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To determine the safety and efficacy, we have developed and validated the RP-HPLC method for simultaneous quantification of cinnarizine, its five specified impurities and two degradation products in cinnarizine API, tablets and capsules and including two antioxidants in an oral suspension formulation. The chromatographic separation was achieved in gradient elution mode with 1.00mL/min flow on an Ascentis Express C18 (150mm, 4.6mm and 2.7µm particle size) column at 40.0°C column temperature using 0.05% acetic acid in mixtures of 10mM ammonium acetate and acetonitrile. All peaks are eluted within 30 minutes with a 10µL injection volume and detected at a 230nm wavelength. The results of the validation of the proposed RP-HPLC method as per ICH guidelines revealed that the method is specific, accurate, precise, linear and robust for quantification purposes. The recoveries for all specified impurities, degradation products and cinnarizine at a lower concentration were found in the range of 100.0±10.0%. While the assay values were within 100.0±2.0% for cinnarizine and antioxidants (methylparaben and propylparaben). The LOD and LOQ were 0.1125µg/mL and 0.1875µg/mL, respectively. The linearity curves for all the ten analytes mentioned above showed good linearity (r≥0.999). This research work presents the first RP-HPLC method for simultaneous quantification of all ten analytes with unknown impurities, as well as an HPLC-ESI-MS method for correct identification and confirmation of results.

A new, simple, and stereoselective RP-HPLC method was developed and validated for the simultaneous quantification of tadalafil, its one enantiomer, and two diastereomers in API and tablets. Using varied compositions of water, acetonitrile, and acetic acid as mobile phases in gradient mode at a 0.40 mL/min flow rate and detection at 285 nm, all this separation was achieved on the Lux Cellulose-3 (150 mm x 4.6 mm, 3 µm) column at a 30.0°C oven temperature. All isomers were eluted within 24 minutes, with a resolution of more than 2.3 between any two isomers. With 10.0 µL injection volume, the LOD and LOQ were determined to be 0.06 µg/mL and 0.10 µg/mL, respectively. The linearity of tadalafil (0.10-400 µg/mL), one enantiomer, and two diastereomers (0.10-4.0 µg/mL) was confirmed with a correlation coefficient of 0.999. The forced degradation study revealed the specificity for all the peaks as well as the conversion of tadalafil into diastereomers (6S, 12aR) in acidic conditions and into diastereomers (6R, 12aS) in alkaline conditions. At lower concentrations, the recoveries for all isomers ranged from 100.0 ± 15.0%, while the assay values for tadalafil were within 100.0 ± 2.0%. According to the validation outcome as per ICH guidelines, the proposed method is an accurate, precise, linear, and robust stereoselective method for simultaneous quantification.

This article explains the developed and validated rapid, timesaving, and cost-effective UHPLC method for simultaneous quantification of cinnarizine, its five specified impurities (Impurity-A to E), two degradation products (cinnamyl piperazine and benzhydrol), and two antioxidants (methylparaben and propylparaben). Furthermore, when coupled with a mass spectrometer, the proposed method provides additional advantages for confirmation of results and correct identification based on molecular weight. All analytes were eluted within 15 minutes on an ACQUITY, UPLC, BEH C18 (150 mm x 2.1 mm, 1.7 µm) column at 40.0°C by using two mobile phases containing different compositions of 10 mM ammonium acetate, acetonitrile, and acetic acid in gradient elution mode. The linearity curves of cinnarizine, its impurities, and degradation products showed good results in a correlation coefficient of 0.999 with a lower detection limit (0.1125 μg/ mL) and quantification limit (0.1875 μg/mL) at 230 nm. A forced degradation study on spiked and unspiked solutions proved their specificity with improvements and their significance. This proposed method involves a lower flow rate (0.35 mL/min.) with a shorter run time, which provides faster analysis, reduces wastage, reduces the cost, and specifies the greener advantages. The outcome of the validation as per ICH guidelines proved that the proposed UHPLC method is accurate, precise, and timesaving for simultaneous quantification of all analytes in active pharmaceutical ingredient, tablets, capsules, and oral suspension of cinnarizine.

This article explains the developed and validated rapid, timesaving, and cost-effective UHPLC method for simultaneous quantification of cinnarizine, its five specified impurities (Impurity-A to E), two degradation products (cinnamyl piperazine and benzhydrol), and two antioxidants (methylparaben and propylparaben). Furthermore, when coupled with a mass spectrometer, the proposed method provides additional advantages for confirmation of results and correct identification based on molecular weight. All analytes were eluted within 15 minutes on an ACQUITY, UPLC, BEH C18 (150 mm x 2.1 mm, 1.7 µm) column at 40.0°C by using two mobile phases containing different compositions of 10 mM ammonium acetate, acetonitrile, and acetic acid in gradient elution mode. The linearity curves of cinnarizine, its impurities, and degradation products showed good results in a correlation coefficient of 0.999 with a lower detection limit (0.1125 μg/ mL) and quantification limit (0.1875 μg/mL) at 230 nm. A forced degradation study on spiked and unspiked solutions proved their specificity with improvements and their significance. This proposed method involves a lower flow rate (0.35 mL/min.) with a shorter run time, which provides faster analysis, reduces wastage, reduces the cost, and specifies the greener advantages. The outcome of the validation as per ICH guidelines proved that the proposed UHPLC method is accurate, precise, and timesaving for simultaneous quantification of all analytes in active pharmaceutical ingredient, tablets, capsules, and oral suspension of cinnarizine.

Status epilepticus care and treatment are already being touched by the revolution in data science. New approaches designed to leverage the tremendous potential of "big data" in the clinical sphere are enabling researchers and clinicians to extract information from sources such as administrative claims data, the electronic medical health record, and continuous physiologic monitoring data streams. Algorithmic methods of data extraction also offer potential to fuse multimodal data (including text-based documentation, imaging data, and time-series data) to improve patient assessment and stratification beyond the manual capabilities of individual physicians. Still, the potential of data science to impact the diagnosis, treatment, and minute-to-minute care of patients with status epilepticus is only starting to be appreciated. In this brief review, we discuss how data science is impacting the field and draw examples from the following three main areas: (1) analysis of insurance claims from large administrative datasets to evaluate the impact of continuous electroencephalogram (EEG) monitoring on clinical outcomes; (2) natural language processing of the electronic health record to find, classify, and stratify patients for prognostication and treatment; and (3) real-time systems for data analysis, data reduction, and multimodal data fusion to guide therapy in real time. While early, it is our hope that these examples will stimulate investigators to leverage data science, computer science, and engineering methods to improve the care and outcome of patients with status epilepticus and other neurological disorders. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Purpose – The purpose of this paper is to determine the agility level of a manufacturing system along different timelines. Design/methodology/approach – The fuzzy synthetic extents of agile manufacturing enablers (AMEs), on the basis of their importance, are determined. Then they are integrated with their performance ratings along different timeline for calculating the Fuzzy Agile Manufacturing Index (FAMI). Euclidean distances of FAMI from predetermined agility levels are mapped to determine the agility level of the manufacturing system along different timeline. Findings – The proposed methodology was implemented in an Indian manufacturing organization to determine its agility level. It was concluded from the obtained results that there was significant improvement in the agility level along the timeline. Research limitations/implications – The weights of the AMEs are assumed to be constant along the timeline. Practical implications – The supply chain mangers can easily apply this methodology in their respective manufacturing organizations to assess and determine the agility level. This proposed approach will show the direction to check the performance of agility and evaluate the evolution of agility in their respective manufacturing organizations. Originality/value – The combination of fuzzy synthetic extent of weights and average fuzzy performance ratings of AMEs to calculate the FAMI along the timeline considering judgments of multiple experts is a unique contribution.

Objectives: We sought association of genetic variants in the renin-angiotensin system (RAS) and vitamin D system with acute pancreatitis (AP) development and severity. Background: The endocrine RAS is involved in circulatory homeostasis through the pressor action of angiotensin II at its AT1 receptor. However, local RAS regulate growth and inflammation in diverse cells and tissues, and their activity may be suppressed by vitamin D. Intrapancreatic angiotensin II generation has been implicated in the development of AP. Methods: Five hundred forty-four white patients with AP from 3 countries (United Kingdom, 22; Germany, 136; and The Netherlands 386) and 8487 control subjects (United Kingdom 7833, The Netherlands 717) were genotyped for 8 polymorphisms of the RAS/vitamin D systems, chosen on the basis of likely functionality. Results: The angiotensin-converting enzyme I (rather than D) allele was significantly associated with alcohol-related AP when all cohorts were combined (P = 0.03). The renin rs5707 G (rather than A) allele was associated with AP (P = 0.002), infected necrosis (P = 0.025) and mortality (P = 0.046). Conclusions: The association of 2 RAS polymorphisms with AP suggests the need for further detailed analysis of the role of RAS/vitamin D in the genesis or severity of AP, particularly given the ready potential for pharmacological manipulation of this system using existing marketed agents. However, further replication studies will be required before any such association is considered robust, particularly given the significant heterogeneity of AP causation and clinical course.

In this article, the author calls for a critical visual pedagogy as a means to challenge visually constituted ‘grand narratives’ of poverty and suffering. In the first half, he situates images of poverty in India within a global development discourse termed the ‘end of poverty’, which functions as the rationale for social interventions in the global south and sustains a circuit of ‘poverty capital’. The author critically analyzes the visual aesthetic that accompanies the ‘end of poverty’ narrative, focusing on the visual choices that reinforce difference and promote the perception that marginalized populations need ‘saving’. Using images from his fieldwork with students in a village school in Karnataka, India, about 50 km south of Bangalore, he proposes an alternative visual aesthetic, grounded in visual ethnography, which may serve to counter the ‘end of poverty’, and grand narratives like it, while impacting how and why we participate in poverty alleviation efforts.

ObjectiveCurrent surveillance strategies for duodenal adenomatosis in familial adenomatous polyposis (FAP) miss malignancies and underestimate cancer risk in ampullary disease. This study aimed to evaluate the utility of endoscopic ultrasound (EUS) in the assessment of FAP patients with duodenal and/or ampullary polyposis referred for surgical intervention.DesignA retrospective analysis of FAP patients undergoing index EUS between December 2006 and May 2015 was performed. Follow-up was completed in January 2018, including review of all EUS procedures and surgical interventions (median follow-up 6 years).ResultsFifty-five patients underwent 188 EUS procedures. Six patients (11%) developed malignancy (three duodenal, three ampullary). Ampullary cancer risk was underestimated by Spigelman stage and overestimated by Kashiwagi classification. Ultrasound findings were poor predictors of malignancy, with common bile duct dilatation being the only finding present in one EUS prior to a diagnosis of ampullary cancer. The best predictors of ampullary malignancy were an ampullary polyp size >3 cm and an increase >1 cm in ampullary polyp size. Ampullary polyp size >3 cm provided the best predictive value, correctly identifying two of the three cases of ampullary cancer and both patients with high-grade dysplasia. EUS biopsy failed to detect malignancy later confirmed by surgical histology in two patients.ConclusionEUS surveillance confers little additional benefit to standard endoscopic surveillance in FAP patients. The best predictor of ampullary malignancy is an ampullary polyp >3 cm; this could be regarded as a relative indication for surgery.

Background: Port-site metastases (PSMs) are a rare occurrence after robotic surgery. For robot-assisted radical cystectomy (RARC), isolated cases have been reported but management has not been previously described. We present a case of PSM that occurred after RARC and report the results of our systematic review of previously reported PSMs and describe the treatment options. Search Criteria and Methods: We describe a case of a PSM in a 55-year-old man who had undergone intracorporeal RARC. We performed a systematic review of MEDLINE and Embase databases for previously reported PSMs, detailing the stage and grade of the primary tumor, time to presentation of PSM, treatment offered, and outcomes for the identified cases. Results: We identified 4 cases of PSMs after RARC in published studies and also included our case for analysis. All 5 patients had muscle-invasive bladder cancer at cystectomy (stage ≥ T2) and 3 had local lymph node-positive disease. Our aggressive treatment of chemotherapy, wide surgical excision of PSM, and radiotherapy provided our patient with a 2-year disease-free status. Conclusion: PSMs are a rare event in RARC, with only 4 other cases reported in published studies. The outcomes have not been well reported for these cases. We propose that multimodality treatment consisting of salvage chemotherapy, surgery, and radiotherapy should be considered, although concessions could be needed after consideration of patient factors.

The most important systems being used for the effective and safe operation of an airplane is the Altitude Measurement Systems, a duty carried out by means of an Altimeter. The Altimeter output is affected by the input that is given to it. The input that is used by the Altimeter to show the desired altitude is nothing but the barometric pressure at the height at which the aircraft is travelling in. The barometric pressure is converted to the appropriate altitude by means of either Pitot Tubes or Sensors. The Pitot-tube is being used widely in all commercial airliners. The Pitot-Static systems are extremely susceptible to blockage by foreign bodies in case the aircraft sits on the tarmac for long time. To avoid contamination of the liquid which senses the change in pressure, the pitot-tubes are covered and if this cover is not removed, the pitot-tube gets blocked. Sensors are extremely susceptible to be burdened by ice, and in cases where the heating is not available in the place where the sensors are kept, erratic altitudes may result. It is therefore proposed, theoretically, to make efficient use of a four bar chain mechanism, called the Watt’s Indicator Mechanism , in order to eradicate the effects of blockage by foreign matter and burdening by ice and thereby promoting the effective measurement of Altitude in Airplanes. This mechanism would be able to provide means of measuring altitude if calibrated appropriately.

Little is known about the clonal structure or stem cell architecture of the human small intestinal crypt/villus unit, or how mutations spread and become fixed. Using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion of stem cell progeny, we aimed to provide answers to these questions. Enzyme histochemistry (for cytochrome c oxidase and succinate dehydrogenase) was performed on frozen sections of normal human duodenum. Laser-capture microdissected cells were taken from crypts/villi. The entire mitochondrial genome was amplified using a nested PCR protocol; sequencing identified mutations and immunohistochemistry demonstrated specific cell lineages. Cytochrome c oxidase-deficient small bowel crypts were observed within all sections: negative crypts contained the same clonal mutation and all differentiated epithelial lineages were present, indicating a common stem cell origin. Mixed crypts were also detected, confirming the existence of multiple stem cells. We observed crypts where Paneth cells were positive but the rest of the crypt was deficient. We have demonstrated patches of deficient crypts that shared a common mutation, suggesting that they have divided by fission. We have shown that all cells within a small intestinal crypt are derived from one common stem cell. Partially-mutated crypts revealed some novel features of Paneth cell biology, suggesting that either they are long-lived or a committed Paneth cell-specific long-lived progenitor was present. We have demonstrated that mutations are fixed in the small bowel by fission and this has important implications for adenoma development.

A 52-year old man developed hyperkalaemia on the 11th postoperative day following an extensive open retroperitoneal liposarcoma resection that included splenectomy. Despite thorough investigations, no aetiology for the hyperkalaemia was identified and standard empirical treatment was ineffective. On reconsideration, in view of the patient's concurrent thrombocytosis, a pseudofactual or artefactual hyperkalaemia was suspected. This was confirmed by contemporaneous testing of serum and plasma potassium levels, with the latter value lying within the normal range. Treatment for hyperkalaemia was discontinued, thus averting an iatrogenic and potentially dangerous hypokalaemia. This case highlights pseudohyperkalaemia as an often-neglected cause of elevated serum potassium levels and discusses its association with thrombocytosis following splenectomy.

BACKGROUND: Patients with advanced, metastatic sarcoma have a poor prognosis, and the overall benefit from the few standard-of-care therapeutics available is small. The rarity of this tumor, combined with the wide range of subtypes, leads to difficulties in conducting clinical trials. The authors previously reported the outcome of patients with a variety of common solid tumors who received treatment with drug regimens that were first tested in patient-derived xenografts using a proprietary method ("TumorGrafts"). METHODS: Tumors resected from 29 patients with sarcoma were implanted into immunodeficient mice to identify drug targets and drugs for clinical use. The results of drug sensitivity testing in the TumorGrafts were used to personalize cancer treatment. RESULTS: Of 29 implanted tumors, 22 (76%) successfully engrafted, permitting the identification of treatment regimens for these patients. Although 6 patients died before the completion of TumorGraft testing, a correlation between TumorGraft results and clinical outcome was observed in 13 of 16 (81%) of the remaining individuals. No patients progressed during the TumorGraft-predicted therapy. CONCLUSIONS: The current data support the use of the personalized TumorGraft model as an investigational platform for therapeutic decision-making that can guide treatment for rare tumors such as sarcomas. A randomized phase 3 trial versus physician's choice is warranted.