Investigation of Levan-derived Nanoparticles of Dolutegravir: A Promising Approach for the Delivery of anti-HIV Drug as Milk Admixture.

Nanoparticles composed of Levan and Dolutegravir (DTG) have been successfully synthesized using a spray drying procedure specifically designed for milk/food admixture applications. Levan, obtained from the microorganism Bacillus subtilis, was thoroughly characterized using MALDI-TOF and solid-state NMR technique to confirm its properties. In the present study, this isolated Levan was utilized as a carrier for drug delivery applications. The optimized spray-dried nanoparticles exhibited a smooth surface morphology with particle sizes ranging from 195 to 329 nm. In the in-vitro drug release experiments conducted in water media, the spray-dried nanoparticles showed 100% release, whereas the unprocessed drug exhibited only 50% release at the end of 24 hours. Notably, the drug release in milk was comparable to that in plain media, indicating the compatibility. The improved dissolution rate observed for the nanoparticles could be attributed to the solid-state conversion (confirmed by XRD analysis) of DTG from its crystalline to amorphous state. The stability of the drug was verified using Fourier Transform Infra-Red Spectroscopy and Thermogravimetry-Differential Scanning Calorimetry analysis. To evaluate the in-vitro cellular toxicity, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted, which revealed the CC50 value of 88.88 ± 5.10 µg/mL for unprocessed DTG and 101.08 ± 37.37 µg/mL for DTG nanoparticles. These results indicated that the toxicity of the nanoparticles was comparable to the unprocessed drug. Furthermore, the anti-HIV activity of the nanoparticles in human cell lines was found to be similar to that of the pure drug, emphasizing the therapeutic efficacy of DTG in combating HIV.

Compatibilizing of cotton fabric with hydrophobic drug cover layer for anti-inflammatory performance with the implementation of ibuprofen.

This paper presents active analgesic and anti-inflammatory dressings based on cotton woven material with surface functionalization enabling drug implementation. For this purpose, lactide was polymerized on the surface of cotton textiles to achieve better compatibility with hydrophobic drug and polylactide (PLA)-based macromolecules. Subsequently, ibuprofen-loaded PLA and PLA-PEG were implemented through the exhausting method. Such material was tested for cytotoxicity (toward L929 mouse fibroblasts) and anti-inflammatory activity (towards human Hs68 fibroblasts) based on the secretion of pro-inflammatory cytokines IL-1ß and TNF-α. The results showed that the drug attachment and its performance are influenced by a combination of mercerization, bleaching and polylactide grafting, and the release of ibuprofen depends on the drug-loaded layer structure. Moreover, we show that cotton woven fabric with ibuprofen-loaded PLA and PLA-PEG cover layers had anti-inflammatory properties. These new dressings may open possibilities for developing prolonged analgesic and anti-inflammatory materials for wound healing or transdermal drug delivery.

Spray-dried pH-sensitive chitosan microparticles loaded with Mycobacterium bovis BCG intended for supporting treatment of Helicobacter pylori infection.

Gram-negative spiral-shaped Helicobacter pylori (Hp) bacteria induce the development of different gastric disorders. The growing resistance of Hp to antibiotics prompts to search for new therapeutic formulations. A promising candidate is Mycobacterium bovis BCG (BCG) with immunomodulatory properties. Biodegradable mucoadhesive chitosan is a good carrier for delivering BCG mycobacteria to the gastric mucosal environment. This study aimed to show whether BCG bacilli are able to increase the phagocytic activity of Cavia porcellus-guinea pig macrophages derived from the bone marrow towards fluorescently labeled Escherichia coli. Furthermore, to encapsulate live BCG bacilli, in spray-dried chitosan microparticles (CHI-MPs), and assess the pH-dependent release of mycobacteria in pH conditions mimicking gastric (acidic) or gut (alkaline) milieu. Microparticles (MPs) were made of chitosan and coated with Pluronic F-127-(Plur) or N-Acetyl-D-Glucosamine-(GlcNAc) to increase the MPs resistance to low pH or to increase anti-Hp effect, respectively. Spray-drying method was used for microencapsulation of live BCG. The biosafety of tested CHI-MPs has been confirmed using cell models in vitro and the model of guinea pig in vivo. The CHI-MPs loaded with BCG released live mycobacteria at pH 3.0 (CHI-GlcNAc-MPs) or pH 8.0. (CHI-Plur-MPs). The CHI-MPs loaded with live BCG can be used for per os inoculation of Cavia porcellus to check the effectiveness of delivered mycobacteria in increasing anti-H. pylori host response.

3D printing of dolutegravir-loaded polylactide filaments as a long-acting implantable system for HIV treatment.

3D printing was used to prepare implantable systems or tablets loaded with dolutegravir to explore their potential as long-acting implantables (LAIs). Our strategy relies on preparing a polylactide (PLA) filament loaded with the anti-HIV drug. Subsequently, 3D printing was performed under conditions that allowed the PLA to be simultaneously melted and the drug encapsulated within the printed strand. The dolutegravir release profiles indicated its sustained release for 47 days. Furthermore, neat and drug-loaded tablets were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA), while their morphology was assessed by scanning electron microscopy (SEM). Finally, their biocompatibility was proved by MTT assay against ISO standards recommended L929 mouse and human Hs68 skin fibroblast cells. All the results indicated that the 3D printing of PLA-based tablets could produce customized medications with potential applications against HIV.

Management of primary graft dysfunction after lung transplantation with extracorporeal life support: an evidence-based review.

Primary graft dysfunction (PGD) is a complex inflammatory syndrome that can lead to respiratory failure after lung transplantation (LTx). The pathogenesis of PGD is multifactorial and can be driven by attributes of both the donor and recipient, perioperative characteristics, and technical handling of the graft. Despite significant advancements in patient and donor selection, perioperative management and surgical technique, PGD is still a major contributor to morbidity and mortality after lung transplant. Although there are no known durable treatment options for PGD after LTx, an increasing body of evidence and experience in high-volume lung transplant centers show that extracorporeal life support (ECLS) is a reliable option for both preventing PGD and supporting critically ill patients with PGD. Both veno-venous (V-V) ECLS and veno-arterial (V-A) ECLS are proven and feasible strategies for mitigating the morbidity and mortality associated with post-LTx PGD. In this evidence-based review, we provide an overview of the epidemiology and physiology of PGD as well as a growing body of data that supports ECLS as a major tool to manage PGD. We describe the role of ECMO in PGD prevention and management, worldwide outcomes of LTx with ECLS support, and outline our step-wise approach to managing this complex respiratory syndrome leading up to institution of ECLS.

Perioperative Fluid Management.

The medical complexity of the geriatric patients has been steadily rising. Still, as outcomes of surgical procedures in the elderly are improving, centers are pushing boundaries. There is also a growing appreciation of the importance of perioperative fluid management on postoperative outcomes, especially in the elderly. Optimal fluid management in this cohort is challenging due to the combination of age-related physiological changes in organ function, increased comorbid burden, and larger fluid shifts during more complex surgical procedures. The current state-of-the-art approach to fluid management in the perioperative period is outlined.

Development of an anti-infective urinary catheter composed of polyvinyl alcohol/sodium alginate/methylcellulose/polyethylene glycol by using a pressure-assisted 3D-printing technique.

Catheter-associated urinary tract infections (CAUTI) are a common complication associated with catheterization, leading to urosepsis, bacteriuria, and septicaemia. The present work focuses on 3D printing a urinary catheter with anti-infective properties using various concentrations of polyvinyl alcohol (PVA, e.g., 6-8 %), sodium alginate (NaAlg, e.g. 1-4 %), methylcellulose (MC, 5 %), polyethylene glycol (PEG, 5 %) impregnated with secnidazole, an antibiotic acting against Gram-negative bacteria. To produce suitable polymer ink for Pressure Assisted Microsyringe (PAM) 3D printing, the cross-linked between NaAlg and calcium chloride is necessary to prepare the catheter. The optimised catheter was found to have an outer diameter of 5 mm, an inner diameter of 3.5 mm, and a length of the catheter of 50 mm. The analysis by various methods confirms the successful incorporation of secnidazole in the 3D-printed catheter. A drug-loaded/coated catheter showed an initial drug release of 79 % following a sustained release to reach 100 % within 5 h. Weibull model fits well with the drug release data. The release models suggest the Quasi-Fickian diffusion mechanism from the system. Moreover, the secnidazole 3D printed catheter disrupted biofilms and suppressed all the Quorum sensing mediated virulence factors of two important keystone pathogens causing urinary tract infections.

Biofire pneumonia panel in lung donors: faster detection but limited pathogens.

BACKGROUND: Culture of bronchoalveolar lavage (BAL) specimens takes time to report. We tested whether a molecular diagnostic test could accelerate donor lung assessment and treatment. METHODS: We compared BioFire Film Array Pneumonia Panel (BFPP) with standard of care (SOC) tests on lung allograft samples at three time points: (1) donor BAL at organ recovery, (2) donor bronchial tissue and airway swab at implantation, and (3) first recipient BAL following lung implantation. Primary outcomes were the difference in time to result (Wilcoxon signed-ranked tests) and the agreement in results between BFPP and SOC assays (Gwet's agreement coefficient). RESULTS: We enrolled 50 subjects. In donor lung BAL specimens, BFPP detected 52 infections (14 out of 26 pathogens in the panel). Viral and bacterial BFPP results were reported 2.4 h (interquartile range, IQR 2.0-6.4) following BAL versus 4.6 h (IQR 1.9-6.0, p = 0.625) for OPO BAL viral SOC results and 66 h (IQR 47-87, p < .0001) for OPO BAL bacterial SOC results. Although there was high overall agreement of results between BAL-BFPP versus OPO BAL-SOC tests (Gwet's AC p < .001 for all), the level of agreement differed among 26 pathogens designed in BFPP and differed by types of specimens. BFPP could not detect many infections identified by SOC assays. CONCLUSIONS: BFPP decreased time to detection of lung pathogens among donated lungs, but it cannot replace SOC tests due to the limited number of pathogens in the panel.

Burnout in Medicine: Are We Asking the Right Questions?

After reviewing a substantial amount of published data on academic physician burnout, we were left pondering the question, "Are we on the right track with combating burnout?" This point-counterpoint manuscript details two opposing viewpoints: 1) the current approach to fighting burnout is working, and 2) resources should be diverted and focus placed on other areas because current interventions are failing physicians. In addressing these points, we discuss four poignant questions that we discovered researching this multifaceted issue: 1) Why do current burnout interventions have limited effects on prevalence over time? 2) Who benefits from the current health care structure (is burnout a profitable and desirable consequence of our work environment)? 3) What organizational conceptual frameworks are most beneficial to improve burnout? 4) How do we take responsibility and seize the ground for our own well-being? Though these differing viewpoints provoked an engaging and lively conversation among our writing team, we all agree on one point. Burnout is an immense problem that affects physicians, patients, and society; therefore, it demands our attention and resources.

Burnout in Academic Physicians.

The prevalence of burnout is much higher in physicians than in other occupations. Academic physicians serve important functions, training future physicians and advancing medical research in addition to doing clinical work. However, they are particularly vulnerable to burnout for reasons including low compensation for teaching, pressure to publish despite a lack of time and declining research funds, and a redistribution of clinical workload due to restrictions on trainee work hours. Junior faculty, women, and marginalized groups are the most affected. Beyond poor physician health and worse patient outcomes, burnout is strongly associated with reduced work effort and an intent to leave the profession. Moreover, physicians are leaving the workforce in record numbers, further increasing the stress on remaining physicians. Combined with a worsening of quality of patient care, this increased rate of physician burnout threatens the viability of health care organizations. This review discusses the causes and consequences of faculty burnout, as well as interventions undertaken for its mitigation.

Nanohybrids Composed of Tannic Acid Cross-Linked by Metal Ions Obtained by a Microfluidic Technique.

Naturally occurring compounds, such as tannic acid (TA), are perfect for constructing nanohybrids (NHs) with metal ions due to their anticarcinogenic, antimicrobial, and antioxidant properties. To date, the batch methods are the ones in which such NHs were constructed; however, those methods possess many drawbacks, such as low reproducibility or size variations. To overcome this limitation, microfluidic preparation is proposed for NHs construction composed of TA and iron (III). The spherical particles with a size between 70 and 150 nm and antimicrobial properties can be easily fabricated in a controlled manner.

Lung preservation: from perfusion to temperature.

PURPOSE OF REVIEW: This article will review the evidence behind elements of the lung preservation process that have remained relatively stable over the past decade as well as summarize recent developments in ex-vivo lung perfusion and new research challenging the standard temperature for static cold storage. RECENT FINDINGS: Ex-vivo lung perfusion is becoming an increasingly well established means to facilitate greater travel distance and allow for continued reassessment of marginal donor lungs. Preliminary reports of the use of normothermic regional perfusion to allow utilization of lungs after DCD recovery exist, but further research is needed to determine its ability to improve upon the current method of DCD lung recovery. Also, research from the University of Toronto is re-assessing the optimal temperature for static cold storage; pilot studies suggest it is a feasible means to allow for storage of lungs overnight to allow for daytime transplantation, but ongoing research is awaited to determine if outcomes are superior to traditional static cold storage. SUMMARY: It is crucial to understand the fundamental principles of organ preservation to ensure optimal lung function posttransplant. Recent advances in the past several years have the potential to challenge standards of the past decade and reshape how lung transplantation is performed.

Stereocomplexed microparticles loaded with Salvia cadmica Boiss. extracts for enhancement of immune response towards Helicobacter pylori.

Controlled delivery of therapeutic substance gives numerous advantages (prevents degradation, improves uptake, sustains concentration, lowers side effects). To encapsulate Salvia cadmica extracts (root or aerial part), enriched with polyphenols with immunomodulatory activity, in stereocomplexed microparticles (sc-PLA), for using them to enhance the immune response towards gastric pathogen Helicobacter pylori. Microparticles were made of biodegradable poly(lactic acid) (PLA) and poly(D-lactic acid) (PDLA). Their stereocomplexation was used to form microspheres and enhance the stability of the obtained particles in acidic/basic pH. The release of Salvia cadmica extracts was done in different pH (5.5, 7.4 and 8.0). The obtained polymers are safe in vitro and in vivo (guinea pig model). The sc-PLA microparticles release of S. cadmica extracts in pH 5.5, 7.4, and 8.0. S. cadmica extracts enhanced the phagocytic activity of guinea pig bone marrow-derived macrophages, which was diminished by H. pylori, and neutralized H. pylori driven enhanced production of tumor necrosis factor (TNF)-α and interleukin (IL)-10. The sc-PLA encapsulated S. cadmica extracts can be recommended for further in vivo study in guinea pigs infected with H. pylori to confirm their ability to improve an immune response towards this pathogen.

Polylactide-Based Materials: Synthesis and Biomedical Applications.

Polylactide (PLA) is a biocompatible polyester that can be obtained by polycondensation of lactic acid or the ring-opening polymerization (ROP) of lactide [...].

Intercostal Nerve Cryoanalgesia Versus Thoracic Epidural Analgesia in Lung Transplantation: A Retrospective Single-Center Study.

INTRODUCTION: The optimal pain management strategy after lung transplantation is unknown. This study compared analgesic outcomes of intercostal nerve blockade by cryoanalgesia (Cryo) versus thoracic epidural analgesia (TEA). METHODS: Seventy-two patients who underwent bilateral lung transplantation via clamshell incision at our center from 2016 to 2018 were managed with TEA (N = 43) or Cryo (N = 29). We evaluated analgesic-specific complications, opioid use in oral morphine equivalents (OME), and pain scores (0-10) through postoperative day 7. Adjusted linear regression was used to assess for non-inferiority of Cryo to TEA. RESULTS: The overall mean pain scores (Cryo 3.2 vs TEA 3.8, P = 0.21), maximum mean pain scores (Cryo 4.7 vs TEA 5.5, P = 0.16), and the total opioid use (Cryo 484 vs TEA 705 OME, P = 0.12) were similar in both groups, while the utilization of postoperative opioid-sparing analgesia, measured as use of lidocaine patches, was lower in the Cryo group (Cryo 21% vs TEA 84%, P < 0.001). Analgesic outcomes remained similar between the cohorts after adjustment for pertinent patient and analgesic characteristics (P = 0.26), as well as after exclusion of Cryo patients requiring rescue TEA (P = 0.32). There were no Cryo complications, with four patients requiring subsequent TEA for pain control. Two TEA patients experienced hemodynamic instability following a test TEA bolus requiring code measures. Additionally, TEA placement was delayed beyond postoperative day 1 in 33% owing to need for anticoagulation or clinical instability. CONCLUSIONS: In lung transplantation, Cryo was found to be safe with analgesic effectiveness similar to TEA. Cryo may be advantageous in this complex patient population, as it can be used in all clinical scenarios and eliminates risks and delays associated with TEA.

Spray-dried tenofovir alafenamide-chitosan nanoparticles loaded oleogels as a long-acting injectable depot system of anti-HIV drug.

The development of suitable drug delivery systems for prolonged action against HIV receives great attention in recent research. Herein, a long-acting injectable (LAI) of Tenofovir alafenamide-chitosan polymeric nanoparticles loaded oleogels developed with sesame oil and ethyl cellulose for prolonged release of the drug is reported for the first time. The research resulted with unique long-acting parenteral formulation for chronic anti-retroviral therapy, based on our experimental in-vitro and ex-vivo studies. The chitosan nanoparticles with 49 % drug content were produced through the spray-drying technique and characterized for their size (106-540 nm) and the other physico-chemical features through SEM, FT-IR, XRD, TGA, and DSC. The ethyl cellulose and sesame oil oleogels were developed through a heat-cool process by incorporating the drug-loaded chitosan nanoparticles. The oleogels exhibited extended release (56 %) of the drug for 16 days, which could be prolonged further to achieve the maximum drug release. Also, the ex-vivo permeation studies of the nanoparticles loaded oleogels demonstrated about 10-fold decrease in the flux and the permeation of the drug due to prolonged release of the drug across dual barriers of chitosan nanoparticles and ethyl cellulose gel matrix. The result provided proof-of-evidence that the developed Tenofovir alafenamide-chitosan polymeric nanoparticles loaded with ethyl cellulose oleogels could be potentially used as the long-acting injectable system for the treatment of patients infected with HIV/AIDS.