In-depth Mechanism, Challenges, and Opportunities of Delivering Therapeutics in Brain Using Intranasal Route.

Central nervous system-related disorders have become a continuing threat to human life and the current statistic indicates an increasing trend of such disorders worldwide. The primary therapeutic challenge, despite the availability of therapies for these disorders, is to sustain the drug's effective concentration in the brain while limiting its accumulation in non-targeted areas. This is attributed to the presence of the blood-brain barrier and first-pass metabolism which limits the transportation of drugs to the brain irrespective of popular and conventional routes of drug administration. Therefore, there is a demand to practice alternative routes for predictable drug delivery using advanced drug delivery carriers to overcome the said obstacles. Recent research attracted attention to intranasal-to-brain drug delivery for promising targeting therapeutics in the brain. This review emphasizes the mechanisms to deliver therapeutics via different pathways for nose-to-brain drug delivery with recent advancements in delivery and formulation aspects. Concurrently, for the benefit of future studies, the difficulties in administering medications by intranasal pathway have also been highlighted.

Biosorption of arsenic (III) from aqueous solution using calcium alginate immobilized dead biomass of Acinetobacter sp. strain Sp2b.

This study presents a novel biosorbent developed by immobilizing dead Sp2b bacterial biomass into calcium alginate (CASp2b) to efficiently remove arsenic (AsIII) from contaminated water. The bacterium Sp2b was isolated from arsenic-contaminated industrial soil of Punjab, a state in India. The strain was designated Acinetobacter sp. strain Sp2b as per the 16S rDNA sequencing, GenBank accession number -OP010048.The CASp2b was used for the biosorption studies after an initial screening for the biosorption capacity of Sp2b biomass with immobilized biomass in both live and dead states. The optimum biosorption conditions were examined in batch experimentations with contact time, pH, biomass, temperature, and AsIII concentration variables. The maximum biosorption capacity (qmax = 20.1 ± 0.76 mg/g of CA Sp2b) was obtained at pH9, 35 ̊ C, 20 min contact time, and 120 rpm agitation speed. The isotherm, kinetic and thermodynamic modeling of the experimental data favored Freundlich isotherm (R2 = 0.941) and pseudo-2nd-order kinetics (R2 = 0.968) with endothermic nature (ΔH° = 27.42) and high randomness (ΔS° = 58.1).The scanning electron microscopy with energy dispersive X-ray (SEM-EDX) analysis indicated the As surface binding. The reusability study revealed the reasonable usage of beads up to 5 cycles. In conclusion, CASp2b is a promising, efficient, eco-friendly biosorbent for AsIII removal from contaminated water.

Midperipheral mini-capsulorhexis as an additional step for safe phacoemulsification in white intumescent cataracts.

ABSTRACT: The present article describes a novel surgical technique of a primary mini-capsulorhexis in midperiphery to minimize surgical complications in white intumescent cataracts. Patients with white mature cataracts with a convex anterior capsule or swollen lens fibers were selected. An initial puncture was made 3-4 mm away from the center, in the midperipheral anterior capsule, with a conventional cystitome. A mini-capsulorhexis (2-2.5 mm) was created. Loose cortical matter and fluidic contents were aspirated to reduce the intralenticular pressure. Two cuts were made at the margin of the mini-capsulorhexis, and an adequately sized secondary rhexis was completed, after which phacoemulsification was done. A circular curvilinear capsulorhexis was successfully achieved in all cases, including those with a small pupil. Rhexis could be completed in a patient where an initial extension occurred due to head movement. This refined technique aims to enhance the safety and precision of capsulorhexis in intumescent cataracts, thereby reducing the risk of complications such as the Argentinian flag sign. Further exploration and validation of this approach through clinical trials are warranted to establish its efficacy and safety profile.

Nano-nutraceuticals to Combat Oxidative Stress: Unlocking Newer Paradigms in Adjuvant Therapy.

Nutraceuticals are products that provide both nutritional and therapeutic benefits. These compounds can slow the aging process and provide physiological effects shielding individuals from acute and chronic diseases. People's interests have shifted from allopathic to Ayurvedic to nutraceuticals in recent years. These are often common dietary supplements that have drawn customers worldwide because of their high nutritional safety and lack of adverse effects when used for a long time. Although conventional dosage forms, including pills, tablets, and semi-solids, are still available, they nevertheless have poorer bioavailability, less stability, and less effectiveness for targeted delivery of bioactives. The use of effective nanocomplex systems as nano-antioxidants using nanotechnology has become a promising field. Among its many uses, nanotechnology is mostly used to create foods and nutraceuticals that are more bioavailable, less toxic, and more sustainable. Additionally, it has been emphasized how precisely nano-pharmaceuticals for oxidative stress produce the desired effects. These improvements show improved antioxidant delivery to the target region, reduced leakage, and increased targeting precision. The outcomes demonstrated that oxidative stress-related illnesses can be effectively treated by lowering ROS levels with the use of nanonutraceuticals. The major ideas and uses of nano-nutraceuticals for health are outlined in this review, with an emphasis on reducing oxidative stress.

Solitary Ganglioneuromatous Hamartoma Tongue in a Newborn - A Rare Entity.

Ganglioneuromatous hamartoma is a benign tumour of autonomic ganglia with very few cases reported in head and neck region. In this report, we are presenting a case of ganglioneuromatous hamartoma in a 20 day old female child who presented with a tongue mass. She underwent a surgical excision and the definitive diagnosis was made by histopathology. This case reports discusses presentation and management of a case of ganglioneuromatous hamartoma.

Invasive fungal disease in children with solid tumors: An Australian multicenter 10-year review.

Invasive fungal disease (IFD) occurs less frequently during treatment for solid compared to hematological malignancies in children, and risk groups are poorly defined. Retrospective national multicenter cohort data (2004-2013) were analyzed to document prevalence, clinical characteristics, and microbiology of IFD. Amongst 2067 children treated for solid malignancy, IFD prevalence was 1.9% overall and 1.4% for proven/probable IFD. Of all IFD episodes, 42.5% occurred in patients with neuroblastoma (prevalence 7.0%). Candida species comprised 54.8% of implicated pathogens in proven/probable IFD. In children with solid tumors, IFD is rare, and predominantly caused by yeasts.Routine prophylaxis may not be warranted.

The menace within: bacterial amyloids as a trigger for autoimmune and neurodegenerative diseases.

Bacteria are known to produce amyloids, proteins characterized by a conserved cross-beta sheet structure, which exhibit structural and functional similarities to human amyloids. The deposition of human amyloids into fibrillar plaques within organs is closely linked to several debilitating human diseases, including Alzheimer's and Parkinson's disease. Recently, bacterial amyloids have garnered significant attention as potential initiators of human amyloid-associated diseases as well as autoimmune diseases. This review aims to explore how bacterial amyloid, particularly curli found in gut biofilms, can act as a trigger for neurodegenerative and autoimmune diseases. We will elucidate three primary mechanisms through which bacterial amyloids exert their influence: By delving into these three distinct modes of action, this review will provide valuable insights into the intricate relationship between bacterial amyloids and the onset or progression of neurodegenerative and autoimmune diseases. A comprehensive understanding of these mechanisms may open new avenues for therapeutic interventions and preventive strategies targeting amyloid-associated diseases.

Characterization of G-quadruplex structures in genes involved in survival and pathogenesis of Acinetobacter baumannii as a potential drug target.

Acinetobacter baumannii is a notorious pathogen that commonly thrives in hospital environments and is responsible for numerous nosocomial infections in humans. The burgeoning multi-drug resistance leaves relatively minimal options for treating the bacterial infection, posing a significant problem and prompting the identification of new approaches for tackling the same. This motivated us to focus on non-canonical nucleic acid structures, mainly G-quadruplexes, as drug targets. G-quadruplexes have recently been gaining attention due to their involvement in multiple bacterial and viral pathogenesis. Herein, we sought to explore conserved putative G-quadruplex motifs in A. baumannii. In silico analysis revealed the presence of eight conserved motifs in genes involved in bacterial survival and pathogenesis. The biophysical and biomolecular analysis confirmed stable G-quadruplex formation by the motifs and showed a high binding affinity with the well-reported G-quadruplex binding ligand, BRACO-19. BRACO-19 exposure also decreased the growth of bacteria and downregulated the expression of G-quadruplex-harboring genes. The biofilm-forming ability of the bacteria was also affected by BRACO-19 addition. Taking all these observations into account, we have shown here for the first time the potential of G-quadruplex structures as a promising drug target in Acinetobacter baumannii, for addressing the challenges posed by this infamous pathogen.

The molecular interplay between human and bacterial amyloids: Implications in neurodegenerative diseases.

Neurodegenerative disorders such as Parkinson's (PD) and Alzheimer's diseases (AD) are linked with the assembly and accumulation of proteins into structured scaffold called amyloids. These diseases pose significant challenges due to their complex and multifaceted nature. While the primary focus has been on endogenous amyloids, recent evidence suggests that bacterial amyloids may contribute to the development and exacerbation of such disorders. The gut-brain axis is emerging as a communication pathway between bacterial and human amyloids. This review delves into the novel role and potential mechanism of bacterial amyloids in modulating human amyloid formation and the progression of AD and PD.

Prediction of Effectiveness and Toxicities of Immune Checkpoint Inhibitors Using Real-World Patient Data.

PURPOSE: Although immune checkpoint inhibitors (ICIs) have improved outcomes in certain patients with cancer, they can also cause life-threatening immunotoxicities. Predicting immunotoxicity risks alongside response could provide a personalized risk-benefit profile, inform therapeutic decision making, and improve clinical trial cohort selection. We aimed to build a machine learning (ML) framework using routine electronic health record (EHR) data to predict hepatitis, colitis, pneumonitis, and 1-year overall survival. METHODS: Real-world EHR data of more than 2,200 patients treated with ICI through December 31, 2018, were used to develop predictive models. Using a prediction time point of ICI initiation, a 1-year prediction time window was applied to create binary labels for the four outcomes for each patient. Feature engineering involved aggregating laboratory measurements over appropriate time windows (60-365 days). Patients were randomly partitioned into training (80%) and test (20%) sets. Random forest classifiers were developed using a rigorous model development framework. RESULTS: The patient cohort had a median age of 63 years and was 61.8% male. Patients predominantly had melanoma (37.8%), lung cancer (27.3%), or genitourinary cancer (16.4%). They were treated with PD-1 (60.4%), PD-L1 (9.0%), and CTLA-4 (19.7%) ICIs. Our models demonstrate reasonably strong performance, with AUCs of 0.739, 0.729, 0.755, and 0.752 for the pneumonitis, hepatitis, colitis, and 1-year overall survival models, respectively. Each model relies on an outcome-specific feature set, though some features are shared among models. CONCLUSION: To our knowledge, this is the first ML solution that assesses individual ICI risk-benefit profiles based predominantly on routine structured EHR data. As such, use of our ML solution will not require additional data collection or documentation in the clinic.

Outcomes of Simple Limbal Epithelial Transplantation Without Amniotic Membrane Grafting in Unilateral Limbal Stem Cell Deficiency: A Case Series of 6 Patients.

PURPOSE: This study describes the technique of simple limbal epithelial transplantation (SLET) without amniotic membrane grafting (AMG) in limbal stem cell deficiency (LSCD). METHODS: Retrospective, interventional case series of 6 patients who underwent SLET without AMG were included. The procedure followed the standard technique, involving limbal biopsy from the healthy eye, resection of symblephera, and pannus dissection in the affected eye. Following host bed preparation, limbal explants were placed on the bare cornea and secured with fibrin glue. A large-diameter bandage contact lens was applied post surgery. No amniotic membrane was used. Preoperative data, including age, gender, cause of LSCD, best-corrected visual acuity, and previous ocular surgeries, were recorded. Postoperative clinical information, such as the duration of follow-up and recurrence of LSCD, best-corrected visual acuity, and other ocular examination findings, was recorded in an excel sheet. RESULTS: Preoperatively, 2 patients had total LSCD (secondary to a firecracker injury and excision biopsy for ocular surface squamous neoplasia). 4 patients had partial LSCD (3 chemical injuries, 1 firecracker injury). The mean age of participants was 30.67 ± 15.91 years, with a mean follow-up duration of 9.33 ± 8.04 months. Intraoperatively, all patients exhibited a smooth corneal surface after pannus removal. Postoperatively, all limbal explants remained securely attached, with complete corneal epithelialization achieved within 2 to 3 weeks. The ocular surface remained stable throughout, and no recurrence of LSCD was observed in any patient. No loss of explants was seen. CONCLUSIONS: The present series suggests that AMG may not be a necessary step for performing SLET.

Clinical Value of Timely Targeted Therapy for Patients With Advanced Non-Small Cell Lung Cancer With Actionable Driver Oncogenes.

BACKGROUND: A recent real-world study observed that 24% of patients with advanced non-small cell lung cancer (aNSCLC) with actionable driver oncogenes (ADOs) initiated nontargeted therapies before biomarker test results became available. This study assessed the clinical impact of the timing of first-line (1L) targeted therapies (TTs) in aNSCLC. MATERIALS AND METHODS: This retrospective analysis of a nationwide electronic health record-derived deidentified database included patients aged ≥18 years diagnosed with aNSCLC with ADOs (ALK, BRAF, EGFR, RET, MET, ROS-1, and NTRK) from January 1, 2015, to October 18, 2022, by biomarker testing within 90 days after advanced diagnosis and received 1L treatment. Cohorts were defined by treatment patterns ≤42 days after test results: "Upfront TT" received 1L TT ≤42 days; "Switchers" initiated 1L non-TT before or after testing but switched to TT ≤42 days; and "Non-switchers" initiated non-TT before or after testing and did not switch at any time. Adjusted multivariate Cox regression evaluated real-world progression-free survival, real-world time to next treatment or death, and real-world overall survival. RESULTS: A total of 3540 patients met the study criteria; 78% were treated in a community setting, and 50% underwent next-generation sequencing (NGS). There was no significant difference in outcomes between Switchers and Upfront TT; inferior outcomes were observed in Non-switchers versus Upfront TT. CONCLUSION: Our findings demonstrated improved outcomes with upfront 1L TT versus non-TT in patients with aNSCLC with ADOs and observed timely switching to TT after biomarker test result had similar outcomes to Upfront TT. Opportunities remain to improve the use of NGS for early ADO identification and determination of 1L TT.

Enhancing periodontal defences with nanofiber treatment: recent advances and future prospects.

The term periodontal disease is used to define diseases characterised by inflammation and regeneration of the gums, cementum, supporting bone, and periodontal ligament. The conventional treatment involves the combination of scaling, root planning, and surgical approaches which are invasive and can pose certain challenges. Intrapocket administration of nanofibers can be used for overcoming challenges which can help in speeding up the wound repair process and can also be used to promote osteogenesis. To help make drug delivery more effective, nanofibers are an interesting solution. Nanofibers are nanosized 3D structures that can fill the pockets and have excellent mucoadhesion which prolongs their retention time on the target site. Moreover, their structure mimics the natural extracellular matrix which enables nanomaterials to sense local biological conditions and start cellular-level reprogramming to produce the necessary therapeutic efficacy. In this review, the significance of intrapocket administration of nanofibers using recent research for the management of periodontitis has been discussed in detail. Furthermore, we have discussed polymers used for the preparation of nanofibers, nanofiber production methods, and the patents associated with these developments. This comprehensive compilation of data serves as a valuable resource, consolidating recent developments in nanofiber applications for periodontitis management into one accessible platform.

Intelligent Drug Delivery: Pioneering Stimuli-Responsive Systems to Revolutionize Disease Management- An In-depth Exploration.

In recent years, there has been an escalating interest in stimuli-responsive drug delivery systems (SRDDS) due to their ability to revolutionize the delivery of therapeutics. SRDDSs offer a multitude of benefits in comparison to conventional drug delivery systems (DDS), including spatiotemporal control of drug release, targeted delivery, and improved therapeutic efficacy. The development of various classes of stimuli-responsive DDS, such as pH-responsive, temperature-responsive, photo-responsive, redox responsive systems, has been propelled by advances in materials science, nanotechnology, and biotechnology. These systems exploit specific environmental or physiological cues to trigger drug release in a precisely controlled manner, making them highly promising for the treatment of various diseases. In this review article, an in-depth exploration of the principles, mechanisms, and applications of SRDDS in the context of diverse pathologies such as cancer, arthritis, Alzheimer's disease, atherosclerosis and tissue engineering has been provided. Furthermore, this article delves into the discussion of recent patents, market overview and the progress of research in clinical trials. Overall, this article underscores the transformative potential of SRDDS in enabling personalized, precise, and effective drug delivery for the treatment of the above-mentioned diseases.

Nanoneuroscience: Cutting-edge Approach for Disease Management.

Neurological disorders (ND) have affected a major part of our society and have been a challenge for medical and biosciences for decades. However, many of these disorders haven't responded well to currently established treatment approaches. The fact that many active pharmaceutical ingredients can't get to their specified action site inside the body is one of the main reasons for this failure. Extracellular and intracellular central nervous system (CNS) barriers prevent the transfer of drugs from the blood circulation to the intended location of the action. Utilizing nanosized drug delivery technologies is one possible way to overcome these obstacles. These nano-drug carriers outperform conventional dosage forms in many areas, including good drug encapsulation capacity, targeted drug delivery, less toxicity, and enhanced therapeutic impact. As a result, nano-neuroscience is growing to be an intriguing area of research and a bright alternative approach for delivering medicines to their intended action site for treating different neurological and psychiatric problems. In this review, we have included a short overview of the pathophysiology of neurological diseases, a detailed discussion about the significance of nanocarriers in NDs, and a focus on its recent advances. Finally, we highlighted the patented technologies and market trends, including the predictive analysis for the years 2021-2028.

Racial and Ethnic Inequities at the Practice and Physician Levels in Timely Next-Generation Sequencing for Patients With Advanced Non-Small-Cell Lung Cancer Treated in the US Community Setting.

PURPOSE: Racial/ethnic inequities in next-generation sequencing (NGS) were examined for patients with advanced non-small-cell lung cancer (aNSCLC) at the practice and physician levels to inform policies to improve equitable quality of care. METHODS: This retrospective study used a nationwide electronic health record-derived deidentified database for patients with aNSCLC diagnosed between April 2018 and March 2022 in the community setting. Timely NGS was an NGS result between initial diagnosis and ≤60 days after advanced diagnosis. We studied how inequities were driven by (1) non-Latinx Black (Black) and Latinx patient under-representation at high testing practices versus (2) Black and Latinx patients being tested at lower rates than non-Latinx White (White) patients, even at the same practice. We defined these two concepts as across inequity and within inequity, respectively, with total inequity as their summation. Mean percentage point inequities were estimated using a Bayesian approach. RESULTS: A total of 12,045 patients (9,981 White; 1,528 Black; 536 Latinx) met study criteria. At the practice level, versus White patients, the mean percentage point difference in NGS testing total inequity was 7.49 for Black and 8.26 for Latinx. Within- and across-practice inequities contributed to total inequity in NGS testing for Black (48% v 52%) and Latinx patients (60% v 40%). At the physician level, versus White patients, the mean percentage point difference in total inequity was 7.73 for Black and 8.81 for Latinx patients. Within- versus across-physician inequities contributed to total inequity for Black and Latinx patients (77% v 23% and 67% v 33%). CONCLUSION: Within-practice, across-practice, and across-physician inequities were main contributors to total inequity in NGS testing, requiring a suite of interventions to effectively address inequities.

Predictors of functional impairment and mortality in patients on maintenance hemodialysis.

INTRODUCTION: Numerous factors impact the mortality and functional abilities of patients with end-stage renal disease (ESRD) receiving maintenance hemodialysis (MHD). We aimed to determine the mortality rate at 1 year of MHD, identify predictors of mortality, and assess functional impairments concerning activities of daily living (ADLs) and instrumental ADL (IADL). METHODS: Our study was prospective, observational cohort study that enrolled patients receiving MHD. We collected demographic, clinical, and laboratory data. We also assessed ADLs and IADLs for daily performance. RESULTS: Our study included 167 patients with a mean age of 51.6 ± 13.1 years, and 56.9% were male. Of these, 80 (47.9%) were diabetic, and 145 (86.8%) were hypertensive. The mortality rate after 1 year of MHD was 10.8%, and cardiovascular causes accounted for over 70% of total deaths. Sudden cardiac death was the most frequent cause (38.9%), followed by cardiogenic shock (22.2%). Older age and low parathormone levels (<300 pg/mL) were significantly associated with higher mortality rates. Mean ADL and IADL scores were 4.5 ± 1.3 and 6.3 ± 2.7, respectively. Eighteen (10.8%) and 56 (33.5%) patients had low ADL and IADL scores, respectively. Although statistically insignificant, a higher proportion of non-survivors exhibited low IADL and ADL scores. Older age, longer diabetes duration, and higher BMI levels were significantly associated with lower IADL scores. CONCLUSIONS: Older age and suppressed PTH levels are predictors of mortality in ESRD patients receiving MHD. These patients require regular follow-ups to rule out cardiovascular morbidity. Functional impairment is prevalent but remains underdiagnosed in MHD patients. It should be monitored regularly to improve quality of life in ESRD.

Direct Immunofluorescence Findings and Factors Affecting Conjunctival Biopsy Positivity in Ocular Mucous Membrane Pemphigoid.

PURPOSE: The aim of this study was to describe the direct immunofluorescence (DIF) findings and factors affecting conjunctival biopsy positivity in patients clinically diagnosed with ocular mucous membrane pemphigoid (OMMP). METHODS: This retrospective observational case series included patients with clinical OMMP who underwent conjunctival biopsy for DIF in at least 1 eye between 2018 and 2021 in an institutional setting. The primary outcome measures were association of age and chronic ocular complications with biopsy positivity. RESULTS: Of 61 patients, DIF positivity was seen in 33 (54.1%) clinically suspected cases of OMMP. Of 39 patients who underwent bilateral biopsy, 23 (59%) were positive, of which 12 (52%) were positive in both eyes while 11 (48%) were positive in 1 eye. Of 22 patients who underwent unilateral biopsy, 10 (45%) were positive. Of the 100 biopsied eyes, 45 (45%) were DIF positive. Among the immunoreactants studied, linear deposition of C3 was seen in all 45 positive eyes (100%). Increasing age was significantly associated with higher likelihood of biopsy negativity ( P = 0.032), whereas a greater Sotozono chronic ocular complication score, indicative of disease severity, was associated with low likelihood of biopsy positivity ( P = 0.0042) and lower overall expression of immunoreactants on DIF ( P = 0.0007). CONCLUSIONS: Older patients and patients with more severe ocular surface disease sequelae are likely to have negative DIF results. To optimize the chances of confirming the diagnosis of OMMP by DIF, both eyes should be biopsied early in the disease course. If 1 eye is being biopsied, the less affected eye must be chosen.

Emulgels: a promising topical drug delivery system for arthritis management and care.

BACKGROUND: Emulgels, hybrid formulations of emulsions and gels, offer distinct benefits viz. extended release, enhanced bioavailability, and targeted drug delivery to inflamed joints, thereby minimizing systemic side effects, and maximizing therapeutic efficacy in targeting the diseases. Oral medications and topical creams have limitations viz. limited permeation, efficacy, and side effects. Arthritis is a prevalent chronic inflammatory disorder affecting a substantial global population of about 350 million necessitating the exploration of innovative and effective treatment approaches. Inflammation of one or more joints in the body is referred to generally as arthritis, associated with joint discomfort, edema, stiffness, and decreased motion in the joints. MAIN PART: Emulgels further improve drug solubility and penetration into the affected tissues, augmenting the potential for disease-modifying effects. This review article comprehensively examines recent research for the potential of emulgels (micro- and nanoemulgels) as a potential therapeutic approach for arthritis management, thus showcasing their promising potential in precise treatment regimens. Despite the considerable progress in emulgel-based arthritis therapies, the review emphasizes the need for additional research and translation to clinical trials, thus ascertaining their long-term safety, efficacy, and cost-effectiveness compared to conventional treatments. CONCLUSION: With ongoing advancements in drug delivery, emulgels present an exciting frontier in arthritis-associated conditions, with the potential to revolutionize arthritis treatment and significantly enhance patient life's quality.