Studies on some Heterocycles of Medicinal Interest

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The Dual-Targeted Fusion Inhibitor Clofazimine Binds to the S2 Segment of the SARS-CoV-2 Spike Protein

Clofazimine and Arbidol have both been reported to be effective in vitro SARS-CoV-2 fusion inhibitors. Both are promising drugs that have been repurposed for the treatment of COVID-19 and have been used in several previous and ongoing clinical trials. Small-molecule bindings to expressed constructs of the trimeric S2 segment of Spike and the full-length SARS-CoV-2 Spike protein were measured using a Surface Plasmon Resonance (SPR) binding assay. We demonstrate that Clofazimine, Toremifene, Arbidol and its derivatives bind to the S2 segment of the Spike protein. Clofazimine provided the most reliable and highest-quality SPR data for binding with S2 over the conditions explored. A molecular docking approach was used to identify the most favorable binding sites on the S2 segment in the prefusion conformation, highlighting two possible small-molecule binding sites for fusion inhibitors. Results related to molecular docking and modeling of the structure-activity relationship (SAR) of a newly reported series of Clofazimine derivatives support the proposed Clofazimine binding site on the S2 segment. When the proposed Clofazimine binding site is superimposed with other experimentally determined coronavirus structures in structure-sequence alignments, the changes in sequence and structure may rationalize the broad-spectrum antiviral activity of Clofazimine in closely related coronaviruses such as SARS-CoV, MERS, hCoV-229E, and hCoV-OC43

Which method is best for the induction of labour?: A systematic review, network meta-analysis and cost-effectiveness analysis

Background: More than 150,000 pregnant women in England and Wales have their labour induced each year. Multiple pharmacological, mechanical and complementary methods are available to induce labour. Objective: To assess the relative effectiveness, safety and cost-effectiveness of labour induction methods and, data permitting, effects in different clinical subgroups. Methods: We carried out a systematic review using Cochrane methods. The Cochrane Pregnancy and Childbirth Group’s Trials Register was searched (March 2014). This contains over 22,000 reports of controlled trials (published from 1923 onwards) retrieved from weekly searches of OVID MEDLINE (1966 to current); Cochrane Central Register of Controlled Trials (The Cochrane Library); EMBASE (1982 to current); Cumulative Index to Nursing and Allied Health Literature (1984 to current); ClinicalTrials.gov; the World Health Organization International Clinical Trials Registry Portal; and hand-searching of relevant conference proceedings and journals. We included randomised controlled trials examining interventions to induce labour compared with placebo, no treatment or other interventions in women eligible for third-trimester induction. We included outcomes relating to efficacy, safety and acceptability to women. In addition, for the economic analysis we searched the Database of Abstracts of Reviews of Effects, and Economic Evaluations Databases, NHS Economic Evaluation Database and the Health Technology Assessment database. We carried out a network meta-analysis (NMA) using all of the available evidence, both direct and indirect, to produce estimates of the relative effects of each treatment compared with others in a network. We developed a de novo decision tree model to estimate the cost-effectiveness of various methods. The costs included were the intervention and other hospital costs incurred (price year 2012–13). We reviewed the literature to identify preference-based utilities for the health-related outcomes in the model. We calculated incremental cost-effectiveness ratios, expected costs, utilities and net benefit. We represent uncertainty in the optimal intervention using cost-effectiveness acceptability curves. Results: We identified 1190 studies; 611 were eligible for inclusion. The interventions most likely to achieve vaginal delivery (VD) within 24 hours were intravenous oxytocin with amniotomy [posterior rank 2; 95% credible intervals (CrIs) 1 to 9] and higher-dose (≥ 50 μg) vaginal misoprostol (rank 3; 95% CrI 1 to 6). Compared with placebo, several treatments reduced the odds of caesarean section, but we observed considerable uncertainty in treatment rankings. For uterine hyperstimulation, double-balloon catheter had the highest probability of being among the best three treatments, whereas vaginal misoprostol (≥ 50 μg) was most likely to increase the odds of excessive uterine activity. For other safety outcomes there were insufficient data or there was too much uncertainty to identify which treatments performed ‘best’. Few studies collected information on women’s views. Owing to incomplete reporting of the VD within 24 hours outcome, the cost-effectiveness analysis could compare only 20 interventions. The analysis suggested that most interventions have similar utility and differ mainly in cost. With a caveat of considerable uncertainty, titrated (low-dose) misoprostol solution and buccal/sublingual misoprostol had the highest likelihood of being cost-effective. Limitations: There was considerable uncertainty in findings and there were insufficient data for some planned subgroup analyses. Conclusions: Overall, misoprostol and oxytocin with amniotomy (for women with favourable cervix) is more successful than other agents in achieving VD within 24 hours. The ranking according to safety of different methods was less clear. The cost-effectiveness analysis suggested that titrated (low-dose) oral misoprostol solution resulted in the highest utility, whereas buccal/sublingual misoprostol had the lowest cost. There was a high degree of uncertainty as to the most cost-effective intervention

Datapath architecture for reliable computing in nano-scale technology

Today the process technology is scaling really fast which has given rise to new challenges in Nano\ud electronics. Some of the major challenges are overcoming variations in device threshold voltage, device\ud geometry, doping and flat band voltage resulting in transient and ungraceful degradedation of performance\ud in Integrated Circuits. There are various architecture models proposed to overcome transient and ungraceful\ud degradation, but they are not efficient enough to provide high performance and low power usage. The most\ud commonly method used for reliability enhancement based on redundancy is the Triple Module Redundancy\ud (TMR), which increases the reliability by a factor but it results in power wastage and redundant\ud computations. We propose to overcome this problem by using efficient reliability enhancement framework\ud and using a reliable computing datapath, which is capable of reconfiguring the computing path. In such\ud architecture the performance of the system is not deterministic by design, but it maintains reliability by\ud graceful degradation under time dependent device degradation. The other circuit techniques like the\ud transient fault correction, self-test and configuration is also being utilized. We observed that the\ud performance of the proposed design is more efficient than the conventional datapath architecture. The\ud degradation of the circuit is graceful with minimum errors, better accuracy and with minimum to no latency\ud in transmission of data. We analyzed the performance of the design using area, timing and power report in\ud 90nm technology obtained using Synopsys tools. Our results show that the proposed design saves time and\ud increases reliability of the overall circuit of the processor

Somatostatinoma Presented as Double-Duct Sign

Somatostatinoma is a rare neuroendocrine tumor with an incidence rate of 1 in 40 million people. It presents mostly as asymptomatic tumor diagnosed incidentally on imaging or surgery when evaluating or treating possible causes of abdominal pain. It also can present with vague symptoms, or as a clinical triad of glucose intolerance, steatorrhea, and achlorhydria. The majority of somatostatinomas are present in the pancreatic head, followed by the duodenum, the pancreatic tail, and rarely the ampulla of Vater. The prognosis is poor as more than 77% of cases present as advanced disease with local invasion or distant metastasis. Surgical resection is the main treatment for early stage disease. Other treatment options include somatostatin analogue, molecular targeted therapy, and cytotoxic chemotherapy. The scarcity of somatostatinoma cases led to the lack of fully formulated treatment options. Herein, we present a 43-year old male patient who was referred by his primary care physician to our gastroenterology clinic due to elevated liver function test and double-duct sign on CT scan. We performed an ERCP, which revealed 2 cm ampullary lesion with upstream obstruction. Biopsies were taken and histopathology was unrevealing. He underwent a laparoscopic pancreaticoduodenectomy with histopathology revealed stage IIb somatostatinoma. Treating physicians should hold a high index of suspicion and maintain a broad differential diagnosis of elevated liver enzymes

Clostridium paraputrificum: An atypical and rare case of septic arthritis mimicking an acute sickle cell crisis

Clostridium paraputrificum is an extremely rare species and constitutes only 1% of all clostridium infections in literature. Septic arthritis from Clostridium paraputrificum is even less documented, and currently there is only one known case report. Specifically, patients with sickle cell disease have a well-documented and increased susceptibility to infections with Salmonella, Streptococcus pneumoniae, Hemophilius influenzae, and Enterobacter-klebsiella. Clostridium infection in sickle cell patients has been less studied and described. Here we present a case of septic arthritis from Clostridium paraputrificum in a sickle cell disease patient likely provoked by underlying avascular necrosis of the right shoulder

Clostridium paraputrificum: An atypical and rare case of septic arthritis mimicking an acute sickle cell crisis

Clostridium paraputrificum is an extremely rare species and constitutes only 1% of all clostridium infections in literature. Septic arthritis from Clostridium paraputrificum is even less documented, and currently there is only one known case report. Specifically, patients with sickle cell disease have a well-documented and increased susceptibility to infections with Salmonella, Streptococcus pneumoniae, Hemophilius influenzae, and Enterobacter-klebsiella. Clostridium infection in sickle cell patients has been less studied and described. Here we present a case of septic arthritis from Clostridium paraputrificum in a sickle cell disease patient likely provoked by underlying avascular necrosis of the right shoulder