Does Failure to Rescue Drive Race/Ethnicity-based Disparities in Survival After Heart Transplantation?

OBJECTIVE: The objective was to assess whether race/ethnicity is an independent predictor of failure to rescue (FTR) after orthotopic heart transplantation (OHT). SUMMARY BACKGROUND DATA: Outcomes following OHT vary by patient level factors; for example, non-White patients have worse outcomes than White patients after OHT. Failure to rescue is an important factor associated with cardiac surgery outcomes, but its relationship to demographic factors is unknown. METHODS: Using the United Network for Organ Sharing database, we included all adult patients who underwent primary isolated OHT between 1/1/2006 snd 6/30/2021. FTR was defined as the inability to prevent mortality after at least one of the UNOS-designated postoperative complications. Donor, recipient, and transplant characteristics, including complications and FTR, were compared across race/ethnicity. Logistic regression models were created to identify factors associated with complications and FTR. Kaplan Meier and adjusted Cox proportional hazards models evaluated the association between race/ethnicity and posttransplant survival. RESULTS: There were 33,244 adult, isolated heart transplant recipients included: the distribution of race/ethnicity was 66% (n=21,937) White, 21.2% (7,062) Black, 8.3% (2,768) Hispanic, and 3.3% (1,096) Asian. The frequency of complications and FTR differed significantly by race/ethnicity. After adjustment, Hispanic recipients were more likely to experience FTR than White recipients (OR 1.327, 95% CI[1.075-1.639], P =0.02). Black recipients had lower 5-year survival compared with other races/ethnicities (HR 1.276, 95% CI[1.207-1.348], P <0.0001). CONCLUSIONS: In the US, Black recipients have an increased risk of mortality after OHT compared with White recipients, without associated differences in FTR. In contrast, Hispanic recipients have an increased likelihood of FTR, but no significant mortality difference compared with White recipients. These findings highlight the need for tailored approaches to addressing race/ethnicity-based health inequities in the practice of heart transplantation.

Is Transplantation With Coronavirus Disease 2019-Positive Donor Lungs Safe? A US Nationwide Analysis.

BACKGROUND: Since the beginning of the pandemic, coronavirus disease 2019 (COVID-19) has caused debilitating lung failure in many patients. Practitioners have understandably been hesitant to use lungs from donors with COVID-19 for transplantation. This study aimed to analyze the characteristics and short-term outcomes of lung transplantation from donors with recent positive COVID-19 testing results. METHODS: Lung transplantations performed between January 2020 and June 2022 were queried from the United Network for Organ Sharing database. Pediatric, multiorgan, and repeat lung transplantations were excluded. Propensity scoring matched recipients of lungs from donors with recent positive COVID-19 testing results to recipients of lungs from donors with negative COVID-19 testing results, and comparisons of 30-day mortality, 3-month mortality, and perioperative outcomes were performed. RESULTS: A total of 5270 patients underwent lung transplantation during the study dates, including 51 patients who received lungs from donors with recent positive COVID-19 testing results. Forty-five recipients of lungs from donors with recent positive COVID-19 testing results were matched with 135 recipients of lungs from donors with negative COVID-19 testing results. After matching, there was no difference in 30-day (log-rank P = .42) and 3-month (log-rank P = .42) mortality. The incidence of other perioperative complications was similar between the groups. CONCLUSIONS: The 30-day and 3-month survival outcomes were similar between recipients of lungs from donors with recent positive COVID-19 testing results and recipients of lungs from donors with negative COVID-19 testing results. This finding suggests that highly selected COVID-19-positive donors without evidence of active infection may be safely considered for lung transplantation. Further studies should explore long-term outcomes to provide reassurance about the safety of this practice.

An assessment of the physicochemical characteristics and essential oil composition of Mentha longifolia (L.) Huds. exposed to different salt stress conditions.

Salt stress adversely influences growth, development, and productivity in plants, resulting in a limitation on agriculture production worldwide. Therefore, this study aimed to investigate the effect of four different salts, i.e., NaCl, KCl, MgSO4, and CaCl2, applied at various concentrations of 0, 12.5, 25, 50, and 100 mM on the physico-chemical properties and essential oil composition of M. longifolia. After 45 days of transplantation, the plants were irrigated at different salinities at 4-day intervals for 60 days. The resulting data revealed a significant reduction in plant height, number of branches, biomass, chlorophyll content, and relative water content with rising concentrations of NaCl, KCl, and CaCl2. However, MgSO4 poses fewer toxic effects than other salts. Proline concentration, electrolyte leakage, and DPPH inhibition (%) increase with increasing salt concentrations. At lower-level salt conditions, we had a higher essential oil yield, and GC-MS analysis reported 36 compounds in which (-)-carvone and D-limonene covered the most area by 22%-50% and 45%-74%, respectively. The expression analyzed by qRT-PCR of synthetic Limonene (LS) and Carvone (ISPD) synthetic genes has synergistic and antagonistic relationships in response to salt treatments. To conclude, it can be said that lower levels of salt enhanced the production of essential oil in M. longifolia, which may provide future benefits commercially and medicinally. In addition to this, salt stress also resulted in the emergence of novel compounds in essential oils, for which future strategies are needed to identify the importance of these compounds in M. longifolia.

Public health supply chain for iron and folic acid supplementation in India: Status, bottlenecks and an agenda for corrective action under Anemia Mukt Bharat strategy.

PURPOSE: The IFA supplementation program under the Anemia Mukt Bharat (AMB) program is one of the most ambitious nutrient supplementation programs in India. The delivery of services often suffers due to frequent stock outs and shortages. It is critical to understand the bottleneck in the supply chain adversely affecting the performance and coverage of the program. The paper attempts to identify the bottlenecks of the IFA supply chain in key areas of supply chain i.e., forecasting, procurement, warehousing and inventory management, transportation, distribution, logistic information system and suggests a plan of action aimed at ensuring uninterrupted supplies to the end beneficiaries. DESIGN/METHODOLOGY/APPROACH: The data source for the present paper is the nationwide IFA Supply Chain Assessment (2018-19) conducted across 29 Indian states with a total of 58 districts, 116 blocks, 232 Sub-Centres, 232 Anganwadi centres and 232 schools covered under the assessment as a multi-partner collaborative initiative. Field insights from supply chain strengthening interventions under different public health programs in India and other developing countries were taken to arrive at corrective actions and recommendations. Findings were disseminated to government and an action plan was suggested for connecting service delivery points through an app-based system, developing a micro plan for ensuring fixed distribution schedule, followed by continuous monitoring and review meetings identified for follow up. FINDINGS: The average lead time across states was 35 weeks with top three performing states being Goa, Sikkim, and Telangana. The average per unit cost of procurement was Rs 0.35 for IFA Red, Rs 0.25 for IFA Blue, Rs 0.31 for IFA Pink and Rs 7.30 for IFA syrup. Out of the 704 districts in India, only 213 has IFA Red, only 140 had IFA Blue, 152 had IFA Pink and 163 had IFA Syrup available in four quarters of 2018-19. The key issues identified in the assessment were-a lack of standardized forecasting process, absence of inventory management techniques, no fixed distribution schedule, inadequate availability of transport vehicles and an absence of an integrated MIS. ORIGINALITY/VALUE: The identification of bottlenecks in the IFA supply chain and its impact on the performance of the supply chain would provide policy guidelines for the government as well as development partner agencies to design an effective and efficient supply chain. It would also enable the policy planners to understand the challenges associated with managing different components of a supply chain, their interrelation and impact on the overall performance of the supply chain. The suggested recommendations would equip program managers with the tool to devise and implement field level solutions.

Lipid nanocapsules co-encapsulating paclitaxel and salinomycin for eradicating breast cancer and cancer stem cells.

Cancer stem cells (CSCs) comprise a diminutive population of the tumor but pose major obstacles in cancer treatment, often their presence being correlated with poor prognosis, therapeutic resistance and relapse. Nanocarriers of combined drugs regimes demonstrate improved pharmacokinetics and decreased systemic toxicity by targeting the bulk tumor cells along with CSCs, holding the key to future successful chemotherapy. Herein, we developed lipid nanocapsules (LNCs) with co-encapsulated paclitaxel (PTX) and salinomycin (SAL) to eliminate breast cancer cells (MCF-7; non-bCSCs) and cancer stem cells (bCSCs) respectively. LNCs loaded with either PTX or SAL alone or in combination were fabricated by the phase inversion temperature (PIT) method. Physicochemical properties such as nano-size (90 ±â€¯5 nm) and spherical morphology of LNCs were confirmed by dynamic light scattering (DLS) and scanning electron microscopy (SEM) respectively. More than 98 % encapsulation efficiency of drug, alone or in combination, and their controlled drug release was obtained. Drug loaded LNCs were efficiently internalized and exhibited cytotoxicity in non-bCSCs and bCSCs, with dual drug loaded LNCs offering superior cytotoxicity and anti-bCSCs property. Drug loaded nanocapsules induced apoptosis in bCSCs, potentiated with the co-delivery of paclitaxel and salinomycin. Synergistic cytotoxic effect on both cells, non-bCSCs and bCSCs and effective reduction of the tumor mammospheres growth by co-encapsulated paclitaxel and salinomycin suggest LNCs to be promising for treatment of breast cancer.

Protein-Sugar-Glass Nanoparticle Platform for the Development of Sustained-Release Protein Depots by Overcoming Protein Delivery Challenges.

Therapeutic protein depots have limited clinical success because of the presence of critical preparation barriers such as low encapsulation, uncontrolled release, and activity loss during processing and storage. In the present study, we used our novel protein-nanoencapsulation (into sugar-glass nanoparticle; SGnP) platform to prepare a protein depot to overcome the abovementioned formidable challenges. The SGnP-mediated microparticle protein depot has been validated using four model proteins (bovine serum albumin, horseradish peroxidase, fibroblastic growth factor, and epidermal growth factor) and model biodegradable poly(lactic-co-glycolic acid) polymer system. The results show that our protein-nanoencapsulation-mediated platform provides a new generic platform to prepare a protein depot through the conventional emulsion method of any polymer and single/multiple protein systems. This protein depot has the required pharmaceutical properties such as high encapsulation efficiency, burst-free sustained release, and protein preservation during processing and storage, making it suitable for off-the-shelf use in therapeutic protein delivery and tissue engineering applications.

Fabrication and Characterization of Core-Shell Nanofibers Using a Next-Generation Airbrush for Biomedical Applications.

The core-shell polymeric nanofiber, owing to its better controlled release of embedded or encapsulated drugs in contrast with the single-compartment nanofibers, has been extensively studied for biomedical applications such as tissue engineering and wound healing. Electrospinning with co-axial needles is the dominant technique to fabricate nanofiber mat, however, associated with potential limitations such as high voltage requirement, costly equipment, slow deposition rate, required trained personal, not suitable in situ fabrication, and direct deposition of core-shell nanofibers on the wound at patient bedside. To address the above limitations, the work aims to introduce a novel co-axial airbrushing method to fabricate core-shell nanofibers using a simple setup and low-cost equipment, yet having a unique ability for fabrication at patient bedside and direct deposition on wound bed. Air-brush with a coaxial needle is designed to flow two different polymers solution with model biomolecules through core [PEO (polyethylene oxide)/poly-dl-lactide/PCL (polycaprolactone)] and shell (PCL/PEO) needle for the fabrication of the model core-shell nanofiber. Various processing parameters such as flow rate, air pressure, working distance, and concentration of polymer solution which affect the morphology of core-shell nanofibers were studied and found to have a prominent effect. The PCL-PEO nanofiber possesses a defined shell and core structure, tunable sustained release behavior of model proteins (bovine serum albumin and basic fibroblast growth factor; bFGF), and improved mechanical strength. In vitro interaction of human bone marrow-derived mesenchymal stem cells with core-shell fibers demonstrated the cytocompatibility and proliferative and differentiative (for bFGF loaded) properties of the core-shell nanofiber mat. Co-axial airbrushing can be used as a superior less-expensive technique for the fabrication of biomolecules/drug encapsulated core-shell fibers scaffold at patient bedside, which can mimic complex in vivo environment and could modulate cells behavior close to their in vivo condition for tissue regeneration and wound healing.

Glucose deprivation induced upregulation of phosphoenolpyruvate carboxykinase modulates virulence in Leishmania donovani.

Various physiological stimuli trigger the conversion of noninfective Leishmania donovani promastigotes to the infective form. Here, we present the first evidence of the effect of glucose starvation, on virulence and survival of these parasites. Glucose starvation resulted in a decrease in metabolically active parasites and their proliferation. However, this was reversed by supplementation of gluconeogenic amino acids. Glucose starvation induced metacyclogenesis and enhanced virulence through protein kinase A regulatory subunit (LdPKAR1) mediated autophagy. Glucose starvation driven oxidative stress upregulated the antioxidant machinery, culminating in increased infectivity and greater parasitic load in primary macrophages. Interestingly, phosphoenolpyruvate carboxykinase (LdPEPCK), a gluconeogenic enzyme, exhibited the highest activity under glucose starvation to regulate growth of L. donovani by alternatively utilising amino acids. Deletion of LdPEPCK (Δpepck) decreased virulent traits and parasitic load in primary macrophages but increased autophagosome formation in the mutant parasites. Furthermore, Δpepck parasites failed to activate the Pentose Phosphate Pathway shunt, abrogating NADPH/NADP+ homoeostasis, conferring increased susceptibility towards oxidants following glucose starvation. In conclusion, this study showed that L. donovani undertakes metabolic rearrangements via gluconeogenesis under glucose starvation for acquiring virulence and its survival in the hostile environment.

Activity of a novel sulfonamide compound 2-nitro-N-(pyridin-2-ylmethyl)benzenesulfonamide against Leishmania donovani.

New treatments for visceral leishmaniasis, caused by Leishmania donovani, are needed to overcome sustained toxicity, cost, and drug resistance. The aim of this study was to evaluate the therapeutic effects of 2-nitro-N-(pyridin-2-ylmethyl)benzenesulfonamide (2NB) against promastigote and amastigote forms of L. donovani and examine its effect in combination with amphotericin B (AmB) against AmB-resistant clinical isolates. Effects were assessed against extracellular promastigotes in vitro and intracellular amastigotes in L. donovani-infected macrophages. Levels of inducible nitric oxide and Th1 and Th2 cytokines were measured in infected 2NB-treated macrophages, and levels of reactive oxygen species and NO were measured in 2NB-treated macrophages. 2NB was active against promastigotes and intracellular amastigotes with 50% inhibitory concentration values of 38.5±1.5 µg/mL and 86.4±2.4 µg/mL, respectively. 2NB was not toxic to macrophages. Parasite titer was reduced by >85% in infected versus uninfected macrophages at a 2NB concentration of 120 µg/mL. The parasiticidal activity was associated with increased levels of Th1 cytokines, NO, and reactive oxygen species. Finally, 2NB increased the efficacy of AmB against AmB-resistant L. donovani. These results demonstrate 2NB to be an antileishmanial agent, opening up a new avenue for the development of alternative chemotherapies against visceral leishmaniasis.

Two Chitotriose-Specific Lectins Show Anti-Angiogenesis, Induces Caspase-9-Mediated Apoptosis and Early Arrest of Pancreatic Tumor Cell Cycle.

The antiproliferative activity of two chito-specific agglutinins purified from Benincasa hispida (BhL) and Datura innoxia (DiL9) of different plant family origin was investigated on various cancer cell lines. Both lectins showed chitotriose specificity, by inhibiting lectin hemagglutinating activity. On further studies, it was revealed that these agglutinins caused remarkable concentration-dependent antiproliferative effect on human pancreatic cancerous cells but not on the normal human umbilical vein endothelial cells even at higher doses determined using MTT assay. The GI50 values were approximately 8.4 µg ml(-1) (0.247 µM) and 142 µg ml(-1) (14.8 µM) for BhL and DiL9, respectively, against PANC-1 cells. The growth inhibitory effect of these lectins on pancreatic cancer cells were shown to be a consequence of lectin cell surface binding and triggering G0/G1 arrest, mitochondrial membrane depolarization, sustained increase of the intracellular calcium release and the apoptotic signal is amplified by activation of caspases executing cell death. Interestingly, these lectins also showed anti-angiogenic activity by disrupting the endothelial tubulogenesis. Therefore, we report for the first time two chito-specific lectins specifically binding to tumor glycans; they can be considered to be a class of molecules with antitumor activity against pancreatic cancer cells mediated through caspase dependent mitochondrial apoptotic pathway.

Campylobacter-induced interleukin-8 secretion in polarized human intestinal epithelial cells requires Campylobacter-secreted cytolethal distending toxin- and Toll-like receptor-mediated activation of NF-kappaB.

Campylobacter jejuni and Campylobacter coli colonize and infect the intestinal epithelium and cause acute inflammatory diarrhea. The intestinal epithelium serves as a physical barrier to, and a sensor of, bacterial infection by secreting proinflammatory cytokines. This study examined the mechanisms for Campylobacter-induced secretion of the proinflammatory chemokine interleukin-8 (IL-8) by using polarized T84 human colonic epithelial cells as a model. C. jejuni increased the secretion of both IL-8 and tumor necrosis factor alpha (TNF-alpha) in polarized epithelial cells. However, the increase in IL-8 secretion was independent of Campylobacter-stimulated TNF-alpha secretion. Polarized T84 cells secreted IL-8 predominantly to the basolateral medium independently of the inoculation direction. While there was a significant correlation between the levels of IL-8 secretion and Campylobacter invasion, all 11 strains tested increased IL-8 secretion by polarized T84 cells despite their differences in adherence, invasion, and transcytosis efficiencies. Cell-free supernatants of Campylobacter-T84-cell culture increased IL-8 secretion to levels similar to those induced by live bacterial inoculation. The ability of the supernatant to induce IL-8 secretion was reduced by flagellum and cytolethal distending toxin (CDT) gene mutants, treatment of the supernatant with protease K or heat, or treatment of T84 cells with the Toll-like receptor (TLR) inhibitor MyD88 inhibitory peptide or chloroquine. NF-kappaB inhibitors or cdtB mutation plus MyD88 inhibitor, but not flaA cdtB double mutations, abolished the ability of the supernatant to induce IL-8 secretion. Taken together, our results demonstrate that Campylobacter-induced IL-8 secretion requires functional flagella and CDT and depends on the activation of NF-kappaB through TLR signaling and CDT in human intestinal epithelial cells.

Microwave enhanced solid support synthesis of fluorine containing benzopyrano-triazolo-thiadiazepines as potent anti-fungal agents.

A facile, dry media procedure has been developed for the synthesis of a series of a new class of fluorine containing 3-alkyl-7-chloro-11a,12-dihydro-11-phenyl-12-(substituted aryl)-11H-benzopyrano[4,3-e][1,2,4]-triazolo[3,4-b][1,3,4]-thiadiazepines (4a-k) under microwaves using basic alumina as solid support. The reaction time has been brought down from hours (60-65 h) to minutes (3-5 min) with improved yield as compared to conventional method, demonstrating the versatility of the process. The method reported herein is devoid of the hazards of solution-phase reactions. The synthesized compounds have been screened 'in vitro' for anti-fungal activity against Rhizoctonia solani, Fusarium oxysporum and Collectotrichum capsici. Most of the compounds have shown good activity against these pathogens.

Encrusted cystitis secondary to Corynebacterium matruchotii infection in a horse.

A 17-year-old gelding was evaluated because of dysuria, inappetence, and weight loss. Cystoscopy revealed severe mucosal ecchymoses with luminal hemorrhage and accumulations of crystalloid sludge. Analysis of a urine sample revealed isosthenuria, an alkaline pH, pyuria, hematuria, bacteriuria, and numerous calcium carbonate crystals. Histologic examination of bladder mucosa biopsy specimens revealed severe neutrophilic infiltration with mineralization. A diagnosis of encrusted cystitis exacerbated by sabulous urolithiasis was made. A Corynebacterium sp susceptible to penicillin, sulfonamide, and enrofloxacin was cultured from the urine and the bladder mucosa biopsy specimens. The horse was treated with penicillin G potassium, IV, for 5 days, followed by trimethoprim-sulfamethoxazole for 4 weeks. Bladder lavage was performed daily for the first 3 days with a balanced electrolyte solution and dimethyl sulfoxide in an attempt to aid expulsion of necrotic debris and crystalline sludge from the bladder. Molecular phylogenetic analysis based on the 16S rDNA gene sequence was used to identify the isolate and determine its phylogenetic position. Results indicated that the isolate was closely related to Corynebacterium matruchotii. To our knowledge, encrusted cystitis secondary to C matruchotii has not been previously identified in a horse.