How does active yeast supplementation reduce the deleterious effects of aflatoxins in Wistar rats? A radiolabeled assay and histopathological study.

The aim of this study was to investigate the mechanisms by which yeasts (Saccharomyces cerevisiae) control the toxic effects of aflatoxins, which are not yet fully understood. Radiolabeled aflatoxin B1 (AFB13H) was administered by gavage to Wistar rats fed with aflatoxin (AflDiet) and aflatoxin supplemented with active dehydrated yeast Y904 (AflDiet + Yeast). The distribution of AFB13H and its metabolites were analyzed at 24, 48 and 72 h by tracking back of the radioactivity. No significant differences were observed between the AflDiet and AflDiet + Yeast groups in terms of the distribution of labeled aflatoxin. At 72 h, for the AflDiet group the radiolabeled aflatoxin was distributed as following: feces (79.5%), carcass (10.5%), urine (1.7%), and intestine (7.4%); in the AflDiet + Yeast the following distribution was observed: feces (76%), carcass (15%), urine (2.9%), and intestine (4.9%). These values were below 1% in other organs. These findings indicate that even after 72 h considerable amounts of aflatoxins remains in the intestines, which may play a significant role in the distribution and metabolism of aflatoxins and its metabolites over time. The presence of yeast may not significantly affect this process. Furthermore, histopathological examination of hepatic tissues showed that the presence of active yeast reduced the severity of liver damage caused by aflatoxins, indicating that yeasts control aflatoxin damage through biochemical mechanisms. These findings contribute to a better understanding of the mechanisms underlying the protective effects of yeasts against aflatoxin toxicity.

Influence of anterior chamber depth and vault on anterior chamber angle morphology after phakic posterior chamber intraocular lens implantation.

PURPOSE: This study aims to investigate the influence of anterior chamber depth (ACD) and vault on the anterior chamber angle (ACA) morphology in myopic individuals implanted with posterior chamber phakic intraocular lenses. METHODS: This retrospective case series involved 231 eyes receiving a 13.2-mm implantable collamer lens (ICL). Preoperative anterior chamber anatomy was assessed using anterior segment optical coherence tomography (AS-OCT) and optical tomography, while postoperative evaluation employed AS-OCT. ACA morphology was characterized pre- and postoperatively through trabecular iris angle (TIA750), ACA distance opening (AOD750) and trabecular iris space area (TISA750). The influence of ACD and vault was examined by categorizing the sample into ACD (shallow, average and deep) and vault (low, optimal and high) groups. RESULTS: Preoperative ACA morphology varied based on ACD, with shallower ACDs exhibiting narrower TIA750, smaller AOD750 and TISA750. ICL implantation induced greater ACA narrowing more in the deep ACD group (TIA750 = 20.1 degrees; AOD750 = 0.82 mm and TISA750 = 0.44 mm2) compared to the shallow ACD group (TIA750 = 15.2 degrees; AOD750 = 0.44 mm and TISA750 = 0.21 mm2). Postoperatively, deeper ACDs showed larger ACAs. Increasing vault magnitude led to increased ACA narrowing, with the low vault group exhibiting smaller closure (TIA750 = 14.3 degrees; AOD750 = 0.56 mm and TISA750 = 0.29 mm2) compared to the high vault group (TIA750 = 20.8 degrees; AOD750 = 0.73 mm and TISA750 = 0.36 mm2). The magnitude of ACA narrowing associated with the vault had a consistent effect across different ACD groups. CONCLUSIONS: Posterior chamber intraocular lens implantation results in ACA narrowing, the extent of which is contingent upon preoperative anterior chamber and ACA morphology, with additional influence from vault magnitude.

Rare Presentation of Primary Hyperparathyroidism in a Young Woman.

Even though primary hyperparathyroidism (PHPT) is a common endocrine disorder, due to better and more regular screening, the usual presentation is only seen in less than 15% of cases of PHPT. The authors present the case of a young female patient with a previous medical history of depression and nephrolithiasis, with one year of bone pain, that had become progressively worse and disabling. In the initial work-up, several lytic bone lesions and moderate hypercalcemia were found, leading to admission of the patient in the Internal Medicine ward for investigation and treatment. The ensuing investigation revealed PHPT due to hyperfunctioning parathyroid adenoma. The patient underwent a parathyroidectomy and at the follow-up assessment two months after discharge, she reported no symptoms and a computer tomography scan showed regression of the lytic lesions. This case is a reminder that severe symptomatic PHPT, a rare form in developed countries nowadays, still exists, and even though it is a medical condition, collaboration with surgical specialties is necessary to ensure the best possible treatment and prognosis.

Prediction model of the horizontal trabecular iris angle after phakic posterior chamber implantable intraocular lens surgery.

PURPOSE: To determine the predictors of the postoperative horizontal trabecular iris angle (TIA 750 ) after phakic posterior chamber implantable intraocular lens (IOL) surgery. SETTING: Ophthalmology Clinic Vista Sánchez Trancón, Badajoz, Spain. DESIGN: Retrospective case series. METHODS: 330 eyes implanted with spherical/toric implantable collamer lens (ICL) were included in this study. From 230 eyes implanted with 13.2 mm ICL, these were divided in modeling (n = 180) and evaluation group (n = 50). Two groups implanted with 12.6 mm and 13.7 mm (n = 50 each) were also used as evaluation. Anterior-segment optical coherence tomography was used preoperatively to perform anterior chamber biometry (angle-to-angle [ATA] distance, crystalline lens rise, anterior chamber depth [ACD], cornea sagittal depth, pupil diameter, nasal/temporal TIA 750 ); postoperatively for measuring the vault, pupil diameter and nasal/temporal TIA 750 . Corneal curvature and horizontal visible iris diameter were measured using optical tomography. Bivariate correlation analysis was used to determine associations between preoperative and postoperative horizontal TIA 750 with anterior chamber biometry, ICL-related parameters and age. Finally, a multivariate linear regression model was constructed for predicting the postoperative TIA 750 . RESULTS: Horizontal TIA 750 reduced from 42.9 ± 8.0 degrees preoperatively to 24.4 ± 5.6 degrees postoperatively. Postoperative TIA 750 was positively correlated with the preoperative TIA 750 , cornea sagittal depth and ACD, and negatively associated with the vault. The main predictors of the postoperative TIA 750 were the preoperative parameters, TIA 750 , ICLsize - ATA and pupil diameter (adjusted- R2 = 0.39). The limits of agreement between predicted and real TIA 750 were close to ±10 degrees. CONCLUSIONS: Implantation of a phakic posterior chamber implantable IOL leads to a reduction in TIA 750 and the main factors contributing for this are the preoperative TIA 750 aperture and the vault.

Cell therapies for spinal cord injury: a review of the clinical trials and cell-type therapeutic potential.

Spinal cord injury (SCI) is an as yet untreatable neuropathology that causes severe dysfunction and disability. Cell-based therapies hold neuroregenerative and neuroprotective potential, but, although being studied in SCI patients for more than two decades, long-term efficacy and safety remain unproven, and which cell types result in higher neurological and functional recovery remains under debate. In a comprehensive scoping review of 142 reports and registries of SCI cell-based clinical trials, we addressed the current therapeutical trends and critically analysed the strengths and limitations of the studies. Schwann cells, olfactory ensheathing cells (OECs), macrophages and various types of stem cells have been tested, as well as combinations of these and other cells. A comparative analysis between the reported outcomes of each cell type was performed, according to gold-standard efficacy outcome measures like the ASIA impairment scale, motor and sensory scores. Most of the trials were in the early phases of clinical development (phase I/II), involved patients with complete chronic injuries of traumatic aetiology and did not display a randomized comparative control arm. Bone marrow stem cells and OECs were the most commonly tested cells, while open surgery and injection were the main methods of delivering cells into the spinal cord or submeningeal spaces. Transplantation of support cells, such as OECs and Schwann cells, resulted in the highest ASIA Impairment Scale (AIS) grade conversion rates (improvements in ∼40% of transplanted patients), which surpassed the spontaneous improvement rate expected for complete chronic SCI patients within 1 year post-injury (5-20%). Some stem cells, such as peripheral blood-isolated and neural stem cells, offer potential for improving patient recovery. Complementary treatments, particularly post-transplantation rehabilitation regimes, may contribute highly to neurological and functional recovery. However, unbiased comparisons between the tested therapies are difficult to draw, given the great heterogeneity of the design and outcome measures used in the SCI cell-based clinical trials and how these are reported. It is therefore crucial to standardize these trials when aiming for higher value clinical evidence-based conclusions.

A multi-task convolutional neural network for classification and segmentation of chronic venous disorders.

Chronic Venous Disorders (CVD) of the lower limbs are one of the most prevalent medical conditions, affecting 35% of adults in Europe and North America. Due to the exponential growth of the aging population and the worsening of CVD with age, it is expected that the healthcare costs and the resources needed for the treatment of CVD will increase in the coming years. The early diagnosis of CVD is fundamental in treatment planning, while the monitoring of its treatment is fundamental to assess a patient's condition and quantify the evolution of CVD. However, correct diagnosis relies on a qualitative approach through visual recognition of the various venous disorders, being time-consuming and highly dependent on the physician's expertise. In this paper, we propose a novel automatic strategy for the joint segmentation and classification of CVDs. The strategy relies on a multi-task deep learning network, denominated VENet, that simultaneously solves segmentation and classification tasks, exploiting the information of both tasks to increase learning efficiency, ultimately improving their performance. The proposed method was compared against state-of-the-art strategies in a dataset of 1376 CVD images. Experiments showed that the VENet achieved a classification performance of 96.4%, 96.4%, and 97.2% for accuracy, precision, and recall, respectively, and a segmentation performance of 75.4%, 76.7.0%, 76.7% for the Dice coefficient, precision, and recall, respectively. The joint formulation increased the robustness of both tasks when compared to the conventional classification or segmentation strategies, proving its added value, mainly for the segmentation of small lesions.

Repeatability and agreement of swept-source optical coherence tomography and partial coherence interferometry biometers in myopes.

CLINICAL RELEVANCE: Biometric measurements in the context of myopia are fundamental to detect eyes at risk of developing myopia and during the follow-up of patients with myopia control treatment. Thus, the accuracy of biometers has high clinical relevance. BACKGROUND: The Myopia Master is a new biometer based on partial coherence interferometry especially dedicated to the follow-up of myopic patients. This study aims to assess the repeatability of the Myopia Master and evaluate its agreement with a swept-source optical coherence interferometry biometer (IOL Master 700). METHODS: This cross-sectional prospective study assessed the biometric parameters of two groups of myopes (age range: 8-16 years old), spectacle corrected (n = 60) and orthokeratology contact lens wearers (n = 60). One senior optometrist performed two consecutive measurements per instrument, which included axial length, mean keratometry and horizontal visible iris diameter (HVID). The repeatability of each device and the agreement between devices were assessed by the dispersion of the measurement differences, for AL, mean keratometry, corneal astigmatism and HVID. RESULTS: The two biometers measured approximately the same value in both measurements. Test-retest repeatability tended to be lower than clinical significant thresholds, in particular, for AL and mean keratometry. Corneal-related parameters tended to have lower repeatability in the orthokeratology group, especially mean keratometry. The agreement between instruments revealed statistically significant differences between devices with the SS-OCT measuring longer eyes, steeper corneas and larger HVID. CONCLUSIONS: In a paediatric population, the Myopia Master showed clinically acceptable repeatability levels, but the IOL Master 700 demonstrated superior repeatability. Eyes treated with orthokeratology may compromise the repeatability of the corneal-related parameters. The Myopia Master and the IOL Master 700 are repeatable devices appropriate for monitoring myopia progression, but the differences observed do not allow their use interchangeably.

Surgical treatment of an all-spine epidural empyema.

Spinal epidural empyema (SEE) is a severe infectious disease of the spine which may cause significant morbidity and mortality. Surgical drainage of the empyema is a key feature. However, approach-related morbidity may be significant in very extensive collections. We present the case of a 55-year-old female with an empyema due to methicillin-susceptible Staphylococcus aureus spawning from C2 to S1. She underwent drainage of the pus through skip-level laminectomies and catheter epidural saline irrigation. The technique described was both safe and effective at treating the SEE, and the patient returned to normal life.

Computational Study of the pH-Dependent Ionic Environment around ß-Lactoglobulin.

Ions are involved in multiple biological processes and may exist bound to biomolecules or may be associated with their surface. Although the presence of ions in nucleic acids has traditionally gained more interest, ion-protein interactions, often with a marked dependency on pH, are beginning to gather attention. Here we present a detailed analysis on the binding and distribution of ions around ß-lactoglobulin using a constant-pH MD (CpHMD) method, at a pH range 3-8, and compare it with the more traditional Poisson-Boltzmann (PB) model and the existing experimental data. Most analyses used ion concentration maps built around the protein, obtained from either the CpHMD simulations or PB calculations. The requirements of approximate charge neutrality and ionic strength equal to bulk, imposed on the MD box, imply that the absolute value of the ion excess should be half the protein charge, which is in agreement with experimental observation on other proteins ( Proc. Natl. Acad. Sci. U.S.A. 2021, 118, e2015879118) and lends support to this protocol. In addition, the protein total charge (including territorially bound ions) estimated with MD is in excellent agreement with electrophoretic measurements. Overall, the CpHMD simulations show good agreement with the nonlinear form of the PB (NLPB) model but not with its linear form, which involves a theoretical inconsistency in the calculation of the concentration maps. In several analyses, the observed pH-dependent trends for the counterions and co-ions are those generally expected, and the ion concentration maps correctly converge to the bulk ionic strength as one moves away from the protein. Despite the overall similarity, the CpHMD and NLPB approaches show some discrepancies when analyzed in more detail, which may be related to an apparent overestimation of counterion excess and underestimation of co-ion exclusion by the NLPB model, particularly at short distances from the protein.

Vault differences in eyes implanted with spherical and toric implantable collamer lenses: an inter-eye analysis.

PURPOSE: To determine the influence of implantable collamer lenses (ICL) geometry, i.e. spherical and toric on the vault, and report the refractive and visual outcomes of patients bilaterally implanted with the two ICL geometries. METHODS: This retrospective case series analysed 41 patients implanted with a spherical ICL (sICL) in one eye and an equal sized toric ICL (tICL) in the fellow eye. The anatomical and ICL-related parameters were assessed using anterior-segment optical coherence tomography (AS-OCT Visante, Zeiss Meditec AG) and optical tomography (Pentacam, OCULUS). The influence of the anatomical and ICL-related parameters on the vault was determined using generalised estimating equations (GEE) to incorporate inter-eye correlations. RESULTS: Postoperative spherical equivalent was within ± 0.50D in 66% and 83% of the eyes, respectively implanted with sICL and tICL. The efficacy index in the sICL group was 1.06 and 1.14 in the tICL group. The mean inter-eye vault difference was -1.46 µm, anatomical and ICL-related parameters showed similar associations with the vault for sICL and tICL. The GEE identified the ICL size minus the anterior chamber width, the ICL spherical power and ICL central thickness as significant factors influencing the vault. CONCLUSIONS: Spherical and toric ICL showed good efficacy for the correction of myopia and astigmatism. Patients implanted bilaterally with sICL and tICL tend to present similar vaults. The vault produced by both types of ICL was mainly regulated by the oversizing of the ICL. This suggests that the ICL geometry (spherical vs toric) is a factor with limited influence on the vault, thus the sizing method of a sICL and tICL should be similar.

Characterization of the Workspace and Limits of Operation of Laser Treatments for Vascular Lesions of the Lower Limbs.

The increase of the aging population brings numerous challenges to health and aesthetic segments. Here, the use of laser therapy for dermatology is expected to increase since it allows for non-invasive and infection-free treatments. However, existing laser devices require doctors' manually handling and visually inspecting the skin. As such, the treatment outcome is dependent on the user's expertise, which frequently results in ineffective treatments and side effects. This study aims to determine the workspace and limits of operation of laser treatments for vascular lesions of the lower limbs. The results of this study can be used to develop a robotic-guided technology to help address the aforementioned problems. Specifically, workspace and limits of operation were studied in eight vascular laser treatments. For it, an electromagnetic tracking system was used to collect the real-time positioning of the laser during the treatments. The computed average workspace length, height, and width were 0.84 ± 0.15, 0.41 ± 0.06, and 0.78 ± 0.16 m, respectively. This corresponds to an average volume of treatment of 0.277 ± 0.093 m3. The average treatment time was 23.2 ± 10.2 min, with an average laser orientation of 40.6 ± 5.6 degrees. Additionally, the average velocities of 0.124 ± 0.103 m/s and 31.5 + 25.4 deg/s were measured. This knowledge characterizes the vascular laser treatment workspace and limits of operation, which may ease the understanding for future robotic system development.

Accommodative and binocular vision dysfunctions in a Portuguese clinical population

Background: Several studies have suggested that accommodative and non-strabismic binocular dysfunctions are commonly encountered in optometric practice. This study aims to verify whether these findings apply to a Portuguese clinical population.MethodsThis study included consecutive nonpresbyopic subjects that came to two Portuguese optometric clinics over a period of six months. A complete visual exam was conducted and included the measurement of visual acuity (VA), refraction, near point of convergence (NPC), distance and near phoria, near and distance fusional vergences, amplitude of accommodation (AA), monocular accommodative facility (MAF), relative accommodation and lag of accommodation.Results156 subjects with a mean age of 24.9 ± 5.3 years (from 18 to 35 years old) participated in the study. Of all subjects, 32 % presented binocular vision and/or accommodative disorders accompanied or not by refractive errors. Moreover, 21.1 % had accommodative disorders, and 10.9 % had a binocular vision dysfunction. Accommodative insufficiency (11.5 %) was the most prevalent disorder, followed by convergence insufficiency (7.1 %) and accommodative infacility (5. 8 %).ConclusionsClinicians should be aware that about one third of the optometric clinical population could have accommodative and/or non-strabismic binocular disorders. Accommodative insufficiency was the most prevalent dysfunction presented in the studied population, followed by accommodative infacility and convergence insufficiency. (AU)

FixBox: A General Algorithm to Fix Molecular Systems in Periodic Boxes.

Periodic boundary conditions (PBCs) are a standard feature of molecular simulations, and their mathematical and computational aspects are well-understood and relatively straightforward. However, they can in practice be a nuisance when simulating heterogeneous systems, especially when different types of molecules change their relative positions during the simulation. Although the translation required to fix a broken molecular complex of interest can in most cases be easily inferred by visual inspection, it typically depends on the type of system, its configuration, and the box geometry, making automated procedures problematic. We present here a general algorithm, named FixBox, that can fix a molecular complex of interest from a minimal set of definitions of its assembling parts and intended arrangement in the simulation box. It uses a unified triclinic framework for the box geometric periodicity, does not require a full molecular topology, and is applicable to various types of systems and configurations, making it possible to fully and easily automate the fixing of a broken molecular complex. The performance of the algorithm is illustrated with problematic configurations of various types of simulated systems. The presented formal framework can generally be useful for algorithms that need to perform geometrical transformations on systems with PBCs.

Classification of Chronic Venous Disorders using an Ensemble Optimization of Convolutional Neural Networks.

Chronic Venous Disorders (CVD) of lower limbs are one of the most prevalent medical conditions, affecting 35% of adults in Europe and North America. The early diagnosis of CVD is critical, however, the diagnosis relies on a visual recognition of the various venous disorders which is time- consuming and dependent on the physician's expertise. Thus, automatic strategies for the classification of the CVD severity are claimed. This paper proposed an automatic ensemble-based strategy of Deep Convolutional Neural Networks (DCNN) for the classification of CVDs severity from medical images. First, a clinical dataset containing 1376 images of patients' legs with CVD of 5 different levels of severity was constructed. Then, the constructed dataset was randomly split into training, testing, and validation datasets. Subsequently, a set of DCNN were individually applied to the images for classification. Finally, instead of a traditional voting ensemble strategy, extracted feature vectors from each DCNN were concatenated and fed into a new ensemble optimization network. Experiments showed that the proposed strategy achieved a classification with 93.8%, 93.4%, 92.4% of accuracy, precision, and recall, respectively. Moreover, compared to the traditional ensemble strategy, improvement in the accuracy of ~2% was registered. The proposed strategy showed to be accurate and robust for the diagnosis of CVD severity from medical images. Nevertheless, further research using an extensive clinical database is required to validate the potential of this strategy. Clinical Relevance- An automatic classification of CVD to reduce the probability of underdiagnoses and promote the treatment of CVD in the early stages.

TGF-ß regulates the stem-like state of PD-1+ TCF-1+ virus-specific CD8 T cells during chronic infection.

Recent studies have defined a novel population of PD-1+ TCF-1+ stem-like CD8 T cells in chronic infections and cancer. These quiescent cells reside in lymphoid tissues, are critical for maintaining the CD8 T cell response under conditions of persistent antigen, and provide the proliferative burst after PD-1 blockade. Here we examined the role of TGF-ß in regulating the differentiation of virus-specific CD8 T cells during chronic LCMV infection of mice. We found that TGF-ß signaling was not essential for the generation of the stem-like CD8 T cells but was critical for maintaining the stem-like state and quiescence of these cells. TGF-ß regulated the unique transcriptional program of the stem-like subset, including upregulation of inhibitory receptors specifically expressed on these cells. TGF-ß also promoted the terminal differentiation of exhausted CD8 T cells by suppressing the effector-associated program. Together, the absence of TGF-ß signaling resulted in significantly increased accumulation of effector-like CD8 T cells. These findings have implications for immunotherapies in general and especially for T cell therapy against chronic infections and cancer.

Approach to Study pH-Dependent Protein Association Using Constant-pH Molecular Dynamics: Application to the Dimerization of ß-Lactoglobulin.

Protein-protein association is often mediated by electrostatic interactions and modulated by pH. However, experimental and computational studies have often overlooked the effect of association on the protonation state of the protein. In this work, we present a methodological approach based on constant-pH molecular dynamics (MD), which aims to provide a detailed description of a pH-dependent protein-protein association, and apply it to the dimerization of ß-lactoglobulin (BLG). A selection of analyses is performed using the data generated by constant-pH MD simulations of monomeric and dimeric forms of bovine BLG, in the pH range 3-8. First, we estimate free energies of dimerization using a computationally inexpensive approach based on the Wyman-Tanford linkage theory, calculated in a new way through the use of thermodynamically based splines. The individual free energy contribution of each titratable site is also calculated, allowing for identification of relevant residues. Second, the correlations between the proton occupancies of pairs of sites are calculated (using the Pearson coefficient), and extensive networks of correlated sites are observed at acidic pH values, sometimes involving distant pairs. In general, strongly correlated sites are also slow proton exchangers and contribute significantly to the pH-dependency of the dimerization free energy. Third, we use ionic density as a fingerprint of protein charge distribution and observe electrostatic complementarity between the monomer faces that form the dimer interface, more markedly at the isoionic point (where maximum dimerization occurs) than at other pH values, which might contribute to guide the association. Finally, the pH-dependent dimerization modes are inspected using PCA, among other analyses, and two states are identified: a relaxed state at pH 4-8 (with the typical alignment of the crystallographic structure) and a compact state at pH 3-4 (with a tighter association and rotated alignment). This work shows that an approach based on constant-pH MD simulations can produce rich detailed pictures of pH-dependent protein associations, as illustrated for BLG dimerization.

Accommodative and binocular vision dysfunctions in a Portuguese clinical population.

BACKGROUND: Several studies have suggested that accommodative and non-strabismic binocular dysfunctions are commonly encountered in optometric practice. This study aims to verify whether these findings apply to a Portuguese clinical population. METHODS: This study included consecutive nonpresbyopic subjects that came to two Portuguese optometric clinics over a period of six months. A complete visual exam was conducted and included the measurement of visual acuity (VA), refraction, near point of convergence (NPC), distance and near phoria, near and distance fusional vergences, amplitude of accommodation (AA), monocular accommodative facility (MAF), relative accommodation and lag of accommodation. RESULTS: 156 subjects with a mean age of 24.9 ± 5.3 years (from 18 to 35 years old) participated in the study. Of all subjects, 32 % presented binocular vision and/or accommodative disorders accompanied or not by refractive errors. Moreover, 21.1 % had accommodative disorders, and 10.9 % had a binocular vision dysfunction. Accommodative insufficiency (11.5 %) was the most prevalent disorder, followed by convergence insufficiency (7.1 %) and accommodative infacility (5. 8 %). CONCLUSIONS: Clinicians should be aware that about one third of the optometric clinical population could have accommodative and/or non-strabismic binocular disorders. Accommodative insufficiency was the most prevalent dysfunction presented in the studied population, followed by accommodative infacility and convergence insufficiency.

Author Correction: Commensal-driven immune zonation of the liver promotes host defence.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03346-0.