A comprehensive quality control and cost comparison study of branded and generic angiotensin receptor blockers.

This study was designed to assess both the quality and cost aspects of various branded and generic formulations of angiotensin receptor blockers, specifically Irbesartan, Losartan Potassium, Olmesartan Medoxomil, Telmisartan, and Valsartan. The collected samples underwent distinct quality evaluations using the methods outlined in different global Pharmacopoeias (British Pharmacopoeia/European Pharmacopoeia, Indian Pharmacopoeia and United States Pharmacopoeia). These drugs were characterized using Fourier-Transform Infrared Spectroscopy and Nuclear Magnetic Resonance techniques, while their quality and concentration were analysed using High Performance Liquid Chromatography. The release profile of the drugs was examined through dissolution testing. Additionally, a cost comparison analysis was carried out by determining the prevailing market prices of the drugs. The evaluated branded and generic angiotensin receptor blockers were found to meet the established standards for impurities, active drug content, and dissolution as set by these Pharmacopoeias, indicating their optimal quality. Notably, the generic drugs exhibited significantly lower costs compared to their branded counterparts. This study confirms that the quality of generic angiotensin receptor blockers is equivalent to that of their branded counterparts. Consequently, these findings support the practicality of utilizing generic drugs as a more economically sustainable and cost-effective approach to managing diseases, especially those of chronic nature.

Activity-Based Nitric Oxide-Responsive Porphyrin for Site-Selective and Nascent Cancer Ablation.

Nitric oxide (NO) generated within the tumor microenvironment is an established driver of cancer progression and metastasis. Recent efforts have focused on leveraging this feature to target cancer through the development of diagnostic imaging agents and activatable chemotherapeutics. In this context, porphyrins represent an extraordinarily promising class of molecules, owing to their demonstrated use within both modalities. However, the remodeling of a standard porphyrin to afford a responsive chemical that can distinguish elevated NO from physiological levels has remained a significant research challenge. In this study, we employed a photoinduced electron transfer strategy to develop a panel of NO-activatable porphyrin photosensitizers (NOxPorfins) augmented with real-time fluorescence monitoring capabilities. The lead compound, NOxPorfin-1, features an o-phenylenediamine trigger that can effectively capture NO (via N2O3) to yield a triazole product that exhibits a 7.5-fold enhancement and a 70-fold turn-on response in the singlet oxygen quantum yield and fluorescence signal, respectively. Beyond demonstrating excellent in vitro responsiveness and selectivity toward NO, we showcase the potent photodynamic therapy (PDT) effect of NOxPorfin-1 in murine breast cancer and human non-small cellular lung cancer cells. Further, to highlight the in vivo efficacy, two key studies were executed. First, we utilized NOxPorfin-1 to ablate murine breast tumors in a site-selective manner without causing substantial collateral damage to healthy tissue. Second, we established a nascent human lung cancer model to demonstrate the unprecedented ability of NOxPorfin-1 to halt tumor growth and progression completely. The results of the latter study have tremendous implications for applying PDT to target metastatic lesions.

Parallel pathogens: Coexistence of chickenpox and idiopathic thrombocytopenic purpura-A case report.

This case report documents the unusual co-occurrence of immune thrombocytopena (ITP) and chickenpox in a 15-year-old girl. Initial symptoms included shortness of breath, chest pain, and heavy menstrual bleeding. Laboratory results revealed significant anemia and thrombocytopenia. Treatment involved blood transfusions, prednisolone, and iron supplementation. The patient's vesicular skin rash emerged 8 weeks later, prompting the combined diagnosis of ITP and chickenpox. Antiviral treatments, blood transfusions, and supportive care were used in the course of treatment, leading to full recovery. This case emphasizes the importance of prompt diagnosis, appropriate management, and regular follow-up for patients with both chickenpox and ITP. The coexistence of chickenpox and ITP poses a clinical challenge due to the complex interaction between the viral infection and the immune system. The exact mechanism linking these two conditions remains unclear, making it a baffling case that warrants investigation and further understanding. As low is the occurrence of hemorrhagic chickenpox, the presentation of simultaneous chicken pox with or following ITP was found to be rarer, and thus is this enigmatic case presented. Healthcare providers should remain vigilant about such co-occurrences to prevent complications. In order to improve treatment for instances with comparable clinical presentations and advance our collective knowledge, further study is required to better understand the mechanisms relating viral infections and ITP.

Synthetic phage and its application in phage therapy.

Synthetic phage analysis has been implemented in progressive various areas of biology, such as genetics, molecular biology, and synthetic biology. Many phage-derived technologies have been altered for developing gene circuits to program biological systems. Due to their extremely potent potency, phages also provide greater medical availability against bacterial agents and bacterial diagnostic agents. Its host specificity and our growing ability to manipulate, them further expand its possibility. New Phages also genetically redesign programmable biomaterials with highly tunable properties. Moreover, new phages are central to powerful directed evolution platforms. It is used to enhance existing biological, functions to create new phages. In other sites, the mining of antibiotics, and the emergence and dissemination of more than one type of drug-resistant microbe, a human health concerns. The major point in controlling and treating microbial infections. At present, genetic modifications and biochemical treatments are used to modify phages. Among these, genetic engineering involves the identification of defective proteins, modification of host bodies, recognized receptors, and disruption of bacterial phage resistance signaling gateways.

Activity-based bioluminescence probes for in vivo sensing applications.

Bioluminescence imaging is a highly sensitive technique commonly used for various in vivo applications. Recent efforts to expand the utility of this modality have led to the development of a suite of activity-based sensing (ABS) probes for bioluminescence imaging by 'caging' of luciferin and its structural analogs. The ability to selectively detect a given biomarker has presented researchers with many exciting opportunities to study both health and disease states in animal models. Here, we highlight recent (2021-2023) bioluminescence-based ABS probes with an emphasis on probe design and in vivo validation experiments.

Inferior Vesical Fissure-A Rare Variant of Exstrophy Bladder: Case Report With Literature Review.

Exstrophy variants are uncommon developmental anomalies of the bladder; the variants involving only the bladder neck are extremely rare. There are only three case reports of inferior vesical fissure (IVF) to date, and usually it's uncommonly associated with other malformations. A combination of inferior vesical fistula (IVF) as an exstrophy variant with urethral atresia and anorectal malformation has not been described previously. We report a case of IVF in a 4-year-old male previously operated for anorectal malformation who was managed with fistula closure with bladder neck reconstruction of lay open of stenosed urethra. Recognition of the exstrophy variant is important because the treatment and prognosis are very different.

Hydrolysis-Resistant Ester-Based Linkers for Development of Activity-Based NIR Bioluminescence Probes.

Activity-based sensing (ABS) probes equipped with a NIR bioluminescence readout are promising chemical tools to study cancer biomarkers owing to their high sensitivity and deep tissue compatibility. Despite the demand, there is a dearth of such probes because NIR substrates (e.g., BL660 (a NIR luciferin analog)) are not equipped with an appropriate attachment site for ABS trigger installation. For instance, our attempts to mask the carboxylic acid moiety with standard self-immolative benzyl linkers resulted in significant background signals owing to undesirable ester hydrolysis. In this study, we overcame this longstanding challenge by rationally designing a new hydrolysis-resistant ester-based linker featuring an isopropyl shielding arm. Compared to the parent, the new design is 140.5-fold and 67.8-fold more resistant toward spontaneous and esterase-mediated hydrolysis, respectively. Likewise, we observed minimal cleavage of the ester moiety when incubated with a panel of enzymes possessing ester-hydrolyzing activity. These impressive in vitro results were corroborated through a series of key experiments in live cells. Further, we showcased the utility of this technology by developing the first NIR bioluminescent probe for nitroreductase (NTR) activity and applied it to visualize elevated NTR expression in oxygen deficient lung cancer cells and in a murine model of non-small cell lung cancer. The ability to monitor the activity of this key biomarker in a deep tissue context is critical because it is associated with tumor hypoxia, which in turn is linked to drug resistance and aggressive cancer phenotypes.

Activity-based Photoacoustic Probes Reveal Elevated Intestinal MGL and FAAH Activity in a Murine Model of Obesity.

Obesity is a chronic health condition characterized by the accumulation of excessive body fat which can lead to and exacerbate cardiovascular disease, type-II diabetes, high blood pressure, and cancer through systemic inflammation. Unfortunately, visualizing key mediators of the inflammatory response, such as monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH), in a selective manner is a profound challenge owing to an overlapping substrate scope that involves arachidonic acid (AA). Specifically, these enzymes work in concert to generate AA, which in the context of obesity, has been implicated to control appetite and energy metabolism. In this study, we developed the first selective activity-based sensing probes to detect MGL (PA-HD-MGL) and FAAH (PA-HD-FAAH) activity via photoacoustic imaging. Activation of PA-HD-MGL and PA-HD-FAAH by their target enzymes resulted in 1.74-fold and 1.59-fold signal enhancements, respectively. Due to their exceptional selectivity profiles and deep-tissue photoacoustic imaging capabilities, these probes were employed to measure MGL and FAAH activity in a murine model of obesity. Contrary to conflicting reports suggesting levels of MGL can be attenuated or elevated, our results support the latter. Indeed, we discovered a marked increase of both targets in the gastrointestinal tract. These key findings set the stage to uncover the role of the endocannabinoid pathway in obesity-mediated inflammation.

Repurposing Cyanine Photoinstability To Develop Near-Infrared Light-Activatable Nanogels for In Vivo Cargo Delivery.

The favorable properties of cyanines (e.g., near-infrared (NIR) absorbance and emission) have made this class of dyes popular for a wide variety of biomedical applications. However, many cyanines are prone to rapid photobleaching when irradiated with light. In this study, we have exploited this undesirable trait to develop NIR-nanogels for NIR light-mediated cargo delivery. NIR-nanogels feature a photolabile cyanine cross-linker (Cy780-Acryl) that can cleave via dioxetane chemistry when irradiated. This photochemical process results in the formation of two carbonyl fragments and concomitant NIR-nanogel degradation to facilitate cargo release. In contrast to studies where cyanines are utilized as photocages, our approach does not require direct chemical attachment to the cargo, thus expanding our ability to deliver molecules that cannot be covalently modified. We showcase this feature by encapsulating a palette of small-molecule chemotherapeutics that feature a structurally diverse chemical architecture. To demonstrate site-selective release in vivo, we generated a murine model of breast cancer. Relative to nonlight irradiated and drug-free controls, treatment with NIR-nanogels loaded with paclitaxel (a potent cytotoxic agent) and NIR light resulted in significant attenuation of tumor growth. Moreover, we show via histological staining of the vital organs that minimal off-target effects are observed.

Cefixime induced Steven Johnson syndrome: A case report from Bangladesh.

Introduction: Stevens Jonson syndrome, a type IV mediated hypersensitivity reaction is a rare mucocutaneous disorder accounting for <10% of TBSA. It affects skin, oral mucosa, eyes, esophagus, mouth, pharynx, larynx, skin and genitals. SJS is caused mainly due to drugs, infectious agents, immunization, and radiation therapy. Presentation of case: We present a case of a 40 years old male who developed SJS after being administered cefixime for a short period. Given the patient's past profile, he was admitted due to RTA and was under treatment with cefixime. Irrespective of any symptoms of SJS in the past, he started developing symptoms soon after being treated with cefixime giving us a clue about cefixime-induced SJS. Discussion: Steven-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are opposite ends of a spectrum of diseases arising usually from an adverse reaction to medications. The most common drug reactions include penicillin in antibiotics, carbamazepine in antiepileptics and allopurinol in gout treatment in the Asian community. In our case, the patient was under Cefixime for 6 days after which cutaneous manifestations were seen. SJS is a fatal condition, with a global mortality rate stretching between 10% and 34%. The first step in its management is to identify the culprit drug and stop its use. Other is symptomatic, with special attention to airway and hemodynamic stability, wound care, and pain alleviation measures. Medical therapy include corticosteroids, cyclosporine, intravenous immunoglobulin (IVIG), and TNF- α inhibitors. Conclusion: Cephalosporin group, like cefixime, is a commonly prescribed drug in developing countries due to its efficacy and cost-effectiveness. Therefore, physicians must beforehand be mindful of the consequences of its use and advice patients to visit the hospital with even the slightest cutaneous manifestation.

An Automated Wavelet-Based Sleep Scoring Model Using EEG, EMG, and EOG Signals with More Than 8000 Subjects.

Human life necessitates high-quality sleep. However, humans suffer from a lower quality of life because of sleep disorders. The identification of sleep stages is necessary to predict the quality of sleep. Manual sleep-stage scoring is frequently conducted through sleep experts' visually evaluations of a patient's neurophysiological data, gathered in sleep laboratories. Manually scoring sleep is a tough, time-intensive, tiresome, and highly subjective activity. Hence, the need of creating automatic sleep-stage classification has risen due to the limitations imposed by manual sleep-stage scoring methods. In this study, a novel machine learning model is developed using dual-channel unipolar electroencephalogram (EEG), chin electromyogram (EMG), and dual-channel electrooculgram (EOG) signals. Using an optimum orthogonal filter bank, sub-bands are obtained by decomposing 30 s epochs of signals. Tsallis entropies are then calculated from the coefficients of these sub-bands. Then, these features are fed an ensemble bagged tree (EBT) classifier for automated sleep classification. We developed our automated sleep classification model using the Sleep Heart Health Study (SHHS) database, which contains two parts, SHHS-1 and SHHS-2, containing more than 8455 subjects with more than 75,000 h of recordings. The proposed model separated three classes if sleep: rapid eye movement (REM), non-REM, and wake, with a classification accuracy of 90.70% and 91.80% using the SHHS-1 and SHHS-2 datasets, respectively. For the five-class problem, the model produces a classification accuracy of 84.3% and 86.3%, corresponding to the SHHS-1 and SHHS-2 databases, respectively, to classify wake, N1, N2, N3, and REM sleep stages. The model acquired Cohen's kappa (κ) coefficients as 0.838 with SHHS-1 and 0.86 with SHHS-2 for the three-class classification problem. Similarly, the model achieved Cohen's κ of 0.7746 for SHHS-1 and 0.8007 for SHHS-2 in five-class classification tasks. The model proposed in this study has achieved better performance than the best existing methods. Moreover, the model that has been proposed has been developed to classify sleep stages for both good sleepers as well as patients suffering from sleep disorders. Thus, the proposed wavelet Tsallis entropy-based model is robust and accurate and may help clinicians to comprehend and interpret sleep stages efficiently.

Impact of pathological factors on survival in patients with upper tract urothelial carcinoma: a systematic review and meta-analysis

ABSTRACT Introduction: There is an ongoing need to identify various pathological factors that can predict various survival parameters in patients with upper tract urothelial carcinoma (UTUC). With this review, we aim to scrutinize the impact of several pathological factors on recurrence free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) in patients with UTUC. Materials and Methods: Systematic electronic literature search of various databases was conducted for this review. Studies providing multivariate hazard ratios (HR) for various pathological factors such as tumor margin, necrosis, stage, grade, location, architecture, lymph node status, lymphovascular invasion (LVI), carcinoma in situ (CIS), multifocality and variant histology as predictor of survival parameters were included and pooled analysis of HR was performed. Results: In this review, 63 studies with 35.714 patients were included. For RFS, all except tumor location (HR 0.94, p=0.60) and necrosis (HR 1.00, p=0.98) were associated with worst survival. All the pathological variables except tumor location (HR 0.95, p=0.66) were associated with worst CSS. For OS, only presence of CIS (HR 1.03, p=0.73) and tumor location (HR 1.05, p=0.74) were not predictor of survival. Conclusions: We noted tumor grade, stage, presence of LVI, lymph node metastasis, hydronephrosis, variant histology, sessile architecture, margin positivity and multifocality were associated with poor RFS, CSS and OS. Presence of CIS was associated with poor RFS and CSS but not OS. Tumor necrosis was associated with worst CSS and OS but not RFS. Tumor location was not a predictor of any of the survival parameters.

Activity-Based NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide.

Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO's contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO's impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo, and fewer yet are practical in cancer models where the NO concentration is <200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated two dietary studies which examine the impact of fat intake on NO and the TME. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet, which became obese with larger tumors, compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of inducible nitric oxide synthase which in turn can drive tumor progression.

Impact of pathological factors on survival in patients with upper tract urothelial carcinoma: a systematic review and meta-analysis.

INTRODUCTION: There is an ongoing need to identify various pathological factors that can predict various survival parameters in patients with upper tract urothelial carcinoma (UTUC). With this review, we aim to scrutinize the impact of several pathological factors on recurrence free survival (RFS), cancer-specific survival (CSS) and overall survival (OS) in patients with UTUC. MATERIALS AND METHODS: Systematic electronic literature search of various databases was conducted for this review. Studies providing multivariate hazard ratios (HR) for various pathological factors such as tumor margin, necrosis, stage, grade, location, architecture, lymph node status, lymphovascular invasion (LVI), carcinoma in situ (CIS), multifocality and variant histology as predictor of survival parameters were included and pooled analysis of HR was performed. RESULTS: In this review, 63 studies with 35.714 patients were included. For RFS, all except tumor location (HR 0.94, p=0.60) and necrosis (HR 1.00, p=0.98) were associated with worst survival. All the pathological variables except tumor location (HR 0.95, p=0.66) were associated with worst CSS. For OS, only presence of CIS (HR 1.03, p=0.73) and tumor location (HR 1.05, p=0.74) were not predictor of survival. CONCLUSIONS: We noted tumor grade, stage, presence of LVI, lymph node metastasis, hydronephrosis, variant histology, sessile architecture, margin positivity and multifocality were associated with poor RFS, CSS and OS. Presence of CIS was associated with poor RFS and CSS but not OS. Tumor necrosis was associated with worst CSS and OS but not RFS. Tumor location was not a predictor of any of the survival parameters.

A general strategy to optimize the performance of aza-BODIPY-based probes for enhanced photoacoustic properties.

In this chapter, we describe a generalizable strategy to obtain a high PA output platform that is optimized for ratiometric imaging. Our approach entails conformationally restricting pendant aryl rings on the aza-BODIPY core to enhance orbital overlap which consequently increases the extinction coefficient. This strategy can potentially be applied to other dye platforms to enhance their signal intensity. We provide detailed protocols for the synthesis, in vitro characterization, and in vivo application.

Comparison of efficacy and safety of various management options for large upper ureteric stones a systematic review and network meta-analysis.

To compare the safety and efficacy of various surgical modalities to manage large (> 1 cm) upper ureter stones. Systematic literature search was conducted to include all randomized studies comparing various treatment options for large (> 1 cm) upper ureteric stones. This review included 13 randomized studies with 1871 patients. Laparoscopic ureterolithotomy (LUL) and percutaneous nephrolithotomy (PNL) were superior to ureteroscopy (URS) and shockwave lithotripsy (SWL) for stone-free rates and need for auxiliary treatments. LUL and PNL were equally effective for stone-free rates and the need for auxiliary treatments. According to SUCRA values for stone-free rates and the need for auxiliary treatments, LUL was the best, followed by PNL. For the duration of surgery, there was no significant difference among all the techniques on network analyses, and SWL was the best according to SUCRA values. Length of hospital stay was significantly shorter for URS than LUL and PNL from network analysis, but there was no significant difference for the rest of the comparisons. Overall complications were similar in all the groups. According to the CINeMa approach, the confidence rating ranged from "very low" to "moderate" for various comparisons. LUL followed by PNL is the most efficacious treatment modality for upper ureteric stones compared to SWL and URS in terms of stone-free rates. However, due to the poor quality of included studies, further high-quality randomized studies are needed.

A General Approach to Convert Hemicyanine Dyes into Highly Optimized Photoacoustic Scaffolds for Analyte Sensing*.

Most photoacoustic (PA) imaging agents are based on the repurposing of existing fluorescent dye platforms that exhibit non-optimal properties for PA applications. Herein, we introduce PA-HD, a new dye scaffold optimized for PA probe development that features a 4.8-fold increase in sensitivity and a red-shift of the λabs from 690 nm to 745 nm to enable ratiometric imaging. Computational modeling was used to elucidate the origin of these enhanced properties. To demonstrate the generalizability of our remodeling efforts, we developed three probes for ß-galactosidase activity (PA-HD-Gal), nitroreductase activity (PA-HD-NTR), and H2 O2 (PA-HD-H2 O2 ). We generated two cancer models to evaluate PA-HD-Gal and PA-HD-NTR. We employed a murine model of Alzheimer's disease to test PA-HD-H2 O2 . There, we observed a PA signal increase at 735 nm of 1.79±0.20-fold relative to background, indicating the presence of oxidative stress. These results were confirmed via ratiometric calibration, which was not possible using the parent HD platform.

Acoustic-based chemical tools for profiling the tumor microenvironment.

Acoustic-based imaging modalities (e.g. ultrasonography and photoacoustic imaging) have emerged as powerful approaches to noninvasively visualize the interior of the body due to their biocompatibility and the ease of sound transmission in tissue. These technologies have recently been augmented with an array of chemical tools that enable the study and modulation of the tumor microenvironment at the molecular level. In addition, the application of ultrasound and ultrasound-responsive materials has been used for drug delivery with high spatiotemporal control. In this review, we highlight recent advances (in the last 2-3 years) in acoustic-based chemical tools and technologies suitable for furthering our understanding of molecular events in complex tumor microenvironments.