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Supplementary Video 4 from Integrated Optical Coherence Tomography and Microscopy for Ex Vivo Multiscale Evaluation of Human Breast Tissues

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Supplementary Video 1 from Integrated Optical Coherence Tomography and Microscopy for Ex Vivo Multiscale Evaluation of Human Breast Tissues

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Canine RPGRIP1-cone-rod dystrophy (CRD), a model for human inherited retinal diseases (IRDs), was originally identified as autosomal recessive early-onset blindness. However, later studies revealed extensive phenotypic variability among RPGRIP1 mutants. This led to the identification of a homozygous MAP9 variant as a modifier associated with early-onset disease. Based on further phenotypic variation affecting cone photoreceptor function, we report mapping of L3 as an additional modifier locus, within a 4.1-Mb locus on canine chromosome 30. We establish the natural disease history of RPGRIP1-CRD based on up to 9-year long-term functional and structural retinal data from 58 dogs including 44 RPGRIP1 mutants grouped according to the modifier status. RPGRIP1 mutants affected by both MAP9 and L3 modifiers exhibited the most severe phenotypes with rapid disease progression. MAP9 alone was found to act as an overall accelerator of rod and cone diseases, while L3 had a cone-specific effect. Ultrastructural analysis of photoreceptors revealed varying degrees of rod and cone damage, while the connecting cilia appeared structurally preserved in all groups. We conclude that RPGRIP1-CRD is an oligogenic disease with at least three loci contributing to the pathogenesis. While the RPGRIP1 variant is required for developing the disease, MAP9 and L3 modifiers exacerbate the phenotype, individually and cumulatively. Oligogenic canine RPGRIP1-CRD illustrates the impact of multiple genetic modifiers on disease phenotype and thus has the potential to reveal new targets for broad-spectrum therapies for oligogenic or polygenic forms of human IRDs.

Optical coherence tomography (OCT) has been widely adopted in research on coronary atherosclerosis and adopted clinically to optimize percutaneous coronary intervention. In this Review, Jang and colleagues summarize this rapidly progressing field, with the aim of standardizing the use of OCT in coronary atherosclerosis.Since optical coherence tomography (OCT) was first performed in humans two decades ago, this imaging modality has been widely adopted in research on coronary atherosclerosis and adopted clinically for the optimization of percutaneous coronary intervention. In the past 10 years, substantial advances have been made in the understanding of in vivo vascular biology using OCT. Identification by OCT of culprit plaque pathology could potentially lead to a major shift in the management of patients with acute coronary syndromes. Detection by OCT of healed coronary plaque has been important in our understanding of the mechanisms involved in plaque destabilization and healing with the rapid progression of atherosclerosis. Accurate detection by OCT of sequelae from percutaneous coronary interventions that might be missed by angiography could improve clinical outcomes. In addition, OCT has become an essential diagnostic modality for myocardial infarction with non-obstructive coronary arteries. Insight into neoatherosclerosis from OCT could improve our understanding of the mechanisms of very late stent thrombosis. The appropriate use of OCT depends on accurate interpretation and understanding of the clinical significance of OCT findings. In this Review, we summarize the state of the art in cardiac OCT and facilitate the uniform use of this modality in coronary atherosclerosis. Contributions have been made by clinicians and investigators worldwide with extensive experience in OCT, with the aim that this document will serve as a standard reference for future research and clinical application.

PURPOSE: To describe a case of monocular retinopathy of prematurity (ROP)-like vasculopathy without oxygen supplementation in the dog. METHODS: Fundus photographs (RetCam), spectral-domain optical coherence tomography (sdOCT), confocal scanning laser ophthalmoscopy (cSLO), and fluorescein angiography (FA), as well as postmortem histology and immunohistochemistry (Collagen IV and anti-vWF antibodies), were carried out to characterize the vascular abnormalities. RESULTS: Ophthalmic examination showed peripheral and mid-temporal avascular areas in the tapetal region, neovascularization and abnormally dilated and tortuous retinal vessels in the left eye. sdOCT demonstrated not only cross-sectional views of preretinal fibrovascular proliferation but also extensive proliferation extraretinally into the vitreous. FA emphasized demarcation of vascular and avascular zones with neovascular tufts “popcorns.” Histology and immunohistochemistry confirmed presence of abnormally dilated vessels and the intravitreal blood vessels. CONCLUSIONS: ROP is a disease of abnormally developed retinal vascularization associated with oxygen supplementation therapy, potentially causing blindness in premature infants. Although the mechanism of ROP-like vasculopathy in our case is unclear, it is important to appreciate that the abnormal vascular pattern seen in ROP in premature infants can occur in canines without oxygen administration.

OBJECTIVE: To describe the in vivo structural characteristics of multifocal and geographic retinal dysplasia visualized with advanced retinal imaging including confocal scanning laser ophthalmoscopy (cSLO), optical coherence tomography (OCT), en face OCT and the novel vascular imaging technique OCT angiography (OCTA). DOGS STUDIED AND PROCEDURES: Two dogs were diagnosed with unilateral multifocal or geographic retinal dysplasia and underwent advanced retinal imaging under general anesthesia at the Retinal Disease Studies Facility of the University of Pennsylvania. RESULTS: In both cases the morphological pattern of the lesions were similar including outer retinal folds that invaginated and formed tubular retinal rosettes, surrounding a central inner retinal thickening (multifocal) or plaque (geographic). The two dogs had multiple vascular anomalies in the lesions such as increased tortuosity, abnormal change of vessel diameter including aneurysms and capillary network disruption. We also identified increased autofluorescence by AF cSLO with short wavelength light source (488 nm and barrier filter at 500 nm), and several areas of photoreceptor loss associated with the lesions. CONCLUSION: The use of OCTA allowed the identification of microvascular abnormalities associated with multifocal and geographic retinal dysplasia in two dogs. To our knowledge, this is the first report where the dye-free OCTA technique is used to study vascular lesions in canine retinas.

“What time should I take my medicine?” is an increasingly important question. Current knowledge of time-of-day effects for specific medications in hospitalized patients with cardiovascular disease is very limited. In such patients, increased medication efficiency could potentially reduce dose use and/or the length of time in the Intensive Care Unit (ICU) and/or hospital – potentially improving patient outcomes and patient and family quality of life, and reducing financial costs. We studied whether the time of day or night a patient is given a diuretic affects urine volume response. In this observational study, data were from 7,704 patients (63% male, 18 to 98 years old) admitted to one hospital’s acute care cardiac units, cardiac ICUs, cardiac surgery ICUs, and/or non-cardiac ICUs, who received intravenous furosemide (a diuretic), had measurements of urine volume, were hospitalized for ≥ 3 days between January 2016 to July 2021 and were older than 18 years. We used machine learning (ML) techniques to analyze the data. The ML technique identified factors that were expected to predict urine volume response to the diuretic: sex, age, medication dose and time, creatinine concentration, diagnosis, and hospital unit. The ML technique also identified medication administration time 00:00–06:00 as a predictor of higher urine volume response. Randomized controlled trials should be conducted to quantify the relative effect of modifiable factors, such as time of medication administration.

The purpose of this study was to evaluate rod and cone function and outer retinal structure within macular lesions, and surrounding extralesional areas of patients with autosomal dominant Best vitelliform macular dystrophy caused by BEST1 mutations.Seventeen patients from seven families were examined with dark- and light-adapted chromatic perimetry and optical coherence tomography. Subsets of patients had long-term follow-up (14-22 years, n = 6) and dark-adaptation kinetics measured (n = 5).Within central lesions with large serous retinal detachments, rod sensitivity was severely reduced but visual acuity and cone sensitivity were relatively retained. In surrounding extralesional areas, there was a mild but detectable widening of the subretinal space in some patients and some retinal areas. Available evidence was consistent with subretinal widening causing slower dark-adaptation kinetics. Over long-term follow-up, some eyes showed formation of de novo satellite lesions at retinal locations that years previously demonstrated subretinal widening. A subclinical abnormality consisting of a retina-wide mild thickening of the outer nuclear layer was evident in many patients and thickening increased in the subset of patients with long-term follow-up.Outcome measures for future clinical trials should include evaluations of rod sensitivity within central lesions and quantitative measures of outer retinal structure in normal-appearing regions surrounding the lesions.

To characterize the progression of vascular changes that occur in each retinal plexus, in three canine models of inherited retinal degeneration.In this retrospective cohort study, we examined the retinal imaging records of 44 dogs from a research colony that had undergone optical coherence tomography angiography (OCTA) imaging. Animals enrolled included crd2/NPHP5 and xlpra2/RPGR mutant dogs imaged at different stages of photoreceptor loss, as well as RHOT4R/+ dogs after acute light-induced rod degeneration. Also included were normal controls imaged at similar ages. OCT angiograms of the superficial vascular plexus combined with the intermediate capillary plexus (SVP + ICP), and the deep capillary plexus (DCP) were analyzed using the AngioTool software to calculate vessel density and other vascular parameters.A reduction in vessel density was seen over time in both the SVP + ICP and DCP in all mutant dogs but was more pronounced in the DCP. Scans were subclassified based on outer nuclear layer (ONL) thinning compared to age-matched normal controls. When ONL loss was 0% to 50%, vessel density in the DCP was significantly lower than in age-matched controls. In all cases, when ONL loss exceeded 87.5%, vessel density in the SVP + ICP was significantly reduced as well. In the acute light-induced rod degeneration model, the vascular regression changes were observed mainly in the DCP.Vessel density reduction in dogs undergoing retinal degeneration is first detected by OCTA in the DCP, and only at later stages in the SVP + ICP.

The inherited childhood blindness caused by mutations in NPHP5, a form of Leber congenital amaurosis, results in abnormal development, dysfunction and degeneration of photoreceptors. A naturally occurring NPHP5 mutation in dogs results in a phenotype that very nearly duplicates the human retinopathy in terms of the photoreceptors involved, spatial distribution of degeneration and the natural history of vision loss. We show that AAV-mediated NPHP5 gene augmentation of mutant canine retinas at the time of active degeneration and peak cell death stably restores photoreceptor structure, function, and vision with either the canine or human NPHP5 transgenes. Mutant cone photoreceptors, which failed to form outer segments during development, reform this structure after treatment. Degenerating rod photoreceptor outer segments are stabilized and develop normal structure. This process begins within 8 weeks following treatment, and remains stable throughout the 6 month post treatment period. In both photoreceptor cell classes, mislocalization of rod and cone opsins is minimized or reversed. Retinal function and functional vision are restored. Efficacy of gene therapy in this large animal ciliopathy model of Leber congenital amaurosis provides a path for translation to human treatment.

Inflammation is the physiologic reaction to cellular and tissue damage caused by trauma, ischemia, infection, and other pathologic conditions. Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not well established. Here we studied inflammatory recovery from trauma, ischemia, and infection by tracking longitudinal dynamics of clinical laboratory measurements in hospitalized patients. We identified a universal recovery trajectory defined by exponential WBC decay and delayed linear growth of platelet count (PLT). Co-regulation of WBC-PLT dynamics is a fundamental mechanism of acute inflammatory recovery and provides a generic approach for identifying high-risk patients: 32x relative risk (RR) of adverse outcomes for cardiac surgery, 9x RR of death from COVID-19, 9x RR of death from sepsis, and 5x RR of death from myocardial infarction.

To provide an overview of the role of remote monitoring tools in management of critically-ill patients requiring acute mechanical circulatory support (MCS).Tele-critical care systems have received new interest during the COVID-19 pandemic, which has stretched the capacity of health systems everywhere. At the same time, utilization of MCS and extracorporeal membrane oxygenation (ECMO) technologies has increased during the pandemic. The opportunity for remote monitoring and clinical decision support for ECMO and acute MCS devices has been recognized by industry partners, with several major platforms implementing technology infrastructure for it in available products. Healthcare systems face challenges interfacing multiple devices from multiple manufacturers with each other and with their designated electronic health records. Furthermore, the availability of data must be combined with algorithms for alerting on clinical events and with implementation systems to act upon these alerts. Studies are not yet published validating remote monitoring platforms for ECMO and MCS in clinical care.Remote monitoring for MCS devices represents a major opportunity for further investigation to improve the utilization of these devices and better serve patients.

Objective Current cardiac surgery risk models do not address a substantial fraction of procedures. We sought to create models to predict the risk of operative mortality for an expanded set of cases. Methods Four supervised machine learning models were trained using preoperative variables present in the Society of Thoracic Surgeons (STS) data set of the Massachusetts General Hospital to predict and classify operative mortality in procedures without STS risk scores. A total of 424 (5.5%) mortality events occurred out of 7745 cases. Models included logistic regression with elastic net regularization (LogReg), support vector machine, random forest (RF), and extreme gradient boosted trees (XGBoost). Model discrimination was assessed via area under the receiver operating characteristic curve (AUC), and calibration was assessed via calibration slope and expected-to-observed event ratio. External validation was performed using STS data sets from Brigham and Women's Hospital (BWH) and the Johns Hopkins Hospital (JHH). Results Models performed comparably with the highest mean AUC of 0.83 (RF) and expected-to-observed event ratio of 1.00. On external validation, the AUC was 0.81 in BWH (RF) and 0.79 in JHH (LogReg/RF). Models trained and applied on the same institution's data achieved AUCs of 0.81 (BWH: LogReg/RF/XGBoost) and 0.82 (JHH: LogReg/RF/XGBoost). Conclusions Machine learning models trained on preoperative patient data can predict operative mortality at a high level of accuracy for cardiac surgical procedures without established risk scores. Such procedures comprise 23% of all cardiac surgical procedures nationwide. This work also highlights the value of using local institutional data to train new prediction models that account for institution-specific practices.

The only approved retinal gene therapy is for biallelic RPE65 mutations which cause a recessive retinopathy with a primary molecular defect located at the retinal pigment epithelium (RPE). For a distinct recessive RPE disease caused by biallelic BEST1 mutations, a pre-clinical proof-of-concept for gene therapy has been demonstrated in canine eyes. The current study was undertaken to consider potential outcome measures for a BEST1 clinical trial in patients demonstrating a classic autosomal recessive bestrophinopathy (ARB) phenotype. Spatial distribution of retinal structure showed a wide expanse of abnormalities including large intraretinal cysts, shallow serous retinal detachments, abnormalities of inner and outer segments, and an unusual prominence of the external limiting membrane. Surrounding the central macula extending from 7 to 30 deg eccentricity, outer nuclear layer was thicker than expected from a cone only retina and implied survival of many rod photoreceptors. Co-localized however, were large losses of rod sensitivity despite preserved cone sensitivities. The dissociation of rod function from rod structure observed, supports a large treatment potential in the paramacular region for biallelic bestrophinopathies.

Eadweard Muybridge's Pacific Coast photographs provide an important site for investigating Victorian visual practices of the “wide.” They do not simply expand a referential frame to encompass novel subjects; they also, and more critically, register powerful narratives of temporality and modernity. This essay's analysis of the “wide” as an incipient concept of critical spatiality is not set against the more familiar temporal dimension of the long nineteenth century (a false and ultimately unproductive opposition). Rather, it places these two concerns in some tension with each other, though the argument is less about periodicity than about the representation of timescales in nineteenth-century media. In Muybridge's photographs, thinking about the representational possibilities of width is impossible without also confronting temporality. The Pacific Coast photographs are important both as explorations of timescales and artifacts in an influential nineteenth-century medium and prompts to reconsider the politico-economic networks that were central to the progress of expeditionary photography itself.

SignificanceCanine models of inherited retinal diseases have helped advance adeno-associated virus (AAV)-based gene therapies targeting specific cells in the outer retina for treating blinding diseases in patients. However, therapeutic targeting of diseases such as congenital stationary night blindness (CSNB) that exhibit defects in ON-bipolar cells (ON-BCs) of the midretina remains underdeveloped. Using a leucine-rich repeat, immunoglobulin-like and transmembrane domain 3 (

Regenerative therapies aimed at replacing photoreceptors are a promising approach for the treatment of otherwise incurable causes of blindness. However, such therapies still face significant hurdles, including the need to improve subretinal delivery and long-term survival rate of transplanted cells, and promote sufficient integration into the host retina. Here, we successfully delivered in vitro-derived human photoreceptor precursor cells (PRPCs; also known as immature photoreceptors) to the subretinal space of seven normal and three rcd1/PDE6B mutant dogs with advanced inherited retinal degeneration. Notably, while these xenografts were rejected in dogs that were not immunosuppressed, transplants in most dogs receiving systemic immunosuppression survived up to 3-5 months postinjection. Moreover, differentiation of donor PRPCs into photoreceptors with synaptic pedicle-like structures that established contact with second-order neurons was enhanced in rcd1/PDE6B mutant dogs. Together, our findings set the stage for evaluating functional vision restoration following photoreceptor replacement in canine models of inherited retinal degeneration.

Made available in DSpace on 2022-05-01T11:07:40Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-01 Despite being a preventable and curable disease, Tuberculosis (TB) is the world's top infectious killer. Development of new drugs is urgently needed. In this work, the synthesis and characterization of new silver(I) complexes, that include N′-[(E)-(pyridine-2-ylmethylene)pyrazine-2-carbohydrazide, HPCPH, as main ligand and substituted aryl-phosphines as auxiliary ligands, is reported. HPCPH was synthesized from pyrazinoic acid, the active metabolite of the first-line antimycobacterial drug pyrazinamide. Complexes [Ag(HPCPH)(PPh3)2]OTf (1), [Ag(HPCPH)((P(p-tolyl)3)2]OTf (2) and [Ag(HPCPH)(P(p-anisyl)3)2]OTf (3) were characterized in solid state and in solution by elemental analysis and FTIR and NMR spectroscopies (OTf[dbnd]triflate). Crystal structures of (1,2) were determined by XRD. The Ag atom is coordinated to azomethine and pyridine nitrogen atoms of HPCPH ligand and to the phosphorous atom of each aryl-phosphine co-ligand. Although HPCPH did not show activity, the Ag(I) compounds demonstrated activity against Mycobacterium tuberculosis (MTB), H37Rv strain, and multi-drug resistant clinical isolates (MDR-TB). Globally, results showed that the compounds are not only effective against the sensitive strain, but are more potent against MDR-TB than antimycobacterial drugs used in therapy. The compounds showed low to moderate selectivity index values (SI) towards the bacteria, using MRC-5 cells (ATCC CCL-171) as mammalian cell model. Interaction with DNA was explored to get insight into the potential mechanism of action against the pathogen. No significant interaction was detected, allowing to discard this biomolecule as a potential molecular target. Compound 1 was identified as a hit compound (MIC90 2.23 μM; SI 4.4) to develop further chemical modifications in the search for new drugs. Escuela de Ingeniería Química Facultad de Ingeniería Química y Textil Universidad Nacional de Ingeniería Laboratorio de Biopolímeros y Metalofármacos LIBIPMET Facultad de Ciencias Universidad Nacional de Ingeniería Área Química Inorgánica Facultad de Química Universidad de la República Faculdade de Ciências Farmacêuticas UNESP Facultad de Ingeniería Eléctrica y Electrónica Universidad Nacional de Ingeniería Faculdade de Ciências Farmacêuticas UNESP

Los tumores neuroendocrinos pancreáticos representan del 2-10 % de todos los tumores del páncreas y aproximadamente el 7 % de todos los tumores neuroendocrinos. Estos se clasifican como funcionales o no funcionales según la presencia o ausencia de síndromes clínicos asociados con la hipersecreción hormonal. Los insulinomas son los tumores neuroendocrinos pancreáticos funcionales más frecuentes (45 % de los casos) y la causa más frecuente de hipoglucemia hiperinsulinémica endógena persistente en adultos. Además, el 10 % de los tumores neuroendocrinos pancreáticos se asocian con neoplasia endocrina múltiple tipo 1. La insulinomatosis es una entidad clínica distinta en la que existen múltiples insulinomas. Objetivos: exponer los casos reportados hasta el momento de insulinomatosis y describir las causas genéticas, las características clínicas, el tratamiento, y el pronóstico de la insulinomatosis. Métodos: se realizó una búsqueda sobre insulinomatosis y los factores que controlan la proliferación de las células ? en las bases de datos PubMed, Medline y Google Scholar hasta Julio 2020. Resultados: 108 casos con insulinomatosis se han reportado hasta la fecha, siendo recurrente y rara vez malignos. Múltiples protooncogenes y supresores de tumores controlan de forma local y sistémica el crecimiento de las células ?; sin embargo, solo la mutación de MafA en p.Ser64Phe ha sido asociada. Conclusión: la insulinomatosis se caracteriza por la aparición sincrónica y metacrónica de insulinomas. Tiene un fenotipo histológico, clínico y genético diferente a los tumores neuroendocrinos pancreáticos; la mutación MEN-1 es negativa; puede ser esporádica o hereditaria; y MafA podría ser una mutación conductora.

Recombinant adeno-associated viral (rAAV) vector-mediated gene therapy is being developed to treat X-linked retinitis pigmentosa (XLRP) in patients with mutations in the retinitis pigmentosa GTPase...

Group A rotavirus (RVA) and bovine coronavirus (BCoV) are the two main viral enteropathogens associated with neonatal calf diarrhea. The aim of the present survey was to investigate the epidemiology and the role of RVA and BCoV in the presentation of dairy and beef calf diarrhea in Lerma Valley of Salta province, within the Northwest region of Argentina. Stool samples of calves with or without diarrhea younger than 2 months of age were collected from 19 dairy farms and 20 beef farms between the years 2014 and 2016. Stool samples were screened for RVA and BCoV detection by ELISA. Heminested multiplex RT-PCR was used for RVA typing and RT-PCR to confirm BCoV. Positive samples were submitted to sequencing analysis. Bovine RVA and BCoV were circulating in 63% (12/19) and 10.52% (2/19) of the dairy farms, respectively, where 9.5% (46/484) of the calves were positives to RVA and 0.4% (2/484) to BCoV. In beef herds, RVA was detected in 40% (8/20) of the farms and in 6.75% (21/311) of the calves, without positives cases of BCoV. Molecular analysis showed that in dairy farms, G6P[11] and G10P[11] were the prevalent RVA strains, while in beef farms, G10P[11] was the prevalent. The main finding was the detection for the first time of a G15P[11] causing diarrhea in beef calves of Argentina that represents a new alert to be consider for future vaccine updates. Analysis of detected BCoV showed that it is related to the other circulating strains of Argentina. Fil: Bertoni, Emiliano. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; Argentina Fil: Aduriz, Miguel Angel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina Fil: Bok, Marina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina Fil: Vega, Celina Guadalupe. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina Fil: Saif, L.. Ohio State University; Estados Unidos Fil: Aguirre, D.. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias. Instituto de Investigación Animal del Chaco Semiárido; Argentina Fil: Cimino, Rubén Oscar. Universidad Nacional de Salta; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Miño, Orlando Samuel. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina Fil: Parreño, Gladys Viviana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Nacional de Tecnologia Agropecuaria. Centro de Investigacion En Ciencias Veterinarias y Agronomicas. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit | Consejo Nacional de Investigaciones Cientificas y Tecnicas. Oficina de Coordinacion Administrativa Pque. Centenario. Instituto de Virologia E Innovaciones Tecnologicas. Grupo Vinculado Incuinta Al Ivit.; Argentina

OBJECTIVE: To evaluate a grading scheme for conjunctival staining patterns with lissamine green ocular dye in the diagnosis of tear film deficiencies in dogs. PROCEDURES: Client‐owned and research colony dogs were enrolled in a prospective study between February and October 2018 in which slit‐lamp biomicroscopy, Schirmer tear test (STT), tear film breakup time (TFBUT), conjunctival lissamine green staining (LGS), and intraocular pressure (IOP) measurement were performed in both eyes of all dogs. Lissamine green staining of the temporal bulbar conjunctiva was graded from 0‐3, with a higher grade corresponding to an increased stain intensity. RESULTS: Fifty‐four dogs (107 eyes), comprising 31 males and 23 females with a mean age of 5.0 ± 3.9 years (range 0.5‐14.3), were enrolled in the study. STT was

The issue of transborder mobility posed a dilemma for U.S. labor organizations and for border communities that embraced workers, customers, and family connections from Mexico. Labor leaders including Ernesto Galarza of the National Farm Labor Union (NFLU) and César Chávez of the United Farm Workers (UFW) had to find ways of protecting U.S. citizen workers and yet humanely addressing the plight of resident aliens, permitted commuters, and undocumented workers from Mexico. Their strategies involved knowledge production and had to accommodate emotions. The article focuses on the Imperial-Mexicali borderlands, 1950s–1970s.

PURPOSE: To describe the in vivo microanatomy of typical and atypical chorioretinal and juxtapapillary colobomas in the dog. METHODS: Three crossbreed dogs were found to be affected with colobomas. Two of the cases were NEHJ1 homozygous and Collie Eye Anomaly (CEA) affected and had the typical optic nerve head colobomas seen with the disease. The third case had an unexpected atypical coloboma. In vivo retinal photography and non-invasive retinal imaging by confocal scanning laser ophthalmoscope (cSLO) and optical coherence tomography (OCT) was done, and the eye affected with the atypical coloboma was collected and processed for histopathological evaluation. RESULTS: The majority of the defining features within the CEA defects were similar, with the extent of change to the choroid being of note. Similar to the first two cases, the atypical coloboma demonstrated absent normal retina, RPE and choroid within the coloboma. Prominent intercalary membranes and vitreal strands attached to the depth of the coloboma were also apparent in all affected eyes. However, unlike the CEA associated colobomas, the atypical coloboma possessed normal choroid surrounding the lesion and the depth of the lesion was apparent throughout. CONCLUSIONS: Advanced retinal imaging enables the appreciation of microanatomical changes that occur in the living eye. The ability of OCT to enhance visualization of abnormal retinal structures and detect subtle neurosensory retinal defects has allowed for the in vivo characterization of features observed in typical and atypical colobomas, as well as the appreciation of some of the resulting structural changes not visible by ophthalmoscopy alone.

Identification of genetic mutations responsible for inherited retinal degenerations in a variety of breeds of dogs, coupled with phenotypic characterization of the natural history of disease has provided large animal models that have had a significant impact in translating preclinical discoveries in retinal gene therapies to humans. More than 20 years ago, proof of concept studies conducted in a dog model of childhood blindness led to the first retinal gene therapy to receive market approval in the US and EU. Since this first breakthrough success, vision scientists from the Schools of Veterinary Medicine and Medicine of the University of Pennsylvania have pursued the use of patient-relevant canine models to test and move to the clinic novel retinal gene therapies for five additional diseases. Key-Words: dog, canine model, retina, degeneration, dystrophy, gene therapy

Atherosclerosis is a lipid-driven inflammatory disorder that narrows the arterial lumen and can induce life-threatening complications from coronary artery disease, cerebrovascular disease and peripheral artery disease. On a mechanistic level, the development of novel cellular-resolution intravital microscopy imaging approaches has recently enabled in vivo studies of underlying biological processes governing disease onset and progress. In particular multi-photon microscopy has emerged as a promising intravital imaging tool utilizing two-photon-excited fluorescence and second-harmonic generation that provides sub-cellular resolution and increased imaging depths beyond confocal and epifluorescence microscopy. In this chapter, we describe the state-of-the-art multi-photon microscopy applied to the study of murine atherosclerosis.

Retinal degenerative diseases result from apoptotic photoreceptor cell death. As endogenously produced gaseous molecules such as hydrogen sulfide (H(2)S) and nitric oxide (NO) play a key role in apoptosis, we compared the expression levels of genes and proteins involved in the production of these molecules in the retina of normal dogs and three canine models (rcd1, crd2, and xlpra2) of human inherited retinal degeneration (IRD). Using qRT-PCR, western blot, and immunohistochemistry (IHC), we showed that mRNA and protein levels of cystathionine β–synthase (CBS), an enzyme that produces H(2)S in neurons, are increased in retinal degeneration, but those of cystathionine γ-lyase (CSE), an enzyme involved in the production of glutathione (GSH), an antioxidant, are not. Such findings suggest that increased levels of H(2)S that are not counterbalanced by increased antioxidant potential may contribute to disease in affected retinas. We also studied the expression of neuronal and inducible nitric oxide synthase (nNOS and iNOS), the enzymes responsible for NO production. Western blot and IHC results revealed increased levels of nNOS and iNOS, resulting in increased NO levels in mutant retinas. Finally, photoreceptors are rich in polyunsaturated fatty acids (PUFAs) that can make these cells vulnerable to oxidative damage through reactive oxygen species (ROS). Our results showed increased levels of acrolein and hydroxynonenal (4HNE), two main toxic products of PUFAs, surrounding the membranes of photoreceptors in affected canines. Increased levels of these toxic products, together with increased NO and ROS, likely render these cells susceptible to an intrinsic apoptotic pathway involving mitochondrial membranes. To assess this possibility, we measured the levels of BCL2, an anti-apoptotic protein in the mitochondrial membrane. Western blot results showed decreased levels of BCL2 protein in affected retinas. Overall, the results of this study identify alterations in the expression of enzymes directly involved in maintaining the normal redox status of the retina during retinal degeneration, thereby supporting future studies to investigate the role of H(2)S and NO in retinal degeneration and apoptosis.

To the European Space Agency for the imagery of the Sentinel Missions and its open access. Special thanks to Radoslaw Guzinski for share and make accessible (https://github.com/radosuav/pyDMS) the implemented software for the used sharpening process (likewise to Hector Nieto for the implemented TSEB-PT, https://github.com/hectornieto/pyTSEB).To the Group of Castillo de Canena for the use of their farm as an experimental site and their people for continuous cooperation. We also give special thanks to Andrew S. Kowalski for his advice and suggestions. We would like also to express our gratitude to the anonymous reviewers for their comments and suggestions that enhanced this work. This work was supported by the Spanish Ministry of Science and Innovation through project CGL2017-83538-C3-1-R (ELEMENTAL) and PID2020-117825GB-C21 (INTEGRATYON3) Including European Union ERDF funds [grant number PRE2018-085638]. Funding for open access charge: Universidad de Granada/CBUA., Precipitation deficit and more extreme drought and precipitation events are expected to increase in the Mediterranean region due to global warming. A great part of this region is covered by olive orchards, representing 97.5% of the world’s olive agricultural area. Thus, the adaptation of olive cultivation demands climate-smart management, such as the optimization of water use efficiency, since evapotranspiration is one of the most important components of the water balance. The novelty of this work is the combination of the remote sensing data fusion and the Two Source Energy Balance (TSEB) model (through Sentinel-2 and Sentinel-3 imagery) to estimate the actual daily evapotranspiration (ETd), at high spatial (20 m) and temporal (daily) resolution, in an olive orchard under two management regimes: herbaceous free (HF) and herbaceous-cover (HC); along a three years period, based on the hypothesis that TSEB is still able to track and estimate the evapotranspiration over more complex canopies. The study was carried out from 2016 to 2019 in an olive orchard in the South of Spain, where the flux estimates were validated and assessed by in situ eddy covariance (EC) measurements. The results show better agreement in HC for net radiation (Rn) and the soil heat flux (G), but similar for both surfaces regarding the sensible (H) and latent (λE) heat fluxes, as well as ETd. On both surfaces greater differences obtained at higher H, and the magnitude of overestimation of λE and ETd were influenced by the EC energy imbalance. By contrast, G was overestimated with HC probably influenced by herbs, and equally underestimated for HF surfaces. The obtained results are in agreement with similar studies in tree crop orchards, and show the consistency of the used methodology and its usefulness for some farming activities, even on the more heterogeneous surface., Spanish Government CGL2017-83538-C3-1-R PID2020-117825GB-C21, European Commission PRE2018-085638, Universidad de Granada/CBUA

Photopharmacological compounds such as azobenzene-based photoswitches have been shown to control the conductivity of ionic channels in a light-dependent manner and are considered a potential strategy to restore vision in patients with end-stage photoreceptor degeneration. Here, we report the effects of DENAQ, a second-generation azobenzene-based photoswitch on retinal ganglion cells (RGC) in canine retinas using multi-electrode array (MEA) recordings (from nine degenerated and six WT retinas). DENAQ treatment conferred increased light sensitivity to RGCs in degenerated canine retinas. RGC light responses were observed in degenerated retinas following ex vivo application of 1 mM DENAQ (n = 6) or after in vivo DENAQ injection (n = 3, 150 μL, 3–10 mM) using 455 nm light at intensities as low as 0.2 mW/cm2. The number of light-sensitive cells and the per cell response amplitude increased with light intensity up to the maximum tested intensity of 85 mW/cm2. Application of DENAQ to degenerated retinas with partially preserved cone function caused appearance of DENAQ-driven responses both in cone-driven and previously non-responsive RGCs, and disappearance of cone-driven responses. Repeated stimulation slowed activation and accelerated recovery of the DENAQ-driven responses. The latter is likely responsible for the delayed appearance of a response to 4 Hz flicker stimulation. Limited aqueous solubility of DENAQ results in focal drug aggregates associated with ocular toxicity. While this limits the therapeutic potential of DENAQ, more potent third-generation photoswitches may be more promising, especially when delivered in a slow-release formulation that prevents drug aggregation.

PURPOSE: To describe the ophthalmoscopic, in-vivo imaging, fluorescein angiography, and therapeutic photocoagulation outcome in a case of bilateral optic nerve colobomas associated with focal unilateral retinal detachment in a dog. METHODS: Pretraining eye examination of a 1.6-year-old female German shepherd service dog showed a focal juxta-papillary bullous retinal separation in the right eye. In vivo imaging and angiography were performed under general anesthesia using optical coherence tomography. Nonoverlapping diode laser burns were applied through an operating microscope adapter to selected areas along the leading margins of the detachment. RESULTS: The funduscopic examination and in-vivo imaging revealed bilateral optic nerve colobomas associated with a focal bullous detachment in the right eye. Fluorescein angiography showed absence of blood vessel leakage and absence of staining inside of the retinal elevation. Photocoagulation induced immediate changes in retinal layer reflectivity. Three months post-photocoagulation, the retinal detachment had improved and scarring of the burns was visible. One and two years post-procedure, the retinal detachment resolved. CONCLUSIONS: Optical coherence tomography (OCT) imaging provides a detailed analysis of the retinal abnormalities associated with the clinical lesion. Laser retinopexy is a valid therapeutic option to limit the extension of the detachment.

Background: Adeno-associated virus (AAV)-mediated gene therapies are rapidly advancing to the clinic, and AAV engineering has resulted in vectors with increased ability to deliver therapeutic genes. Although the choice of vector is critical, quantitative comparison of AAVs, especially in large animals, remains challenging. Methods: Here, we developed an efficient single-cell AAV engineering pipeline (scAAVengr) to simultaneously quantify and rank efficiency of competing AAV vectors across all cell types in the same animal. Results: To demonstrate proof-of-concept for the scAAVengr workflow, we quantified – with cell-type resolution – the abilities of naturally occurring and newly engineered AAVs to mediate gene expression in primate retina following intravitreal injection. A top performing variant identified using this pipeline, K912, was used to deliver SaCas9 and edit the rhodopsin gene in macaque retina, resulting in editing efficiency similar to infection rates detected by the scAAVengr workflow. scAAVengr was then used to identify top-performing AAV variants in mouse brain, heart, and liver following systemic injection. Conclusions: These results validate scAAVengr as a powerful method for development of AAV vectors. Funding: This work was supported by funding from the Ford Foundation, NEI/NIH, Research to Prevent Blindness, Foundation Fighting Blindness, UPMC Immune Transplant and Therapy Center, and the Van Sloun fund for canine genetic research., eLife digest Gene therapy is an experimental approach to treating disease that involves altering faulty genes or replacing them with new, working copies. Most often, the new genetic material is delivered into cells using a modified virus that no longer causes disease, called a viral vector. Virus-mediated gene therapies are currently being explored for degenerative eye diseases, such as retinitis pigmentosa, and neurological disorders, like Alzheimer’s and Parkinson’s disease. A number of gene therapies have also been approved for treating some rare cancers, blood disorders and a childhood form of motor neuron disease. Despite the promise of virus-mediated gene therapy, there are significant hurdles to its widespread success. Viral vectors need to deliver enough genetic material to the right cells without triggering an immune response or causing serious side effects. Selecting an optimal vector is key to achieving this. A type of viruses called adeno-associated viruses (AAV) are prime candidates, partly because they can be easily engineered. However, accurately comparing the safety and efficacy of newly engineered AAVs is difficult, due to variation between test subjects and the labor and cost involved in careful testing. Öztürk et al. addressed this issue by developing an experimental pipeline called scAAVengr for comparing gene therapy vectors head-to-head. The process involves tagging potential AAV vectors with unique genetic barcodes, which can then be detected and quantified in individual cells using a technique called single-cell RNA sequencing. This means that when several vectors are used to infect lab-grown cells or a test animal at the same time, they can be tracked. The vectors can then be ranked on their ability to infect specific cell types and deliver useful genetic material. Using scAAVengr, Öztürk et al. compared viral vectors designed to target the light-sensitive cells of the retina, which allow animals to see. First, a set of promising viral vectors were evaluated using the scAAVengr pipeline in the eyes of marmosets and macaques, two small primates. Precise levels and locations of gene delivery were quantified. The top-performing vector was then identified and used to deliver Cas9, a genome editing tool, to primate retinas. Öztürk et al. also used scAAVengr to compare viral vectors in mice, analysing the vectors’ ability to deliver their genetic cargo to the brain, heart, and liver. These experiments demonstrated that scAAVengr can be used to evaluate vectors in multiple tissues and in different organisms. In summary, this work outlines a method for identifying and precisely quantifying the performance of top-performing viral vectors for gene therapy. By aiding the selection of optimal viral vectors, the scAAVengr pipeline could help to improve the success of preclinical studies and early clinical trials testing gene therapies.

OBJECTIVE Aortic valve disease is a risk factor for atrial fibrillation (AF), and AF is associated with increased late mortality and morbidity after cardiac surgery. The evolution of alternative approaches to AF prophylaxis, including less invasive technologies and medical therapies, has altered the balance between risk and potential benefit for prophylactic intervention at the time of surgical aortic valve replacement (SAVR). Such interventions impose incremental risk, however, making an understanding of predictors of new onset AF that persists beyond the perioperative episode relevant. METHODS We conducted a retrospective single-institution cohort analysis of patients undergoing SAVR with no history of preoperative AF (n = 1014). These patients were cross-referenced against an institutional electrocardiogram (ECG) database to identify those with ECGs 3-12 months after surgery. Logistic regression was used to identify predictors of late AF. RESULTS Among the 401 patients (40%), who had ECGs in our institution 3-12 months after surgery, 16 (4%) had late AF. Patients with late AF were older than patients without late AF (73 vs. 65, p = .025), and underwent procedures that were more urgent/emergent (38% vs. 15%, p = .015), with higher predicted risk of mortality (2.2% vs. 1.3%, p = .012). Predictors associated with the development of late AF were advanced age, higher preoperative creatinine level and urgent/emergent surgery. CONCLUSIONS The incidence of late AF 3-12 months after SAVR, is low. Prophylactic AF interventions at the time of SAVR may not be warranted.

AAV gene therapies aimed at curing inherited retinal diseases to date have typically focused on photoreceptors and retinal pigmented epithelia within the relatively accessible outer retina. However, therapeutic targeting in diseases such as congenital stationary night blindness (CSNB) that involve defects in ON-bipolar cells (ON-BCs) within the mid-retina has been challenged by the relative inaccessibility of the target cell in intact retinas, the limited transduction efficiency of these cells by existing AAV serotypes, poor availability of established ON-BC-specific promoters, and absence of appropriate patient-relevant large animal models. Here, we demonstrate safe and effective ON-BC targeting by AAV gene therapy in a recently characterized naturally-occurring canine model of CSNB, LRIT3-CSNB. To effectively target ON-BCs, new AAV capsid variants with ON-BC tropism and ON-BC specific modified GRM6 promoters were adopted to ensure cell-specific transgene expression. Notably, subretinal injection of one vector, AAVK9#4-shGRM6-cLRIT3-WPRE, significantly recovered rod-derived b-wave in all treated eyes (6/6) of adult dogs injected at 1-3 years of age. The robust therapeutic effect was evident 7 weeks post-injection and was sustained for at least 1 year in all treated eyes. Scotopic vision was significantly improved in treated eyes based on visually-guided obstacle course navigation. Restoration of LRIT3 signals was confirmed by immunohistochemistry. Thus, we report on the first ON-BC functional rescue in a large animal model using a novel AAV capsid variant and modified promoter construct optimized for ON-BC specificity, thereby establishing both proof-of-concept and a novel translational platform for treatment of CSNB in patients with defects in photoreceptor-to-bipolar signaling.

The goal of the present study was to propose a set of preliminary regional diagnostic reference levels (DRLs) for pediatric interventional cardiology (IC) procedures in Latin America and the Caribbean countries, classified by age and weight groups. The study was conducted in the framework of the Optimization of Protection in Pediatric Interventional Radiology in Latin America and the Caribbean program coordinated by the World Health Organization and the Pan American Health Organization in cooperation with the International Atomic Energy Agency. The first step of the program was focused on pediatric IC. Dose data from diagnostic and therapeutic procedures were collected between December 2020 and December 2021. Regional DRLs were set as the third quartile of patient dose data (kerma area product) collected in 18 hospitals from 10 countries in an initial sample of 968 procedures. DRLs were set for four age bands and five weight ranges. The values obtained for the four age bands (2 for diagnostic procedures, and 4.0, 5.0, 10.0 and 38.1 Gy cm2 for therapeutic procedures, respectively. The values obtained for the five weight bands (2 for diagnostic procedures and 3.7, 4,3, 7.3, 16.1 and 53.4 Gy cm2 for therapeutic procedures, respectively. While initial data were collected manually as patient dose management systems (DMSs) were not available in most of the hospitals involved in the program, a centralized automatic DMS for the collection and management of patient dose indicators has now been introduced and is envisaged to increase the sample size. The possibility of alerting on high dose values and introducing corrective actions will help in optimization.

In this work, we present the characterization of a Form 3 Stereolithography (SLA) FormLabs 3D printer which will be used for the fabrication of optical components. The characterization consisted of the measurement of the refraction index, absorbance & transmittance values, as well as geometrical parameters like radius of curvature, thickness, roundness, and angles. This study proved that with the Form 3 SLA additive technology components with good quality that meet the design parameters can be fabricated.

Inflammation is the physiologic reaction to cellular and tissue damage caused by pathologic processes including trauma, infection, and ischemia1. Effective inflammatory responses integrate molecular and cellular functions to prevent further tissue damage, initiate repair, and restore homeostasis, while futile or dysfunctional responses allow escalating injury, delay recovery, and may hasten death2. Elevation of white blood cell count (WBC) and altered levels of other acute phase reactants are cardinal signs of inflammation, but the dynamics of these changes and their resolution are not established3,4. Patient responses appear to vary dramatically with no clearly defined signs of good prognosis, leaving physicians reliant on qualitative interpretations of laboratory trends4,5.We retrospectively, observationally studied the human acute inflammatory response to trauma, ischemia, and infection by tracking the longitudinal dynamics of cellular and serum markers in hospitalized patients. Unexpectedly, we identified a conserved pattern of recovery defined by co-regulation of WBC and platelet (PLT) populations. Across all inflammatory conditions studied, recovering patients followed a consistent WBC-PLT trajectory shape that is well-approximated by exponential WBC decay and delayed linear PLT growth. This recovery trajectory shape may represent a fundamental archetype of human physiologic response at the cellular population scale, and provides a generic approach for identifying high-risk patients: 32x relative risk of adverse outcomes for cardiac surgery patients, 9x relative risk of death for COVID-19, and 5x relative risk of death for myocardial infarction.

The Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) estimates mortality risk only for certain common procedures (eg, coronary artery bypass or valve surgery) and is cumbersome, requiring greater than 60 inputs. We hypothesized that deep learning can estimate postoperative mortality risk based on a preoperative chest radiograph for cardiac surgeries in which STS-PROM scores were available (STS index procedures) or unavailable (non-STS index procedures).We developed a deep learning model (CXR-CTSurgery) to predict postoperative mortality based on preoperative chest radiographs in 9283 patients at Massachusetts General Hospital (MGH) having cardiac surgery before April 8, 2014. CXR-CTSurgery was tested on 3615 different MGH patients and externally tested on 2840 patients from Brigham and Women's Hospital (BWH) having surgery after April 8, 2014. Discrimination for mortality was compared with the STS-PROM using the C-statistic. Calibration was assessed using the observed-to-expected ratio (O/E ratio).For STS index procedures, CXR-CTSurgery had a C-statistic similar to STS-PROM at MGH (CXR-CTSurgery: 0.83 vs STS-PROM: 0.88; P = .20) and BWH (0.74 vs 0.80; P = .14) testing cohorts. The CXR-CTSurgery C-statistic for non-STS index procedures was similar to STS index procedures in the MGH (0.87 vs 0.83) and BWH (0.73 vs 0.74) testing cohorts. For STS index procedures, CXR-CTSurgery had better calibration than the STS-PROM in the MGH (O/E ratio: 0.74 vs 0.52) and BWH (O/E ratio: 0.91 vs 0.73) testing cohorts.CXR-CTSurgery predicts postoperative mortality based on a preoperative CXR with similar discrimination and better calibration than the STS-PROM. This may be useful when the STS-PROM cannot be calculated or for non-STS index procedures.

Plaque rupture is the most common cause of acute coronary syndromes and sudden cardiac death. Characteristics and pathobiology of vulnerable plaques prone to plaque rupture have been studied extensively over two decades in humans using optical coherence tomography (OCT), an intravascular imaging technique with micron scale resolution. OCT studies have identified key features of plaque vulnerability and described the in vivo characteristics and spatial distribution of thin cap fibroatheromas as major precursors to plaque rupture. In addition, OCT data supports the evolving understanding of coronary heart disease as a panvascular process associated with inflammation. In the setting of high atherosclerotic burden, plaque ruptures often occur at multiple sites in the coronary arteries and plaque progression and healing are dynamic processes modulated by systemic risk factors. This review details major investigations with intravascular OCT into the biology and clinical implications of plaque vulnerability and plaque rupture.

Ancestry Informative Markers InDels (AIM-InDels) show high allele frequency variation between ancestral populations and are useful to estimate individual and population ancestry. This work determined the African, European and Native American admixture proportions in a population sample of 126 individuals from Tunja, Department of Boyaca, Colombia. This region is located close to the center of the country and has a diverse population. To estimate the African, European and Native American admixture proportions, in the sample there were used as parental populations, the genetic profiles of 319 individuals (Africans: 105, Europeans: 154, and Native Americans: 60). The ancestry analysis of this population revealed a main European contribution (55%) with an important contribution of Native American ancestry (40.8%) and only 4.2% contribution of African descent. The results obtained from this type of studies allow us to have a real approximation of the state of the different Colombian populations, after a history of colonialism and years of war with high levels of displacement of the civilian population.