Isolation, derivatization, in-vitro, and in-silico studies of potent butyrylcholinesterase inhibitors from Berberis parkeriana Schneid.

Seven known isoquinoline alkaloids 1-7 were isolated from the root extracts of Berberis parkeriana Schneid. Nine new derivatives 8-16 of one of the isolated compounds, jatrorrhizine (7), were synthesized. All the isolated as well as derivatized compounds were evaluated for their in-vitro acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) inhibitory activity. Functionalized compounds selectively exhibited a potent-to-moderate activity with IC50 = 5.5 ± 0.3-124.5 ± 0.4 µM against butyrylcholinesterase enzyme. Among them, compound 15 was a potent BChE inhibitor (IC50 = 5.5 ± 0.3 µM), as compared to the standard drug galantamine hydrobromide (IC50 = 40.83 ± 0.37 µM). Active compounds were further subjected to kinetic, and molecular docking studies to predict their modes of inhibition, and interactions with the receptor (BChE), respectively. Enzyme kinetics studies showed that compounds 9 (IC50 = 25.3 ± 0.5 µM), and 14 (IC50 = 23.9 ± 0.5 µM) were non-competitive inhibitors, while compound 15 exhibited a competitive inhibition. In addition, these compounds were found to be non-cytotoxic against human fibroblast (BJ) cell line, except 9 (IC50 = 17.1 ± 1.0 µM), and 10 (IC50 = 18.4 ± 0.3 µM). Inhibition of cholinesterases is an important approach for development of drugs against Alzheimer's disease, and thus discoveries presented here deserve further investigation.

Surgical intervention in aggressive ulcerative pyoderma gangrenosum.

Pyoderma Gangrenosum (PG) is a rare, debilitating, and painful disease of the skin. Its aetiology and pathophysiology are not well understood. However, it is known that PG is not bacterial in origin, as previously believed. A significant number of cases of PG report a phenomenon called pathergy, which is characterized by the appearance of new lesions after the application of trauma to the skin. This represents a unique challenge for surgeons in cases that are refractory to medical therapy. The objective of this study is to review past literature and report a case of PG in a 19-year old woman, who presented with recurrence, after undergoing skin grafting one year back. The patient was referred for split thickness skin grafting (STSG) to reduce the psychological and physical morbidity as a result of this disease.

Blend of guar gum and Eudragit shows excellent drug release retarding behavior in sustained release tablets.

The objective of the current study was to compare sustained release behavior of natural and synthetic polymers in matrix tablets of lisinopril and hydrochlorothiazide combination. Guar gum was used as a hydrophilic natural polymer while Eudragit L 100-55 was used as synthetic polymer. Tablets were formulated by direct compression method using different ratios and combinations of both polymers. Various physical tests were performed. After that, in vitro drug release patterns were investigated by performing dissolution in pH 6.8 phosphate buffer. Results indicated that tablets with combination of both guar gum and Eudragit L 100-55 (formulation F10) were having the best drug release retarding behavior. All formulations followed zero order kinetics indicating the drug release was independent of the concentration. Higuchi model revealed drug release by diffusion mechanism while Korsmeyer Peppas model suggested that formulations followed the non-fickian release behavior.

Staged dental extraction and three interim prostheses for implants based rehabilitation in a periodontally compromised subject.

Studies have shown that the presence of advanced periodontal disease lowers the success of dental implants. The recommended approach for such cases is the delayed placement and delayed loading of implants. The present paper reports a case of a subject who presented with severe periodontally compromised dentition. Placement and early loading of 12 implants was done using a staged approach. Three different sets of fixed-type dental prostheses were employed in the interim period. The final prostheses were cement retained metallo-ceramic fixed bridge. Use of staged extraction and using three sets of interim prostheses helped the patient to maintain his aesthetics and function during the entire treatment period. This approach can be a predictable management option in cases of advanced periodontitis. The key is proper planning and execution of the implant surgery and prosthetics.

Mismatch repair deficiency screening in colorectal carcinoma by a four-antibody immunohistochemical panel in Pakistani population and its correlation with histopathological parameters.

BACKGROUND: Microsatellite instability (MSI) operates as the second major pathway in the colorectal carcinogenesis. Although genetic testing remains the gold standard for the detection of MSI, the College of American Pathologists (CAP) recommends an initial immunohistochemical workup with a four-antibody panel (MLH1, PMS2, MSH2, and MSH6) to screen for a defective mismatch repair system. An increased trend towards young age colorectal carcinoma (CRC) has been noticed in our population over recent years; however, neither screening for MSI by immunohistochemistry (IHC)/genetic testing was done nor were its morphological features studied. We aimed to determine the frequency of mismatch repair deficiency (dMMR) by loss of IHC expression of the aforementioned enzymes in CRC patients and its correlatation with clinicopathologic parameters. METHODS: This was a retrospective study conducted at Liaquat National Hospital, Karachi, between 2012 and 2015. A total of 100 cases of CRC were included in the study that underwent surgical resection. IHC stains using antibodies MLH1, PMS2, MSH2, and MSH6 were performed by DAKO EnVision method on representative tissue blocks. The results were interpreted by senior histopathologists and correlated with clinico-pathological parameters. RESULTS: A total of 100 cases of CRC were studied that included 51 males and 49 females. Thirty-four percent (n = 34) of the patients showed loss of IHC staining for MMR markers. Combined loss of expression for MLH1/PMS2 were observed in 16% (n = 16) of the cases. Loss of MSH2/MSH6 were seen in 6% (n = 6) of the cases. Loss of expression for all markers were noted in 7% (n = 7) of the cases. There were 5% (n = 5) of the cases that showed isolated loss of MLH1 only. The tumors with dMMR status were significantly associated with right-sided location (p = 0.013), exhibited intra-tumoral lymphocytosis (p = 0.007), and lymphovascular invasion (p = 0.043). No significant association was seen with gender, age, tumor stage, grade, or other morphological features. CONCLUSION: The frequency of mismatch repair deficiency in CRC patients was found to be 34% in Pakistani population which warrants further genetic testing to exclude Lynch syndrome. Moreover, right-sided location and intra-tumoral lymphocyte count may be used to identify patients who may need further workup.

A review of the failed cases of dental implants at a university hospital in Karachi, Pakistan.

The retrospective study was conducted to assess the dental implants that experienced failure. It was conducted at the dental clinic of the Aga Khan University Hospital, Karachi, and comprised record of dental implants from July 2010 to June 2015. Variables such as patient age, gender and systemic status, length and diameter of implants, bone grafting, type of definitive prosthesis (crown or bridge or overdenture), nature of retention (cement versus screw retained), loading strategy (immediate versus delayed loading), etc. were analysed. Of the 220 implants placed, 6(2.7%) failed to integrate (as revealed by torque test) at the beginning of prosthetic phase. Besides, 1(0.5%) implant failed after six months of function. The 7(3.2%) failed cases had common variables like deficient bone volume in maxilla (or placement of bone graft), non-submerged placement protocol, early loading with prosthesis and the presence of diabetes.

A 6-year Evaluation of 223 Tapered Dental Implants and associated prosthesis in 92 patients at a University Hospital.

The aim of the retrospective study was to assess the clinical and radiographic outcome of the dental implant surgery and prosthetics. It was conducted at the Aga Khan University Hospital, Karachi, and comprised of medical charts and radiographic records of patients visiting between 2010 and 2015. Variables such as implant dimensions, final prosthesis, method of retention, loading protocol and patient factors were analysed. A total of 223 implants (143(64.1%) in maxilla and 80(35.9%) in mandible) were placed in 92 subjects (50(54.3%) males and 42(45.7%) females). All implants were Zimmer tapered screw-vent. Length of 108(48.4%) implants was 11.5mm and diameter of 84(37.7%) implants was 4.7mm. Besides, 6(2.7%) implants failed to osseointegrate, whereas 1(0.4%) implant failed at 12 months of loading. Among the 216(96.9%) successful implants, 140(64.8%) served as bridge abutments, 72(33.3%) were single crown abutments and 4(1.9%) were overdenture abutments. Also, 37(17.1%) implants were immediately loaded. The six-year survival rate of implants was 96.9%.

Deep enteroscopy with a conventional colonoscope: initial multicenter study by using a through-the-scope balloon catheter system.

BACKGROUND AND AIMS: The advent of capsule endoscopy has revolutionized evaluation of the small bowel. Capsule endoscopy has become the criterion standard as the initial examination to diagnose small-bowel abnormalities, but does not allow for tissue sampling or therapeutic intervention. Deep enteroscopy can be performed by using a balloon-assisted device or a spiral overtube for both diagnostic and therapeutic interventions of the small bowel. Deep enteroscopy is time-consuming and requires special endoscopes and accessories to perform the examination. We studied a novel through-the-scope balloon catheter system used for deep enteroscopy that uses a conventional colonoscope and standard accessories. METHODS: We performed a 9-center, retrospective study using a novel TTS balloon system for small-bowel evaluation. The new through-the-scope device is an on-demand balloon catheter that is inserted through the instrument channel of a standard colonoscope and enables deep advancement into the small bowel in either the anterograde or retrograde approach. It consists of a balloon inflation/deflation system and a single-use balloon catheter designed for anchoring in the small bowel. The balloon is inflated to an anchoring pressure in the small intestine, and a repetitive push-pull technique is performed, with the endoscope sliding over the guiding catheter to the inflated balloon. The catheter may be removed and reinserted to allow for therapeutic intervention while maintaining the endoscope position. RESULTS: A total of 98 patients were included; 52% were male, and the mean age was 55 years old (range 15-94 years). Indications included abdominal pain, iron-deficiency anemia, occult GI bleeding, diarrhea, abnormal capsule endoscopy, weight loss, protein losing enteropathy, retained foreign body, altered anatomy ERCP, and small-bowel strictures. Anterograde enteroscopy was performed in 65 patients. The average depth of insertion was 158 cm (range 50-350 cm) from the pylorus. Retrograde enteroscopy was performed in 33 cases. The average depth of insertion was 89 cm (range 20-150 cm) beyond the ileocecal valve. Overall, diagnostic yield was 44%. The average advancement time for the anterograde and retrograde enteroscopy cases was 15.5 minutes. There were no procedural adverse outcomes reported in the 98 cases. CONCLUSIONS: The TTS advancing balloon is a safe and effective way to perform deep enteroscopy by using a conventional colonoscope without the need for an overtube. Procedure time is shorter than that of other forms of deep enteroscopy. Diagnostic yield and depth of insertion are on par with other forms of deep enteroscopy. This is the largest reported study using this novel technology to diagnose and treat small-bowel disease.

Role of peritoneal washing cytology in ovarian malignancies: correlation with histopathological parameters.

BACKGROUND: Peritoneal dissemination of ovarian tumors is a major prognostic parameter in ovarian malignancies. Analysis of peritoneal washing cytology serves as a useful predictor of ovarian surface involvement and peritoneal metastasis even in the absence of clinical omental spread. The aim of the current study is to correlate peritoneal cytology with various histologic features of ovarian cancers in our setup. METHODS: A total of 60 cases of ovarian tumors were included in the study that underwent total abdominal hysterectomy with bilateral salpingo-oophorectomy and omental and lymph node sampling during 2009 till 2014 at the Liaquat National Hospital, Karachi. Any free abdominal fluid was aspirated at the time of surgery. In the absence of free fluid, peritoneal washing was done with 50-100 ml of normal saline. Four cytospin preparations were done along with a cell block preparation. Correlation of peritoneal cytology with various histologic parameters was performed. RESULTS: Out of the 60 cases of ovarian tumors involved in the study, 56 were surface epithelial tumors, 2 germ cell tumors, and 2 metastatic carcinomas. The mean tumor size was 9.6 cm. Capsular invasion was seen in 61 % of the cases, and omental metastasis in 51 % of the cases. Serous carcinoma was found to have a significantly higher frequency of positive peritoneal cytology (76.9 %) compared to endometrioid and mucinous carcinomas (44 and 25 %, respectively). A significant positive correlation was seen between positive peritoneal cytology and capsular invasion and omental metastasis with a p value of <0.001. CONCLUSIONS: Positive peritoneal washing cytology has been implemented in ovarian cancer guidelines because of its prognostic significance in ovarian tumors. In addition to being an indicator of peritoneal metastasis, positive cytology also correlates with capsular invasion and histologic type in ovarian tumors. Therefore, it should always be used as an adjunctive tool in the surgical management of ovarian tumors.

Arsenic in the Food Chain in Pakistan: Assessing Risks to Human Health and Ensuring Food Security Through Comprehensive Contamination Mitigation Strategies.

Arsenic is a natural element found in the earth's crust and is extensively present in various environmental components. Anthropogenic activities and a few natural events have generated contaminants that have led to massive environmental pollution, one form of which is arsenic contamination. Arsenic enters the human food chain via contaminated crops, water, seafood, and dairy products. In Pakistan, the increasing concentration of arsenic in the water is causing major health problems. Due to the serious health risks posed by arsenic, it is crucial to design and implement strategies for reducing and preventing the bioaccumulation of arsenic and its entry into the human food chain. There is a need for an institutional framework for arsenic mitigation, accountability, and systemic checks and balances. Targeted short- and long-term policies are required for effective and sustainable management.

A nurse driven care management program to engage older diabetes patients in personalized goal setting and disease management.

Background and Aims: Multiple diabetes care guidelines have called for the personalization of risk factor goals, medication management, and self-care plans among older patients. Study of the implementation of these recommendations is needed. This study aimed to test whether a patient survey embedded in the Electronic Healthcare Record (EHR), coupled with telephonic nurse care management, could engage patients in personalized goal setting and chronic disease management. Methods: We conducted a single-center equal-randomization delayed comparator trial at the primary care clinics of the University of Chicago Medicine from 2018.6 to 2019.12. Patients over the age of 65 years with type 2 diabetes with an active patient portal account were recruited and randomized to receive an EHR embedded goal setting and preference survey immediately in the intervention arm or after 6 months in the delayed intervention control arm. In the intervention arm, nurses reviewed American Diabetes Association recommendations for A1C goals based on health status class, established personalized goals, and provided monthly telephonic care management phone calls for a maximum of 6 months. Our primary outcome was the documentation of a personalized A1C goal in the EHR. Results: A total of 100 patients completed the trial (mean age, 72.51 [SD, 5.22] years; mean baseline A1C, 7.14% [SD, 1.06%]; 68% women). The majority were in the Healthy (59%) followed by Complex (30%) and Very Complex (11%) health status classes. Documentation of an A1C goal in the EHR increased from 42% to 90% (p < 0.001) at 6 months in the intervention group and from 54% to 56% in the control group. Across health status classes, patients set similar A1C goals. Conclusions: Older patients can be engaged in personalized goal setting and disease management through an embedded EHR intervention. The clinical impact of the intervention may differ if deployed among older patients with more complex health needs and higher glucose levels. Trial Registration: ClinicalTrials.gov Identifier: NCT03692208.

Multidrug-Resistant Pathogens in Wound Infections: A Systematic Review.

This systematic review aimed to explore the antimicrobial activity of a silver-containing gelling fiber dressing against multidrug-resistant organisms (MDROs) in wound infections. It particularly focuses on burn wounds and evaluates its potential clinical significance in combating antimicrobial resistance. A comprehensive literature search was conducted across multiple databases over the past ten years. It is used to identify relevant studies addressing MDRO infections in wound care and exploring novel antimicrobial approaches. The included studies underwent rigorous methodological assessment. Additionally, the data were synthesized to evaluate the efficacy of silver-containing dressings in inhibiting MDRO growth and eradicating biofilm-associated bacteria. Moreover, this review revealed that silver-containing dressings have constant in vitro antimicrobial activity against 10 MDROs over seven days in simulated wound fluid. However, inhibitory and bactericidal effects were consistently observed against free-living and biofilm phenotypes. The findings suggest potential clinical significance in managing MDRO infections in wounds. This highlights its role in mitigating treatment failure and antimicrobial resistance. Despite the promising implications for wound management practices, this study acknowledges some limitations. In vitro models and the absence of direct clinical validation have also been included. However, the review explains the importance of new approaches. Nanotechnology has been used to address antimicrobial resistance in wound care. Thus, further research and innovation are needed to improve patient outcomes and combat antimicrobial resistance.

Incidence and Risk of Secondary Malignancy in Patients with Waldenström Macroglobulinemia: A Population-Based Analysis.

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic lymphoma which may predispose individuals to development of secondary malignancies (SMs). The Surveillance, Epidemiology, and End Results (SEER) database is a comprehensive registry of cancer patients in the United States reporting on a wide set of demographic variables. Using the SEER-18 dataset, analyzing patients from 2000 to 2018, we aimed to assess the incidence of SMs in WM patients. Patient characteristics such as gender, age, race, and latency were identified, and respective standardized incidence ratios (SIRs) and absolute excess risks (AERs) were calculated to compare to the general population. Of the 4,112 eligible WM patients identified, SMs were reported in 699 (17%) patients. The overall risk of developing SM, second primary malignancy, and secondary hematological malignancy was significantly higher in WM patients compared to the general population. Our findings show that WM patients had a 53% higher risk of SMs relative to the general population, and an AER of 102.69 per 10,000. Although the exact mechanism is unclear, the risk of SM development may be due to genetic predisposition, immune dysregulation, or treatment-induced immune suppression.

Cerebellar Liponeurocytoma: Publication Trends, Scientometrics Analysis, and Critical Review.

BACKGROUND: The literature on cerebellar liponeurocytoma (CL) has never been systematically assessed using bibliometric analytic methodologies. We quantitatively analyzed the major trends and scientific output regarding CL, highlighting potential avenues for research. METHODS: Elsevier's Scopus database was used to collect all published studies relevant to cerebellar liponeurocytoma from 1978 to 2021. The specific bibliometric parameters were extracted and analyzed with R v4.1.2. RESULTS: Our search yielded 108 documents published in 67 sources from 1978 to 2021. The annual growth rate of publications regarding CL has been 7.47% per year since 1978. Journals with the most publications on CL include Clinical Neuropathology and Neurology India (n = 5), followed by Acta Neuropathologica and Journal of Neuro-oncology (n = 4). A total of 529 authors have published on CL and they have been cited 598 times. The 10 most influential authors in the field were determined using their total number of citations and the local H-index. Kleihues P has the highest number of citations (n = 177) with a local H index of 3, followed by Chimelli L with 167 citations and a local H index of 4. Davis DG has 149 citations and a local H index of 3. China had the most single country publications followed by India, Italy, and the USA. France and Austria have the most multiple country publications followed by China, Tunisia, Brazil, United Kingdom, Egypt, and Israel. CONCLUSIONS: Our study is the first bibliometric analysis evaluating the present literature and publication trends in CL. Generally, the current literature has a few studies regarding CL relative to other neuro-oncological pathologies. This can be due to the low incidence of the disease and highlights a need for high volume database studies that can offer high quality evidence on the subject.

Use of Novel Open-Source Deep Learning Platform for Quantification of Ki-67 in Neuroendocrine Tumors - Analytical Validation.

Background: Neuroendocrine tumors (NETs) represent a diverse group of neoplasms that arise from neuroendocrine cells, with Ki-67 immunostaining serving as a crucial biomarker for assessing tumor proliferation and prognosis. Accurate and reliable quantification of Ki-67 labeling index is essential for effective clinical management. Methods: We aimed to evaluate the performance of open-source/open-access deep learning cloud-native platform, DeepLIIF (https://deepliif.org), for the quantification of Ki-67 expression in gastrointestinal neuroendocrine tumors and compare it with the manual quantification method. Results: Our results demonstrate that the DeepLIIF quantification of Ki-67 in NETs achieves a high degree of accuracy with an intraclass correlation coefficient (ICC) = 0.885 with 95% CI (0.848-0.916) which indicates good reliability when compared to manual assessments by experienced pathologists. DeepLIIF exhibits excellent intra- and inter-observer agreement and ensures consistency in Ki-67 scoring. Additionally, DeepLIIF significantly reduces analysis time, making it a valuable tool for high-throughput clinical settings. Conclusion: This study showcases the potential of open-source/open-access user-friendly deep learning platforms, such as DeepLIIF, for the quantification of Ki-67 in neuroendocrine tumors. The analytical validation presented here establishes the reliability and robustness of this innovative method, paving the way for its integration into routine clinical practice. Accurate and efficient Ki-67 assessment is paramount for risk stratification and treatment decisions in NETs and AI offers a promising solution for enhancing diagnostic accuracy and patient care in the field of neuroendocrine oncology.

Snap-on Adaptor for Microtiter Plates to Enable Continuous-Flow Microfluidic Screening and Harvesting of Crystalline Materials.

Microtiter plate assay is a conventional and standard tool for high-throughput (HT) screening that allows the synthesis, harvesting, and analysis of crystals. The microtiter plate screening assays require a small amount of solute in each experiment, which is adequate for a solid-state crystal analysis such as X-ray diffraction (XRD) or Raman spectroscopy. Despite the advantages of these high-throughput assays, their batch operational nature results in a continuous decrease in supersaturation due to crystal nucleation and growth. Continuous-flow microfluidic mixer devices have evolved as an alternate technique for efficiently screening crystals under controlled supersaturation. However, such a microfluidic device requires a minimum of two inlets per micromixer to create cyclonic flow, thereby creating physical limitations for implementing such a device for HT screening. Additionally, the monolithic design of these microfluidic devices makes it challenging to harvest crystals for post-screening analysis. Here, we develop a snap-on adapter that can be reversibly attached to a microtiter plate and convert it into a continuous-flow microfluidic mixer device. The integration of the snap-on adapter with a flow distributor and concentration gradient generator provides greater control over screening conditions while minimizing the number of independent inlets and pumps required. The three-dimensional (3D)-printed snap-on adaptor is plugged into a 24-well plate assay to demonstrate salt screening of naproxen crystals. Different naproxen salts are crystallized using four different salt formers (SFs)-sodium hydroxide, potassium hydroxide, pyridine, and arginine-and four different solvents-ethanol, methanol, isopropyl alcohol, and deionized water. The wells are further inspected under an optical microscope to identify their morphological forms and yields. The crystals are then harvested for solid-state characterization using XRD and Fourier transform infrared spectroscopy, followed by measurement of their dissolution rates. The flexibility of the snap-on adapter to fit on a wide range of microtiter plates and the ease in harvesting and analyzing crystals postscreening are two significant advantages that make this device versatile for various applications.

Hegemonic masculinity: representation of women surgeons in leadership positions in Pakistan.

PURPOSE: Surgery is predominantly a masculine profession worldwide and has largely excluded women in leadership positions. This paper aims to examine the representation of women surgeons in leadership positions in Pakistan. DESIGN/METHODOLOGY/APPROACH: Data were drawn from larger qualitative research examining the experiences of women surgeons in Pakistani hospitals. The data comprises in-depth interviews with ten doctors working in the Rawalpindi and Islamabad cities. The participants were selected by using the purposive sampling method and data were analyzed using thematic analysis. FINDINGS: This study included participants from diverse surgical specialties from different stages of their career with two having leadership experience. Based on participants' perspectives several factors are responsible for this exclusion of women in leadership positions. The most prominent among these were long working hours for surgical leaders, greater responsibilities assigned to leadership positions, gender stereotypes and work-family conflict. Due to masculine hegemony, women were considered less capable and they were expected to have masculine traits to work as successful leaders. Interestingly, some participants had internalized such stereotypes and showed a lack of interest and lack of capabilities for surgical leadership as evident from their narratives. RESEARCH LIMITATIONS/IMPLICATIONS: The findings of this paper are drawn from the perspectives of ten women surgeons working in Islamabad and Rawalpindi cities of Pakistan who were selected using a convenient sampling method. Hence, the results cannot be generalized to the larger population of women surgeons working in other cities of the country. Nevertheless, this study is unique in the sense that it provides useful insight into the experiences of the women surgeons and their perspectives on surgical leadership in Pakistani hospitals. Academically, it contributes to the global debates on surgical leadership by providing empirical evidence from Pakistan. ORIGINALITY/VALUE: This paper contributes to the larger debates on the under-representation of women in leadership positions in surgery by unveiling the experiences of female surgeons from Pakistan. It calls for the need for structural changes in health management and policy to accommodate women surgeons. Organizational efforts could minimize some hurdles and encourage more women to take on more formal leadership roles. The authors also call for an increasing number of women in surgery to pave the way for creating new leadership opportunities.

Primary squamous cell carcinoma of liver. First case report from Pakistan and South Asia.

INTRODUCTION AND IMPORTANCE: Primary squamous cell carcinoma (PSCC) of liver is quite rare and very few cases reported in literature. It has high metastatic rate with poor prognosis. The pathogenesis is unclear, but is generally considered to be correlated with the long-term inflammation or metaplasia of biliary epithelial cells or congenital cyst of the liver. We report here a case of PSCC of liver which mimicked a complex hydatid cyst. CASE PRESENTATION: A 25 years male admitted with right hypochondrium pain associated with fever and yellowish discoloration of eyes for 20 days. He was jaundiced with epigastric tenderness and deranged liver function tests. When thoroughly investigated with ultrasound, CT abdomen and MRI liver, he was found to have a large cystic lesion in right lobe of the liver. He underwent right hepatectomy, peri-cystectomy of the cyst and T-tube placement in common bile duct. Histopathology of the resected sample showed primary squamous cell carcinoma of liver. Patient was discharged after 7 days and died after 6 months due to acute liver failure. CLINICAL DISCUSSION: Because of a very low incidence of hepatic SCC, there is not a single definite therapeutic regime and various different methods of management include surgical resection, generalized chemotherapy, radiotherapy, Hepatic Arterial ChemoEmbolization (HACE) and the combinations of these therapies. CONCLUSION: PSCC is a rare condition of the liver and is associated with other benign liver conditions such as non-parasitic and epidermoid cysts. Histopathology with radiological investigations are needed to diagnose and treat this aggressive tumor before it metastasizes.

In-line measurement of liquid-liquid phase separation boundaries using a turbidity-sensor-integrated continuous-flow microfluidic device.

Liquid-liquid phase separation (LLPS), also known as oiling-out, is the appearance of the second liquid phase preceding the crystallization. LLPS is an undesirable phenomenon that can occur during the crystallization of active pharmaceutical ingredients (APIs), proteins, and polymers. It is typically avoided during crystallization due to its detrimental impacts on crystalline products due to lowered crystallization rate, the inclusion of impurities, and alteration in particle morphology and size distribution. In situ monitoring of phase separation enables investigating LLPS and identifying the phase separation boundaries. Various process analytical technologies (PATs) have been implemented to determine the LLPS boundaries prior to crystallization to prevent oiling out of compounds. The LLPS measurements using PATs can be time-consuming, expensive, and challenging. Here, we have implemented a fully integrated continuous-flow microfluidic device with a turbidity sensor to quickly and accurately evaluate the LLPS boundaries for a ß-alanine, water, and IPA mixture. The turbidity-sensor-integrated continuous-flow microfluidic device is also placed under an optical microscope to visually track and record the appearance and disappearance of oil droplets. Streams of an aqueous solution of ß-alanine, pure solvent (water), and pure antisolvent (IPA or ethanol) are pumped into the continuous-flow microfluidic device at various flow rates to obtain the compositions at which the solution becomes turbid. The onset of turbidity is measured using a custom-designed, in-line turbidity sensor. The LLPS boundaries can be estimated using the turbidity-sensor-integrated microfluidic device in less than 30 min, which will significantly improve and enhance the workflow of the pharmaceutical drug (or crystalline material) development process.

Machine Learning-Driven, Sensor-Integrated Microfluidic Device for Monitoring and Control of Supersaturation for Automated Screening of Crystalline Materials.

Integrating sensors in miniaturized devices allow for fast and sensitive detection and precise control of experimental conditions. One of the potential applications of a sensor-integrated microfluidic system is to measure the solute concentration during crystallization. In this study, a continuous-flow microfluidic mixer is paired with an electrochemical sensor to enable in situ measurement of the supersaturation. This sensor is investigated as the predictive measurement of the supersaturation during the antisolvent crystallization of l-histidine in the water-ethanol mixture. Among the various metals tested in a batch system for their sensitivity toward l-histidine, Pt showed the highest sensitivity. A Pt-printed electrode was inserted in the continuous-flow microfluidic mixer, and the cyclic voltammograms of the system were obtained for different concentrations of l-histidine and different water-to-ethanol ratios. The sensor was calibrated for different ratios of antisolvent and concentrations of l-histidine with respect to the change of the measured anodic slope. Additionally, a machine-learning algorithm using neural networks was developed to predict the supersaturation of l-histidine from the measured anodic slope. The electrochemical sensors have shown sensitivity toward l-histidine, l-glutamic acid, and o-aminobenzoic acid, which consist of functional groups present in almost 80% of small-molecule drugs on the market. The machine learning-guided electrochemical sensors can be applied to other small molecules with similar functional groups for automated screening of crystallization conditions in microfluidic devices.