Therapeutic Potential of Nanocarrier Mediated Delivery of Peptides for Wound Healing: Current Status, Challenges and Future Prospective.

Wound healing presents a complex physiological process that involves a sequence of events orchestrated by various cellular and molecular mechanisms. In recent years, there has been growing interest in leveraging nanomaterials and peptides to enhance wound healing outcomes. Nanocarriers offer unique properties such as high surface area-to-volume ratio, tunable physicochemical characteristics, and the ability to deliver therapeutic agents in a controlled manner. Similarly, peptides, with their diverse biological activities and low immunogenicity, hold great promise as therapeutics in wound healing applications. In this review, authors explore the potential of peptides as bioactive components in wound healing formulations, focusing on their antimicrobial, anti-inflammatory, and pro-regenerative properties. Despite the significant progress made in this field, several challenges remain, including the need for standardized characterization methods, optimization of biocompatibility and safety profiles, and translation from bench to bedside. Furthermore, developing multifunctional nanomaterial-peptide hybrid systems represents promising avenues for future research. Overall, the integration of nanomaterials made up of natural or synthetic polymers with peptide-based formulations holds tremendous therapeutic potential in advancing the field of wound healing and improving clinical outcomes for patients with acute and chronic wounds.

What to Know about Antimicrobial Coatings in Arthroplasty: A Narrative Review.

Periprosthetic joint infections (PJIs) are one of the most worrying complications orthopedic surgeons could face; thus, methods to prevent them are evolving. Apart from systemic antibiotics, targeted strategies such as local antimicrobial coatings applied to prosthetics have been introduced. This narrative review aims to provide an overview of the main antimicrobial coatings available in arthroplasty orthopedic surgery practice. The search was performed on the PubMed, Web of Science, SCOPUS, and EMBASE databases, focusing on antimicrobial-coated devices used in clinical practice in the arthroplasty world. While silver technology has been widely adopted in the prosthetic oncological field with favorable outcomes, recently, silver associated with hydroxyapatite for cementless fixation, antibiotic-loaded hydrogel coatings, and iodine coatings have all been employed with promising protective results against PJIs. However, challenges persist, with each material having strengths and weaknesses under investigation. Therefore, this narrative review emphasizes that further clinical studies are needed to understand whether antimicrobial coatings can truly revolutionize the field of PJIs.

Remarkable enhancement of cinnamaldehyde antimicrobial activity encapsulated in capped mesoporous nanoparticles: A new "nanokiller" approach in the era of antimicrobial resistance.

Combating antimicrobial resistance is one of the biggest health challenges because of the ineffectiveness of standard biocide treatments. This challenge could be approached using natural products, which have demonstrated powerful therapeutics against multidrug-resistant microbes. In the present work, a nanodevice consisting of mesoporous silica nanoparticles loaded with an essential oil component (cinnamaldehyde) and functionalized with the polypeptide ε-poly-l-lysine is developed and used as an antimicrobial agent. In the presence of the corresponding stimuli (i.e., exogenous proteolytic enzymes from bacteria or fungi), the polypeptide is hydrolyzed, and the cinnamaldehyde delivery is enhanced. The nanodevice's release mechanism and efficacy are evaluated in vitro against the pathogenic microorganisms Escherichia coli, Staphylococcus aureus, and Candida albicans. The results demonstrate that the new device increases the delivery of the cinnamaldehyde via a biocontrolled uncapping mechanism triggered by proteolytic enzymes. Moreover, the nanodevice notably improves the antimicrobial efficacy of cinnamaldehyde when compared to the free compound, ca. 52-fold for E. coli, ca. 60-fold for S. aureus, and ca. 7-fold for C. albicans. The enhancement of the antimicrobial activity of the essential oil component is attributed to the decrease of its volatility due to its encapsulation in the porous silica matrix and the increase of its local concentration when released due to the presence of microorganisms.

Producción científica peruana sobre resistencia a los antimicrobianos de bacterias priorizadas por la OMS / Peruvian scientific production on antimicrobial-resistant bacteria prioritized by WHO

Introducción: La resistencia a los antimicrobianos (RAM) es una crisis de salud pública a nivel mundial. La Organización Mundial de la Salud (OMS) estableció una lista de bacterias resistentes priorizadas para orientar investigaciones y alternativas de mejora. Objetivo: Describir la producción científica del Perú sobre RAM de bacterias priorizadas por la Organización Mundial de la Salud, entre 2012 y 2021. Métodos: Estudio descriptivo observacional de tipo bibliométrico en revistas indexadas en Scopus durante el período 2012-2021. La selección de los estudios y la extracción de datos se realizó manualmente por duplicado. Se clasificaron las bacterias resistentes estudiadas, según las prioridades (crítica, alta y media). Resultados: Se incluyeron 118 artículos. Durante el período 2014-2021 hubo un aumento de publicaciones. El 61,9 por ciento fueron artículos publicados en inglés, 98,3 por ciento con filiación en Perú y el 77,1 por ciento fueron realizados en Lima. Se publicaron más estudios sobre las bacterias de prioridad crítica que sobre las de alta o media. El 79,7 por ciento buscó determinar la prevalencia o caracterizar y el 26,1 por ciento mencionó algún financiamiento de instituciones del país. Conclusión: La producción científica peruana sobre RAM ha aumentado en los últimos años y se cuenta con más publicaciones de bacterias de prioridad crítica. Sin embargo, estos estudios se centran en Lima y solo la cuarta parte ha sido financiada por alguna entidad peruana(AU)

Introduction: Antimicrobial resistance (AMR) is a worldwide public health crisis. The World Health Organization (WHO) established a priority list of resistant bacteria to guide research and alternatives for improvement. Objective: To describe the scientific production of Peru on AMR of bacteria prioritized by the World Health Organization, between 2012 and 2021. Methods: Observational descriptive study of bibliometric type in journals indexed in Scopus during the period 2012-2021. The selection of studies and data extraction were performed manually in duplicate. Resistant bacteria studied were classified based on priority (critical, high, and medium). Results: A total of 118 articles were included. During the period 2014-2021, the number of publications increased. The articles published in English accounted for 61.9 percent, 98.3 percent had their affiliation in Peru, and 77.1 percent were conducted in Lima. Most publications focused on bacteria of critical priority than high and medium priority. A total of 79.7 percent sought to determine prevalence or characterize and 26.1 percent referred to funding from Peruvian institutions. Conclusions: Peruvian scientific production on AMR has increased in recent years and there are more publications on critical priority bacteria. However, these studies are centered in Lima and only a quarter of them have been financed by a Peruvian entity(AU)

Protocolo clínico ­ Manejo das exacerbações pulmonares agudas da fibrose cística / Clinical protocol ­ Management of acute pulmonary exacerbations of cystic fibrosis

A fibrose cística é uma desordem genética de caráter multissistêmico originada por variações no gene CFTR, que é responsável pela síntese da proteína homônima conhecida como "cystic fibrosis transmembrane conductance regulator", localizado no cromossomo 7. A manifestação predominante da doença é pulmonar, que se mantém como a principal causa de morbidade e mortalidade entre os indivíduos acometidos. As crises de exacerbação pulmonar se caracterizam por episódios de agravamento abrupto do quadro respiratório, demandando intervenção médica imediata, visto que tais episódios podem ocasionar danos irreversíveis e deterioração da função pulmonar, mesmo após a resolução dos sintomas agudos. O propósito do presente estudo foi a elaboração de um protocolo clínico direcionado ao manejo da exacerbação pulmonar aguda em pacientes portadores de fibrose cística, para ser implementado Hospital do Servidor Público Municipal. O protocolo proposto repousa sobre quatro pilares: continuidade ou intensificação do tratamento crônico em curso, emprego criterioso de corticosteroides em situações específicas, utilização de suporte ventilatório apropriado e seleção de terapêuticas antivirais e antimicrobianas. Palavras-chave: Fibrose cística. Exacerbação pulmonar. Antimicrobianos. Antivirais. Suporte ventilatório.

Nifuroxazide ameliorates pulmonary fibrosis by blocking myofibroblast genesis: a drug repurposing study.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious interstitial lung disease with a complex pathogenesis and high mortality. The development of new drugs is time-consuming and laborious; therefore, research on the new use of old drugs can save time and clinical costs and even avoid serious side effects. Nifuroxazide (NIF) was originally used to treat diarrhoea, but more recently, it has been found to have additional pharmacological effects, such as anti-tumour effects and inhibition of inflammatory diseases related to diabetic nephropathy. However, there are no reports regarding its role in pulmonary fibrosis. METHODS: The therapeutic effect of NIF on pulmonary fibrosis in vivo was measured by ELISA, hydroxyproline content, H&E and Masson staining, immunohistochemistry (IHC) and western blot. Immune cell content in lung tissue was also analysed by flow cytometry. NIF cytotoxicity was evaluated in NIH/3T3 cells, human pulmonary fibroblasts (HPFs), A549 cells and rat primary lung fibroblasts (RPLFs) using the MTT assay. Finally, an in vitro cell model created by transforming growth factor-ß1 (TGF-ß1) stimulation was assessed using different experiments (immunofluorescence, western blot and wound migration assay) to evaluate the effects of NIF on the activation of NIH/3T3 and HPF cells and the epithelial-mesenchymal transition (EMT) and migration of A549 cells. RESULTS: In vivo, intraperitoneal injection of NIF relieved and reversed pulmonary fibrosis caused by bleomycin (BLM) bronchial instillation. In addition, NIF inhibited the expression of a variety of cellular inflammatory factors and immune cells. Furthermore, NIF suppressed the activation of fibroblasts and EMT of epithelial cells induced by TGF-ß1. Most importantly, we used an analytical docking experiment and thermal shift assay to further verify that NIF functions in conjunction with signal transducer and activator of transcription 3 (Stat3). Moreover, NIF inhibited the TGF-ß/Smad pathway in vitro and decreased the expression of phosphorylated Stat3 in vitro and in vivo. CONCLUSION: Taken together, we conclude that NIF inhibits and reverses pulmonary fibrosis, and these results support NIF as a viable therapeutic option for IPF treatment.

The Potential Use of Propolis as a Primary or an Adjunctive Therapy in Respiratory Tract-Related Diseases and Disorders: A Systematic Scoping Review.

Propolis is a resinous beehive product that is collected by the bees from plant resin and exudates, to protect and maintain hive homeostasis. Propolis has been used by humans therapeutically to treat many ailments including respiratory tract-related diseases and disorders. The aim of the present systematic scoping review is to evaluate the experimental evidence to support the use of propolis as a primary or an adjunctive therapy in respiratory tract-related diseases and disorders. After applying the exclusion criteria, 158 research publications were retrieved and identified from Scopus, Web of Science, Pubmed, and Google Scholar. The key themes of the included studies were pathogenic infection-related diseases and disorders, inflammation-related disorders, lung cancers, and adverse effects. Furthermore, the potential molecular and biochemical mechanisms of action of propolis in alleviating respiratory tract-related diseases and disorders are discussed. In conclusion, the therapeutic benefits of propolis have been demonstrated by various in vitro studies, in silico studies, animal models, and human clinical trials. Based on the weight and robustness of the available experimental and clinical evidence, propolis is effective, either as a primary or an adjunctive therapy, in treating respiratory tract-related diseases.

Safety of continuous 12-hour delivery of antimicrobial doses of inhaled nitric oxide during ex vivo lung perfusion.

INTRODUCTION: High-dose nitric oxide (NO) has been shown effective against a variety of micro-organisms in vitro, including common bacteria found in donor organs. However, clinical obstacles related to its implementation in vivo are the formation of methemoglobin and the accumulation of toxic nitrogen compounds. Ex vivo lung perfusion (EVLP) is a platform that allows for organ maintenance with an acellular perfusion solution, thus overcoming these limitations. The present study explores the safety of continuous high-dose inhaled (iNO) during EVLP for an extended period of 12 hours. METHODS: Lungs procured from Yorkshire pigs were randomized into control (standard ventilation) and treatment (standard ventilation + 200 ppm iNO) groups, then perfused with an acellular solution for 12 hours (n = 4/group). Lung physiology and biological markers were evaluated. RESULTS: After 12 hours of either standard EVLP or EVLP + 200 ppm iNO, we did not notice any significant physiologic difference between the groups: pulmonary oxygenation (P = .586), peak airway pressures (P = .998), and dynamic (P = .997) and static (P = .908) lung compliances. In addition, no significant differences were seen among proinflammatory cytokines measured in perfusate and lung tissue. Importantly, most common toxic compounds were kept at safe levels throughout the treatment course. CONCLUSIONS: High-dose inhaled NO delivered continuously over 12 hours appears to be safe without inducing any significant pulmonary inflammation or deterioration in lung function. These findings support further efficacy studies to explore the use of iNO for the treatment of infections in donor lungs during EVLP.

Do Adhesive Drapes Have an Effect on Infection Rates in Orthopaedic Surgery? A Systematic Review and Meta-Analysis.

BACKGROUND: Adhesive surgical drapes are purported to reduce the rates of surgical site infection. Despite that, international surgical guidelines generally recommend against the use of such drapes; however, this is primarily based on nonorthopaedic evidence. QUESTIONS/PURPOSES: (1) Does the use of adhesive drapes decrease the risk of wound contamination? (2) Does intraoperative drape peeling (intentional or inadvertent) increase the risk of wound contamination? (3) Does the use of adhesive drapes decrease the risk of surgical site infection? METHODS: A systematic review of the MEDLINE and Embase databases was performed according to the Cochrane Handbook methods for randomized controlled trials (RCTs) published since 2000 and comparing adhesive drapes with controls. All databases were searched from inception to March 1, 2021. A pooled meta-analysis was performed, where possible. The Cochrane Risk of Bias Assessment Tool was used to assess risk of bias among the included studies. From among 417 search results, five eligible RCTs were identified and included, all of which were published between 2018 and 2020. There were a total of 2266 patients, with 1129 (49.8%) in the adhesive drape groups, and 1137 (50.2%) in the control groups. The studies included hip and knee surgery trials (n = 3 trials; 1020 patients in intervention groups and 1032 patients in control groups) as well as trials on shoulder arthroscopy (n = 1 trial; 65 patients in the intervention group and 61 patients in the control group) and lumbar spine surgery (n = 1 trial; 44 patients in each group). The data for all three outcomes (wound contamination, impact of intraoperative peeling, and surgical site infection) revealed low heterogeneity based on random-effects models (I2 = 14%, 0%, and 0%, respectively). RESULTS: Based on data from pooled wound swab culture results from four studies, a reduction in wound contamination was associated with the use of adhesive drapes (odds ratio 0.49 [95% CI 0.34 to 0.72]; p < 0.001). The available evidence was inconclusive to determine whether intraoperative drape peeling (intentional or inadvertent) influenced the risk of wound contamination. Three studies did not report on this outcome, one study found an increased infection rate with drape peel back, and another study found a reduced treatment effect of adhesive drapes when peel back occurred in a subgroup analysis. The two studies that analyzed surgical site infections reported no infections in either arm; therefore, we could not answer the question of whether adhesive drapes affect risk of surgical site infection. CONCLUSION: The findings of this review suggest that adhesive drapes, including those with antimicrobial properties, decrease the risk of wound contamination during orthopaedic procedures. In circumstances where drape adhesion is compromised and peel back occurs at the wound edge, there is an increased risk of wound contamination with the use of adhesive drapes. The best currently available evidence is indeterminate as to the effect of adhesive drapes on the risk of surgical site infections; however, if used, care should be taken to avoid or minimize drape peel back. LEVEL OF EVIDENCE: Level I, therapeutic study.

Intravenous immunoglobulin is effective in alleviating hepatic ischemia-reperfusion injury: a rat model study.

BACKGROUND: Hepatic ischemia-reperfusion injury (I/R) is an important factor affecting the prognosis of patients undergoing liver surgery. This study aimed to explore the value of intravenous immunoglobulin (IVIG) in hepatic I/R and its mechanism in a rat model. MATERIALS AND METHODS: Forty eight adult male Sprague-Dawley (SD) rats were divided into six groups randomly: (1-2) treated with normal saline (NS) without ischemia or reperfusion; (3-4) treated with NS + 30 min ischemia; (5-6) treated with IVIG + 30 min ischemia. Rats of group 1/3/5 were euthanized at 12 h after operation (sham + NS + 12 h, I/R + NS + 12 h, I/R + IVIG + 12 h group) while group 2/4/6 were euthanized at 24 h (sham + NS + 24 h, I/R + NS + 24 h, I/R + IVIG + 24 h group). Interleukin 10 (IL-10), interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) were quantified as well as serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Hepatic pathological changes were observed while nuclear factor kappa B p65 (NF-κB p65), Inhibitory Subunit of NF Kappa B Alpha (IKB-alpha) and cleaved caspase-3 were detected. CONCLUSION: ALT, AST, IL-6, TNF-alpha, NF-κB p65 and cleaved caspase-3 were increased by I/R whereas IL-10 and IKB-alpha were decreased. However, IVIG pretreatment reduced ALT, AST, IL-6, TNF-alpha, NF-κB p65 and cleaved caspase-3, but increased IL-10 and IKB-alpha. IVIG treatment attenuates the infiltration of inflammatory cell and cell apoptosis which were observed in I/R groups. IVIG may alleviate hepatic I/R in rats by inhibiting the classical NF-κB signaling pathway, reducing IL-6, TNF-alpha, promoting IL-10, and inhibiting cell apoptosis.

Toxicity Assessment of Long-Term Exposure to Non-Thermal Plasma Activated Water in Mice.

Non-thermal plasma activated water (PAW) has recently emerged as a powerful antimicrobial agent. Despite numerous potential bio-medical applications, studies concerning toxicity in live animals, especially after long-term exposure, are scarce. Our study aimed to assess the effects of long-term watering with PAW on the health of CD1 mice. PAW was prepared from distilled water with a GlidArc reactor according to a previously published protocol. The pH was 2.78. The mice received PAW (experimental group) or tap water (control group) daily for 90 days as the sole water source. After 90 days, the following investigations were performed on the euthanatized animals: gross necropsy, teeth mineral composition, histopathology, immunohistochemistry, hematology, blood biochemistry, methemoglobin level and cytokine profile. Mice tolerated PAW very well and no adverse effects were observed during the entire period of the experiment. Histopathological examination of the organs and tissues did not reveal any structural changes. Moreover, the expression of proliferation markers PCNA and Ki67 has not been identified in the epithelium of the upper digestive tract, indicating the absence of any pre- or neoplastic transformations. The results of our study demonstrated that long-term exposure to PAW caused no toxic effects and could be used as oral antiseptic solution in dental medicine.

Polyphenol rich extracts of Geranium L. species as potential natural antioxidant and antimicrobial agents.

OBJECTIVE: Plants and plant extracts are of great scientific interest due to the chemical diversity and pharmacological properties of present bioactive molecules. The Geranium L. species are widely used in ethnomedicine. In the current study, the total phenolic and tannin content, antioxidant and antimicrobial activity of methanol extracts of eight Geranium species were investigated. MATERIALS AND METHODS: The total phenolic and tannin content were determined by the FC method. Antioxidant capacity was evaluated in FRAP, DPPH, and biochemical assays, while antimicrobial activity was examined using the broth microdilution method. RESULTS: The high total phenolic (170.64-636.32 mg GAE/g dry extract) and tannin content (37.80-414.02 mg GAE/g DE), along with significant total antioxidant (FRAP values 1.13-8.80 mmol Fe2+/g) and DPPH radical scavenging activity (SC50 values 4.24-34.52 µg/mL) were observed. The prominent antioxidant capacity was confirmed in biochemical assays (OS values -1.47 - -13.02). The extracts exhibited significant antimicrobial activity against ATTC strains (MICs dominantly in the range of 12.5-200 µg/mL) as well as against clinical isolates of E. coli (MICs mostly 50 and 100 µg/mL). The pronounced antioxidant and antimicrobial activity can be due to the high phenolic content, particularly due to the presence of hydrolyzable tannins. CONCLUSIONS: Based on the high content of polyphenols, pronounced antioxidant and antimicrobial activities, the examined extracts are promising natural antioxidant and antimicrobial agents with the potential medicinal purpose and use as a functional food.

Metabolism is not a Major Contributor to the Toxicity of Piperaquine, a Long-acting Antimalarial Agent in Artemisinin-based Combination Therapy.

BACKGROUND: Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic after cumulative doses. OBJECTIVES: The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity was investigated. METHODS: The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity. RESULTS: Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by PQ or M1. CONCLUSION: PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB inflammatory pathway and p53 apoptosis pathway.

Restarting Neglected Tropical Diseases Programs in West Africa during the COVID-19 Pandemic: Lessons Learned and Best Practices.

Countries across West Africa began reporting COVID-19 cases in February 2020. By March, the pandemic began disrupting activities to control and eliminate neglected tropical diseases (NTDs) as health ministries ramped up COVID-19-related policies and prevention measures. This was followed by interim guidance from the WHO in April 2020 to temporarily pause mass drug administration (MDA) and community-based surveys for NTDs. While the pandemic was quickly evolving worldwide, in most of West Africa, governments and health ministries took quick action to implement mitigation measures to slow the spread. The U.S. Agency for International Development's (USAID) Act to End NTDs | West program (Act | West) began liaising with national NTD programs in April 2020 to pave a path toward the eventual resumption of activities. This process consisted of first collecting and analyzing COVID-19 epidemiological data, policies, and standard operating procedures across the program's 11 countries. The program then developed an NTD activity restart matrix that compiled essential considerations to restart activities. By December 2020, all 11 countries in Act | West safely restarted MDA and certain surveys to monitor NTD prevalence or intervention impact. Preliminary results show satisfactory MDA program coverage, meaning that enough people are taking the medicine to keep countries on track toward achieving their NTD disease control and elimination goals, and community perceptions have remained positive. The purpose of this article is to share the lessons and best practices that have emerged from the adoption of strategies to limit the spread of the novel coronavirus during MDA and other program activities.

Deep Femoral Vein Reconstruction for Abdominal Aortic Graft Infections is Associated with Low Aneurysm Related Mortality and a High Rate of Permanent Discontinuation of Antimicrobial Treatment.

OBJECTIVE: Aortic prosthesis infection is a devastating complication of aortic surgery. In situ reconstruction with the neo-aorto-iliac system (NAIS) bypass technique has become increasingly used and is recommended in recent treatment guidelines. The main aim was to evaluate NAIS procedural outcomes when undertaken after previous open or endovascular aortic repair in Sweden. METHODS: In this retrospective study, The National Quality Registry for Vascular Surgery (Swedvasc) was used to identify Swedish centres that offered the NAIS bypass procedure for aortic prosthesis infection between 2008 and 2018. Variables of special interest were procedural details, short and long term survival, renal and other complications, and the durtion of antimicrobial treatment. RESULTS: Forty patients (36 males, four females [mean age 69 years], 32 open repairs, seven endovascular aortic repairs [EVAR] and one fenestrated EVAR; 21 presented with aorto-enteric fistula) operated on with NAIS bypass were reviewed. The median time from the primary aortic intervention to the NAIS bypass procedure was 32 months (range 0 - 252 months). Mean ± standard deviation operating time was 645 ± 160 minutes, mean blood loss was 6 277 ± 6 525 mL, mean length of intensive care unit stay was 5.3 ± 3.7 days, and mean length of overall hospital stay was 21.2 ± 11.4 days. Thirty-five patients (88%) had a positive microbial culture; the most commonly isolated pathogen was Candida spp. The majority of patients survived for 30 days (n = 35 [88%]), and 33 (83%) and 32 (80%) patients survived for 90 days and one year, respectively. The number of surviving patients free from antimicrobial treatment at 90 days, six months, and one year was 19 (58%), 29 (88%), and 30 (94%). After a mean long term follow up of 69.9 ± 44.7 months, 20 patients were still alive. CONCLUSION: The NAIS bypass procedure offered reasonable survival and functional outcomes, and was associated with a high cure rate, defined as freedom from any antimicrobial treatment.

Drug-induced resistance evolution necessitates less aggressive treatment.

Increasing body of experimental evidence suggests that anticancer and antimicrobial therapies may themselves promote the acquisition of drug resistance by increasing mutability. The successful control of evolving populations requires that such biological costs of control are identified, quantified and included to the evolutionarily informed treatment protocol. Here we identify, characterise and exploit a trade-off between decreasing the target population size and generating a surplus of treatment-induced rescue mutations. We show that the probability of cure is maximized at an intermediate dosage, below the drug concentration yielding maximal population decay, suggesting that treatment outcomes may in some cases be substantially improved by less aggressive treatment strategies. We also provide a general analytical relationship that implicitly links growth rate, pharmacodynamics and dose-dependent mutation rate to an optimal control law. Our results highlight the important, but often neglected, role of fundamental eco-evolutionary costs of control. These costs can often lead to situations, where decreasing the cumulative drug dosage may be preferable even when the objective of the treatment is elimination, and not containment. Taken together, our results thus add to the ongoing criticism of the standard practice of administering aggressive, high-dose therapies and motivate further experimental and clinical investigation of the mutagenicity and other hidden collateral costs of therapies.

The effect of additional antimicrobial therapy on the outcomes of patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis.

BACKGROUND: The effect of additional antimicrobial agents on the clinical outcomes of patients with idiopathic pulmonary fibrosis (IPF) is unclear. METHODS: We performed comprehensive searches of randomized control trials (RCTs) that compared the clinical efficacy of additional antimicrobial agents to those of placebo or usual care in the treatment of IPF patients. The primary outcome was all-cause mortality, and the secondary outcomes were changes in forced vital capacity (FVC), diffusing capacity of the lung for carbon monoxide (DLCO), and the risk of adverse events (AEs). RESULTS: Four RCTs including a total of 1055 patients (528 receiving additional antibiotics and 527 receiving placebo or usual care) were included in this meta-analysis. Among the study group, 402 and 126 patients received co-trimoxazole and doxycycline, respectively. The all-cause mortality rates were 15.0% (79/528) and 14.0% (74/527) in the patients who did and did not receive additional antibiotics, respectively (odds ratio [OR] 1.07; 95% confidence interval [CI] 0.76 to 1.51; p = 0.71). No significant difference was observed in the changes in FVC (mean difference [MD], 0.01; 95% CI - 0.03 to 0.05; p = 0.56) and DLCO (MD, 0.05; 95% CI - 0.17 to 0.28; p = 0.65). Additional use of antimicrobial agents was also associated with an increased risk of AEs (OR 1.65; 95% CI 1.19 to 2.27; p = 0.002), especially gastrointestinal disorders (OR 1.54; 95% CI 1.10 to 2.15; p = 0.001). CONCLUSIONS: In patients with IPF, adding antimicrobial therapy to usual care did not improve mortality or lung function decline but increased gastrointestinal toxicity.

Enhanced Neovascularization Using Injectable and rhVEGF-Releasing Cryogel Microparticles.

Cryogels are gel networks or scaffolds with a large porous structure; they can be tailored for injectability and for possessing a shape-memory ability. Herein, a growth factor-releasing cryogel microparticle (CMP) system is fabricated, and the therapeutic efficacy of recombinant human vascular endothelial growth factor (rhVEGF)-loaded CMP (V-CMP) for neovascularization is investigated. To prepare the cryogels, both methacrylated chitosan (Chi-MA) and methacrylated chondroitin sulfate (CS-MA) are used, and crosslinking using a radical crosslinking reaction is established. The physical, mechanical, and biological properties of the cryogels are analyzed by varying the amount of CS-MA used. The cryogels are then pulverized, and microsized CMPs are fabricated. CMPs dispersed in saline demonstrate a shear-thinning property, and can thus be extruded through a 23G needle. Additionally, V-CMP exhibit a sustained release profile of rhVEGF and enhance the in vitro proliferation of endothelial cells. Finally, neovascularization and effective tissue necrosis prevention are observed when V-CMPs are injected into a hindlimb ischemia mouse model. Thus, the injectable V-CMP system developed herein demonstrates a high potential utility in various tissue regeneration applications based on cell or growth factor delivery.