Tailoring lipid nanoparticles for T-cell targeting in allergic asthma: Insights into efficacy and specificity.

Asthma impacts over 300 million patients globally, with significant health implications, especially in cases of its allergic subtype. The disease is characterized by a complex interplay of airway inflammation and immune responses, often mediated by Th2 cell-related cytokines. In this study, we engineered lipid nanoparticles (LNPs) to specifically deliver therapeutic siRNA via the transferrin receptor to T cells. Strain-promoted azide-alkyne cycloaddition (SPAAC) was employed for the conjugation of transferrin ligands to PEGylated lipids in the LNPs, with the goal of enhancing cellular uptake and gene knockdown. The obtained LNPs exhibited characteristics that make them suitable for pulmonary delivery. Using methods such as nanoparticle tracking analysis (NTA) and enzyme-linked immunosorbent assay (ELISA), we determined the average number of transferrin molecules bound to individual LNPs. Additionally, we found that cellular uptake was ligand-dependent, achieving a GATA3 knockdown of more than 50% in relevant in vitro and ex vivo models. Notably, our findings highlight the limitations inherent to modifying the surface of LNPs, particularly with regard to their targeting capabilities. This work paves the way for future research aimed at optimizing targeted LNPs for the treatment of immunologic diseases such as allergic asthma.

Gastrointestinal Mucormycosis: A Clinical Review.

Mucormycosis is a devastating fungal infection that is usually seen in immunocompromised hosts. It is caused by fungi of the subphylum Mucoromycotina, order Mucorales, with most cases caused by Mucor, Rhizopus, or Rhizomucor species. It can involve any organ system and can disseminate in severe cases. Lately, there has been an increased number of reports for mucormycosis infection in immunocompetent patients. Gastrointestinal system involvement is rare compared to other organ systems but has been increasingly reported in the literature. Mucormycosis can affect any part of the gastrointestinal tract and lead to different presentations depending on the area of involvement. Due to the paucity of the condition, there has been no specific guidelines on how to treat gastrointestinal mucormycosis. In this review, we discuss the risk factors of gastrointestinal mucormycosis, clinical presentation, approach to diagnosis, and most recent treatment modalities for gastrointestinal mucormycosis.

Strongyloides stercoralis Infection in Humans: A Narrative Review of the Most Neglected Parasitic Disease.

Strongyloidiasis is a helminth infection affecting 613.9 million people annually, mainly in the tropics and subtropics. The reported seroprevalence in the United States is 4% with most of the cases reported in immigrants. Human T-lympho-tropic virus 1 (HTLV-1) infections, hypogammaglobulinemia, immunosuppressant use - particularly steroid use, alcoholism, and malnutrition have been associated with an increased risk of strongyloidiasis. Recently, cases of strongyloidiasis hyperinfection syndrome have been described in coronavirus disease 2019 (COVID-19) patients treated with steroids as well. This brief review discusses the epidemiology, clinical features, management, and prevention of strongyloidiasis including some facts about the infection in pregnancy, transplant recipients, and COVID-19 patients. We conducted an online search using the PubMed, Scopus, and Google Scholar databases. Strongyloidiasis can be asymptomatic or present with mild symptoms. Strongyloides stercoralis is known to cause autoinfection. In immunocompromised individuals, it can present with severe symptoms, hyperinfection, or disseminated disease. Reported mortality in cases of disseminated Strongyloidiasis is 87.1%. Serology and detection of larvae in stool by direct microscopy are the most commonly used methods to diagnose strongyloidiasis. The drug of choice for the treatment is ivermectin. However, the use of ivermectin in human pregnancy is not well studied, and its teratogenic risks are unknown. Proactive screening of strongyloidiasis is necessary in immunocompromised individuals to prevent severe disease.

Synthesis and application of spermine-based amphiphilic poly(ß-amino ester)s for siRNA delivery.

Small interfering RNA (siRNA) can trigger RNA interference (RNAi) to therapeutically silence disease-related genes in human cells. The approval of siRNA therapeutics by the FDA in recent years generated a new hope in novel and efficient siRNA therapeutics. However, their therapeutic application is still limited by the lack of safe and efficient transfection vehicles. In this study, we successfully synthesized a novel amphiphilic poly(ß-amino ester) based on the polyamine spermine, hydrophobic decylamine and 1,4-butanediol diacrylate, which was characterized by 1H NMR spectroscopy and size exclusion chromatography (SEC, Mn = 6000 Da). The polymer encapsulated siRNA quantitatively from N/P 5 on as assessed by fluorescence intercalation while maintaining optimal polyplex sizes and zeta potentials. Biocompatibility and cellular delivery efficacy were also higher than those of the commonly used cationic, hyperbranched polymer polyethylenimine (PEI, 25 kDa). Optimized formulations mediated around 90% gene silencing in enhanced green fluorescence protein expressing H1299 cells (H1299-eGFP) as determined by flow cytometry. These results suggest that spermine-based, amphiphilic poly(ß-amino ester)s are very promising candidates for efficient siRNA delivery.

Diagnosis and Outcomes of Fungal Co-Infections in COVID-19 Infections: A Retrospective Study.

The SARS-CoV-2 pandemic has resulted in a public health emergency with unique complications such as the development of fungal co-infections. The diagnosis of fungal infections can be challenging due to confounding imaging studies and difficulty obtaining histopathology. In this retrospective study, 173 patients with COVID-19 receiving antifungal therapy due to concern for fungal co-infection were evaluated. Patient characteristics, clinical outcomes, and the utility of fungal biomarkers were then evaluated for continuation of antifungal therapy. Data were collected from the electronic health record (EPIC) and analyzed using SPSS (version. 28, IBM, Inc., Armonk, NY, USA) Data are presented as mean ± SD or percentages. A total of 56 COVID-19 patients were diagnosed with fungal co-infection and 117 COVID-19 + patients had no fungal infection. Significantly fewer female patients were in the fungal+ group compared to COVID-19 control patients (29% in fungal+ compared to 51% in controls p = 0.005). Fungal diagnostics were all significantly higher in fungal+ patients. These include 1,4-beta-D-glucan (BDG), fungal culture, and bronchoalveolar lavage galactomannan (BAL GM). Intensive care unit hospitalization, mechanical ventilation, and mortality in fungal+ patients with COVID-19 were significantly higher than in control patients. Finally, significantly more fungal+ patients received voriconazole, isavuconazonium, or amphotericin B therapies, whereas control patients received significantly more short-course fluconazole. COVID-19+ patients with fungal co-infection were significantly more likely to be in the ICU and mechanically ventilated, and they result in higher mortality compared to control COVID-19 patients. The use of fungal diagnostics markers were helpful for diagnosis.

Accuracy of medication histories derived from an Australian cloud-based repository of prescribed and dispensed medication records.

BACKGROUND: Obtaining accurate medication histories at transitions of care is challenging, but important for patient safety. Prescription exchange services (PES) securely transfer electronic prescription and dispensing records between prescribers and pharmacies, which is potentially useful data for determining medication histories. AIM: To evaluate the accuracy of PES-derived medication histories. METHODS: Prospective observational study, at two Australian tertiary-referral health services. A convenience sample of adult inpatients was recruited. The main outcome measure was: proportion of patients with ≥1 errors in their PES-derived pre-admission medication histories, compared with gold-standard best-possible medication histories, including prescribed and non-prescribed medications, obtained by pharmacists using multiple sources including patient/carer interview. RESULTS: Of 154 patients (median age 76 years; interquartile range (IQR) 64-84 years; median 10.0 pre-admission medications; IQR 6.0-14.0), 153 (99.4%) had ≥1 errors in their PES-derived medication history (median 6.0 errors per patient; IQR 4.0-9.0). Excluding when-required medications, 146 (94.8%) patients had >1 errors (median 4.0 errors per patient; IQR 2.0-6.0). Omission was the most common error, affecting 549 (33.3%) of 1648 current medications (median 3.0; IQR 1.0-5.0 per patient); 396 (72.1%) omissions were over-the-counter medicines. Dose-regimen errors affected 276 (25.1%) of 1099 current medications captured in PES-derived medication histories (median 1.0 error per patient; IQR 0.0-3.0). Commission errors (medications in PES-derived histories that were not current) affected 224 (16.9%) of 1323 medications (median 1.0 error per patient; IQR 1.0-2.0). CONCLUSIONS: Medication histories derived solely from a cloud-based medication record repository had a high error rate compared with patients' actual medication use. Like all medication history sources, data from cloud-based repositories need to be verified with additional sources including the patient and/or their carer.

Improved Medication Management With Introduction of a Perioperative and Prescribing Pharmacist Service.

BACKGROUND: The medication lists in pre-admission clinic (PAC) questionnaires completed by patients prior to surgery are often inaccurate, potentially leading to medication errors during hospitalization. Studies have shown pharmacists are more accurate when obtaining a medication history and transcribing prescription orders, thereby reducing errors. OBJECTIVE: To evaluate the impact of a PeRiopErative and Prescribing (PREP) pharmacist on postoperative medication management. METHODS: A randomized prospective interventional study enrolled elective surgery patients at high risk for medication misadventure to receive PREP pharmacy service or usual care (control group). A best possible medication history (BPMH) was obtained by the PREP pharmacist and was available to surgical staff on admission. The PREP pharmacist also prepared discharge prescriptions for their patients. The primary outcomes for the study were accuracy of BPMH and discharge prescriptions compared to usual care. The study was powered to 80% with 2-tailed significance α of .05. RESULTS: The medication history in the PREP pharmacist group had fewer errors than the control group: 9% (5/53) versus 96% (49/51; P < .001). Discharge prescriptions prepared by the PREP pharmacist had fewer errors than control group: 25% versus 78% (P < .001). Significantly, more PREP pharmacist patients received a discharge summary with a complete medication list: 75% versus 33% (P = .001). Inpatient prescribing was more accurate in the PREP pharmacist patients: 0.64 versus 1.31 errors per patient (P = .047). CONCLUSION: Inclusion of the PREP pharmacist role in the elective surgery multidisciplinary team improved the accuracy of medication histories, inpatient prescribing, and discharge prescriptions for patients at high risk of medication misadventure.

Troglitazone stimulates beta-arrestin-dependent cardiomyocyte contractility via the angiotensin II type 1A receptor.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) agonists are commonly used to treat cardiovascular diseases, and are reported to have several effects on cardiovascular function that may be due to PPAR gamma-independent signaling events. Select angiotensin receptor blockers (ARBs) interact with and modulate PPAR gamma activity, thus we hypothesized that a PPAR gamma agonist may exert physiologic effects via the angiotensin II type 1(A) receptor (AT1(A)R). In AT1(A)R-overexpressing HEK 293 cells, both angiotensin II (Ang II) and the PPAR gamma agonist troglitazone (Trog) enhanced AT1(A)R internalization and recruitment of endogenous beta-arrestin 1/2 (beta arr1/2) to the AT1(A)R. A fluorescence assay to measure diacylglycerol (DAG) accumulation showed that although Ang II induced AT1(A)R-G(q) protein-mediated DAG accumulation, Trog had no impact on DAG generation. Trog-mediated recruitment of beta arr1/2 was selective to AT1(A)R as the response was prevented by an ARB- and Trog-mediated beta arr1/2 recruitment to beta1-adrenergic receptor (beta 1AR) was not observed. In isolated mouse cardiomyocytes, Trog increased both % and rate of cell shortening to a similar extent as Ang II, effects which were blocked with an ARB. Additionally, these effects were found to be beta arr2-dependent, as cardiomyocytes isolated from beta arr2-KO mice showed blunted contractile responses to Trog. These findings show for the first time that the PPAR gamma agonist Trog acts at the AT1(A)R to simultaneously block G(q) protein activation and induce the recruitment of beta arr1/2, which leads to an increase in cardiomyocyte contractility.