Formulation Devlopment Of Mesoporous Silica Nanoparticles As An Injectable Delivery System

Our long term goal is to develop a versatile and robust injectable carrier based on Mesoporous Silica Nanoparticles (MSN) for drug/drug combination therapies. The objective of my dissertation was to optimize surface functionality, particle shape and methods of colloidal stabilization of mesoporous silica by PEG for delivery of drug/drug combinations. This was achieved by pursuing the following three aims: 1. Optimize surface functionality of MSN for high drug loading and controlled release 2. Investigate the effect of particle shape and PEGylation on drug delivery in hypoxic tumor cells 3. Develop MSN capable of delivering drug/drug combinations To investigate the effect of surface functionalization of MSN on crystallization, loading, release and activity of mitoxantrone (MTX), we synthesized thiol (SH), mixed thiol/amine (SH/NH2) and amine (NH2) functionalized MSN by sol-gel process. We observed that NH2 modification of MSN has limited MTX loading. In contrast, modifications of MSN with SH resulted in significant enhancement of MTX loading. MTX loading was controlled by pH of the loading media and surface charge of MSN. The SH-MSN particles maintained a strong negative charge due to silanol and thiol surface groups while amine modified MSN resulted in an overall positive charge. Differences in the loading were due to decrease in the electrostatic interaction between MTX and MSN. Based on the observed pH-dependence of MTX loading, we hypothesized that surface functionalization will provide a simple method of pH controlled MTX release from MSN. Indeed, we observed strong pH-dependence of MTX release in SH-MSN with rapid release in acidic pH and very slow release in neutral pH. In comparison, MTX was released rapidly from NH2-MSN regardless of the pH. Similar to loading, the differences in the release behavior are due to differences in interactions of the drug with the silica matrix. Another important aspect of mesoporous silica is amorphization or crystalline-to-amorphous transformation of drugs in the porous nanoconfinement. We found strong effect of surface functionalization of MSN on crystallization of MTX. In SH-MSN particles, MTX was found to be in the amorphous form while semi-crystalline MTX was present in the NH2-MSN. This is a very interesting feature as surface functionalization serves as a simple tool to allow control over MTX loading, its crystallization and release profile. After optimizing surface functionality, we investigated the effect of surface PEGylation and particle shape on loading and release profile of MTX in hypoxic tumor cells. We synthesized thiol functionalized mesoporous silica nanorods (MSNR) and stabilized them with different amount of covalently attached PEG. The focus on rod-shaped particles was based on studies showing beneficial properties of nanorods for increased blood circulation and tumor accumulation compared with spherical particles. We found that PEGylation decreased zeta potential of MSNR with improved colloidal stability but reduced overall MTX loading as a function of PEG content. PEGylation also increased the rate of MTX release compared to release from non PEGylated MSNR. We found that MTX had better anticancer activity in hypoxic than normoxic conditions, while no clear effect of particle shape was observed. Flow cytometry study confirmed that increased activity of MTX formulations in hypoxic conditions was due to increased cell uptake and retention of the drug in the cells. To achieve our long-term goal of developing a robust and versatile drug delivery carrier, we investigated feasibility of co-loading of hydrophilic-hydrophobic and hydrophobic-hydrophobic drug combinations in MSN. We found that loading of hydrophobic molecules such as PTX and 17-AAG depends on the polarity of solvent, with less polar solvents improving drug loading. We have successfully co-loaded PTX and 17-AAG into the same particles. We observed that PEGylation decreases loading of hydrophobic molecules. We hypothesize that this decrease in the drug loading was due to blocking of access to the pores. This is a new observation and we are currently investigating alternative ways to stabilize co-loaded MSN without compromising drug loading. Inorganic particles like MSN offer an interesting alternative to organic drug delivery systems like polymeric nanoparticles, micelles and liposomes due to high drug loading capacity and biocompatibility. We demonstrated the effect of surface functionalization and PEGylation of MSN on crystallization, drug loading and release, and colloidal stability. We showed effective delivery of MTX using PEGylated MSN in hypoxic conditions that has significant promise in the treatment of clinically important triple negative as well as estrogen positive breast cancers. We also showed MSN are capable of delivering drug-drug combinations for cancer treatment

VIBRATION ANALYSIS OF DRILLING OPERATION

Vibrations are produced during any machining process. For drilling operation, analysis of these vibrations plays an important role in order to predict phenomenon of ‘chatter’. This paper emphasizes the analysis of vibration during drilling operation. The output results of analysis are useful to find out amplitude of vibrations produced with respect to drill size and spindle speed for standard rate of recommended feed/min. Analysis is quantified and tabulated as per available machining parameters of ‘THAKUR PELTER DRILLING MACHINE’ which is present in the Workshop of Fr. Conceiceo Rodrigues Institute of Technology, Vashi, Navi Mumbai. The optimum values of spindle speed and feed for maximium amplitude of transverse vibrations with respect to drill size are highlighted in the table and brought to the notice of Workshop Superintendent. The table of formulated results is displayed near this drilling machine

Evaluation of the role of posterior malleolus fixation in trimalleolar ankle fractures: a prospective study

Background: Trimalleolar ankle fractures are relatively rare and complex ankle injuries, the prognosis of which is worse than bimalleolar fracture. The three malleoli are bony restraints of the ankle and all three are fractured in trimalleolar fractures. Hence, there is disruption of the weight bearing portion of the tibial plafond along with talus dislocation/subluxation. Management of such fractures is challenging and confounded by the dilemma of posterior malleolus fixation. Aim: The aim of the present study was to evaluate the radiological and clinical outcome of fixation of large (>25%) posterior malleolus fragment in trimalleolar fractures.Methods: 25 patients underwent fixation of the three malleoli and evaluated prospectively. Different methods for fixation from plating to lag screws were used for posterior malleolus.Results: 92% of patients in our series had excellent to good clinical outcome. Radiologically, there was anatomical reduction of the ankle joint and none of the patient had postoperative talus subluxation or arthrosis.Conclusions: Our study shows that there is consistent and reproducible clinical advantage of fixing the posterior malleolus in trimalleolar ankle fractures.

Effects of foliar application of melatonin on gas exchange and certain biochemical characteristics broccoli cv. Palam Samridhi

Considering the rich nutritional status and possibility of broccoli in improving the profitable yield, and wide role of Mel in regulating the plant physiological process, an investigation was carried out at the division of Basic Sciences and Humanities during 2017 to investigate the effect of foliar application of Mel on leaf photosynthetic and biochemical attributes broccoli. Thirty days old and uniform seedlings of broccoli cv. Palam Samridhi were transplanted in the field at a spacing of 45 × 45cm. Different concentrations of Mel, viz. 0, 20, 40, 60 and 80 ppm were sprayed on the plant foliage at 15 days after transplanting (DAT) replicating each treatment four times. Leaf gas exchange and biochemical attributes were tested following the standard procedures. The Results showed the lowest stipulated rate of photosynthesis (10.87 µmole.m-2.sec-1), stomatal conductance (301.44 mole H2O.m-2ses-1) and leaf transpiration (1. 14 mole H2O.m-2ses-1) in untreated plants.  Different doses of Mel significantly increased the values of these attributes and the highest values of photosynthesis (18.63 µmole.m-2.sec-1), stomatal conductance (324.37 mmole.m-2.ses-1) and leaf transpiration (3.23 mmole.m-2.ses-1) with Mel 60 ppm were recorded. The alterations in different biochemical attributes were also evident due to foliar application of Mel and maximum leaf sugar (77.0 and 85.9µg/g), protein (56.9 and 77.3 µg/g), total phenols (260.1 and 339.9 mg/100g), antioxidants (142.8 and 159.9 mg GAE /100g DW) and MSI (94.89 and 97.43 percent) values with Mel 60ppm at 30 and 60DAT, respectively. Therefore, the present study signifies the useful effects of Mel in regulating the physio-biochemical properties of broccoli

A Prospective Multicenter Study Evaluating Learning Curves and Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography Among Advanced Endoscopy Trainees: The Rapid Assessment of Trainee Endoscopy Skills (RATES) Study

Background and aims Based on the Next Accreditation System, trainee assessment should occur on a continuous basis with individualized feedback. We aimed to validate endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) learning curves among advanced endoscopy trainees (AETs) using a large national sample of training programs and to develop a centralized database that allows assessment of performance in relation to peers. Methods ASGE recognized training programs were invited to participate and AETs were graded on ERCP and EUS exams using a validated competency assessment tool that assesses technical and cognitive competence in a continuous fashion. Grading for each skill was done using a 4-point scoring system and a comprehensive data collection and reporting system was built to create learning curves using cumulative sum analysis. Individual results and benchmarking to peers were shared with AETs and trainers quarterly. Results Of the 62 programs invited, 20 programs and 22 AETs participated in this study. At the end of training, median number of EUS and ERCP performed/AET was 300 (range 155-650) and 350 (125-500). Overall, 3786 exams were graded (EUS:1137; ERCP–biliary 2280, pancreatic 369). Learning curves for individual endpoints, and overall technical/cognitive aspects in EUS and ERCP demonstrated substantial variability and were successfully shared with all programs. The majority of trainees achieved overall technical (EUS: 82%; ERCP: 60%) and cognitive (EUS: 76%; ERCP: 100%) competence at conclusion of training. Conclusions These results demonstrate the feasibility of establishing a centralized database to report individualized learning curves and confirm the substantial variability in time to achieve competence among AETs in EUS and ERCP

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416

Competence in Endoscopic Ultrasound and Endoscopic Retrograde Cholangiopancreatography, From Training Through Independent Practice.

BACKGROUND & AIMS: It is unclear whether participation in competency-based fellowship programs for endoscopic ultrasound (EUS) and endoscopic retrograde cholangiopancreatography (ERCP) results in high-quality care in independent practice. We measured quality indicator (QI) adherence during the first year of independent practice among physicians who completed endoscopic training with a systematic assessment of competence. METHODS: We performed a prospective multicenter cohort study of invited participants from 62 training programs. In phase 1, 24 advanced endoscopy trainees (AETs), from 20 programs, were assessed using a validated competence assessment tool. We used a comprehensive data collection and reporting system to create learning curves using cumulative sum analysis that were shared with AETs and trainers quarterly. In phase 2, participating AETs entered data into a database pertaining to every EUS and ERCP examination during their first year of independent practice, anchored by key QIs. RESULTS: By the end of training, most AETs had achieved overall technical competence (EUS 91.7%, ERCP 73.9%) and cognitive competence (EUS 91.7%, ERCP 94.1%). In phase 2 of the study, 22 AETs (91.6%) participated and completed a median of 136 EUS examinations per AET and 116 ERCP examinations per AET. Most AETs met the performance thresholds for QIs in EUS (including 94.4% diagnostic rate of adequate samples and 83.8% diagnostic yield of malignancy in pancreatic masses) and ERCP (94.9% overall cannulation rate). CONCLUSIONS: In this prospective multicenter study, we found that although competence cannot be confirmed for all AETs at the end of training, most meet QI thresholds for EUS and ERCP at the end of their first year of independent practice. This finding affirms the effectiveness of training programs. Clinicaltrials.gov ID NCT02509416

Correction to: Two years later: Is the SARS-CoV-2 pandemic still having an impact on emergency surgery? An international cross-sectional survey among WSES members

Background: The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. Methods: A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. Results: 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. Conclusions: The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years