Molecular, morphological and histopathological evidence of Spirometra mansoni in wild and domestic animals from Costa Rica.

Spirometra mansoni is a diphyllobothroid cestode and one of the causing agents of sparganosis, a zoonotic foodborne and waterborne infection in humans. This parasite has an indirect life cycle with domestic and wild canids or felids as definitive hosts. The last report of S. mansoni in Costa Rica was done in 2004 by morphological assessment of worms, whereas molecular evidence of this species was obtained recently in the Americas. Herein, we present seven cases of spirometrosis in four dogs, three cats and a coyote from different regions of Costa Rica occurring in a time span of a year. Dog cases presented vomiting, hyporexia, lethargy and diarrhea, whereas cats were mostly asymptomatic. Moreover, the coyote was found with Spirometra sp. proglottids incidentally. Cytochrome oxidase subunit 1 (cox1) sequences of eggs or proglottids derived from all cases were analyzed with a Bayesian Inference phylogenetic tree and a haplotype network. These analyses showed the clustering of S. mansoni from Costa Rica with other sequences derived from Asia and America. Moreover, cox1 sequences clustered in two separate haplotypes, suggesting the high genetic diversity of the species. The present cases represent the first molecular evidence of the parasite in Central America; thus, extending its known range in the American continent.

Social media as a tool for detecting underdiagnosed parasitic infections: the case of spirocercosis.

Spirocercosis is a parasitic disease caused by the nematode Spirocerca lupi that affects several canids around the world. In Costa Rica, few spirocercosis cases have been reported; however, it is suspected that the infection is currently underdiagnosed. As seen during the COVID-19 pandemic, social media has sped up the spread of scientific knowledge, raising practioner's awareness of the epidemiology and signs and manifestations of infections. The aim of this work was to use social media as a tool for increasing awareness of spirocercosis among veterinarians and investigate the frequency of cases occurring in Costa Rica. Infographic material about the infection was disseminated by Whatsapp, Facebook, and Instagram from January 2021 to July 2022 using a public account of the Laboratory of Helminthology of the University of Costa Rica. In addition, Google Forms questionnaires were completed by veterinarians to report the number of spirocercosis cases in their clinics, associated manifestations, diagnosis, treatment, and outcome of the disease. Remarkably, since 2020, a six-fold increase in the number of cases per year was noted. Clinical manifestations matched those reported elsewhere, and one of every three dogs infected with S. lupi died spontaneously or required euthanasia because of the infection. This work suggests that S. lupi infection in Costa Rica may have been underdiagnosed in the last decade, and the knowledge and awareness of clinical personnel play a major role in the detection of this and other infectious diseases.

Sleep disturbances and behavior in Smith-Magenis syndrome.

BACKGROUND: The Smith-Magenis syndrome (SMS) shows a collection of neurodevelopmental problems including mild to moderate intellectual disability, change-related anxiety, impulsivity, speech delay, Attention-Deficit/Hyperactivity Disorder (ADH) and sleep disturbances. Sleep disorders, when present, have been treated in several populations with consecutive improvements in cognitive and behavioral aspects. AIMS: To better understand the existing relationships between sleep disturbances and behavioral problems in SMS syndrome this study describes the sleep and behavior problems in the SMS and explores the possible relation between both. METHODS AND PROCEDURES: 17 individuals with SMS (50% males; 11.2 ± 4.9 years old) and 12 individuals with typical development (50% male; 11.1 ± 4.4 years old) were investigated using the Sleep Disturbance Scale for Children and the Child Behavior Checklist. RESULTS: A high percentage (60%) of individuals with SMS have an indication of sleep disorders, being the most frequent disorders the sleep-wake transition disorders, and disorders of initiating and maintaining sleep with sleep latency higher than acceptable and total sleep time below acceptable. More than 94% of the SMS group presented clinical or borderline scores on the total behavioral problems scale. The most common behavioral problems were Externalizing Problems, Thought and Attention, ADH and Aggressive problems. There was a positive correlation between disorders of initiating and maintaining sleep, sleep-wake transition disorders, disorders of arousal, disorders of excessive somnolence and behavioral problems. CONCLUSIONS AND IMPLICATIONS: The worse the sleep disturbances investigated, the more severe the behavioral problems characteristics reinforcing the importance to address the sleep problems in the treatment of SMS individuals.

Standardization and Chemical Characterization of Intravenous Therapy in Adult Patients: A Step Further in Medication Safety.

BACKGROUND: Intravenous drug administration is associated with potential complications, such as phlebitis. The physiochemical characteristics of the infusate play a very important role in some of these problems. AIM: The aim of this study was to standardize the dilutions of intravenous drugs most commonly used in hospitalized adult patients and to characterize their pH, osmolarity and cytotoxic nature to better guide the selection of the most appropriate vascular access. METHODS: The project was conducted in three phases: (i) standardization of intravenous therapy, which was conducted using a modified double-round Delphi method; (ii) characterization of the dilutions agreed on in the previous phase by means of determining the osmolarity and pH of each of the agreed concentrations, and recording the vesicant nature based on the information in literature; and (iii) algorithm proposal for selecting the most appropriate vascular access, taking into account the information gathered in the previous phases. RESULTS: In total, 112 drugs were standardized and 307 different admixtures were assessed for pH, osmolarity and vesicant nature. Of these, 123 admixtures (40%), had osmolarity values >600 mOsm/L, pH < 4 or > 9, or were classified as vesicants. In these cases, selection of the most suitable route of infusion and vascular access device is crucial to minimize the risk of phlebitis-type complications. CONCLUSIONS: Increasing safety of intravenous therapy should be a priority in the healthcare settings. Knowing the characteristics of drugs to assess the risk involved in their administration related to their physicochemical nature may be useful to guide decision making regarding the most appropriate vascular access and devices.

Erratum: Mangas-Sanjuán, V.; et al. Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence. Pharmaceutics 2019, 11, 503.

The authors wish to make the following corrections to this paper [...].

Relationship between rheological properties, in vitro release and in vivo equivalency of topical formulations of diclofenac.

Determination of bioequivalence remains a challenge in generic topical drug development. To support pharmacokinetic studies, strategies to demonstrate microstructure sameness of the products being compared include in vitro evaluations, such as the comparison of rheological properties, droplet size and in vitro release rates. Nevertheless, defining the appropriate acceptance range to consider equivalence between test and reference formulation is complex. To shed more light into this issue, in vitro release and rheological properties were compared to in vivo bioequivalence data (systemic blood measurements within a clinical trial) after topical application of a single dose. Test and reference formulations of diclofenac diethylamine emulgels were evaluated. While the test formulation met the requirements for equivalence in both the in vivo bioequivalence and in vitro release study, the rheological properties were considered equivalent depending on the criteria used. The 90% confidence interval of the ratios between geometric mean values of both formulations were within the limits of 75-133%, but outside the 90-111% limit under discussion in the scientific community. Altogether these data indicate that differences beyond ±10% between rheological parameters of test and reference formulation might not translate into meaningful release nor bioavailability divergence.

Assessment of the Inter-Batch Variability of Microstructure Parameters in Topical Semisolids and Impact on the Demonstration of Equivalence.

Demonstration of similar microstructure is essential for demonstrating the equivalence of generic topical products since the microstructure of semisolids may affect the drug release. The objective of this study was to compare the microstructure-defining physical parameters of different batches of a reference ointment containing calcipotriol and betamethasone (Daivobet 50 µg/0.5 mg/g) in order to define the acceptance range that allows concluding equivalence between these batches. Being batches of the same reference product, they are expected to be clinically equivalent and possess similar microstructure. The 90% confidence intervals for the test/reference ratio of these physical parameters were calculated with parametric and non-parametric approaches. Both methods conclude that equivalent microstructure between batches cannot be demonstrated with a reasonable sample size when the acceptance range was set at ±10%, since several physical parameters exhibit inter-batch variability >10%. An acceptance range of ±10% is therefore too strict to conclude equivalence in the microstructure of semisolid dosage forms, given the inter-batch variability observed between batches of the reference product. A wider fixed acceptance range or an acceptance range widened based on the inter-batch variability of the reference product would be advisable.

Validation of an Objective Keratoconus Detection System Implemented in a Scheimpflug Tomographer and Comparison With Other Methods.

PURPOSE: To validate a recently developed program for automatic and objective keratoconus detection (Keratoconus Assistant [KA]) by applying it to a new population and comparing it with other methods described in the literature. METHODS: KA uses machine learning and 25 Pentacam-derived parameters to classify eyes into subgroups, such as keratoconus, keratoconus suspect, postrefractive surgery, and normal eyes. To validate this program, it was applied to 131 eyes diagnosed separately by experienced corneal specialists from 2 different centers (Fondation Rothschild, Paris, and Antwerp University Hospital [UZA]). The agreement of the KA classification with 7 other indices from the literature was assessed using interrater reliability and confusion matrices. The agreement of the 2 clinical classifications was also assessed. RESULTS: For keratoconus, KA agreed in 92.6% of cases with the clinical diagnosis by UZA and in 98.0% of cases with the diagnosis by Rothschild. In keratoconus suspect and forme fruste detection, KA agreed in 65.2% (UZA) and 100% (Rothschild) of cases with the clinical assessments. This corresponds with a moderate agreement with a clinical assessment (κ = 0.594 and κ = 0.563 for Rothschild and UZA, respectively). The agreement with the other classification methods ranged from moderate (κ = 0.432; Score) to low (κ = 0.158; KISA%). Both clinical assessments agreed substantially (κ = 0.759) with each other. CONCLUSIONS: KA is effective at detecting early keratoconus and agrees with trained clinical judgment. As keratoconus detection depends on the method used, we recommend using multiple methods side by side.

SyntEyes KTC: higher order statistical eye model for developing keratoconus.

PURPOSE: To present and validate a stochastic eye model for developing keratoconus to e.g. improve optical corrective strategies. This could be particularly useful for researchers that do not have access to original keratoconic data. METHODS: The Scheimpflug tomography, ocular biometry and wavefront of 145 keratoconic right eyes were collected. These data were processed using principal component analysis for parameter reduction, followed by a multivariate Gaussian fit that produces a stochastic model for keratoconus (SyntEyes KTC). The output of this model is filtered to remove the occasional incorrect topography patterns by either an automatic or manual procedure. Finally, the output of this keratoconus model is matched to that of the original model for normal eyes using the non-corneal biometry to obtain a description of keratoconus development. RESULTS: The synthetic data generated by the model were found to be significantly equal to the original data (non-parametric Mann-Whitney equivalence test; 145/154 passed). The variability of the synthetic data, however, was often significantly less than that of the original data, especially for the higher order Zernike terms of corneal elevation (non-parametric Levene test; p < 0.05/154). These results remained generally the same after applying either filter procedure to remove the synthetic eyes with incorrect topographies. Interpolation between matched pairs of normal and keratoconic SyntEyes appears to provide an adequate model for keratoconus progression. CONCLUSION: The synthetic data provided by the proposed keratoconus model closely resembles actual clinical data and may be used for a range of research applications when (sufficient) real data is not available.

Evaluation of a Machine-Learning Classifier for Keratoconus Detection Based on Scheimpflug Tomography.

PURPOSE: To evaluate the performance of a support vector machine algorithm that automatically and objectively identifies corneal patterns based on a combination of 22 parameters obtained from Pentacam measurements and to compare this method with other known keratoconus (KC) classification methods. METHODS: Pentacam data from 860 eyes were included in the study and divided into 5 groups: 454 KC, 67 forme fruste (FF), 28 astigmatic, 117 after refractive surgery (PR), and 194 normal eyes (N). Twenty-two parameters were used for classification using a support vector machine algorithm developed in Weka, a machine-learning computer software. The cross-validation accuracy for 3 different classification tasks (KC vs. N, FF vs. N and all 5 groups) was calculated and compared with other known classification methods. RESULTS: The accuracy achieved in the KC versus N discrimination task was 98.9%, with 99.1% sensitivity and 98.5% specificity for KC detection. The accuracy in the FF versus N task was 93.1%, with 79.1% sensitivity and 97.9% specificity for the FF discrimination. Finally, for the 5-groups classification, the accuracy was 88.8%, with a weighted average sensitivity of 89.0% and specificity of 95.2%. CONCLUSIONS: Despite using the strictest definition for FF KC, the present study obtained comparable or better results than the single-parameter methods and indices reported in the literature. In some cases, direct comparisons with the literature were not possible because of differences in the compositions and definitions of the study groups, especially the FF KC.

How Abnormal Is the Noncorneal Biometry of Keratoconic Eyes?

PURPOSE: To determine whether the noncorneal biometry in keratoconic eyes deviates from that in healthy eyes. METHODS: The right eyes of 200 healthy subjects and 76 patients with keratoconus were measured with an autorefractometer, a Scheimpflug tomographer, and an optical biometer. The analysis consisted of a general linear model (GLM), correcting for age and gender effects, comparing keratoconic eyes with healthy eyes, and emmetropic eyes. Next, 20 patients with mild keratoconus in one eye and moderate keratoconus in the fellow eye were analyzed to assess the effect of disease stage. RESULTS: As expected the keratoconic group differed significantly from both the healthy and the emmetropic groups for most refractive, corneal, and anterior chamber parameters (GLM, P < 0.001). For the vitreous depth V and the axial length L, the keratoconic group showed significantly larger values than the emmetropic group (V: +0.68 ± 0.19 mm, P = 0.001; L: +0.63 ± 0.14 mm, P < 0.001), but not larger than the healthy group (V: +0.18 ± 0.20 mm, P = 0.364; L: +0.09 ± 0.14 mm, P = 0.519). Besides the corneal parameters, the stage of the disease led to a significantly deeper aqueous depth (+0.07 ± 0.02 mm; Wilcoxon signed rank, P = 0.002), but no significant difference in axial length (P = 0.940). CONCLUSIONS: Current analysis does not confirm the previously suggested association between keratoconus and higher amounts of axial myopia, which may have been the result of selection bias by using emmetropic eyes as a healthy control group.

Subjective Grading of Subclinical Vitreous Floaters.

PURPOSE: This study aimed to objectively grade the perception of subclinical floaters in an asymptomatic cohort. DESIGN: A prospective observational cohort study. METHODS: One hundred eighty-two volunteers (49 men, 133 women) with ages ranging from 17.7 to 78.6 years were recruited for floater assessment. Participants were assessed by a light box and by vitreoscope, after which they graded the floaters using a graphic classification system. They also completed a questionnaire to estimate the impact of floaters on daily life. In addition, biometric and refractive data were documented for all participants. RESULTS: Using the light box method, 67.6% of participants reported seeing transparent floaters, which increased to 84.1% when using the vitreoscope. Opaque floaters were seen by 15.9% (light box) and 6.5% (vitreoscope). Reported levels of floater discomfort varied between participants, with 80.2% of participants reporting no discomfort and 6.6% reporting moderate to manifest discomfort. The perceived discomfort was weakly correlated with the amount of visualized floaters (light box: Pearson r = 0.323, P < 0.001; vitreoscope: r = 0.174, P < 0.001). Both floater perception and discomfort increased with age (r = 0.203, P = 0.006; r = 0.194, P = 0.009, respectively), although neither changed with axial length or refraction (P = 0.131, P = 0.070, respectively). CONCLUSIONS: The light box and the vitreoscope demonstrate that subclinical floaters are very common, even in nonsymptomatic subjects. The amount of perceived floaters in this cohort correlates only weakly with floater-related discomfort.

Repeatability and inter-device agreement for three different methods of keratometry: Placido, Scheimpflug, and color LED corneal topography.

PURPOSE: To determine the repeatability of a color LED corneal topographer (Cassini; iOptics, The Hague, The Netherlands) and compare it with Placido and Scheimpflug based devices (EyeSys 2000; EyeSys Laboratories, Houston, TX, and Pentacam HR; Oculus Optikgeräte GmbH, Wetzlar, Germany). METHODS: This prospective study involved 20 healthy volunteers (20 eyes) recruited from the staff of the Antwerp University Hospital. For each eye, three measurements were taken using each device, from which eight parameters describing keratometry and astigmatism were derived. Repeatability was assessed using intrasession, within-subject analysis of variance. Agreement was evaluated between pairs of devices with Bland- Altman plots and 95% confidence intervals. RESULTS: The repeatability values were good for all three devices, although slightly worse for the Cassini than for the other two devices for steep, flat, and mean keratometry. The EyeSys showed worse repeatability for the astigmatism axis. EyeSys and Pentacam agreed well with each other in terms of mean keratometry, whereas the Cassini gave consistently higher values by 0.52 diopters (D) when compared with the EyeSys (P < .05, paired t test) and by 0.38 D when compared with the Pentacam (P < .05, paired t test). The Cassini provided similar repeatability values (2.31°) for the astigmatism axis to the Pentacam (2.22°), in contrast to the EyeSys, which produced much more variable axes (9.0°) (P < .05, paired t test). CONCLUSIONS: Overall, the three devices display comparable repeatability. The one exception is the astigmatism axis measurement of the EyeSys. The Cassini provides higher keratometry values than the other two devices, but the astigmatism axis agrees well with that provided by the Pentacam.

Normative values for corneal densitometry analysis by Scheimpflug optical assessment.

PURPOSE: To describe the normative data for corneal Scheimpflug densitometry based on a cohort of normal participants. METHODS: A total of 445 healthy participants were recruited for assessment (794 eyes). Left and right eyes were considered separately. All participants were assessed using the corneal densitometry analysis add-on to the standard software of the Oculus Pentacam. Densitometry measurements were obtained and expressed in standardized grayscale units (GSU). RESULTS: All participants were Caucasian; 42% were male and 58% were female. The mean age was 48.0 ± 15.3 years (range, 20.2-84.2 years). Mean corneal densitometry over the 12-mm-diameter area was 19.74 ± 3.89 GSU. When divided by radial zone, densitometry values were lowest in the central zone (16.76 ± 1.87 GSU) and highest in the periphery (27.36 ± 7.47 GSU). There was no difference between central zone and the surrounding 2- to 6-mm annulus (P > 0.05), though the 6- to 10-mm and the 10- to 12-mm zones displayed higher densitometry values (P < 0.001). When divided by depth, the anterior layer displayed the highest densitometry reading of 25.81 ± 5.14 GSU, which was significantly higher than that of both the central (P < 0.001) and the posterior layers (P < 0.001). Changes in corneal densitometry were correlated with age, though not within the central 6-mm-diameter ring. No sex difference was seen within the cohort. CONCLUSIONS: This add-on to the standard imaging software allows rapid and objective assessment of the corneal densitometry. We provide normative data that may be used as a reference facilitating research and complementing clinical examination.

The in-orbit performances of GIOVE clocks.

The Galileo In-Orbit Validation Element (GIOVE) is an experiment led by the European Space Agency (ESA) aimed at supporting the on-going implementation of Galileo, the European global navigation satellite system (GNSS). Among the objectives of the GIOVE Mission are the validation and characterization of the on-board clock technologies. The current baseline technologies for on-board clocks are the rubidium atomic frequency standard (RAFS) and the passive hydrogen maser (PHM). Both technologies have been validated and qualified on ground and are now being further validated in a representative in-orbit environment aboard 2 spacecrafts, GIOVE-A and GIOVE-B. This paper presents the results obtained in the frame of the GIOVE experimentation. The behavior and performances of the clock technologies on board both spacecrafts has been investigated and analyzed in terms of operation, frequency stability, and clock prediction error after more than 3 years of operation for GIOVE-A and almost one year for GIOVE-B. In addition, relativistic frequency shifts of GIOVE spacecrafts have been investigated.