Macrophage-targeted versus free calcitriol as host-directed adjunct therapy against Mycobacterium tuberculosis infection in mice is bacteriostatic and mitigates tissue pathology.

Host-directed therapy (HDT) with vitamin D in tuberculosis (TB) is beneficial only if the subject is deficient in vitamin D. We investigated pulmonary delivery of 1,25-dihydroxy vitamin D3 (calcitriol) in mice infected with Mycobacterium tuberculosis (Mtb). We made two kinds of dry powder inhalations (DPI)- soluble particles or poly(lactide) (PLA) particles. We compared treatment outcomes when infected mice were dosed with a DPI alone or as an adjunct to standard oral anti-TB therapy (ATT). Mice infected on Day 0 were treated between Days 28-56 and followed up on Days 57, 71, and 85. Neither DPI significantly reduced Mtb colony forming units (CFU) in the lungs. Combining DPI with ATT did not significantly augment bactericidal activity in the lungs, but CFU were 2-log lower in the spleen. CFU showed a rising trend on stopping treatment, sharper in groups that did not receive calcitriol. Lung morphology and histology improved markedly in animals that received PLA DPI; with or without concomitant ATT. Groups receiving soluble DPI had high mortality. DPI elicited cathelicidin, interleukin (IL)-1 and induced autophagy on days 57, 71, and 85. Macrophage-targeted calcitriol is therefore bacteriostatic, evokes innate microbicidal mechanisms, and mitigates pathology arising from the host response to Mtb.

Leveraging existing mid-end ultrasound machine for point-of-care intestinal ultrasound in low-resource settings: Prospective, real-world impact on clinical decision-making.

BACKGROUND: Point-of-care ultrasound (POCUS) has transformed inflammatory bowel disease (IBD) management, but the cost to purchase high-end equipment can be prohibitive. AIM: To assess prospectively the feasibility of POCUS using pre-existing mid-end ultrasound equipment without incurring additional cost. METHODS: Consecutive IBD patients underwent POCUS with or without faecal calprotectin (FCP) using a mid-end ultrasound machine. If POCUS with or without FCP could not guide management, we performed additional ileocolonoscopy or cross-sectional imaging. We evaluated the impact of POCUS on IBD management and its correlation with ileocolonoscopy or cross-sectional imaging. We analysed pregnant, paediatric and post-operative patients separately. RESULTS: Among 508 patients with IBD, we analysed 419 (60.4% Crohn's disease [CD]; 61.3% male, age [years]: 36 [18-78]) undergoing 556 POCUS sessions. POCUS with or without FCP independently influenced clinical management in 42.8% of patients with CD and 49.7% with ulcerative colitis (UC). POCUS helped avoid colonoscopy in 51.4% of patients with CD and 51.8% with UC, and cross-sectional imaging in 38.1% of suspected active small bowel CD. In patients with additional diagnostics, POCUS-based decisions remained unchanged in 81.2% with CD and 85% with UC. Sensitivity and specificity of POCUS compared to ileocolonoscopy were 80% and 94.4% for CD and 80.8% and 92.8% for UC, respectively. Sensitivity and specificity compared to cross-sectional imaging were 87.2% and 87.5%, respectively. CONCLUSION: POCUS using existing mid-end ultrasound equipment in low-resource settings influenced IBD clinical decision-making with excellent accuracy, often avoiding colonoscopy and cross-sectional imaging.

Mycobacteriophages: therapeutic approach for mycobacterial infections.

Tuberculosis (TB) is a significant global health threat, and cases of infection with non-tuberculous mycobacteria (NTM) causing lung disease (NTM-LD) are rising. Bacteriophages and their gene products have garnered interest as potential therapeutic options for bacterial infections. Here, we have compiled information on bacteriophages and their products that can kill Mycobacterium tuberculosis or NTM. We summarize the mechanisms whereby viable phages can access macrophage-resident bacteria and not elicit immune responses, review methodologies of pharmaceutical product development containing mycobacteriophages and their gene products, mainly lysins, in the context of drug regulatory requirements and we discuss industrially relevant methods for producing pharmaceutical products comprising mycobacteriophages, emphasizing delivery of mycobacteriophages to the lungs. We conclude with an outline of some recent case studies on mycobacteriophage therapy.

Modulation of nuclear receptor 4A1 expression improves insulin secretion in a mouse model of chronic pancreatitis.

OBJECTIVES: Diabetes secondary to chronic pancreatitis (CP) presents clinical challenges due to insulin secretory defects and associated metabolic alterations. Owing to lack of molecular understanding, no pharmacotherapies to treat insulin secretory defects have been approved to date. We aimed to delineate the molecular mechanism of ß-cell dysfunction in CP. METHODS: Transcriptomic analysis was conducted to identify endocrine specific receptor expression in mice and human CP on microarray. The identified receptor (NR4A1) was overexpressed in MIN6 cells using PEI linear transfection. RNA-Seq analysis on NovaSeq 6000 of NR4A1 overexpressed (OE) MIN6 cells was performed to identify aberrant metabolic pathways. Upstream trigger for NR4A1OE was studied by InBio Discover and cytokine exposure. Downstream effect of NR4A1OE was examined by Fura2 AM based fluorometric and imaging studies of intracellular calcium. Mice with CP were treated with IFN-γ neutralizing monoclonal antibodies to assess NR4A1 expression and insulin secretion. RESULTS: Increased expression of NR4A1 associated with decreased insulin secretion in islets (humans: controls 9 ± 0.2, CP 3.7 ± 0.2, mice: controls 8.5 ± 0.2, CP 2.1 ± 0.1 µg/L). NR4A1OE in MIN6 cells (13.2 ± 0.1) showed reduction in insulin secretion (13 ± 5 to 0.2 ± 0.1 µg/mg protein/minute, p = 0.001) and downregulation of calcium and cAMP signaling pathways. IFN-γ was identified as upstream signal for NR4A1OE in MIN6. Mice treated with IFN-γ neutralizing antibodies showed decreased NR4A1 expression 3.4 ± 0.11-fold (p = 0.03), improved insulin secretion (4.4 ± 0.2-fold, p = 0.01), associated with increased Ca2+ levels (2.39 ± 0.06-fold, p = 0.009). CONCLUSIONS: Modulating NR4A1 expression can be a promising therapeutic strategy to improve insulin secretion in CP.

Fostering the unleashing potential of nanocarriers-mediated delivery of ocular therapeutics.

Ocular delivery is the most challenging aspect in the field of pharmaceutical research. The major hurdle for the controlled delivery of drugs to the eye includes the physiological static barriers such as the complex layers of the cornea, sclera and retina which restrict the drug from permeating into the anterior and posterior segments of the eye. Recent years have witnessed inventions in the field of conventional and nanocarrier drug delivery which have shown considerable enhancement in delivering small to large molecules across the eye. The dynamic challenges associated with conventional systems include limited drug contact time and inadequate ocular bioavailability resulting from solution drainage, tear turnover, and dilution or lacrimation. To this end, various bioactive-based nanosized carriers including liposomes, ethosomes, niosomes, dendrimer, nanogel, nanofibers, contact lenses, nanoprobes, selenium nanobells, nanosponge, polymeric micelles, silver nanoparticles, and gold nanoparticles among others have been developed to circumvent the limitations associated with the conventional dosage forms. These nanocarriers have been shown to achieve enhanced drug permeation or retention and prolong drug release in the ocular tissue due to their better tissue adherence. The surface charge and the size of nanocarriers (10-1000 nm) are the important key factors to overcome ocular barriers. Various nanocarriers have been shown to deliver active therapeutic molecules including timolol maleate, ampicillin, natamycin, voriconazole, cyclosporine A, dexamethasone, moxifloxacin, and fluconazole among others for the treatment of anterior and posterior eye diseases. Taken together, in a nutshell, this extensive review provides a comprehensive perspective on the numerous facets of ocular drug delivery with a special focus on bioactive nanocarrier-based approaches, including the difficulties and constraints involved in the fabrication of nanocarriers. This also provides the detailed invention, applications, biodistribution and safety-toxicity of nanocarriers-based therapeutcis for the ophthalmic delivery.

Recent Advancement and Future Perspective of Per Oral Endoscopic Myotomy.

Per oral endoscopic myotomy (POEM) has emerged as a preferred approach for the treatment of idiopathic achalasia and various esophageal motility disorders, offering a minimally invasive alternative to traditional laparoscopic Heller's myotomy. Over the past decade, POEM has solidified its status as the primary therapeutic choice in these conditions through constant improvements. Its evolution has been marked by continuous progress, driven by the integration of innovative technologies and sophisticated techniques. Notable advancements in the techniques include the advent of shorter myotomies and sling fiber-preserving gastric myotomies. The introduction of novel image-enhanced endoscopic techniques, such as red dichromatic imaging and much safer bipolar devices, promises to enhance safety and reduce the technical demands of the POEM procedure. Furthermore, significant strides have been made in understanding gastroesophageal reflux (GERD) following POEM, enabling the differentiation of "true reflux" from acidification resulting from fermentation through manual pH tracing assessment. This distinction aids in identifying cases necessitating treatment with proton pump inhibitors. Other treatment strategies of post-POEM GERD have expanded to the incorporation of NOTES fundoplication and device-assisted fundoplication if the necessity arises. This comprehensive review delves into recent developments in POEM, encompassing technical variations, the assessment and management of post-POEM reflux, outcomes in special populations, and future prospects. By exploring these facets, we aim to provide a comprehensive overview of the current state of POEM, shedding light on its evolution and the promising directions it is poised to take in the field of third-space endoscopy.

Endoscopic full thickness resection: techniques, applications, outcomes.

INTRODUCTION: Endoscopic full-thickness resection (EFTR) represents a pivotal advancement in the minimally invasive treatment of gastrointestinal lesions, offering a novel approach for the management of lesions previously deemed challenging or unreachable through conventional endoscopic techniques. AREAS COVERED: This review discusses the development, methodologies, applications, and clinical outcomes associated with EFTR, including exposed and device-assisted EFTR, the integration of endoscopic mucosal resection with EFTR in hybrid techniques, and the collaborative approach between laparoscopic and endoscopic surgery (LECS). It encapsulates a comprehensive analysis of the various EFTR techniques tailored to specific lesion characteristics and anatomical locations, underscoring the significance of technique selection based on the lesion's nature and situational context. EXPERT OPINION/COMMENTARY: The review underscores EFTR's transformative role in expanding therapeutic horizons for gastrointestinal tumors, emphasizing the importance of technique selection tailored to the unique attributes of each lesion. It highlights EFTR's capacity to facilitate organ-preserving interventions, thereby significantly enhancing patient outcomes and reducing procedural complications. EFTR is a cornerstone in the evolution of gastrointestinal surgery, marking a significant leap forward in the pursuit of precision, safety, and efficacy in tumor management.

Application of machine-learning model to optimize colonic adenoma detection in India.

AIMS: There is limited data on the prevalence and risk factors of colonic adenoma from the Indian sub-continent. We aimed at developing a machine-learning model to optimize colonic adenoma detection in a prospective cohort. METHODS: All consecutive adult patients undergoing diagnostic colonoscopy were enrolled between October 2020 and November 2022. Patients with a high risk of colonic adenoma were excluded. The predictive model was developed using the gradient-boosting machine (GBM)-learning method. The GBM model was optimized further by adjusting the learning rate and the number of trees and 10-fold cross-validation. RESULTS: Total 10,320 patients (mean age 45.18 ± 14.82 years; 69% men) were included in the study. In the overall population, 1152 (11.2%) patients had at least one adenoma. In patients with age > 50 years, hospital-based adenoma prevalence was 19.5% (808/4144). The area under the receiver operating curve (AUC) (SD) of the logistic regression model was 72.55% (4.91), while the AUCs for deep learning, decision tree, random forest and gradient-boosted tree model were 76.25% (4.22%), 65.95% (4.01%), 79.38% (4.91%) and 84.76% (2.86%), respectively. After model optimization and cross-validation, the AUC of the gradient-boosted tree model has increased to 92.2% (1.1%). CONCLUSIONS: Machine-learning models may predict colorectal adenoma more accurately than logistic regression. A machine-learning model may help optimize the use of colonoscopy to prevent colorectal cancers. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT04512729).

Plasma Metabolite Profiling Identifies Nondiabetic Chronic Pancreatitis Patients With Metabolic Alterations Progressing to Prediabetes Before HbA1c.

INTRODUCTION: Diabetes (T3cDM) secondary to chronic pancreatitis (CP) arises due to endocrine dysfunction and metabolic dysregulations. Currently, diagnostic tests are not available to identify patients who may progress from normoglycemia to hyperglycemia in CP. We conducted plasma metabolomic profiling to diagnose glycemic alterations early in the course of disease. METHODS: Liquid chromatography-tandem mass spectrometry was used to generate untargeted, targeted plasma metabolomic profiles in patients with CP, controls (n = 445) following TRIPOD guidelines. Patients were stratified based on glucose tolerance tests following ADA guidelines. Multivariate analysis was performed using partial least squares discriminant analysis to assess discriminatory ability of metabolites among stratified groups. COMBIROC and logistic regression were used to derive biomarker signatures. AI-ML tool (Rapidminer) was used to verify these preliminary results. RESULTS: Ceramide, lysophosphatidylethanolamine, phosphatidylcholine, lysophosphatidic acid (LPA), phosphatidylethanolamine, carnitine, and lysophosphatidylcholine discriminated T3cDM CP patients from healthy controls with AUC 93% (95% CI 0.81-0.98, P < 0.0001), and integration with pancreatic morphology improved AUC to 100% (95% CI 0.93-1.00, P < 0.0001). LPA, phosphatidylinositol, and ceramide discriminated nondiabetic CP with glycemic alterations (pre-diabetic CP); AUC 66% (95% CI 0.55-0.76, P = 0.1), and integration enhanced AUC to 74% (95% CI 0.55-0.88, P = 0.86). T3cDM was distinguished from prediabetic by LPA, phosphatidylinositol, and sphinganine (AUC 70%; 95% CI 0.54-0.83, P = 0.08), and integration improved AUC to 83% (95% CI 0.68-0.93, P = 0.05). CombiROC cutoff identified 75% and 78% prediabetes in validation 1 and 2 cohorts. Random forest algorithm assessed performance of integrated panel demonstrating AUC of 72% in predicting glycemic alterations. DISCUSSION: We report for the first time that a panel of metabolites integrated with pancreatic morphology detects glycemia progression before HbA1c in patients with CP.

Therapeutic endoscopy: Recent updates and future directions.

The landscape of therapeutic endoscopy has undergone a remarkable evolution over the past few decades, carving out a niche that merges innovative technology with advanced clinical practice. As we venture further into the 21st century, the horizon of this field continues to expand, driven by rapid advancements in technology and a deeper understanding of gastrointestinal pathology. This review article aims to shed light on the recent advances and future trajectories of therapeutic endoscopy, focusing on pivotal areas such as third space endoscopy, endoscopic resection techniques, artificial endoscopy, endoscopic ultrasound (EUS), the integration of artificial intelligence (AI), and endoscopic anti-reflux therapies.

Highly Stereoselective Diels-Alder-Based Strategy for the Synthesis of 3-epi-Formicin A and 1-epi-Formicin B.

The first enantioselective approach based on a highly stereoselective Diels-Alder reaction for the synthesis of 3-epi-formicin A and 1-epi-formicin B with rare N-acetylcysteamine-containing indenone thioesters is reported. The strategy utilizes a key Diels-Alder reaction to form the core hydrindane system with three contiguous stereocenters in very high levels of diastereo- and regioselectivity and one-pot oxidation/isomerization/dehydrogenation. The scope of this method was tested with different substrates to give cycloadducts in a highly diastereoselective manner.

Effect of Drill Induced Noise on Contralateral Normal Ear Following Cortical Mastoidectomy.

INTRODUCTION: Chronic suppurative otitis media (CSOM) is a long standing infection of the middle ear cleft. Mastoidectomy, with or without tympanoplasty, is the preferred treatment for CSOM. However, the drill used during ear surgery generates noise that may potentially cause hearing damage in both the operated and opposite inner ear, leading to temporary or permanent hearing loss. MATERIALS AND METHODS: The study included patients diagnosed with CSOM who underwent surgeries in the Otorhinolaryngology department. Postoperatively, all patients were followed up on the 7th day and 1 month after the surgery. Pure Tone Audiometry (PTA) was performed to evaluate the hearing outcomes. RESULTS: A total of 61 patients were included in the study. The mean preoperative PTA of contralateral ear bone conduction among the study participants was 6.48. At the 7th day post-operation, the mean post-operative PTA of contralateral ear bone conduction for the same participants was 7.77. This difference was statistically significant according to the Paired T-test (P = 0.001).However, when evaluating the mean preoperative PTA of contralateral ear bone conduction (6.48) and the mean post-operative PTA at 1st month (6.02), the difference was not statistically significant (P = 0.208).Additionally, there was no statistical difference in air conduction and air-bone gap before and after surgery. CONCLUSION: The study suggests that mastoid drilling is associated with a significant temporary hearing loss in the contralateral ear immediately after surgery, which eventually recovers within a month. However, the hearing loss is considered negligible and not statistically significant in the long term. It is worth considering additional audiological investigations, such as otoacoustic emissions, to detect this type of hearing loss more accurately.

Total Synthesis and Revision of Stereochemistry of a Natural Benzo[g]isochromene Stereodiad Isolated from Rubia philippinensis.

This study presents a total synthesis and revision of the stereochemical configuration of the conformationally flexible natural product benzo[g]isochromene stereodiad alongside its diastereomeric counterparts. The highlights of the synthesis are the TiCl4-mediated diastereoselective aldol reaction, Pd-catalyzed lactonization, and Schmidt glycosidation. Our efforts using total synthesis disclosed herein proved that a previously assigned structure required revision.

Oxidative Control of Photoinduced Cascade Electrocyclizations in Aromatic Azido Imines to Access Complex Fused Imidazoles or Pyrazoles.

Photoinduced cascade of two 6π-electron six- and five-center electrocyclizations in aromatic azido imines is oxidatively controlled to yield complex fused benzimidazoles or indazoles. Formation of benzimidazoles occurs via an unprecedented carbon-to-nitrogen o-iminoaryl 1,2-shift.

Atmospheric aerosol chemistry and source apportionment of PM10 using stable carbon isotopes and PMF modelling during fireworks over Hyderabad, southern India.

This study examined the influence of fireworks on atmospheric aerosols over the Southern Indian city of Hyderabad during festival of Diwali using mass closure, stable carbon isotopes and the EPA-PMF model. Identification of chemical species in day and night time aerosol samples for 2019 and 2020 Diwali weeks showed increased concentrations of NH4+, NO3-, SO42-, K+, organic carbon (OC), Ba, Pb and Li, which were considered as tracers for fireworks. PM10 source apportionment was done using inorganic (trace elements, major ions) and carbonaceous (organic and elemental carbon; OC & EC) constituents, along with stable isotopic compositions of TC and EC. K+/Na+ ∼1 and K+nss/OC > 0.5 indicated contribution from fireworks. High NO3-, NH4+, Na+, Cl- and SO42- suggested the presence of deliquescent salts NaCl, NH4NO3 and (NH4)2SO4. TAE/TCE >1 suggested H+ exclusion, indicating possible presence of H2SO4 and NH4HSO4 in the aerosols. Ba, Pb, Sb, Sr and Fe increased by 305 (87), 12 (11), 12 (3), 3 (2) and 3 (4) times on Diwali nights, compared to pre-Diwali of 2019 (2020), and are considered as metallic tracers of fireworks. δ13CTC and δ13CEC in aerosols closely resembled that of diesel and C3 plant burning emissions, with meagre contribution from firecrackers during Diwali period. The δ13CEC was relatively depleted than δ13CTC and δ13COC. For both years, δ13COC-EC (δ13COC - δ13CEC) were positive, suggesting photochemical aging of aerosols during long-range transport, while for pre-Diwali 2019 and post-Diwali 2020, δ13COC-EC were negative with high OC/EC ratio, implying secondary organic aerosols formation. High toluene during Diwali week contributed to fresh SOA formation, which reacted with precursor 12C, leading to 13C depletions. Eight-factored EPA-PMF source apportionment indicated highest contribution from residue/waste burning, followed by marine/dust soil and fireworks, while least was contributed from solid fuel/coal combustion.