Clinical and Pathological Correlation in Concomitant Celiac Disease and Eosinophilic Esophagitis Suggests Separate Etiologies.

Introduction. Recently, an increased risk of celiac disease or eosinophilic esophagitis has been postulated among patients with either of these disorders, prompting some to suggest a common underlying mechanism, whereas others maintain that their co-existence is coincidental. Methods. We compared clinical and pathological features of 29 patients meeting criteria for both celiac disease and eosinophilic esophagitis to 26 celiac disease and 26 eosinophilic esophagitis controls to determine whether any distinguished study patients from controls. Results. Eight (28%) study patients presented with symptoms of both celiac disease and eosinophilic esophagitis, whereas 14 (48%) had celiac disease symptoms only and 5 had (17%) esophageal symptoms only. Study patients had similar autoimmune and atopic conditions seen in both control groups. Histological severity of disease, including Marsh II-III duodenal histology (study specimens: 87%; controls: 89%), mean peak esophageal eosinophil counts (study specimens: 55/400x field; controls: 80/400X field, P = .1), and presence of eosinophil microabscesses, scale crust, and subepithelial fibrosis were also similar to controls. Gluten-free diet resolved celiac disease-related symptoms (19 of 20, 95%) and histology (10 of 12, 83%), but not esophageal symptoms or eosinophilia in most study patients. Conclusion. Patients with concomitant celiac disease and eosinophilic esophagitis lack distinguishing features compared to controls with celiac disease or eosinophilic esophagitis alone. The occurrence of both disorders is likely coincidental in most cases.

Validation of a multiplex microsphere immunoassay for detection of antibodies to Trypanosoma cruzi in dogs.

The vector-borne protozoan parasite Trypanosoma cruzi causes Chagas disease in humans, dogs, and many other mammalian hosts. Canine Chagas disease is increasingly diagnosed in dogs of the southern United States where triatomine insect vectors occur, and there are limited veterinary testing options; only the indirect fluorescent antibody (IFA) test is offered at a single accredited diagnostic laboratory. We evaluated a multiplex microsphere immunoassay (MIA) for the detection of antibodies against T. cruzi in dogs and compared it with existing serologic methods to establish cutoff values and relative sensitivity and specificity. We tested 135 canine sera that had been characterized using the IFA and off-label use of 2 commercial rapid assays with our multiplex MIA against 12 antigens: 9 T. cruzi antigens, a negative control recombinant protein (green fluorescent protein, GFP), a Leishmania antigen, and a canine parvovirus antigen (used as an antibody control given near-ubiquitous parvoviral vaccination). The median fluorescence intensity (MFI) ratio between each T. cruzi antigen and GFP was calculated for every sample. Samples with an antigen:GFP MFI ratio > 4 SDs above the mean of 25 known-negative sera were considered positive to that antigen. Samples testing positive to ≥ 2 antigens were considered positive for T. cruzi antibodies. Compared to the IFA, our multiplex MIA had a relative sensitivity of 100% and specificity of 97.0%. Given its precision, high-throughput format, potential for automation, and lack of subjective interpretation, our multiplex MIA should be considered a valid and improved assay for T. cruzi antibodies in dogs.

Influence of Headgroups in Ethylene-Tetrafluoroethylene-Based Radiation-Grafted Anion Exchange Membranes for CO2 Electrolysis.

The performance of zero-gap CO2 electrolysis (CO2E) is significantly influenced by the membrane's chemical structure and physical properties due to its effects on the local reaction environment and water/ion transport. Radiation-grafted anion-exchange membranes (RG-AEM) have demonstrated high ionic conductivity and durability, making them a promising alternative for CO2E. These membranes were fabricated using two different thicknesses of ethylene-tetrafluoroethylene polymer substrates (25 and 50 µm) and three different headgroup chemistries: benzyl-trimethylammonium, benzyl-N-methylpyrrolidinium, and benzyl-N-methylpiperidinium (MPIP). Our membrane characterization and testing in zero-gap cells over Ag electrocatalysts under commercially relevant conditions showed correlations between the water uptake, ionic conductivity, hydration, and cationic-head groups with the CO2E efficiency. The thinner 25 µm-based AEM with the MPIP-headgroup (ion-exchange capacities of 2.1 ± 0.1 mmol g-1) provided balanced in situ test characteristics with lower cell potentials, high CO selectivity, reduced liquid product crossover, and enhanced water management while maintaining stable operation compared to the commercial AEMs. The CO2 electrolyzer with an MPIP-AEM operated for over 200 h at 150 mA cm-2 with CO selectivities up to 80% and low cell potentials (around 3.1 V) while also demonstrating high conductivities and chemical stability during performance at elevated temperatures (above 60 °C).

Facing the Unknown: Idiopathic Giant Cell Hepatitis.

Giant cell hepatitis is a rare infiltrative disease associated with several viruses, drugs, malignancies, and autoimmune conditions. To date, treatment aims at controlling the underlying etiology, and there are limited data on the clinical course and treatment of idiopathic cases. We present a case of idiopathic giant cell hepatitis in an otherwise healthy adult man and review the literature regarding treatment and outcomes in this population.

Pharmacokinetic/Pharmacodynamic Index Linked to In Vivo Efficacy of the Ampicillin-Ceftriaxone Combination against Enterococcus faecalis.

Combination therapy with ampicillin plus ceftriaxone (AMP+CRO) is the first-line therapy for treating severe infections due to Enterococcus faecalis. However, the pharmacokinetic/pharmacodynamic (PK/PD) index linked to the in vivo efficacy of the combination is not yet defined, hindering dose optimization in the clinic. Because classical PK/PD indices are not directly applicable to antimicrobial combinations, two novel indices were tested in the optimized murine model of infection by E. faecalis to delineate the potentiation of AMP by CRO: the time above the CRO threshold (T>threshold) and the time above the AMP instantaneous MIC (T>MICi). The potential clinical relevance was evaluated by simulating human doses of AMP and CRO. Hill's equation fitted well the exposure-response data in terms of T>threshold, with a CRO threshold of 1 mg/L. The required exposures were 46%, 49%, and 52% for stasis and 1- and 2-log10 killing, respectively. Human ceftriaxone doses of 2 g every 12 h (q12h) would reach the target in >90% of strains with thresholds ≤64 mg/L. The AMP T>MICi index also fitted well, and the required exposures were 37%, 41%, and 46% for stasis and 1- and 2-log10 killing, respectively. In humans, the addition of CRO would allow use of lower AMP doses to reach the same T>MICi and to treat strains with higher MICs. This is the first report of the PK/PD indices and required magnitudes linked to AMP+CRO against E. faecalis; these results can be used as the basis to guide the design of clinical trials to improve combined therapy against enterococci.

Toxicidad por marcador corneal en Femto-LASIK. Reporte de caso / Toxicity by corneal marker in Femto-LASIK. Case report

La violeta de genciana es un colorante orgánico sintético, descrito por primera vez por Charles Lauth en 1861. Tiene propiedades antibacterianas, antifúngicas, antihelmínticas, antitripanosómicas, antiantiogénicas y antitumorales. Tiene diversos mecanismos de acción, entre los que principalmente se encuentra bloquear la actividad de las nicotinamida adenina dinucleótido fosfato oxidasas, evitando la generación de radicales superoxidativos y la posterior inflamación. En los últimos años se ha utilizado en marcadores para procedimientos en diferentes especialidades médicas, incluidos los de oftalmología. La tinta de violeta de genciana se describe por el fabricante como no tóxica, sin embargo existe evidencia clínica y experimental que sugiere que puede ser tóxica para el endotelio corneal y puede llegar a generar queratitis lamelar difusa posterior a LASIK y Femto-LASIK. Se describe el caso de una paciente de 23 años de edad, que presentó diversas patologías en la córnea después del uso de marcador quirúrgico durante procedimiento refractivo Femto-LASIK.

Gentian violet is a synthetic and organic dye. First described by Charles Lauth in 1861. It has antibacterial, antifungal, anthelmintic, antitrypanosomal, antiangiogenic, and antitumoral properties. It has various mechanisms of action, among which is mainly blocking the activity of nicotinamide adenine dinucleotide phosphate oxidases, preventing the generation of superoxidative radicals and subsequent inflammation. In recent years, it has been used as markers for procedures in different medical specialties, including ophthalmology. Gentian violet ink is described by the manufacturer as non-toxic, however, there is clinical and experimental evidence suggesting that it may be toxic to the corneal endothelium and may cause diffuse lamellar keratitis after LASIK and Femto-LASIK. The case about a 23-year-old female patient who presented various pathologies in the cornea after the use of a surgical marker during the Femto-LASIK refractive procedure is described.

Improving Deproteinization in Colombian Latex from Hevea brasiliensis: A Bibliometric Approximation.

Natural Rubber Field Latex (NRFL) allergens restrict its use in some markets due to health-threatening allergic reactions. These molecules are proteins that are related to asymptomatic sensitization and hypersensitivity mediated by immunoglobulin E (IgE). Although NRFL allergens have been investigated since the 1980s, there are still gaps in knowledge regarding the development of deproteinized natural rubber (DPNR). Therefore, in this study, the deproteinization of NRFL from the lower basin of the Cauca River, Antioquia-Colombia was evaluated using eight systems. The highest removal value was 84.4% and was obtained from the treatment containing SDS (Sodium dodecyl sulfate), Urea, and Ethanol. It was also possible to determine that at high concentrations of SDS, removal percentages higher than 70% are reached. On the other hand, all deproteinizing systems decreased NRFL Zeta potentials without self-coagulation, suggesting enhanced colloidal stability in DPNR latex. On the other hand, the bibliometric analysis presented technological advances in DPRN through different parameters and bibliometric networks. The analysis presented makes an important contribution from the bibliometric approach that could be positive for the development of research on DPNR.

Rhinoplasty with Recycled Dorsum Preservation: Technique and Outcomes.

Rhinoplasty is one of the first surgical procedures described with evidence in the history of medicine. At first, these were performed for the reconstruction of traumatic defects caused by punishments, sequels of war, and then it had been reused after suffering from diseases such as syphilis. Many techniques have been developed from the need of aesthetics outcomes in this field. The objective of our work is to describe a modified approach of recycled dorsum preservation procedure that we have proposed as a safe and reliable technique. In this work, we have showed that this technique has a marked advantage of preserving the natural tissue with satisfactory postoperative result. We had no functional complications up to date. We recommend that every specialist in the field of rhinoplasty should be able to use it as a reproducible and feasible alternative.

Synthesis of BiOI/Mordenite Composites for Photocatalytic Treatment of Organic Pollutants Present in Agro-Industrial Wastewater.

Recently, bismuth oxyiodide (BiOI) is an attractive semiconductor to use in heterogeneous photocatalysis processes. Unfortunately, BiOI individually shows limited photocatalytic efficiency, instability, and a quick recombination of electron/holes. Considering the practical application of this semiconductor, some studies show that synthetic zeolites provide good support for this photocatalyst. This support material permits a better photocatalytic efficiency because it prevents the quick recombination of photogenerated pairs. However, the optimal conditions (time and temperature) to obtain composites (BiOI/ synthetic zeolite) with high photocatalytic efficiency using a coprecipitation-solvothermal growth method have not yet been reported. In this study, a response surface methodology (RSM) based on a central composite design (CCD) was applied to optimize the synthesis conditions of BiOI/mordenite composites. For this purpose, eleven BiOI/mordenite composites were synthesized using a combined coprecipitation-solvothermal method under different time and temperature conditions. The photocatalytic activities of the synthesized composites were evaluated after 20 min of photocatalytic oxidation of caffeic acid, a typical organic pollutant found in agro-industrial wastewater. Moreover, BiOI/mordenite composites with the highest and lowest photocatalytic activity were physically and chemically characterized using nitrogen adsorption isotherms, scanning electron microscopy (SEM), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), and diffuse reflectance spectroscopy (DRS). The optimal synthesis conditions prove to be 187 °C and 9 h. In addition, the changes applied to the experimental conditions led to surface property modifications that influenced the photocatalytic degradation efficiency of the BiOI/mordenite composite toward caffeic acid photodegradation.

Coaxial electrospray of uniform polylactide core-shell microparticles for long-acting contraceptive.

Despite its high efficacy and good patient compliance, the only long-acting injectable (LAI) contraceptive currently available in the US, depot medroxyprogesterone acetate (DMPA), is limited by significant side effects and a delayed return to fertility for up to 10 months after its intended duration of action. To overcome these limitations, we sought to develop an injectable poly(D,l-lactide) (PLA) microparticle for sustained release of contraceptive hormone, etonogestrel (ENG). A one-step technique, coaxial electrospray method was applied to prepare uniform ENG loaded core-shell structured and slow-degrading PLA microparticles (ENG-cs-MPs) to provide release control while minimizing polymer content. By adjusting voltage, polymer concentration and flow rate of the coaxial jetting solution, the prepared ENG-cs-MPs exhibited uniformly small particle size with volume mean diameter of 14.7 ± 0.5 µm and a shell thickness of 2.5 ± 0.1 µm, high drug loading of ~54%, high encapsulation efficiency of ~99%, and initial 1-day burst release of just ~10%. Long-term in vitro release of ENG was continuous for more than 3 months without change of the shell structure in 6 months. In PK studies, ENG-cs-MPs achieved a steady and continuous drug release for approximately 3 months and then quickly tapered off within 3 weeks. Hence, ENG-cs-MPs prepared by the coaxial electrospray method may be useful as a LAI contraceptive with an improved PK profile relative to DMPA.

Educational Case: Staphylococcus aureus Bacteremia: Utilization of Rapid Diagnostics for Bloodstream Pathogen Identification and Prediction of Antimicrobial Susceptibility.

The following fictional case is intended as a learning tool within the Pathology Competencies for Medical Education (PCME), a set of national standards for teaching pathology. These are divided into three basic competencies: Disease Mechanisms and Processes, Organ System Pathology, and Diagnostic Medicine and Therapeutic Pathology. For additional information, and a full list of learning objectives for all three competencies, see http://journals.sagepub.com/doi/10.1177/2374289517715040. 1.

Clinical significance of pathologic abnormalities in biopsy samples from the appendiceal orifice.

AIMS: Appendiceal orifice mucosa often appears inflamed endoscopically, even when other colonic segments appear normal. Histological findings in biopsy samples taken from endoscopically abnormal mucosa may simulate a variety of inflammatory colitides. We performed this study to evaluate the clinical implications of inflammatory changes isolated to the appendiceal orifice. METHODS AND RESULTS: In this double cohort study, biopsy samples from 26 histologically abnormal appendiceal orifices were reviewed. Twenty-five control cases were culled from endoscopically normal (n = 11) and abnormal (n = 14) appendiceal orifices that were histologically normal. Histological findings were correlated with presentation, medication history, findings at other colonic sites and clinical outcomes. Study cases displayed active inflammation (n = 12), chronic active inflammation (n = 13) or features simulating collagenous colitis (n = 1). Eighteen patients had biopsies taken from other colonic sites; these revealed benign polyps (n = 10) or displayed active (n = 4) or chronic active (n = 4) inflammation. All patients with findings isolated to the appendiceal orifice were asymptomatic at most recent clinical follow-up. Four of eight (50%) of the patients with inflammation in other biopsy samples were ultimately diagnosed with ulcerative colitis, in keeping with the well-established role of the appendix as a 'skip lesion' in that disorder. Control patients presented for screening colonoscopy (n = 19), iron deficiency anaemia (n = 3) or change in bowel habits (n = 3) and none reported gastrointestinal symptoms upon follow-up, regardless of the endoscopic appearance of the appendiceal orifice. CONCLUSION: Isolated inflammation of the appendiceal orifice mucosa should not be regarded as a feature of evolving inflammatory bowel disease or other types of chronic colitis.

Descripción clínica y epidemiológica de pacientes con pancreatitis crónica en un hospital de alta complejidad en Cali, 2011 a 2017 / Clinical and epidemiological description of patients with chronic pancreatitis treated at a quaternary care hospital in Cali, 2011-2017

Resumen Introducción: la pancreatitis crónica (PC) es una inflamación progresiva del páncreas que puede llevar a su destrucción e insuficiencia irreversibles. Es una patología desafiante para el médico, debido a que establecer su diagnóstico puede tomar meses e incluso años, el seguimiento de pacientes suele ser problemático y el conocimiento sobre la clínica y epidemiología en Colombia es incompleto. Este estudio pretende hacer una descripción de pacientes con PC en un centro de referencia en gastroenterología de Cali, Colombia. Metodología: estudio de corte transversal de pacientes adultos con PC confirmada por criterios clínicos y radiológicos entre 2011 y 2017. Resultados: se incluyeron 36 pacientes con PC. La mayoría fueron hombres (72,2%) y la media de edad fue 56 (+ 15,1) años. El dolor abdominal crónico fue la presentación clínica más común (83,3%). Cerca de un cuarto de pacientes presentaba diabetes mellitus (22,2%). Se consideró etiología idiopática en 58,3%, alcohólica en el 11,0% y biliar en el 11,0%. La tomografía axial computarizada (TAC), resonancia magnética (RMN) y colangiopancreatografía por RMN fueron los métodos diagnósticos más usados (60,5%), con los que en su mayoría se visualizó atrofia (53,1%), dilatación de conductos (49,0%) y calcificaciones del páncreas (34,7%). Conclusión: los síntomas inespecíficos de la PC en fases iniciales y su largo curso clínico favorecen al subdiagnóstico de esta patología. Los resultados presentados pueden contribuir a la futura creación de escalas clínicas locales que orienten estudios radiológicos y genéticos tempranos, con el fin de lograr un diagnóstico oportuno y mejorar la calidad de vida de estos pacientes.

Abstract Introduction: Chronic pancreatitis (CP) is a progressive inflammation of the pancreas that can lead to irreversible damage and failure. This condition poses great challenges to physicians since its diagnosis can take months or even years. Patient follow-up is often problematic and knowledge about its clinical presentation and epidemiology in Colombia is scarce. This study aims to describe patients with CP treated at a gastroenterology reference center in Cali, Colombia. Methodology: Cross-sectional study in adult patients with CP confirmed based on clinical and radiological criteria between 2011 and 2017. Results: 36 patients with CP were included. The majority were men (72.2%), and the mean age was 56 (+15.1) years. Chronic abdominal pain was the most common clinical presentation (83.3%). About a quarter of patients had diabetes mellitus (22.2%). Etiology was idiopathic in 58.3%, alcoholic in 11.0%, and biliary in 11.0%. Computed tomography (CT), magnetic resonance imaging (MRI), and MRI cholangiopancreatography were the most commonly used diagnostic methods (60.5%), showing mostly atrophy (53.1%), duct dilation (49.0%), and pancreatic calcifications (34.7%). Conclusion: Nonspecific symptoms of CP in early stages and its long clinical course favor the underdiagnosis of this condition. The results presented may contribute to the future creation of local clinical scales that guide early radiological and genetic studies to achieve a timely diagnosis and improve the quality of life of these patients.

Features That Aid Identification of Autoimmune Gastritis in a Background of Active Helicobacter pylori Infection.

CONTEXT.­: Helicobacter pylori-associated and autoimmune gastritis may coexist in a subset of patients who require treatment for both disorders. OBJECTIVE.­: To delineate findings that identify autoimmune gastritis in the background of H pylori infection. DESIGN.­: We examined cases of (1) patients with H pylori-associated gastritis who had successful eradication therapy and subsequent biopsies diagnostic of autoimmune gastritis and (2) H pylori-associated gastritis wherein pathologists noted features of autoimmune gastritis during original interpretation. Control patients underwent H pylori eradication but lacked evidence of autoimmune gastritis or H pylori infection after 10 years of follow-up. RESULTS.­: Eight subjects had H pylori-associated gastritis followed by H pylori-negative sampling that showed autoimmune gastritis. Review of original samples showed full-thickness inflammation of oxyntic mucosa in 8 of 8 and oxyntic gland loss in 7 of 8 cases. Enterochromaffin-like (ECL) cell hyperplasia, pyloric metaplasia, and intestinal metaplasia were present in 4 of 8 (80% of 5 tested cases), 4 of 8, and 3 of 8 cases, respectively. Features of autoimmune gastritis were noted at the time of their original H pylori diagnosis in 11 study subjects. Ten of 11 samples displayed full-thickness inflammation of oxyntic mucosa and/or partial loss of oxyntic glands, 8 of 11 had ECL cell hyperplasia (all tested cases), 6 of 11 showed pyloric metaplasia, and 4 of 11 harbored intestinal metaplasia. Except for full-thickness oxyntic mucosa inflammation, these features were absent in control cases. CONCLUSIONS.­: Full-thickness inflammation combined with oxyntic gland loss and ECL cell hyperplasia may help to identify autoimmune gastritis in patients with concomitant H pylori infection.

Epidemiology of Vector-Borne Pathogens Among U.S. Government Working Dogs.

Surveillance of U.S. domestic dogs for exposure to vector-borne pathogens can identify regions of transmission that are relevant for human and animal health. Working dogs with high levels of outdoor exposure may be sensitive indicators of local risk, owing to increased contact with vectors. We randomly selected 476 high-value government working dogs from 40 states to determine the prevalence of infection with Dirofilaria immitis and Rickettsia spp., and exposure to Ehrlichia spp., Anaplasma spp., and Borrelia burgdorferi, and identify risk factors for positivity. Additionally, we tested 100 of these dogs from Texas for Leishmania spp. where sand fly vectors occur. Previously published Trypanosoma cruzi infection data on these dogs were used to identify coinfection or co-exposures. Infection prevalence was 0.84% for D. immitis, and all dogs were negative for Rickettsia spp. DNA. Seroprevalence of each pathogen was: B. burgdorferi 0.84%, Ehrlichia spp. 1.3%, Anaplasma spp. 1.5%, Leishmania spp. 2.0%, and T. cruzi 12.2%. Coinfection or co-exposure took place in four (0.84%) dogs. In bivariable analysis, we found that D. immitis-positive and Ehrlichia-seropositive dogs were significantly older than negative dogs (p < 0.05). Furthermore, seroprevalence of Anaplasma spp. was significantly higher among dogs in the Northeast United States relative to other areas of the country (4.7% vs. ≤1.4%; p = 0.041). Although autochthonous Leishmania infections have been described in the United States, the cases reported herein may represent imported Leishmania infection. Most federal working dogs are bred in Europe, where the parasite is endemic and congenitally transmitted. Serological cross-reaction between T. cruzi and Leishmania spp. complicates diagnosis. In this study, the use of multiple testing strategies in a comparative complementary manner provided evidence for these dogs' true exposures. Comprehensive surveillance for vector-borne pathogens in dogs can improve clinician awareness and target prevention and treatment in a One Health manner.

Effects of Orange Pulp Conservation Methods (Dehydrated or Ensiled Sun-Dried) on the Nutritional Value for Finishing Pigs and Implications on Potential Gaseous Emissions from Slurry.

The inclusion of orange pulp (OP) in pig diets may promote the circular economy, but drying procedures might influence its nutritional value and environmental impact. The purpose of this study was to determine the energy value and nutrient digestibility of dehydrated (DOP) and ensiled sun dried (ESDOP) orange pulp. The potential ammonia (NH3) and methane (CH4) emissions derived from slurry were also measured. Digestible energies of 14.2 and 13.2 MJ/kg DM for DOP and ESDOP, respectively, were estimated by difference after a 500 g/kg substitution of a basal diet with OPs. A high fiber digestion efficiency was observed for both OPs. Pigs fed the basal diet showed a higher intake and a greater excretion of urine N than pigs fed with OP, but fecal N excretion did not differ among diets. A higher benzoic and hippuric acid content in urine was observed in OP than in basal diet. Altogether, these findings explained a lower pH in slurry of OP diets and a reduction of potential NH3 emissions. The biochemical CH4 potential also decreased, especially with ESDOP. Overall, both OP are relevant sources of energy for pig diets. Their inclusion in feeds generate favorable changes of slurry characteristics that reduce potential NH3 and CH4 emissions.

Population Pharmacokinetic Models of Antituberculosis Drugs in Patients: A Systematic Critical Review.

BACKGROUND: Tuberculosis (TB) remains one of the most important infectious diseases. Population pharmacokinetic (pop-PK) models are widely used to individualize dosing regimens of several antibiotics, but their application in anti-TB drug studies is scant. The aim of this study was to provide an insight regarding the status of pop-PK for these drugs and to compare results obtained through both parametric and nonparametric approaches to design precise dosage regimens. METHODS: First, a systematic approach was implemented, searching in PubMed and Google Scholar. Articles that did not include human patients, that lacked an explicit structural model, that analyzed drugs inactive against M. tuberculosis, or were without full-text access, were excluded. Second, the PK parameters were summarized and categorized as parametric versus nonparametric results. Third, a Monte Carlo simulation was performed in Pmetrics using the results of both groups, and an error term was built to describe the imprecision of each PK modeling approach. RESULTS: Thirty-three articles reporting at least 1 pop-PK model of 19 anti-TB drug were found; 46 different models including PK parameter estimates and their relevant covariates were also reported. Only 9 models were based on nonparametric approaches. Rifampin was the drug most studied, but only using parametric approaches. The simulations showed that nonparametric approaches improve the error term compared with parametric approaches. CONCLUSIONS: More and better models, ideally using nonparametric approaches linked with clear pharmacodynamic goals, are required to optimize anti-TB drug dosing, as recommended in the WHO End TB strategy.

Application of the Milan System for Reporting Salivary Gland Cytopathology: Experience of an academic institution in a tertiary academic medical center.

BACKGROUND: The Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) represents a standardized reporting system for salivary gland lesions. The recent literature has demonstrated a wide range of data regarding range of malignancy (ROM) and interobserver variability. The objective of the current study was to evaluate the reproducibility and interobserver agreement of MSRSGC, and establish the ROM in a unique patient population residing within a designated Health Professional Shortage Area. METHODS: A total of 380 salivary gland fine-needle aspiration cases were obtained over a 3-year period. Corresponding cytology reports and slides were reviewed in a blinded fashion by a panel of cytopathologists and recategorized using MSRSGC. ROM was calculated by cytohistologic correlation in 176 cases. Agreement between review of reports and slides and interobserver reliability were determined using kappa statistics. RESULTS: The ROMs per MSRSGC category based on review of reports and slides were as follows: 4% and 0%, respectively, for nonneoplastic; 22% and 0%, respectively, for nondiagnostic; 42.9% and 48%, respectively, for atypia of undetermined significance; 1.6% and 1.9%, respectively, for benign-neoplastic; 17.9% and 15.6%, respectively, for salivary gland neoplasm of uncertain malignant potential; 81.8% and 71.4%, respectively, for suspicious for malignancy; and 100% and 90.5%, respectively, for malignant. There was a 59.2% overall agreement between review of reports and slides with regard to recategorizing salivary gland lesions (kappa, 0.51). The interobserver reliability demonstrated a 64.6% agreement (weighted kappa, 0.59). CONCLUSIONS: The ROMs at the study institution appeared comparable to those in the published literature. There was moderate overall agreement among cytopathologists and low interobserver agreement with regard to the indeterminate categories. Image-guided fine-needle aspiration specimens; rapid onsite adequacy; and integration of clinical, imaging, and ancillary studies can improve diagnostic accuracy among indeterminate lesions.

A new pharmacodynamic approach to study antibiotic combinations against enterococci in vivo: Application to ampicillin plus ceftriaxone.

The combination of ampicillin (AMP) and ceftriaxone (CRO) is considered synergistic against Enterococcus faecalis based on in vitro tests and the rabbit endocarditis model, however, in vitro assays are limited by the use of fixed antibiotic concentrations and the rabbit model by poor bacterial growth, high variability, and the use of point dose-effect estimations, that may lead to inaccurate assessment of antibiotic combinations and hinder optimal translation. Here, we tested AMP+CRO against two strains of E. faecalis and one of E. faecium in an optimized mouse thigh infection model that yields high bacterial growth and allows to define the complete dose-response relationship. By fitting Hill's sigmoid model and estimating the parameters maximal effect (Emax) and effective dose 50 (ED50), the following interactions were defined: synergism (Emax increase ≥2 log10 CFU/g), antagonism (Emax reduction ≥1 log10 CFU/g) and potentiation (ED50 reduction ≥50% without changes in Emax). AMP monotherapy was effective against the three strains, yielding valid dose-response curves in terms of dose and the index fT>MIC. CRO monotherapy showed no effect. The combination AMP+CRO against E. faecalis led to potentiation (59-81% ED50 reduction) and not synergism (no changes in Emax). Against E. faecium, the combination was indifferent. The optimized mouse infection model allowed to obtain the complete dose-response curve of AMP+CRO and to define its interaction based on pharmacodynamic parameter changes. Integrating these results with the pharmacokinetics will allow to derive the PK/PD index bound to the activity of the combination, essential for proper translation to the clinic.

Metabolic engineering of phosphite metabolism in Synechococcus elongatus PCC 7942 as an effective measure to control biological contaminants in outdoor raceway ponds.

BACKGROUND: The use of cyanobacteria and microalgae as cell factories to produce biofuels and added-value bioproducts has received great attention during the last two decades. Important investments have been made by public and private sectors to develop this field. However, it has been a challenge to develop a viable and cost-effective platform for cultivation of cyanobacteria and microalgae under outdoor conditions. Dealing with contamination caused by bacteria, weedy algae/cyanobacteria and other organisms is a major constraint to establish effective cultivation processes. RESULTS: Here, we describe the implementation in the cyanobacterium Synechococcus elongatus PCC 7942 of a phosphorus selective nutrition system to control biological contamination during cultivation. The system is based on metabolic engineering of S. elongatus to metabolize phosphite, a phosphorus source not normally metabolized by most organisms, by expressing a bacterial phosphite oxidoreductase (PtxD). Engineered S. elongatus strains expressing PtxD grow at a similar rate on media supplemented with phosphite as the non-transformed control supplemented with phosphate. We show that when grown in media containing phosphite as the sole phosphorus source in glass flasks, the engineered strain was able to grow and outcompete biological contaminants even when the system was intentionally inoculated with natural competitors isolated from an irrigation canal. The PtxD/phosphite system was successfully used for outdoor cultivation of engineered S. elongatus in 100-L cylindrical reactors and 1000-L raceway ponds, under non-axenic conditions and without the need of sterilizing containers and media. Finally, we also show that the PtxD/phosphite system can be used as selectable marker for S. elongatus PCC 7942 transgenic strains selection, eliminating the need of antibiotic resistance genes. CONCLUSIONS: Our results suggest that the PtxD/phosphite system is a stable and sufficiently robust strategy to control biological contaminants without the need of sterilization or other complex aseptic procedures. Our data show that the PtxD/phosphite system can be used as selectable marker and allows production of the cyanobacterium S. elongatus PCC 7942 in non-axenic outdoor reactors at lower cost, which in principle should be applicable to other cyanobacteria and microalgae engineered to metabolize phosphite.