, full disclosure, sense of satisfaction with one's own health and patient's perception of having good access to health-care services. Adherence was inversely proportional to virological failure (IRR 0.55, 95%CI 0.44-0.69 p<0.001). Drug toxicity and stigma-related barriers were significantly associated with virological failure, while forgetfulness was not associated with virological failure. CONCLUSION: Our study highlights the overall high level of medication adherence among individuals initiating ART within the Indian national program. Primary factors contributing towards poor adherence and subsequent virological failure in the proportion of individuals with poor adherence included drug toxicity, perceived stigma and poor access to health care services. Strategies that may contribute towards improved adherence include minimizing drug interruptions for medical reasons, use of newer ART regimens with better safety profiles and increasing access with more link ART centers that decentralize ART dispensing systems to individuals.

Development and Implementation of an Electronic Decision Support to Manage the Health of a High-Risk Population: The enhanced Electronic Medical Record Aging Brain Care Software (eMR-ABC).

INTRODUCTION: Health care systems in the United States are transitioning from volume-based purchasing models to value-based purchasing models that demand both delivery of personalized care for each patient and cost-effective population health management. The enhanced medical record for aging brain care (eMR-ABC) software is an electronic decision support system that facilitates the management of a high-risk population suffering from aging brain disorders such as dementia. METHODS: Using the lenses of the Complex Adaptive System and the Reflective Adaptive Process, we assembled an interdisciplinary team of clinicians, health services researchers, and software developers who designed, implemented, evaluated, and continuously modified the eMR-ABC to meet the needs of care coordinators who manage the health of a targeted high-risk population. RESULTS: The eMR-ABC captures and monitors the cognitive, functional, behavioral, and psychological symptoms of a registry of patients suffering from dementia or depression as well as the burden of patients' family caregivers. It provides decision support to care coordinators to create a personalized care plan that includes evidence-based nonpharmacological protocols, self-management handouts, and alerts of medications with potentially adverse cognitive effects. The software's built-in engine tracks patient visits and on-demand functionality to generate population reports for specified indicators. DISCUSSION: Population health programs depend on data collection and information systems with the ability to provide valuable and timely feedback on an ongoing basis. Following these guidelines, the eMR-ABC was designed specifically to meet the management needs of a high-risk population.