Overview of Antimicrobial Biodegradable Polyester-Based Formulations.

As the clinical complications induced by microbial infections are known to have life-threatening side effects, conventional anti-infective therapy is necessary, but not sufficient to overcome these issues. Some of their limitations are connected to drug-related inefficiency or resistance and pathogen-related adaptive modifications. Therefore, there is an urgent need for advanced antimicrobials and antimicrobial devices. A challenging, yet successful route has been the development of new biostatic or biocide agents and biomaterials by considering the indisputable advantages of biopolymers. Polymers are attractive materials due to their physical and chemical properties, such as compositional and structural versatility, tunable reactivity, solubility and degradability, and mechanical and chemical tunability, together with their intrinsic biocompatibility and bioactivity, thus enabling the fabrication of effective pharmacologically active antimicrobial formulations. Besides representing protective or potentiating carriers for conventional drugs, biopolymers possess an impressive ability for conjugation or functionalization. These aspects are key for avoiding malicious side effects or providing targeted and triggered drug delivery (specific and selective cellular targeting), and generally to define their pharmacological efficacy. Moreover, biopolymers can be processed in different forms (particles, fibers, films, membranes, or scaffolds), which prove excellent candidates for modern anti-infective applications. This review contains an overview of antimicrobial polyester-based formulations, centered around the effect of the dimensionality over the properties of the material and the effect of the production route or post-processing actions.

Silver/Graphene Oxide Nanostructured Coatings for Modulating the Microbial Susceptibility of Fixation Devices Used in Knee Surgery.

Exploring silver-based and carbon-based nanomaterials' excellent intrinsic antipathogenic effects represents an attractive alternative for fabricating anti-infective formulations. Using chemical synthesis protocols, stearate-conjugated silver (Ag@C18) nanoparticles and graphene oxide nanosheets (nGOs) were herein obtained and investigated in terms of composition and microstructure. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) characterizations revealed the formation of nanomaterials with desirable physical properties, while X-ray diffraction (XRD) analyses confirmed the high purity of synthesized nanomaterials. Further, laser-processed Ag@C18-nGO coatings were developed, optimized, and evaluated in terms of biological and microbiological outcomes. The highly biocompatible Ag@C18-nGO nanostructured coatings proved suitable candidates for the local modulation of biofilm-associated periprosthetic infections.

A Theoretical Model for Release Dynamics of an Antifungal Agent Covalently Bonded to the Chitosan.

The aim of the study was to create a mathematical model useful for monitoring the release of bioactive aldehydes covalently bonded to the chitosan by reversible imine linkage, considered as a polymer-drug system. For this purpose, two hydrogels were prepared by the acid condensation reaction of chitosan with the antifungal 2-formyl-phenyl-boronic acid and their particularities; influencing the release of the antifungal aldehyde by shifting the imination equilibrium to the reagents was considered, i.e., the supramolecular nature of the hydrogels was highlighted by polarized light microscopy, while scanning electron microscopy showed their microporous morphology. Furthermore, the in vitro fungicidal activity was investigated on two fungal strains and the in vitro release curves of the antifungal aldehyde triggered by the pH stimulus were drawn. The theoretical model was developed starting from the hypothesis that the imine-chitosan system, both structurally and functionally, can be assimilated, from a mathematical point of view, with a multifractal object, and its dynamics were analyzed in the framework of the Scale Relativity Theory. Thus, through Riccati-type gauges, two synchronous dynamics, one in the scale space, associated with the fungicidal activity, and the other in the usual space, associated with the antifungal aldehyde release, become operational. Their synchronicity, reducible to the isomorphism of two SL(2R)-type groups, implies, by means of its joint invariant functions, bioactive aldehyde compound release dynamics in the form of "kink-antikink pairs" dynamics of a multifractal type. Finally, the theoretical model was validated through the experimental data.

The Role of Information in Managing Interactions from a Multifractal Perspective.

In the framework of the multifractal hydrodynamic model, the correlations informational entropy-cross-entropy manages attractive and repulsive interactions through a multifractal specific potential. The classical dynamics associated with them imply Hubble-type effects, Galilei-type effects, and dependences of interaction constants with multifractal degrees at various scale resolutions, while the insertion of the relativistic amendments in the same dynamics imply multifractal transformations of a generalized Lorentz-type, multifractal metrics invariant to these transformations, and an estimation of the dimension of the multifractal Universe. In such a context, some correspondences with standard cosmologies are analyzed. Since the same types of interactions can also be obtained as harmonics mapping between the usual space and the hyperbolic plane, two measures with uniform and non-uniform temporal flows become functional, temporal measures analogous with Milne's temporal measures in a more general manner. This work furthers the analysis published recently by our group in "Towards Interactions through Information in a Multifractal Paradigm".

Duodenoscope-associated infections: a review.

Flexible digestive endoscopes are used for the management of various conditions with hundreds of thousands of therapeutic procedures performed worldwide each year. Duodenoscopes are indispensable tools for the delivery of minimally invasive vital care of numerous pancreaticobiliary disorders. Despite the fact that nosocomial infections after endoscopic retrograde cholangiopancreatography (ERCP) have always been among the most frequently cited postprocedural complications, recent emergence of duodenoscope-transmitted multiple drug-resistant bacterial infections has led to intense research and debate yet with no clearly delineated solution. Duodenoscope-transmitted nosocomial infections have become one of the most visible topics in the recent literature. Hundreds of high-impact articles have therefore been published in the last decade. This review article discusses how such infections were seen in the past and what is the current situation in both research and practice and thus tries to solve some of the unanswered questions for the future. With the persistence of nosocomial infections despite strict adherence to both manufacturer-issued reprocessing protocols and international guidelines and regulations, an urgent and proper microbiologically driven common action is needed for controlling such nosocomial worldwide threat.

Molecular diversity and phylogeny of indigenous Rhizobium leguminosarum strains associated with Trifolium repens plants in Romania.

The symbiotic nitrogen fixing legumes play an essential role in sustainable agriculture. White clover (Trifolium repens L.) is one of the most valuable perennial legumes in pastures and meadows of temperate regions. Despite its great agriculture and economic importance, there is no detailed available information on phylogenetic assignation and characterization of rhizobia associated with native white clover plants in South-Eastern Europe. In the present work, the diversity of indigenous white clover rhizobia originating in 11 different natural ecosystems in North-Eastern Romania were assessed by a polyphasic approach. Initial grouping showed that, 73 rhizobial isolates, representing seven distinct phenons were distributed into 12 genotypes, indicating a wide phenotypic and genotypic diversity among the isolates. To clarify their phylogeny, 44 representative strains were used in sequence analysis of 16S rRNA gene and IGS fragments, three housekeeping genes (atpD, glnII and recA) and two symbiosis-related genes (nodA and nifH). Multilocus sequence analysis (MLSA) phylogeny based on concatenated housekeeping genes delineated the clover isolates into five putative genospecies. Despite their diverse chromosomal backgrounds, test strains shared highly similar symbiotic genes closely related to Rhizobium leguminosarum biovar trifolii. Phylogenies inferred from housekeeping genes were incongruent with those of symbiotic genes, probably due to occurrence of lateral transfer events among native strains. This is the first polyphasic taxonomic study to report on the MLSA-based phylogenetic diversity of indigenous rhizobia nodulating white clover plants grown in various soil types in South-Eastern Europe. Our results provide valuable taxonomic data on native clover rhizobia and may increase the pool of genetic material to be used as biofertilizers.

RAPD-inferred genetic variability of some indigenous Rhizobium leguminosarum isolates from red clover (Trifolium pratense L.) nodules.

The application of commercial rhizobial inoculants to legume crops is proving to be an alternative to synthetic fertilizer use. The challenge for sustainable agriculture resides in the compatibility between crop, inoculants and environmental conditions. The evaluation of symbiotic efficiency and genetic diversity of indigenous rhizobial strains could lead to the development of better inoculants and increased crop production. The genetic variability of 32 wild indigenous rhizobial isolates was assessed by RAPD (Random Amplified Polymorphic DNA). The strains were isolated from red clover (Trifolium pratense L.) nodules from two distinct geographical regions of Northern and Eastern Romania. Three decamer primers were used to resolve the phylogenetic relationships between the investigated isolates. Cluster analysis revealed a high diversity; most strains clustered together based on their geographical location.

New Fe3O4-Based Coatings with Enhanced Anti-Biofilm Activity for Medical Devices.

With the increasing use of invasive, interventional, indwelling, and implanted medical devices, healthcare-associated infections caused by pathogenic biofilms have become a major cause of morbidity and mortality. Herein, we present the fabrication, characterization, and in vitro evaluation of biocompatibility and anti-biofilm properties of new coatings based on Fe3O4 nanoparticles (NPs) loaded with usnic acid (UA) and ceftriaxone (CEF). Sodium lauryl sulfate (SLS) was employed as a stabilizer and modulator of the polarity, dispersibility, shape, and anti-biofilm properties of the magnetite nanoparticles. The resulting Fe3O4 functionalized NPs, namely Fe3O4@SLS, Fe3O4@SLS/UA, and Fe3O4@SLS/CEF, respectively, were prepared by co-precipitation method and fully characterized by XRD, TEM, SAED, SEM, FTIR, and TGA. They were further used to produce nanostructured coatings by matrix-assisted pulsed laser evaporation (MAPLE) technique. The biocompatibility of the coatings was assessed by measuring the cell viability, lactate dehydrogenase release, and nitric oxide level in the culture medium and by evaluating the actin cytoskeleton morphology of murine pre-osteoblasts. All prepared nanostructured coatings exhibited good biocompatibility. Biofilm growth inhibition ability was tested at 24 h and 48 h against Staphylococcus aureus and Pseudomonas aeruginosa as representative models for Gram-positive and Gram-negative bacteria. The coatings demonstrated good biocompatibility, promoting osteoblast adhesion, migration, and growth without significant impact on cell viability or morphology, highlighting their potential for developing safe and effective antibacterial surfaces.

Subthreshold Laser Ablation Measurements by Langmuir Probe Method for ns Irradiation of HfO2 and ZrO2.

The unbiased Langmuir probe (LP) method was used to perform measurements on HfO2 and ZrO2 samples around the laser ablation threshold on a wide range of irradiation conditions. Important changes in the lifetime (from ms to µs) and the shape of the charge particle current were seen with the increase of the laser fluence. The ablation threshold was estimated by evaluating the overall average ablated charge as a function of the laser fluence. Above the ablation threshold, the generation of high kinetic species is seen, which can reach several keV. An important jump in ion acceleration potential is observed for values above 1 J/cm2, which coincides with the dominant presence of negative ions in the plasma. The evolution of several plasma parameters (ion density, expansion velocity, electron temperature, Debye length) was investigated and correlated with the fundamental ablation mechanism involved in various irradiation regimes. The LP data were correlated with COMSOL simulations on the maximum surface temperature reached during irradiation. Important correlations between the evaporation and melting processes and ablation threshold fluence and ion acceleration phenomena are also reported.

Components of Existing National Surgical Site Infection Surveillance Programs Based on a Case Series of Low- and Middle-Income Countries: Building Blocks for Success and Opportunities for Improvement.

Background: Surgical site infection (SSI) surveillance programs are recommended to be included in national infection prevention and control (IPC) programs, yet few exist in low- or middle-income countries (LMICs). Our goal was to identify components of surveillance in existing programs that could be replicated elsewhere and note opportunities for improvement to build awareness for other countries in the process of developing their own national surgical site infection surveillance (nSSIS) programs. Methods: We administered a survey built upon the U.S. Centers for Disease Control and Prevention's framework for surveillance system evaluation to systematically deconstruct logistical infrastructure of existing nSSIS programs in LMICs. Qualitative analyses of survey responses by thematic elements were used to identify successful surveillance system components and recognize opportunities for improvement. Results: Three respondents representing countries in Europe and Central Asia, sub-Saharan Africa, and South Asia designated as upper middle-income, lower middle-income, and low-income responded. Notable strengths described by respondents included use of local paper documentation, staggered data entry, and limited data entry fields. Opportunities for improvement included outpatient data capture, broader coverage of healthcare centers within a nation, improved audit processes, defining the denominator of number of surgical procedures, and presence of an easily accessible, free SSI surveillance training program for healthcare workers. Conclusions: Outpatient post-surgery surveillance, national coverage of healthcare facilities, and training on how to take local SSI surveillance data and integrate it within a broader nSSIS program at the national level remain areas of opportunities for countries looking to implement a nSSIS program.

Silver Nanoparticles for Fluorescent Nanocomposites by High-Pressure Magnetron Sputtering.

We report on the formation of silver nanoparticles by gas aggregation in a reaction chamber at room temperature. The size distribution of nanoparticles deposited on a silicon substrate for various lengths of an aggregation (high-pressure) chamber was investigated by atomic force microscopy. Nanoparticles were characterized by scanning and transmission electron microscopy and spectral ellipsometry. The physical shape of the nanoparticles and its distribution was correlated with their optical properties. Metal-dielectric nanocomposites were deposited employing simultaneous deposition of Ag NPs via high-pressure magnetron sputtering and the dielectric matrix was deposited via thermal evaporation. Pure and Eu-, Er-, and Yb-doped lithium fluoride was used as the dielectric host matrix. Optical transmittance of lithium fluoride containing silver nanoparticles was measured and their theoretical absorption cross-section calculated. The nanoparticles were also embedded in Eu3+-doped downshifting and Er3+- and Yb3+-doped up-conversion materials to study their influence on emission spectra. Spectra of identical layers with and without nanoparticles were compared. Their transmittance at various annealing temperatures is also presented.

On the Dynamics of Transient Plasmas Generated by Nanosecond Laser Ablation of Several Metals.

The dynamics of transient plasma generated by UV ns-laser ablation of selected metals (Co, Cu, Ag, Bi) were investigated by the Langmuir Probe method in angle- and time-resolved modes. Multiple ionic and electronic structures were seen for all plasmas with some corresponding to anions or nanoparticle-dominated structures. The addition of an Ar atmosphere energetically confined the plasma and increased the charge density by several orders of magnitude. For pressure ranges exceeding 0.5 Pa fast ions were generated in the plasma as a result of Ar ionization and acceleration in the double layer defining the front of the plasma plume. Several correlations between the target nature plasma properties were attempted. The individual plasma structure expansion velocity increases with the melting point and decreases with the atomic mass while the corresponding charged particle densities decrease with the melting point, evidencing the relationship between the volatility of the sample and the overall abated mass.

Theoretical model for the diclofenac release from PEGylated chitosan hydrogels.

Controlled drug delivery systems are of utmost importance for the improvement of drug bioavailability while limiting the side effects. For the improvement of their performances, drug release modeling is a significant tool for the further optimization of the drug delivery systems to cross the barrier to practical application. We report here on the modeling of the diclofenac sodium salt (DCF) release from a hydrogel matrix based on PEGylated chitosan in the context of Multifractal Theory of Motion, by means of a fundamental spinor set given by 2 × 2 matrices with real elements, which can describe the drug-release dynamics at global and local scales. The drug delivery systems were prepared by in situ hydrogenation of PEGylated chitosan with citral in the presence of the DCF, by varying the hydrophilic/hydrophobic ratio of the components. They demonstrated a good dispersion of the drug into the matrix by forming matrix-drug entities which enabled a prolonged drug delivery behavior correlated with the hydrophilicity degree of the matrix. The application of the Multifractal Theory of Motion fitted very well on these findings, the fractality degree accurately describing the changes in hydrophilicity of the polymer. The validation of the model on this series of formulations encourages its further use for other systems, as an easy tool for estimating the drug release toward the design improvement. The present paper is a continuation of the work 'A theoretical mathematical model for assessing diclofenac release from chitosan-based formulations,' published in Drug Delivery Journal, 27(1), 2020, that focused on the consequences induced by the invariance groups of Multifractal Diffusion Equations in correlation with the drug release dynamics.

In Situ Monitoring of Pulsed Laser Annealing of Eu-Doped Oxide Thin Films.

Eu3+-doped oxide thin films possess a great potential for several emerging applications in optics, optoelectronics, and sensors. The applications demand maximizing Eu3+ photoluminescence response. Eu-doped ZnO, TiO2, and Lu2O3 thin films were deposited by Pulsed Laser Deposition (PLD). Pulsed UV Laser Annealing (PLA) was utilized to modify the properties of the films. In situ monitoring of the evolution of optical properties (photoluminescence and transmittance) at PLA was realized to optimize efficiently PLA conditions. The changes in optical properties were related to structural, microstructural, and surface properties characterized by X-ray diffraction (XRD) and atomic force microscopy (AFM). The substantial increase of Eu3+ emission was observed for all annealed materials. PLA induces crystallization of TiO2 and Lu2O3 amorphous matrix, while in the case of already nanocrystalline ZnO, rather surface smoothening0related grains' coalescence was observed.

Syndecan-3 regulates MSC adhesion, ERK and AKT signalling in vitro and its deletion enhances MSC efficacy in a model of inflammatory arthritis in vivo.

Rheumatoid arthritis (RA) is a debilitating and painful inflammatory autoimmune disease characterised by the accumulation of leukocytes in the synovium, cartilage destruction and bone erosion. The immunomodulatory effects of bone marrow derived mesenchymal stem cells (MSCs) has been widely studied and the recent observations that syndecan-3 (SDC3) is selectively pro-inflammatory in the joint led us to hypothesise that SDC3 might play an important role in MSC biology. MSCs isolated from bone marrow of wild type and Sdc3-/- mice were used to assess immunophenotype, differentiation, adhesion and migration properties and cell signalling pathways. While both cell types show similar differentiation potential and forward scatter values, the cell complexity in wild type MSCs was significantly higher than in Sdc3-/- cells and was accompanied by lower spread surface area. Moreover, Sdc3-/- MSCs adhered more rapidly to collagen type I and showed a dramatic increase in AKT phosphorylation, accompanied by a decrease in ERK1/2 phosphorylation compared with control cells. In a mouse model of antigen-induced inflammatory arthritis, intraarticular injection of Sdc3-/- MSCs yielded enhanced efficacy compared to injection of wild type MSCs. In conclusion, our data suggest that syndecan-3 regulates MSC adhesion and efficacy in inflammatory arthritis, likely via induction of the AKT pathway.

A Theoretical Multifractal Model for Assessing Urea Release from Chitosan Based Formulations.

This paper reports the calibration of a theoretical multifractal model based on empirical data on the urea release from a series of soil conditioner systems. To do this, a series of formulations was prepared by in situ hydrogelation of chitosan with salicylaldehyde in the presence of different urea amounts. The formulations were morphologically characterized by scanning electron microscopy and polarized light microscopy. The in vitro urea release was investigated in an environmentally simulated medium. The release data were fitted on five different mathematical models, Korsmeyer-Peppas, Zero order, First order, Higuchi and Hixson-Crowell, which allowed the establishment of a mechanism of urea release. Furthermore, a multifractal model, used for the fertilizer release for the first time, was calibrated using these empirical data. The resulting fit was in good agreement with the experimental data, validating the multifractal theoretical model.

A theoretical mathematical model for assessing diclofenac release from chitosan-based formulations.

The paper reports a new mathematical model for understanding the mechanism delivery from drug release systems. To do this, two drug release systems based on chitosan and diclofenac sodium salt as a drug model, were prepared by in situ hydrogelation in the presence of salicylaldehyde. The morphology of the systems was analyzed by scanning electron microscopy and polarized light microscopy and the drug release was in vitro investigated into a medium mimicking the in vivo environment. The drug release mechanism was firstly assessed by fitting the in vitro release data on five traditional mathematical model. In the context of pharmacokinetics behavioral analysis, a new mathematical procedure for describing drug release dynamics in polymer-drug complex systems was proposed. Assuming that the dynamics of polymer-drug system's structural units take place on continuous and nondifferentiable curves (multifractal curves), it was showed that in a one-dimensional hydrodynamic formalism of multifractal variables the drug release mechanism is given through synchronous dynamics at a differentiable and non-differentiable scale resolutions.

Genetic diversity and structure of Rhizobium leguminosarum populations associated with clover plants are influenced by local environmental variables.

The identification and conservation of indigenous rhizobia associated with legume plants and their application as biofertilizers is becoming an agricultural worldwide priority. However, little is known about the genetic diversity and phylogeny of rhizobia in Romania. In the present study, the genetic diversity and population composition of Rhizobium leguminosarum symbiovar trifolii isolates from 12 clover plants populations located across two regions in Romania were analyzed. Red clover isolates were phenotypically evaluated and genotyped by sequencing 16S rRNA gene, 16S-23S intergenic spacer, three chromosomal genes (atpD, glnII and recA) and two plasmid genes (nifH and nodA). Multilocus sequence typing (MLST) analysis revealed that red clover plants are nodulated by a wide genetic diversity of R. leguminosarum symbiovar trifolii sequence types (STs), highly similar to the ones previously found in white clover. Rhizobial genetic variation was found mainly within the two clover populations for both chromosomal and plasmid types. Many STs appear to be unique for this region and the genetic composition of rhizobia differs significantly among the clover populations. Furthermore, our results showed that both soil pH and altitude contributed to plasmid sequence type composition while differences in chromosomal composition were affected by the altitude and were strongly correlated with distance.

Mesenchymal Stem Cell-Conditioned Medium Reduces Disease Severity and Immune Responses in Inflammatory Arthritis.

We evaluated the therapeutic potential of mesenchymal stem cell-conditioned medium (CM-MSC) as an alternative to cell therapy in an antigen-induced model of arthritis (AIA). Disease severity and cartilage loss were evaluated by histopathological analysis of arthritic knee joints and immunostaining of aggrecan neoepitopes. Cell proliferation was assessed for activated and naïve CD4+ T cells from healthy mice following culture with CM-MSC or co-culture with MSCs. T cell polarization was analysed in CD4+ T cells isolated from spleens and lymph nodes of arthritic mice treated with CM-MSC or MSCs. CM-MSC treatment significantly reduced knee-joint swelling, histopathological signs of AIA, cartilage loss and suppressed TNFα induction. Proliferation of CD4+ cells from spleens of healthy mice was not affected by CM-MSC but reduced when cells were co-cultured with MSCs. In the presence of CM-MSC or MSCs, increases in IL-10 concentration were observed in culture medium. Finally, CD4+ T cells from arthritic mice treated with CM-MSC showed increases in FOXP3 and IL-4 expression and positively affected the Treg:Th17 balance in the tissue. CM-MSC treatment reduces cartilage damage and suppresses immune responses by reducing aggrecan cleavage, enhancing Treg function and adjusting the Treg:Th17 ratio. CM-MSC may provide an effective cell-free therapy for inflammatory arthritis.

Proton pump inhibitors therapy and risk of Clostridium difficile infection: Systematic review and meta-analysis.

AIM: To perform a systematic review and meta-analysis on proton pump inhibitors (PPIs) therapy and the risk of Clostridium difficile infection (CDI). METHODS We conducted a systematic search of MEDLINE/PubMed and seven other databases through January 1990 to March 2017 for published studies that evaluated the association between PPIs and CDI. Adult case-control and cohort studies providing information on the association between PPI therapy and the development of CDI were included. Pooled odds ratios (ORs) estimates with 95% confidence intervals (CIs) were calculated using the random effect. Heterogeneity was assessed by I2 test and Cochran's Q statistic. Potential publication bias was evaluated via funnel plot, and quality of studies by the Newcastle-Otawa Quality Assessment Scale (NOS). RESULTS: Fifty-six studies (40 case-control and 16 cohort) involving 356683 patients met the inclusion criteria and were analyzed. Both the overall pooled estimates and subgroup analyses showed increased risk for CDI despite substantial statistical heterogeneity among studies. Meta-analysis of all studies combined showed a significant association between PPI users and the risk of CDI (pooled OR = 1.99, CI: 1.73-2.30, P < 0.001) as compared with non-users. The association remained significant in subgroup analyses: by design-case-control (OR = 2.00, CI: 1.68-2.38, P < 0.0001), and cohort (OR = 1.98, CI: 1.51-2.59, P < 0.0001); adjusted (OR = 1.95, CI: 1.67-2.27, P < 0.0001) and unadjusted (OR = 2.02, CI: 1.41-2.91, P < 0.0001); unicenter (OR = 2.18, CI: 1.72-2.75, P < 0.0001) and multicenter (OR = 1.82, CI: 1.51-2.19, P < 0.0001); age ≥ 65 years (OR = 1.93, CI: 1.40-2.68, P < 0.0001) and < 65 years (OR = 2.06, CI: 1.11-3.81, P < 0.01). No significant differences were found in subgroup analyses (test for heterogeneity): P = 0.93 for case-control vs cohort, P = 0.85 for adjusted vs unadjusted, P = 0.24 for unicenter vs multicenter, P = 0.86 for age ≥ 65 years and < 65 years. There was significant heterogeneity across studies (I2 = 85.4%, P < 0.001) as well as evidence of publication bias (funnel plot asymmetry test, P = 0.002). CONCLUSION: This meta-analysis provides further evidence that PPI use is associated with an increased risk for development of CDI. Further high-quality, prospective studies are needed to assess whether this association is causal.