Solid Self Nano-Emulsifying Drug Delivery System of Dasatinib: Optimization, In-vitro, Ex-vivo and In-vivo assessment.

Aim: Dasatinib (DST) is an oral tyrosine kinase inhibitor with poor aqueous solubility. To outwit this issue, a solid self-nano emulsifying drug delivery system (S-SNEDDS) of DST was formulated.Methods: I-optimal mixture design was used for optimization of DST-loaded SNEDDS using Linalool, Cremophor RH40 and Transcutol P. S-SNEDDS underwent physicochemical characterization, in-vitro release and ex-vivo permeation, cell-based assays and pharmacokinetic study.Results: DST-S-SNEDDS showed globule size and PDI of 141.53 ± 5.371 nm and 0.282 ± 0.020, respectively. DST-S-SNEDDS revealed significantly lower IC50 (1.825 µg/mL) than free DST (7.298 µg/mL) in MDA-MB-231. In-vivo pharmacokinetic study revealed 1.94-fold increment in AUC0-t for the DST-S-SNEDDS group than free DST.Conclusion: S-SNEDDS could be promising approach for improving bioavailability and efficacy of DST.

[Box: see text].

Neurological glycogen storage diseases and emerging therapeutics.

Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.

Manifesting the Dasatinib-gallic acid co-amorphous system to augment anticancer potential: Physicochemical characterization, in silico molecular simulation, ex vivo permeability, and in vitro efficacy.

Dasatinib (DAB) has been explored for repurposing in the treatment of breast cancer (BC) due to its known effectiveness in treating leukemia, in addition to its role as a tyrosine kinase inhibitor. Gallic acid (GA) was chosen as a co-former due to its anticancer potential in BC, as demonstrated in several previous studies. DAB is a low-solubility drug, which is a significant hurdle for its oral bioavailability. To address this limitation, a DAB and GA co-amorphous (DAB-GA-CA) system was developed using liquid-assisted grinding and ball mill technology to enhance solubility, bioavailability, and anti-tumor efficacy. Physical characterization investigation revealed that the emergence of the halo diffractogram in PXRD, single glass transition temperature (Tg) value at 111.7 °C in DSC thermogram, and irregularly shaped blocks with loose, porous surfaces in SEM analysis indicated the formation of the DAB-GA-CA system at 1:1 M ratio. Furthermore, FTIR, Raman spectroscopy, in-silico molecular docking, and molecular dynamic studies confirmed the intermolecular hydrogen connections between DAB and GA. Moreover, the outcomes of the ligands (DAB and GA) and receptors (BCL-2, mTOR, estrogen receptor, and HER-2) docking studies demonstrated that both DAB and GA could interact with those receptors, leading to preventive action on BC cells. Additionally, the solubility and dissolution rate significantly improved at pH 6.8, and the permeability study indicated that DAB-GA-CA showed 1.9 times higher apparent permeability compared to crystalline DAB. Furthermore, in vitro cytotoxicity assessments of the DAB-GA-CA system revealed 3.42 times lower IC50 than free DAB. The mitochondrial membrane depolarization, apoptotic index, and reactive oxygen species formation in MCF-7 cells were also notably higher in the DAB-GA-CA system than in free DAB. Hence, this research suggests that the DAB-GA-CA system could substantially enhance oral delivery, solubility, and therapeutic efficacy.

Assessment of fluid responsiveness after tidal volume challenge in renal transplant recipients: a nonrandomized prospective interventional study.

Background: When applying lung-protective ventilation, fluid responsiveness cannot be predicted by pulse pressure variation (PPV) or stroke volume variation (SVV). Functional hemodynamic testing may help address this limitation. This study examined whether changes in dynamic indices such as PPV and SVV, induced by tidal volume challenge (TVC), can reliably predict fluid responsiveness in patients undergoing renal transplantation who receive lung-protective ventilation. Methods: This nonrandomized interventional study included renal transplant recipients with end-stage renal disease. Patients received ventilation with a 6 mL/kg tidal volume (TV), and the FloTrac system was attached for continuous hemodynamic monitoring. Participants were classified as responders or nonresponders based on whether fluid challenge increased the stroke volume index by more than 10%. Results: The analysis included 36 patients, of whom 19 (52.8%) were responders and 17 (47.2%) were nonresponders. Among responders, the mean ΔPPV6-8 (calculated as PPV at a TV of 8 mL/kg predicted body weight [PBW] minus that at 6 mL/kg PBW) was 3.32±0.75 and ΔSVV6-8 was 2.58±0.77, compared to 0.82±0.53 and 0.70±0.92 for nonresponders, respectively. ΔPPV6-8 exhibited an area under the curve (AUC) of 0.97 (95% confidence interval [CI], 0.93-1.00; P≤0.001), with an optimal cutoff value of 1.5, sensitivity of 94.7%, and specificity of 94.1%. ΔSVV6-8 displayed an AUC of 0.93 (95% CI, 0.84-1.00; P≤0.001) at the same cutoff value of 1.5, with a sensitivity of 94.7% and a specificity of 76.5%. Conclusions: TVC-induced changes in PPV and SVV are predictive of fluid responsiveness in renal transplant recipients who receive intraoperative lung-protective ventilation.

A review on microbes mediated resource recovery and bioplastic (polyhydroxyalkanoates) production from wastewater.

BACKGROUND: Plastic is widely utilized in packaging, frameworks, and as coverings material. Its overconsumption and slow degradation, pose threats to ecosystems due to its toxic effects. While polyhydroxyalkanoates (PHA) offer a sustainable alternative to petroleum-based plastics, their production costs present significant obstacles to global adoption. On the other side, a multitude of household and industrial activities generate substantial volumes of wastewater containing both organic and inorganic contaminants. This not only poses a threat to ecosystems but also presents opportunities to get benefits from the circular economy. Production of bioplastics may be improved by using the nutrients and minerals in wastewater as a feedstock for microbial fermentation. Strategies like feast-famine culture, mixed-consortia culture, and integrated processes have been developed for PHA production from highly polluted wastewater with high organic loads. Various process parameters like organic loading rate, organic content (volatile fatty acids), dissolved oxygen, operating pH, and temperature also have critical roles in PHA accumulation in microbial biomass. Research advances are also going on in downstream and recovery of PHA utilizing a combination of physical and chemical (halogenated solvents, surfactants, green solvents) methods. This review highlights recent developments in upcycling wastewater resources into PHA, encompassing various production strategies, downstream processing methodologies, and techno-economic analyses. SHORT CONCLUSION: Organic carbon and nitrogen present in wastewater offer a promising, cost-effective source for producing bioplastic. Previous attempts have focused on enhancing productivity through optimizing culture systems and growth conditions. However, despite technological progress, significant challenges persist, such as low productivity, intricate downstream processing, scalability issues, and the properties of resulting PHA.

Refinement of rice blast disease resistance QTLs and gene networks through meta-QTL analysis.

Rice blast disease is the most devastating disease constraining crop productivity. Vertical resistance to blast disease is widely studied despite its instability. Clusters of genes or QTLs conferring blast resistance that offer durable horizontal resistance are important in resistance breeding. In this study, we aimed to refine the reported QTLs and identify stable meta-QTLs (MQTLs) associated with rice blast resistance. A total of 435 QTLs were used to project 71 MQTLs across all the rice chromosomes. As many as 199 putative rice blast resistance genes were identified within 53 MQTL regions. The genes included 48 characterized resistance gene analogs and related proteins, such as NBS-LRR type, LRR receptor-like kinase, NB-ARC domain, pathogenesis-related TF/ERF domain, elicitor-induced defense and proteins involved in defense signaling. MQTL regions with clusters of RGA were also identified. Fifteen highly significant MQTLs included 29 candidate genes and genes characterized for blast resistance, such as Piz, Nbs-Pi9, pi55-1, pi55-2, Pi3/Pi5-1, Pi3/Pi5-2, Pikh, Pi54, Pik/Pikm/Pikp, Pb1 and Pb2. Furthermore, the candidate genes (42) were associated with differential expression (in silico) in compatible and incompatible reactions upon disease infection. Moreover, nearly half of the genes within the MQTL regions were orthologous to those in O. sativa indica, Z. mays and A. thaliana, which confirmed their significance. The peak markers within three significant MQTLs differentiated blast-resistant and susceptible lines and serve as potential surrogates for the selection of blast-resistant lines. These MQTLs are potential candidates for durable and broad-spectrum rice blast resistance and could be utilized in blast resistance breeding.

Incidence of Rebleed Following Cerebrospinal Fluid (CSF) Drainage in Poor Grade Subarachnoid Hemorrhage: An Institutional Experience.

BACKGROUND: The outcome of poor grade subarachnoid hemorrhage (SAH) is dismal. Some of these patients need cerebrospinal fluid (CSF) drainage procedure for the hydrocephalus and intraventricular hemorrhage (IVH) which may precipitate rebleeding. However, aneurysmal rebleed following CSF drainage procedure is controversial. OBJECTIVE: Our study aimed at analyzing the effect of CSF drainage procedure on aneurysmal rebleeding. MATERIAL AND METHODS: We retrospectively analyzed the records of all the consecutive patients diagnosed with poor grade aneurysmal SAH over three year period. Patients initially requiring either external ventricular drainage (EVD) or lumbar drain (LD) were included in the study group, and the rest (not requiring drainage) were included in the control group. Rebleeding was confirmed on computed tomography. The factors affecting rebleeding were analyzed. RESULTS: Overall 194 patients with poor grade SAH were enrolled in the study (91 males: 103 females; mean age: 50.6 years). The study group had 91 patients (83 EVD and 8 LD) while 103 patients were in the control group. Posterior circulation aneurysms, poor grade SAH, hydrocephalus, and IVH were more common in the study group P < 0.001. The rebleeding rate was 7.6% in the study group and 8.7% in the control group. On univariate analysis size >1 cm, multiplicity, multilobularity, vasospasm, and CSF drainage were significant risk factors for rebleeding (P < 0.001). On multivariate analysis aneurysm size >1 cm, CSF overdrainage >250 ml/day were significantly associated with risk of rebleeding. CONCLUSION: Ventricular drainage is essential to relieve acute hydrocephalus and drain IVH in SAH and we found no significant association between CSF drainage and rebleeding. However, rapid overdrainage of CSF can lead to aneurysm rupture, hence controlled controlled CSF drainage should be undertaken.

Lysine L-lactylation is the dominant lactylation isomer induced by glycolysis.

Lysine L-lactylation (Kl-la) is a novel protein posttranslational modification (PTM) driven by L-lactate. This PTM has three isomers: Kl-la, N-ε-(carboxyethyl)-lysine (Kce) and D-lactyl-lysine (Kd-la), which are often confused in the context of the Warburg effect and nuclear presence. Here we introduce two methods to differentiate these isomers: a chemical derivatization and high-performance liquid chromatography analysis for efficient separation, and isomer-specific antibodies for high-selectivity identification. We demonstrated that Kl-la is the primary lactylation isomer on histones and dynamically regulated by glycolysis, not Kd-la or Kce, which are observed when the glyoxalase system was incomplete. The study also reveals that lactyl-coenzyme A, a precursor in L-lactylation, correlates positively with Kl-la levels. This work not only provides a methodology for distinguishing other PTM isomers, but also highlights Kl-la as the primary responder to glycolysis and the Warburg effect.

Healthcare Worker's Satisfaction Assessment for a Healthcare Adverse Event Reporting Framework and the Management Approach for Such Reporting in the Emergency Department of Rural Government Hospitals.

BACKGROUND: The healthcare adverse event (HAE) reporting framework is more than just a tool. It is a crucial pillar in our pursuit of patient safety, quality improvement, trust maintenance, regulatory compliance, and ethical standards in healthcare delivery. AIM: To assess healthcare workers' satisfaction with the HAE reporting framework and the management approach towards such reporting in the emergency department of rural government hospitals by conducting a satisfaction survey. MATERIALS AND METHOD: This prospective observational research was conducted in the Department of Emergency Medicine of the Uttar Pradesh University of Medical Sciences, Saifai, and adjoining district hospitals from November 2023 to January 2024. The study involved 320 healthcare professionals working in the emergency department. The quantitative survey research used a questionnaire and a quality Likert scale response. The data were analyzed on an ordinal measurement scale using nonparametric statistical methods. The sample data were analyzed using frequency tables, percentage pie charts, and comparison bar graphs. In nonparametric statistical tests, the one-sample Wilcoxon signed rank test was used to infer the population's central tendency, and the Kruskal-Wallis test was used to make inferences about the population categories. RESULTS: The satisfaction of healthcare professionals with the HAE reporting framework and the management approach was diverse. When surveyed about the HAE reporting framework in the emergency department, out of the 320 healthcare professionals, 50% (161) expressed dissatisfaction, 47% (149) were satisfied, and 3% (10) did not comment. Paramedics were most dissatisfied (61% of 133). When asked about the management approach while dealing with such reporting, 50% (159) were satisfied, 46% (147) were unsatisfied, and 4% (14) did not comment. On comparing professions, 43% (29) of 33 doctors and 62% (83) of 133 paramedics were unsatisfied, giving a poor response. Additionally, 61% (72) of the 119 nursing staff were satisfied. The non-parametric inferential tests yielded a p-value of less than 0.001 for both questions, indicating a notable difference in the population's response to the HAE reporting framework and management approach. On pairwise comparison, there was a significant difference in perception (p<0.001) between the occupation groups, except for doctors and paramedics (p = 0.638) in the HAE reporting framework. CONCLUSION: By encouraging reporting, standardizing processes, analyzing incidents thoroughly, and using data-driven insights to inform improvement efforts, healthcare organizations can enhance patient safety, improve quality of care, and prevent future adverse events. The management approach to HAE reporting involves fostering a culture of safety and transparency, implementing standardized reporting systems, providing education and training to healthcare staff, establishing feedback mechanisms, conducting robust analysis of reported events, promoting continuous improvement, and ensuring transparency and accountability.

DHODH inhibition enhances the efficacy of immune checkpoint blockade by increasing cancer cell antigen presentation.

Pyrimidine nucleotide biosynthesis is a druggable metabolic dependency of cancer cells, and chemotherapy agents targeting pyrimidine metabolism are the backbone of treatment for many cancers. Dihydroorotate dehydrogenase (DHODH) is an essential enzyme in the de novo pyrimidine biosynthesis pathway that can be targeted by clinically approved inhibitors. However, despite robust preclinical anticancer efficacy, DHODH inhibitors have shown limited single-agent activity in phase 1 and 2 clinical trials. Therefore, novel combination therapy strategies are necessary to realize the potential of these drugs. To search for therapeutic vulnerabilities induced by DHODH inhibition, we examined gene expression changes in cancer cells treated with the potent and selective DHODH inhibitor brequinar (BQ). This revealed that BQ treatment causes upregulation of antigen presentation pathway genes and cell surface MHC class I expression. Mechanistic studies showed that this effect is (1) strictly dependent on pyrimidine nucleotide depletion, (2) independent of canonical antigen presentation pathway transcriptional regulators, and (3) mediated by RNA polymerase II elongation control by positive transcription elongation factor B (P-TEFb). Furthermore, BQ showed impressive single-agent efficacy in the immunocompetent B16F10 melanoma model, and combination treatment with BQ and dual immune checkpoint blockade (anti-CTLA-4 plus anti-PD-1) significantly prolonged mouse survival compared to either therapy alone. Our results have important implications for the clinical development of DHODH inhibitors and provide a rationale for combination therapy with BQ and immune checkpoint blockade.

The potential of genome editing to create novel alleles of resistance genes in rice.

Rice, a staple food for a significant portion of the global population, faces persistent threats from various pathogens and pests, necessitating the development of resilient crop varieties. Deployment of resistance genes in rice is the best practice to manage diseases and reduce environmental damage by reducing the application of agro-chemicals. Genome editing technologies, such as CRISPR-Cas, have revolutionized the field of molecular biology, offering precise and efficient tools for targeted modifications within the rice genome. This study delves into the application of these tools to engineer novel alleles of resistance genes in rice, aiming to enhance the plant's innate ability to combat evolving threats. By harnessing the power of genome editing, researchers can introduce tailored genetic modifications that bolster the plant's defense mechanisms without compromising its essential characteristics. In this study, we synthesize recent advancements in genome editing methodologies applicable to rice and discuss the ethical considerations and regulatory frameworks surrounding the creation of genetically modified crops. Additionally, it explores potential challenges and future prospects for deploying edited rice varieties in agricultural landscapes. In summary, this study highlights the promise of genome editing in reshaping the genetic landscape of rice to confront emerging challenges, contributing to global food security and sustainable agriculture practices.

Outcomes of endoscopic ultrasound-guided gallbladder drainage: A multicenter study from India (with video).

BACKGROUND: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) offers a safe and minimally invasive alternative for percutaneous cholecystostomy (PCC) in acute cholecystitis patients with high-surgical risk. Additionally, EUS-GBD serves as a rescue biliary drainage in malignant distal biliary obstruction. Despite its widespread application, data within the Indian context remains sparse. This study aims to report the outcomes of EUS-GBD through the first multi-center study from India. METHODS: We retrospectively analyzed patients undergoing EUS-GBD at six tertiary care centers of India from March 2022 to November 2023. EUS-GBD was performed by free hand or over-the-guidewire technique with lumen-apposing metal stent (LAMS) or large caliber metal stent (LCMS). The primary outcome was technical success (defined as successful deployment of stent between gallbladder and stomach/duodenal lumen). The secondary outcomes were clinical success (defined as resolution of symptoms of acute cholecystitis and more than > 50% reduction in bilirubin level within two weeks in distal biliary obstruction), adverse event rate, 30-day mortality rate and 90-day reintervention rate. RESULTS: Total 29 patients (mean age 65.86 ± 12.91, 11 female) underwent EUS-GBD. The indication for EUS-GBD were acute cholecystitis (79.31%) and rescue biliary drainage for malignant distal biliary obstruction (20.69%). LAMS was deployed in 92.86%, predominantly by free-hand technique (78.57%). Technical and clinical success rates were 96.55% and 82.75%, respectively. Adverse events occurred in 27.59% patients, with severe adverse events (bile leak and bleeding) being uncommon (10%). Both 30-day mortality rate and 90-day reintervention rate were 13.79% in patients. Cholecysto-duodenal fistula facilitated cholecystoscopic intervention and stone removal in one patient and transgastric EUS-GBD did not hamper bilio-enteric anastomosis during Whipple surgery in two patients. CONCLUSION: EUS-GBD is a safe and effective technique for managing acute cholecystitis in high-risk patients and for biliary drainage in cases with malignant distal biliary obstruction.

Surgical Management of Extradural Tumors at the Craniovertebral Junction - Insights from a Tertiary Care Center.

BACKGROUND: Craniovertebral junction (CVJ) tumors are challenging due to their unique anatomical location. This study aimed to evaluate the complexities in dealing with such precarious CVJ extradural lesions over the decade. METHODS: Twenty-seven patients of extradural CVJ tumors operated between 2009 and 2018 were included. The demographic details, neurological status, surgical approach, extent of resection, type of fixation, complications, and outcome at final follow-up were recorded for each patient. RESULTS: The mean age of the patients was 39.5 ± 20 years. Most (17/27) of the patients had involvement of a single level. Clivus was the most common (9/17) involved region followed by atlas (7/17) vertebrae. Majority of the patients (13/27) were operated through the posterior-only approach. About 15 patients (55.5%) had instability or extensive lesions that necessitated posterior fixation. None of the patients underwent anterior fixation. Gross and near total excision were achieved in 10 patients (37%) and 3 patients (11%) respectively while 14 patients underwent subtotal excision of tumor. On histopathological analysis, clival chordoma (8/27) was found to be the most common pathology followed by giant cell tumor (6/27), plasmacytoma (4/27), and multiple myeloma (2/27). Most patients (13 out of 27) had the same neurological status after the surgery. Six patients (22%) improved post-operatively with decreased weakness and spasticity. Thirteen (48%) patients underwent adjuvant radiotherapy. CONCLUSIONS: This retrospective study provides valuable insights into managing extradural CVJ tumors and highlights the importance of individualized approaches for optimal outcome.

Cisternostomy as an Adjuvant or Standalone Approach for Management of Traumatic Brain Injury: A Systematic Review and Network Meta-Analysis.

BACKGROUND: Traumatic brain injury (TBI) is a leading cause of morbidity in all age groups worldwide. Decompressive craniectomy (DC) is a salvage procedure in patients with TBI. The outcome and quality of life following DC is questionable. Basal cisternostomy (BC) has been proposed to reduce edema and lead to brain relaxation. It was initially used as an adjunct in TBI patients, thereby improving outcomes. With gaining popularity among neurosurgeons, BC was used as a standalone approach in TBI patients. This network meta-analysis aims to analyze the role of BC either as an adjunct or as a standalone approach in managing TBI patients. METHODS: A comprehensive search of electronic databases (PubMed and SCOPUS) was performed using the search strategy using the field terms and medical subheading terms (MeSH Terms) to retrieve studies describing the role of BC in patients with TBI either as an adjunct with DC or standalone treatment and their outcome. RESULTS: Thirty-one articles were selected for full-text review and 18 articles were selected for the final analysis. BC alone group was found to have minimum in-hospital mortality (odds ratio [OR], 0.348; 95% credible interval [CrI], 0.254 to 0.477) followed by DC combined with BC group (OR, 0.645; 95% CrI, 0.476 to 0.875). DC combined with the BC group was found to have a minimum duration of mechanical ventilation (OR, 0.114; 95% CrI, 0.005 to 2.451) followed by the BC alone group (OR, 0.604; 95% CrI, 0.024 to 15.346). DC combined with the BC group were found to have the maximum Glasgow Outcome Scale score (OR, 1.661; 95% CrI, 0.907 to 3.041) followed by the BC alone group (OR, 1.553; 95% CrI, 0.907 to 3.041). CONCLUSIONS: Our analysis showed that BC alone was associated with lower in-hospital mortality rates in TBI patients. DC with BC had decreased the requirement of mechanical ventilation. However, larger multi-centric studies from other parts of the world are required to confirm these findings.

Unlocking the potential of flavonoid-based co-crystal and co-amorphous systems.

Flavonoids are polyphenolic compounds that have multiple benefits in treating various life-threatening diseases. Despite their diverse pharmacological activities, the market potential of flavonoids is hampered due to their poor solubility and low bioavailability after oral administration. The current review highlights the role of co-crystals and co-amorphous systems (CAMs) in enhancing the solubility, permeability, bioavailability, and therapeutic efficacy of flavonoids. It also explains the significance of flavonoid-based co-formers in the formation of co-crystals and CAMs with other APIs to improve their efficacy. Future perspectives, patented formulations, commercial medications (including their phases of clinical trials), and challenges associated with the use of flavonoid-based co-crystals and CAMs are also mentioned in the review.

Naringenin-Zinc Oxide Nanocomposites Amalgamated Polymeric Gel Augmented Drug Delivery and Attenuated Experimental Cutaneous Candidiasis in Balb/c Mice: In Vitro and In Vivo Studies.

Naringenin (NRG) inhibits the fungal 17ß-hydroxysteroid dehydrogenase accountable for ergosterol synthesis in Candida albicans (C. albicans), a causative agent for cutaneous candidiasis. In present research, NRG was complexed with ZnO nanomaterial (NRG-Zn2+) to synthesize NRG-Zn2+ nanocomposites. The particle size and ζ-potential of NRG-Zn2+ nanocomposites were respectively estimated to be 180.33 ± 1.22-nm and - 3.92 ± 0.35-mV. In silico data predicted the greater affinity of NRG-Zn2+ nanocomposite for 14α-demethylase and ceramide in comparison to NRG alone. Later, NRG-Zn2+ nanocomposites solution was transformed in to naringenin-zinc oxide nanocomposites loaded chitosan gel (NRG-Zn-CS-Gel) with viscosity and firmness of 854806.7 ± 52386.43 cP and 698.27 ± 10.35 g, respectively. The ex-vivo skin permeation demonstrated 70.49 ± 5.22% skin retention, significantly greater (P < 0.05) than 44.48 ± 3.06% of naringenin loaded chitosan gel (NRG-CS-Gel) and 31.24 ± 3.28% of naringenin solution (NRG Solution). NRG-Zn-CS-Gel demonstrated 6.71 ± 0.84% permeation of NRG with a flux value of 0.046 ± 0.01-µg/cm2/h. The MIC50 of NRG-Zn-CS-Gel against C. albicans was estimated to be 0.156-µg/mL with FICI (fractional inhibitory concentration index) of 0.018 that consequently exhibited synergistic efficacy. Further, NRG-Zn-CS-Gel demonstrated superior antifungal efficacy in C. albicans induced cutaneous candidiasis infection in Balb/c mice. The fungal burden in NRG-Zn-CS-Gel treated group was 109 ± 25 CFU/mL, significantly lower (P < 0.05) than positive control (2260 ± 446 CFU/mL), naringenin loaded chitosan gel (NRG-CS-Gel; 928 ± 127 CFU/mL) and chitosan gel (CS-Gel; 2116 ± 186 CFU/mL) treated mice. Further, histopathology examination and cytokine profiling of TNF-α, IL-1ß and IL-10 revealed the healing of skin and inflammation associated with cutaneous candidiasis infection. In conclusion, NRG-Zn-CS-Gel may be a potential candidate for translating in to a clinical viable topical nanotherapeutic.

Endobronchial Inflammatory Myofibroblastic Tumour Masquerading as a Ruptured Hydatid Cyst.

Inflammatory myofibroblastic tumours (IMTs) represent a rare group of neoplastic lesions characterized by a diverse clinical presentation. Endobronchial involvement is infrequently reported, and its manifestation mimicking the symptoms of a ruptured hydatid cyst adds an additional layer of complexity to the diagnostic challenge. This case report delves into an exceptional clinical scenario where an endobronchial IMT masqueraded as a ruptured hydatid cyst, initially confounding the diagnostic team. Through a detailed examination of the patient's clinical history, radiological imaging, bronchoscopy findings and subsequent histopathological analysis, we aim to contribute to the existing medical literature and shed light on the nuances encountered in accurately identifying and differentiating these two entities.

SPACe (Swift Phenotypic Analysis of Cells): an open-source, single cell analysis of Cell Painting data.

Phenotypic profiling by high throughput microscopy has become one of the leading tools for screening large sets of perturbations in cellular models. Of the numerous methods used over the years, the flexible and economical Cell Painting (CP) assay has been central in the field, allowing for large screening campaigns leading to a vast number of data-rich images. Currently, to analyze data of this scale, available open-source software ( i.e. , CellProfiler) requires computational resources that are not available to most laboratories worldwide. In addition, the image-embedded cell-to-cell variation of responses within a population, while collected and analyzed, is usually averaged and unused. Here we introduce SPACe ( S wift P henotypic A nalysis of Ce lls), an open source, Python-based platform for the analysis of single cell image-based morphological profiles produced by CP experiments. SPACe can process a typical dataset approximately ten times faster than CellProfiler on common desktop computers without loss in mechanism of action (MOA) recognition accuracy. It also computes directional distribution-based distances (Earth Mover's Distance - EMD) of morphological features for quality control and hit calling. We highlight several advantages of SPACe analysis on CP assays, including reproducibility across multiple biological replicates, easy applicability to multiple (∼20) cell lines, sensitivity to variable cell-to-cell responses, and biological interpretability to explain image-based features. We ultimately illustrate the advantages of SPACe in a screening campaign of cell metabolism small molecule inhibitors which we performed in seven cell lines to highlight the importance of testing perturbations across models.

Outcomes of Decompressive Surgery for Patients With Severe Cerebral Venous Thrombosis: DECOMPRESS2 Observational Study.

BACKGROUND: Decompressive neurosurgery is recommended for patients with cerebral venous thrombosis (CVT) who have large parenchymal lesions and impending brain herniation. This recommendation is based on limited evidence. We report long-term outcomes of patients with CVT treated by decompressive neurosurgery in an international cohort. METHODS: DECOMPRESS2 (Decompressive Surgery for Patients With Cerebral Venous Thrombosis, Part 2) was a prospective, international cohort study. Consecutive patients with CVT treated by decompressive neurosurgery were evaluated at admission, discharge, 6 months, and 12 months. The primary outcome was death or severe disability (modified Rankin Scale scores, 5-6) at 12 months. The secondary outcomes included patient and caregiver opinions on the benefits of surgery. The association between baseline variables before surgery and the primary outcome was assessed by multivariable logistic regression. RESULTS: A total of 118 patients (80 women; median age, 38 years) were included from 15 centers in 10 countries from December 2011 to December 2019. Surgery (115 craniectomies and 37 hematoma evacuations) was performed within a median of 1 day after diagnosis. At last assessment before surgery, 68 (57.6%) patients were comatose, fixed dilated pupils were found unilaterally in 27 (22.9%) and bilaterally in 9 (7.6%). Twelve-month follow-up data were available for 113 (95.8%) patients. Forty-six (39%) patients were dead or severely disabled (modified Rankin Scale scores, 5-6), of whom 40 (33.9%) patients had died. Forty-two (35.6%) patients were independent (modified Rankin Scale scores, 0-2). Coma (odds ratio, 2.39 [95% CI, 1.03-5.56]) and fixed dilated pupil (odds ratio, 2.22 [95% CI, 0.90-4.92]) were predictors of death or severe disability. Of the survivors, 56 (78.9%) patients and 61 (87.1%) caregivers expressed a positive opinion on surgery. CONCLUSIONS: Two-thirds of patients with severe CVT were alive and more than one-third were independent 1 year after decompressive surgery. Among survivors, surgery was judged as worthwhile by 4 out of 5 patients and caregivers. These results support the recommendation to perform decompressive neurosurgery in patients with CVT with impending brain herniation.