Search

Fatty liver has been present in the lives of patients and physicians for almost two centuries. Vast knowledge has been generated regarding its etiology and consequences, although a long path seeking novel and innovative diagnostic biomarkers for nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is still envisioned. On the one hand, proteomics and lipidomics have emerged as potential noninvasive resources for NAFLD diagnosis. In contrast, metabolomics has been able to distinguish between NAFLD and NASH, even detecting degrees of fibrosis. On the other hand, genetic and epigenetic markers have been useful in monitoring disease progression, eventually functioning as target therapies. Other markers involved in immune dysregulation, oxidative stress, and inflammation are involved in the instauration and evolution of the disease. Finally, the fascinating gut microbiome is significantly involved in NAFLD and NASH. This review presents state-of-the-art biomarkers related to NAFLD and NASH and new promises that could eventually be positioned as diagnostic resources for this disease. As is evident, despite great advances in studying these biomarkers, there is still a long path before they translate into clinical benefits.

Autism spectrum disorder (ASD) is a disease characterized by reduced social interaction and stereotypic behaviors and related to macroscopic volumetric changes in cerebellar and somatosensory cortices (SPP). Epidemiological and preclinical models have confirmed that a proinflammatory profile during fetal development increases ASD susceptibility after birth. Here, we aimed to globally identify the effect of maternal exposure to high-energy dense diets, which we refer to as cafeteria diet (CAF) on peripheral and central proinflammatory profiles, microglia reactivity, and volumetric brain changes related to assisting defective social interaction in the mice offspring. We found a sex-dependent effect of maternal exposure to CAF diet or inoculation of the dsARN mimetic Poly (I:C) on peripheral proinflammatory and social interaction in the offspring. Notably, maternal exposure to CAF diet impairs social interaction and favors an increase in anxiety in male but not female offspring. Also, CAF diet exposure or Poly (I:C) inoculation during fetal programming promote peripheral proinflammatory profile in the ASD-diagnosed male but not in females. Selectively, we found a robust accumulation of the monocyte chemoattractant protein-1 (MCP-1) in plasma of ASD-diagnosed males exposed to CAF during fetal development. Biological assessment of MCP-1 signaling in brain confirms that systemic injection of MCP-1-neutralizing antibody reestablished social interaction and blocked anxiety, accompanied by a reduction in cerebellar lobule X (CbX) volume and an increase volume of the primary somatosensory (SSP) cortex in male offspring. These data highlight the contribution of diet-dependent MCP-1 signaling on volumetric brain changes and microglia morphology promoting ASD-like behavior in male mice.

Refractoriness remains as one of the challenges in patients with lymphoma under chemotherapy, and among biological regulators in cells driving this type of response are microRNAs (miRNAs). Different genes are constantly turned on or off according to the miRNAs expression profiles affecting the drug response in patients and their stability in serum and plasma makes them potential prognostic biomarkers in several diseases. Here we described a profile of miRNAs in plasma of diffuse large B cell lymphoma (DLBCL) patients. miRNA expression arrays were carried using pre-treatment plasma samples of sixteen patients, followed by a comparison between the responder and the non-responders. After six cycles of R–CHOP treatment, twelve out of sixteen patients were clinically diagnosed with complete response while in four patients no clinical response was observed. Between these groups, a signature of fifteen differential expressed miRNAs was found. The circulating miRNAs in plasma of patients with no response were related to the drug resistance in other types of cancer, by targeting genes involved in cell proliferation and apoptosis, among other cell processes.

Nicotine is the major pharmacologically active substance in tobacco. Several studies have examined genotypes related to nicotine metabolism, but few studies have been performed in the Mexican population. The objective was to identify associations between gene variants in metabolizing enzymes and the urinary levels of nicotine metabolites among Mexican smokers. The levels of nicotine and its metabolites were determined in the urine of 88 young smokers from Mexico, and 167 variants in 24 genes associated with nicotine metabolism were genotyped by next-generation sequencing (NGS). Trans-3′-hydroxy-cotinine (3HC) and 4-hydroxy-4-(3-pyridyl)-butanoic acid were the most abundant metabolites (35 and 17%, respectively). CYP2A6*12 was associated with 3HC (p = 0.014). The rs145014075 was associated with creatinine-adjusted levels of nicotine (p = 0.035), while the rs12471326 (UGT1A9) was associated to cotinine-N-glucuronide (p = 0.030). CYP2A6 and UGT1A9 variants are associated to nicotine metabolism. 4HPBA metabolite was an abundant urinary metabolite in young Mexican smokers.

Como una de las enfermedades tropicales desatendidas (ETD), la leishmaniasis se define como una enfermedad parasitaria transmisible y muy prevalente en regiones tropicales-subtropicales afectando especialmente a poblaciones que viven en la pobreza. Tiene un profundo impacto negativo en las economías en vías de desarrollo. Representa un grupo heterogéneo de síndromes clínicos con un amplio espectro de severidad que va desde lesiones cutáneas que resuelven espontáneamente hasta compromiso visceral diseminado. La leishmaniasis visceral representa su forma más grave, puede afectar a casi todos los órganos del ser humano y suele tener consecuencias fatales, especialmente en pacientes inmunosuprimidos. La afectación cardíaca parece ser rara, pero nunca se ha estudiado en profundidad. En consecuencia, no existen recomendaciones claras para el cribado de las manifestaciones cardíacas en estos pacientes; sin embargo, las complicaciones cardiovasculares pueden ser potencialmente letales. Además, existen publicaciones sobre la potencial cardiotoxicidad provocada por los fármacos utilizados en el tratamiento de esta afección, por lo que el conocimiento de sus efectos secundarios podría tener importantes implicancias. Como parte del proyecto “Neglected Tropical Diseases and other Infectious Diseases affecting the Heart” (Proyecto NET-Heart), el propósito de este artículo es revisar toda la información disponible sobre el compromiso cardiovascular de esta enfermedad y su tratamiento y agregar conocimientos a este campo de estudio, centrándose en las barreras para el diagnóstico y tratamiento y cómo adoptar estrategias para superarlas.

The prevalence of breast cancer in young women (YWBC) has increased alarmingly. Significant efforts are being made to elucidate the biological mechanisms concerning the development, prognosis, and pathological response in early-onset breast cancer (BC) patients. Dysfunctional DNA repair proteins are implied in BC predisposition, progression, and therapy response, underscoring the need for further analyses on DNA repair genes. Public databases of large patient datasets such as METABRIC, TCGA, COSMIC, and cancer cell lines allow the identification of variants in DNA repair genes and possible precision drug candidates. This study aimed at identifying variants and drug candidates that may benefit Latin American (LA) YWBC. We analyzed pathogenic variants in 90 genes involved in DNA repair in public BC datasets from METABRIC, TCGA, COSMIC, CCLE, and COSMIC Cell Lines Project. Results showed that reported DNA repair germline variants in the LA dataset are underrepresented in large databases, in contrast to other populations. Additionally, only six gene repair variants in women under 50 years old from the study population were reported in BC cell lines. Therefore, there is a need for new approaches to study DNA repair variants reported in young women from LA.

This research examines the spatial structure of a sample of breast cancer (BC) cases and their spatial interaction with contaminated areas in the Monterrey Metropolitan Area (MMA). By applying spatial statistical techniques that treat the space as a continuum, degrees of spatial concentration were determined for the different study groups, highlighting their concentration pattern. The results indicate that 65 percent of the BC sample had exposure to more than 56 points of PM10. Likewise, spatial clusters of BC cases of up to 39 cases were identified within a radius of 3.5 km, interacting spatially with environmental contamination sources, particularly with refineries, food processing plants, cement, and metals. This study can serve as a platform for other clinical research by identifying geographic clusters that can help focus health policy efforts., Breast Cancer, PM10, Spatial distribution, Cluster analysis, Mexico

Colorectal cancer (CRC) is one of the main causes of mortality. Recent studies suggest that cancer stem cells (CSCs) can survive after chemotherapy and promote tumor invasiveness and aggression. According to a higher hierarchy complexity of CSC, different protocols for isolation, expansion, and characterization have been used; however, there are no available resistance biomarkers that allow predicting the clinical response of treatment 5-fluorouracil (5FU) and oxaliplatin. Therefore, the primary aim of the present study was to analyze the expression of gene resistance on tumors and CSC-derived isolates from patients CRC. In the present study, adenocarcinomas of the colon and rectum (CRAC) were classified based on an in vitro adenosine triphosphate-based chemotherapy response assay, as sensitive and resistant and the percentage of CD24 and CD44 markers are evaluated by immunohistochemistry. To isolate resistant colon-CSC, adenocarcinoma tissues resistant to 5FU and oxaliplatin were evaluated. Finally, all samples were sequenced using a custom assay with chemoresistance-associated genes to find a candidate gene on resistance colon-CSC. Results showed that 59% of the CRC tissue analyzed was resistant and had a higher percentage of CD44 and CD24 markers. An association was found in the expression of some genes between the tumor-resistant tissue and CSC. Overall, isolates of the CSC population CD44+ resistant to 5FU and oxaliplatin demonstrated different expression profiles; however, the present study was able to identify overexpression of the KRT-18 gene, in most of the isolates. In conclusion, the results of the present study showed overexpression of KRT-18 in CD44+ cells is associated with chemoresistance to 5FU and oxaliplatin in CRAC.

Background: The need to identify patients with hormone receptor-positive (HR+) early invasive breast cancer (EIBC) who could benefit from adjuvant chemotherapy has been enhanced with the development of molecular signature tests. However, due to their high cost and limited availability alternative low-cost prognostic and predictive tests are used in clinical practice. Here, we sought to evaluate the performance of the proliferation marker Ki-67 to identify these patients and explore its association with molecular signatures and risk stratification markers. Methods: From our prospectively maintained multicenter breast cancer registry, we identified EIBC HR+ patients tested with EndoPredict or MammaPrint and Ki-67 as part of their routine workup. Patients were categorized into two groups: Group 1 (2016-2018) was evaluated using EndoPredict and Group 2 (2011 to 2018) with MammaPrint. A ≥20% Ki67 cutoff was utilized for identify high proliferative EIBC and a receiver-operative curve area under the curve (AUC) and kappa concordance were utilized to evaluate the performance of Ki-67 compared to molecular signature tests. Results: In the EndoPredict group, 54/96 patients were considered high-risk by EPclin. 57/96 patients had a Ki-67 ≥20%. However, there was no significant overall concordance between them (59.37%, κ = 0.168, p=0.09). In the MammaPrint group, 21/70 patients were considered high-risk. Ki67 ≥20% was present in 36 patients with a significant overall concordance (67.14%, κ 0.35, pConclusion: There is a fair concordance between Ki-67 and MammaPrint risk stratification of HR + EIBC and no concordance with EndoPredict molecular signature. Cost-effectiveness analysis of these tests in developing countries are needed, until then, the use of Ki-67 seems reasonable to aid clinical decision.

Electroconvulsive therapy (ECT) is an effective treatment for major depressive disorder; yet, its use is confined to1% of individuals with this disorder. The authors aimed to examine barriers to ECT from the perspective of the provider.Qualitative interviews were conducted with U.S.-based ECT providers to identify potential barriers. A quantitative survey was created asking providers to rank-order barriers to starting a new ECT service or expanding existing services.Survey responses were received from 192 physicians. Respondents were representative of all ECT providers found in the Medicare Provider Utilization and Payment Database with respect to gender and geographic distribution. Approximately one-third (N=58, 30%) of survey respondents graduated from one of 12 residency programs. Programs with dedicated hospital space were more likely to have larger services than those borrowing surgical recovery space (χCoordinated efforts to overcome identified barriers may allow ECT to be more broadly implemented. Investments in education may increase the number of competent practitioners.

Articular cartilage injuries remain as a therapeutic challenge due to the limited regeneration potential of this tissue. Cartilage engineering grafts combining chondrogenic cells, scaffold materials, and microenvironmental factors are emerging as promissory alternatives. The design of an adequate scaffold resembling the physicochemical features of natural cartilage and able to support chondrogenesis in the implants is a crucial topic to solve. This study reports the development of an implant constructed with IGF1-transduced adipose-derived mesenchymal stem cells (immunophenotypes: CD105+, CD90+, CD73+, CD14-, and CD34-) embedded in a scaffold composed of a mix of alginate/milled bovine decellularized knee material which was cultivated in vitro for 28 days (3CI). Histological analyses demonstrated the distribution into isogenous groups of chondrocytes surrounded by a de novo dense extracellular matrix with balanced proportions of collagens II and I and high amounts of sulfated proteoglycans which also evidenced adequate cell proliferation and differentiation. This graft also shoved mechanical properties resembling the natural knee cartilage. A modified Bern/O’Driscoll scale showed that the 3CI implants had a significantly higher score than the 2CI implants lacking cells transduced with IGF1 (16/18 vs. 14/18), representing high-quality engineering cartilage suitable for in vivo tests. This study suggests that this graft resembles several features of typical hyaline cartilage and will be promissory for preclinical studies for cartilage regeneration.

Multi-drug resistant (MDR) non-typhoidal Salmonella (NTS) is increasingly common worldwide. While food animals are thought to contribute to the growing antimicrobial resistance (AMR) problem, limited data is documenting this relationship, especially in low and middle-income countries (LMIC). Herein, we aimed to assess the role of non-clinical NTS of bovine origin as reservoirs of AMR genes of human clinical significance. We evaluated the phenotypic and genotypic AMR profiles in a set of 44 bovine-associated NTS. For comparative purposes, we also included genotypic AMR data of additional isolates from Mexico (n = 1,067) that are publicly available. The most frequent AMR phenotypes in our isolates involved tetracycline (40/44), trimethoprim-sulfamethoxazole (26/44), chloramphenicol (19/44), ampicillin (18/44), streptomycin (16/44), and carbenicillin (13/44), while nearly 70% of the strains were MDR. These phenotypes were correlated with a widespread distribution of AMR genes (i.e. tetA, aadA, dfrA12, dfrA17, sul1, sul2, bla-TEM-1, blaCARB-2) against multiple antibiotic classes, with some of them contributed by plasmids and/or class-1 integrons. We observed different AMR genotypes for betalactams and tetracycline resistance, providing evidence of convergent evolution and adaptive AMR. The probability of MDR genotype occurrence was higher in meat-associated isolates than in those from other sources (odds ratio 11.2, 95% confidence interval 4.5–27.9, P < 0.0001). The study shows that beef cattle are a significant source of MDR NTS in Mexico, highlighting the role of animal production on the emergence and spread of MDR Salmonella in LMIC.

Introduction Panniculits presents as an inflammation of the subcutaneous adipose tissue of the skin. In breast, panniculitis is very rare and is usually a manifestation of underlying inflammatory conditions. The typical presentation is palpable tender nodules, which in cases of breast panniculitis, triggers an extensive work up to exclude a malignancy. Herein we present a case of septal and lobar panniculitis in a female with clinical history of invasive ductal carcinoma. Presentation of the case A 52-year old female with past medical history of invasive breast carcinoma 5 years prior to the presentation. The patient's chief complaint was a 1-year history of a subcutaneous nodular lesion on her left breast. A core biopsy of the firm nodule showed marked inflammation of the breast. A second skin biopsy showed an abundant chronic inflammatory infiltrate, with lymphocytic vasculitis and neuritis, suggestive of an underlying autoimmune process. Discussion Subcutaneous panniculitis with or without vasculitis is a rare condition when presenting in the breast. Panniculitis can mimic malignancy and thus, it is important to differentially diagnose it from breast carcinoma. Histologically, it is classified in lobular and septal lymphocytic panniculitis depending on specific diagnostic characteristics. Conclusion Panniculitis of the breast is a rare condition that needs to be included in the differential diagnosis of subcutaneous breast masses. In all cases, but specifically in females with history of breast cancer, panniculitis still should be thought of as a possibility, and imaging as well as other diagnostic techniques can aid in making the correct diagnosis., Highlights • Panniculitis of the Breast is a rare condition. • Panniculitis typically is related to autoinmmune entities. • Differential diagnosis with breast carcinoma.

Background: Type 2 diabetes mellitus (T2DM) is one of the most serious and prevalent diseases worldwide. In the last decade, type 2 sodium-glucose cotransporter inhibitors (iSGLT2) were approved as alternative drugs for the pharmacological treatment of T2DM. The anti-hyperglycemic mechanism of action of these drugs involves glycosuria. In addition, SGLT2 inhibitors cause beneficial effects such as weight loss, a decrease in blood pressure, and others. Objective: This review aimed to describe the origin of SGLT2 inhibitors and analyze their recent development in preclinical and clinical trials. Results: In 2013, the FDA approved SGLT2 inhibitors as a new alternative for the treatment of T2DM. These drugs have shown good tolerance with few adverse effects in clinical trials. Additionally, new potential anti-T2DM agents based on iSGLT2 (O-, C-, and N-glucosides) have exhibited a favorable profile in preclinical evaluations, making them candidates for advanced clinical trials. Conclusion: The clinical results of SGLT2 inhibitors show the importance of this drug class as new anti-T2DM agents with a potential dual effect. Additionally, the preclinical results of SGLT2 inhibitors favor the design and development of more selective new agents. However, several adverse effects could be a potential risk for patients.

Introduction: Ketamine has emerged as a rapid-acting antidepressant. While ongoing treatment can prevent relapse, concerns exist regarding long-term exposure. Objective: We conducted a randomized trial to examine the feasibility and efficacy of cognitive behavioral therapy (CBT) following intravenous ketamine in treatment-resistant depression (TRD). Methods: Subjects with TRD were recruited and treated with 6 intravenous infusions of ketamine over 3 weeks. Subjects who experienced a clinical response (≥50% improvement in depression severity) were then randomized to receiving CBT or treatment as usual (TAU) for an additional 14 weeks, using a sequential treatment model. Results: Of the 42 patients who signed consent, 28 patients achieved a response and were randomized to CBT or TAU. When measured using the Montgomery-Asberg Depression Rating Scale (primary outcome measure), the effect size at the end of the study was moderate (Cohen d = 0.65; 95% CI –0.55 to 1.82), though the group-by-time interaction effect was not significant. There was a significant group-by-time interaction as measured by the Quick Inventory of Depressive Symptomatology (F = 4.58; p = 0.033), favoring a greater sustained improvement in the CBT group. This corresponded to a moderate-to-large effect size of the Cohen d = 0.71 (95% CI –0.30 to 1.70) at the end of the study (14 weeks following the last ketamine infusion). In a subset of patients (N = 20) who underwent cognitive testing using the emotional N-back assessments before and after ketamine, ketamine responders showed improvement in the accuracy of emotional N-back (t[8] = 2.33; p < 0.05) whereas nonresponders did not (t[10] p ns). Conclusions: This proof-of-concept study provides preliminary data indicating that CBT may sustain the antidepressant effects of ketamine in TRD. Further study and optimization of this treatment approach in well-powered clinical trials is recommended.

This paper examines the scope and characteristics of male-to-female intimate partner violence in southern rural Chiapas, Mexico, and its association with depression and anxiety symptoms, highlighting the role of partner controlling behaviors. Participants were selected by random sampling. One-hundred and forty-one women >15 years participated in the study. Data was obtained through an adapted version of the National Survey of the Dynamics of Household Relationships (ENDIREH) intimate partner violence scale, the Patient Health Questionnaire-9 for depression symptoms and the Generalized Anxiety Disorder-7 for anxiety symptoms. Quantitative results indicated a 66.4% lifetime prevalence of physical and/or sexual IPV among ever-partnered women 15 years or older (95% CI: 57.5–74.5%). Forty percent (95% CI: 32.0–49.7%) of them reported having experienced physical and/or sexual violence with high partner control (HC-IPV), and 25.8% (95% CI: 18.5–34.3%) reported having experienced physical and/or sexual violence with low or moderate partner control (MC-IPV). Lifetime experience of HC-IPV was significantly associated with moderate-severe depression symptoms (RR = 5.8) and suicidality (RR = 2.08). While partner alcohol abuse was associated with a 3.06 times higher risk of lifetime physical and/or sexual IPV, 30.9% of women mentioned that their partners were never drunk when violence occurred. Interestingly, high partner alcohol abuse was more frequent among women who reported HC-IPV compared to MC-IPV. Implications for global mental health practice are discussed.

Toxoplasmosis is a common disease caused by Toxoplasma gondii, a parasite with high prevalence in tropical regions. Most infections show minimal symptoms, but immunocompromised patients tend to have a poor prognosis. Cardiovascular manifestations in toxoplasmosis are rare and reported in a limited number of patients. As part of the "Neglected Tropical Diseases and Other Infectious Diseases Affecting the Heart" (NET-Heart) project, this paper aims to systematically review all available information regarding the cardiovascular implications of toxoplasmosis. Relevant studies were identified in the MEDLINE and/or PubMed database, and 48 articles were ultimately included. This was completed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Cardiac compromise in toxoplasmosis mainly involves myocarditis, and complications vary widely in severity. Toxoplasmic myocarditis is challenging to diagnose, as endomyocardial biopsy is usually required. This article provides a summary of cardiac toxoplasmosis, including an original algorithm facilitating diagnosis and treatment.

Massive worldwide serological testing for SARS-CoV-2 is needed to determine the extent of virus exposure in a particular region, the ratio of symptomatic to asymptomatic infected persons, and the duration and extent of immunity after infection. To achieve this aim, the development and production of reliable and cost-effective SARS-CoV-2 antigens is critical.Here, we report the bacterial production of the peptide S-RBDN318-V510, which contains the receptor binding domain of the SARS-CoV-2 spike protein. We purified this peptide using a straightforward approach involving bacterial lysis, his-tag mediated affinity chromatography, and imidazole-assisted refolding. The antigen performances of S-RBDN318-V510 and a commercial full-length spike protein were compared in two distinct ELISAs. In direct ELISAs, where the antigen was directly bound to the ELISA surface, both antigens discriminated sera from non-exposed and exposed individuals. However, the discriminating resolution was better in ELISAs that used the full-spike antigen than the S-RBDN318-V510. Attachment of the antigens to the ELISA surface using a layer of anti-histidine antibodies gave equivalent resolution for both S-RBDN318-V510 and the full length spike protein.Our results demonstrate that ELISA-functional SARS-CoV-2 antigens can be produced in bacterial cultures. S-RBDN318-V510 is amenable to massive production and may represent a cost-effective alternative to the use of structurally more complex antigens in serological COVID-19 testing.

Tumor-infiltrating lymphocytes (TILs) reflect the host immune response against cancer cells. Immunomodulators have been recently suggested as a novel therapeutic strategy against triple-negative breast cancer (TNBC). However, the TIL profile in TNBC has not been thoroughly investigated. In the present study, the percentage, immunophenotype and genetic profiles of TILs in pre-surgical tumor samples of patients with TNBC were evaluated prior to neoadjuvant chemotherapy (NAC). Patients diagnosed with breast cancer at Hospital San Jose TecSalud were consecutively and prospectively enrolled in the present study between August 2011 and August 2015. The pathological response to NAC was evaluated using the de Miller-Payne and MD Anderson Cancer Center system. TIL percentage (low, intermediate, and high) was evaluated using special hematoxylin-eosin staining on the core needle biopsies. The immunophenotype of TILs was assessed by immunohistochemistry (IHC) for CD3+, CD4+ and CD8+. In addition, the gene expression profile of CD3, CD4, CD8, CD20, CD45, forkhead box P3, interleukin 6, programmed cell death 1 and CD274 molecule was assessed in all patients. A total of 26 samples from patients with TNBC prior to NAC were included in the present study. TILs were low in 30.7%, intermediate in 38.4% and elevated in 30.7% of tumors. CD3+ and CD4+ counts were associated with the pathological response to NAC (P=0.04). Finally, an overexpression pattern of CD3, CD4, CD8, CD45 and CD20 genes was observed in patients with a partial or complete pathological response. The present results demonstrated that TILs may predict the pathological response to NAC in patients with TNBC. Furthermore, a more accurate association was identified between the high expression levels of CD3, CD4, CD8, CD45 and CD20 genes and partial and complete pathological response, compared with the association between high expression and IHC alone.

IntroductionHospital mortality due to COVID-19 in Mexico is high (32%) and as of today, effective treatment options are limited. More effective treatments that shorten hospital stay and reduce mortality are needed. Initial reports for the use of convalescent plasma (CP) therapy for COVID-19 appear promising. We describe a case series of eight patients with impending respiratory failure, who underwent CP therapy.MethodsSix male and two female (ages 31 to 79) patients that were admitted to the intensive-care unit for severe COVID-19 were transfused with two doses of CP (250 mL per dose, anti-SARS-CoV-2 IgG titers > 1:100). Donors were six SARS-CoV-2 infected males who remained asymptomatic for > 7 days and were negative for two nasopharyngeal RT-PCR tests. Clinical characteristics, inflammatory and cellular injury markers, chest X-ray findings and viral loads were analyzed before and after CP administration. Viral load association to disease severity was further analyzed on a separate cohort of asymptomatic vs hospitalized patients with COVID-19.ResultsEight patients with respiratory failure were successfully discharged with a median length of stay of 22.5 (IQR 18.25-29.00). After CP therapy, we observed a reduction of C-reactive protein (CRP) (median, 22.80 mg/dL vs. 1.63 mg/dL), and of procalcitonin (median, 0.27 ng/mL vs. 0.13 ng/mL). High-Sensitivity Cardiac Troponin I (hs-cTnI), Brain Natriuretic Peptide (BNP) and Lactate Dehydrogenase (LDH) were lower, and a mild reduction of pulmonary infiltrates by chest X-ray was observed. Lastly, a reduction of viral load was after CP therapy was found. (log, median [IQR], 1.2 [0.70-2.20] vs. 0.25 [0.00-1.78]). We observed no adverse effects.ConclusionsCP could potentially be an effective therapeutic option for patients with severe COVID-19. Clinical benefit needs to be studied further through randomized controlled trials.

Background: Genome-wide association studies (GWAS) for colorectal cancer (CRC) have detected high-risk genetic variants associated with CRC in several ethnic groups, but Latin American communities are still underrepresented. The aim was to identify variants related to CRC in an admixed Latin American population. Methods: The study was performed in 831 cases and 881 controls from Mexico, who were genotyped for 1,006,703 autosomal SNPs. Logistic regression was carried out including covariants, such as sex, age and genetic ancestry. Lastly, we performed a sequence-kernel association test (SKAT) to consider the joint effect of several SNPs lying in genes.Results: Eight chromosomal regions reached genome-wide significance level ( p < 5×10 -8 ): 1p36.22, 1p31.1, 1q42.13, 6p22, 7p14.1, 12q24.32, 16q12.2 and 21q22.2 and 63 variants reached borderline statistical significance ( p < 1×10 − 6 ). SKAT analysis detected 13 loci associated with CRC, none of them previously associated with CRC. Conclusions: We found 8 SNPs and 13 loci associated with CRC. These signals may contribute to enrich the panoply of genes involved with CRC. Further analyses remain to be done to validate the associations in other Latin American populations. This study highlights the importance of conducting GWAS in poorly explored admixed populations.

Acute decompensated heart failure is the leading admitting diagnosis in patients 65 and older with more than 1 million hospitalizations per year in the US alone. Traditional tools to evaluate for and monitor volume status in patients with heart failure, including symptoms and physical exam findings, are known to have limited accuracy. In contrast, point of care lung ultrasound is a practical and evidenced-based tool for monitoring of volume status in patients with heart failure. However, few inpatient clinicians currently use this tool to monitor diuresis. We performed semi-structured interviews of 23 hospitalists practicing in 5 geographically diverse academic institutions in the US to better understand how hospitalists currently assess and monitor volume status in patients hospitalized with heart failure. We also explored their perceptions and attitudes toward adoption of lung ultrasound. Hospitalist participants reported poor reliability and confidence in the accuracy of traditional tools to monitor diuresis and expressed interest in learning or were already using lung ultrasound for this purpose. The time required for training and access to equipment that does not impede workflow were considered important barriers to its adoption by interviewees.

Introduction:Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma.Methods:ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure.Conclusions:ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Nicotinic acetylcholine receptors (nAChRs), particularly the α7 nAChR, are implicated in the pathophysiology of both autism spectrum disorder (ASD) and aggressive behavior. We explored the feasibility, tolerability, and preliminary efficacy of targeting nAChRs using transdermal nicotine to reduce aggressive symptoms in adults with ASD. Eight subjects were randomized in a double-blind crossover trial of seven milligrams transdermal nicotine or placebo, each for one week. All participants tolerated nicotine treatment well. Five subjects contributed data to the primary outcome, Aberrant Behavior Checklist-Irritability (ABC-I) subscale change from baseline, which was improved by nicotine compared to placebo. Sleep ratings were also improved by nicotine and correlated with ABC-I improvement. These findings support further investigation of nAChR agonists for aggression and sleep in ASD.

We describe a patient severely affected with multiple congenital anomalies, including brain malformations and skeletal dysplasia suggestive of cranioectodermal dysplasia (CED) ciliopathy, who unusually carries several homozygosity tracts involving homozygous missense mutations in SPAG17 (exon 8; c.1069G > C; p.Asp357His) and WDR35 (exon 13; c.1415G > A; p.Arg472Gln) as revealed by homozygosity mapping and next generation sequencing. SPAG17 is essential for the function and structure of motile cilia, while WDR35 belongs to the same intraflagellar transport (IFT) gene family whose protein products are part of functional IFT A and B complexes. Formerly, SPAG17 was related – through polymorphic variants – to an influence on individuals’ height; more recently, Spag17−/− mice models were reported to present skeletal and bone defects, reduced mucociliary clearance, respiratory distress, and cerebral ventricular enlargement. Homozygous or compound heterozygous mutations in WDR35 have mainly been related to CED2 or short-rib thoracic dysplasia 7, with only three cases showing some brain anomalies. Given that our patient presents these clinical features and the close functional relationship between SPAG17 and WDR35, it is feasible that the combined effects from both mutations contribute to his phenotype. To our knowledge, this patient is the first to harbor a likely pathogenic homozygous mutation in both genes at the same time. Thus, the resulting complex phenotype of this patient illustrates the heterogeneity associated with ciliopathies and further expands the clinical and mutational spectrum of these diseases. Finally, we highlight the combined use of high-throughput tools to diagnose and support the proper handling of this and other patients.

Background: Triple negative breast cancer (TNBC) presents a very aggressive behavior with a high rate of metastasis. Overexpression of HMGA1 has been reported in TNBC and has been associated with the induction of the Epithelial-Mesenchymal transition (EMT) and metastasis. Therefore, HMGA1 is considered a master regulator of tumor progression in TNBC. The objective of this work was to know which genes are directly or indirectly regulated by HMGA1 to better understand their participation in EMT and their role in aggressive TNBC. Methods: We performed the silencing of the HMGA1 gene using siRNA Silencer® Select Pre-designed (s6667 HMGA1, 4390849 GAPDH, 4390843 Negative control, all from Thermo Fisher, MA, USA) in two TNBC cell lines, HCC-1395 and MDA-MB-231, and we observed the effect of this gene inhibition by microarray global expression analysis using GeneChip Human Genome U133 Plus 2.0 (Affymetrix, CA, USA), comparing the conditions of inhibition versus their own control without inhibition. After the microarray data mining, results for the HMGA1 and PRRX1 genes were validated by qPCR using the Prime Time® Primers for HMGA1 (Hs.PT.58.38699366), PRRX1 (Hs.PT.58.2820749), and GAPDH as endogenous gene (Hs.PT.39a.22214836) with SybrGreen reagent (Roche, Basel, Switzerland). The level of expression of the HMGA1 and PRRX1 proteins was analyzed by Western blot in nuclear protein extracts of each cell line before and after gene silencing. Finally, we performed an in silico analysis using the "Gene 2 promoter" tool in the Genomatix platform to search the promoters and binding proteins of the PRRX1 gene. Results: The silencing of HMGA1 in a non-metastatic TNBC-cell line, HCC-1395, showed deregulation of genes associated with cell proliferation and angiogenesis. Meanwhile the silencing in a TNBC-metastatic cell line, MDA-MB-231, resulted in the deregulation of genes involved in the formation and organization of the cytoskeleton, including the overexpression of PRRX1. Validation of the expression changes of HMGA1 and PRRX1 by qPCR and Western blot was performed and HMGA1 was confirmed to negatively regulate the PRRX1 gene expression. Through in silico studies, we identified several binding sites of HMGA1 to the PRRX1 promoter. Conclusions: The subexpression of PRRX1 is necessary for EMT to occur. In this study, we present the interesting finding that HMGA1 regulates the subexpression of PRRX1, as supported by the experiments of transcriptional and translational expression presented in this work. To our knowledge, this is the first report describing a regulatory role of HMGA1 on PRRX1, which could explain the metastatic capacity of cancers that overexpress HMGA1. Key words: Epithelial-Mesenchymal Transition, Triple Negative Breast Cancer, Mesenchymal-Epithelial Transition, Metastasis. Citation Format: Aguayo-Millán CD, Santuario-Facio SK, Treviño-Alvarado V, Calvo-Anguiano G, Rojas-Martínez A, Camacho-Morales A, Ortíz-López R. HMGA1 negatively regulates the expression of PRRX1 in triple negative breast cancer cells, which favors the progression to metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-08-04.

Androgenetic alopecia (AGA) or male pattern baldness is the most common form of hair loss in humans. Despite being a very frequent dermatological entity, molecular pathophysiology remains unclear. Several authors relate the presentation of AGA with a premature apoptotic process during the anagen phase and with an inflammatory microenvironment in the hair follicle. We evaluated a panel of 30 genes associated with inflammation and apoptosis in 5 AGA patients by targeted RNA-Seq. WNT7A gene was highly expressed in patients in stages 3V to 5 on the Hamilton-Norwood scale compared to patients with 5A stage. CASP7 and TNF genes were overexpressed in stages 3V and 4 compared to stages 5 and 5A. Overexpression of these genes detected only at early stages of AGA proves the role of WNT pathway, apoptosis, and inflammation in the development of this disorder.

e12622 Background: Immunologic biomarkers such as tumor infiltrating lymphocytes (TILs) and programmed death ligand-1 (PD-L1) can provide prognostic information in breast cancer (BC) patients. Specifically, a high TILs level has been associated with pathologic complete response and enhanced disease-free survival (DFS). Furthermore, PD-L1 positivity has been associated with worse DFS and overall survival (OS). However, the interaction of both biomarkers as well as its association with survival outcomes in specific BC subtypes is still a subject of ongoing research. Methods: Medical records of women diagnosed with primary BC between 2013 and 2015 in a center in Monterrey, Mexico were reviewed. Eligible patients had at least 1 year of follow-up, stages I-III at diagnosis, and available tissue for TILs and PD-L1 assessment. PD-L1 positivity was defined as the presence of PD-L1 in ≥1% of tumor-infiltrating immune cells using the VENTANA SP142 assay. Classification of TILs into low ( < 30%) and high (≥30%) levels was performed for analytical purposes. Clinicopathological features were compared with Fisher’s exact tests and logistic regression models, as appropriate. The Kaplan-Meier method was used to calculate recurrence-free survival (RFS), and associations between variables were explored with log-rank or Cox regressions. Results: A total of 195 patients were included. Overall, 12.3% of BC biopsy specimens showed positivity to PD-L1 (8.3% [11/132] in HR+/HER2-, 5.9% [2/34] in HER2+, and 38% [11/29] in TNBC; p < 0.001). PD-L1 positivity was significantly associated with ER-negative status (OR 3.1; p = 0.013), high TILs (OR 5.7; p < 0.001), and high Ki67 expression (HR 12.5; p < 0.001). The median follow-up for the entire cohort was 61 months (95%CI 58-63). RFS in the PD-L1- group was significantly superior to the PD-L1+ group (85% vs. 66% at 5 years; p = 0.021). In a multivariate Cox model, PD-L1 positivity (HR 3.3), low TILs (HR 3.4), advanced stage (HR 2.8), and high histological grade (HR 2.5) were all independent prognostic factors for worse RFS. Based on these results, we further classified our cohort into four prognostic profiles based on PD-L1 and TILs status. The low TILs/PD-L1+ group experienced an inferior RFS than low TILs/PD-L1- patients (45% vs. 85% at 5-years; p-value < 0.001), while no difference was observed in the high TILs groups. Notably, when analyzing HR+/HER2- patients only, a similar statistical difference was observed between low TILs/PD-L1+ and low TILs/PD-L1- groups (HR 5.4, p = 0.009). Conclusions: In our cohort, PD-L1 positivity together with low TILs identified a subset of BC patients with a worse RFS. Interestingly, patients with HR+/HER2- BC fared worse in the low TILs/PD-L1+ subcategory than in the low TILs/PD-L1- group. Future studies are warranted to explore the prognostic value of categorizing patients based on TILs and PD-L1 status in different BC subtypes.

– The International Commission on Radiological Protection (ICRP) first introduced the term ‘diagnostic reference level’ (DRL) in 1996 in Publication 73. The concept was subsequently developed further, and practical guidance was provided in 2001. The DRL has been proven to be an effective tool that aids in optimisation of protection in the medical exposure of patients for diagnostic and interventional procedures. However, with time, it has become evident that additional advice is needed. There are issues related to definitions of the terms used in previous guidance, determination of the values for DRLs, the appropriate interval for re-evaluating and updating these values, appropriate use of DRLs in clinical practice, methods for practical application of DRLs, and application of the DRL concept to newer imaging technologies. This publication is intended as a further source of information and guidance on these issues. Some terminology has been clarified. In addition, this publication recommends quantities for use as DRLs for various imaging modalities, and provides information on the use of DRLs for interventional procedures and in paediatric imaging. It suggests modifications in the conduct of DRL surveys that take advantage of automated reporting of radiation-dose-related quantities, and highlights the importance of including information on DRLs in training programmes for healthcare workers. The target audience for this publication is national, regional, and local authorities; professional societies; and facilities that use ionising radiation for medical purposes, and responsible staff within these facilities. A full set of the Commission’s recommendations is provided.

Highlights • Young patient. • Mucinous carcinoma. • Prognosis. • Hormone receptor., Introduction Mucinous carcinoma is a variant of invasive breast carcinomas representing 2% of them. These tumors frequently develop in postmenopausal females; it is a rare histological variant in young patients. Case presentation A 25-year-old female refers a slow growth mass of 2 years of evolution. Excisional biopsy reveals a pure mucinous carcinoma with positive hormone receptors and negative HER2. She was treated with hormone therapy and surgical resection. Discussion Mucinous carcinoma is a rare variant reported in young patients. Many series report that is frequently found in postmenopausal patients. We present a case of a pure mucinous carcinoma in a 25-year-old female with the importance of being a low-frequency malignancy in young patients. Conclusion Due to its benign course, it is important to know that this lesion can also present in young patients. The importance underlies in the multidisciplinary management at the right time in a proper way.

Germline mutations in BRCA1 and BRCA2 (BRCA1/2) genes are present in about 50% of cases of hereditary breast cancer. Proteins encoded by these genes are key players in DNA repair by homologous recombination (HR). Advances in next generation sequencing and gene panels for breast cancer testing have generated a large amount of data on gene variants implicated in hereditary breast cancer, particularly in genes such as PALB2, ATM, CHEK2, RAD51, MSH2, and BARD1. These genes are involved in DNA repair. Most of these variants have been reported for Caucasian, Jewish, and Asian population, with few reports for other communities, like those in Latin American (LA) countries. We reviewed 81 studies from 11 LA countries published between 2000 and 2019 but most of these studies focused on BRCA1/2 genes. In addition to these genes, breast cancer-related variants have been reported for PALB2, ATM, CHEK2, BARD1, MLH1, BRIP1, MSH2, NBN, MSH6, and PMS2 genes. Some of these variants are unique to LA populations. This analysis may contribute to enhance breast cancer variant characterization, and thus to find therapies and implement precision medicine for LA communities.

Some polymorphisms in genes codifying for fibrinogen have been correlated with plasma levels of this protein, and several studies reported their associations with acute cardiovascular events. In the present study, 118 subjects with unstable and stable coronary diseases were enrolled to determinate the associations among fibrinogen gene polymorphisms, plasma fibrinogen levels, and major cardiovascular adverse events in a sample of southwestern Mexico. The groups, including 81 control subjects, were matched for age, sex, body mass index, and sedentarism. Plasma fibrinogen levels and the polymorphisms 455G/A, -148C/T, +1689T/G, andBclI of the gene of fibrinogen were compared in all groups. Plasma fibrinogen levels (>465 mg/dl) were significant in patients with coronary disease.Fibrinogen plasma values>450 mg/dlwere associated with cardiovascular mortality during the follow-up analysis of the unstable coronary disease group (p=0.04). The allelic loads of -455A and -148T were associated withplasma fibrinogen levels>450 mg/dl(p<0.003andp=0.03, respectively) and with coronary disease (p=0.016andp<0.006, respectively). The follow-up of posterior events after an acute coronary event showed that the genetic load of the -148T allele was associated with major adverse cardiovascular events (RR=1.8,95%CI=1.01‐3.35,p=0.04).Fibrinogen plasmatic levels>450 mg/dland the fibrinogen polymorphisms -455G/A and 148C/T had association with MACE and coronary disease. This study suggests that these gene polymorphisms are associated with cardiovascular risk.

Women remain largely under-represented in cardiology worldwide. This is especially reflected in scientific sessions where panelists have a male preponderant representation. The amount of gender equity in cardiology during scientific activities in the American continent is unknown. The objective was to compare gender distribution of invited panelists in cardiology scientific sessions across the Americas during the period 2019-2020. A retrospective analysis of the cardiology scientific sessions held in North, Central, and South America was conducted. Sessions published on the official site and social networks of the national cardiology societies from January 1, 2019 to August 10, 2020 were included. Gender distribution and all-male panels were compared according to geographic regions, year, roles in the panel, and the main topics of the session. Seven hundred fifty-two scientific sessions were analyzed, with 3786 participants. The median participation of women was 20% (IQR 0%-37.5%). Specifically, the statistics reflected a female participation of 25% (IQR 0%-43.6%) in North America, 12.5% (IQR 0%-43%) in Central America and 10% (IQR 0%-33.3%) in South America (P0.0001). Women participation in the panels was different according to the main topic of the session (P0.0001), with higher proportions in topics such as cardiovascular diseases in women, congenital heart disease and cardio oncology. The frequency of all-male panels was 36.8% (CI95% 33.3-40.1), and it increased over time (2019: 30.9% vs 2020: 40.3%; P = 0.012). There is gender inequity in cardiology scientific sessions held in different regions of the Americas, with low participation of women especially in interventionist panels and leadership roles.

Massive worldwide serological testing for SARS-CoV-2 is needed to determine the extent of virus exposure in a particular region, the ratio of symptomatic to asymptomatic infected persons, and the duration and extent of immunity after infection. To achieve this, the development and production of reliable and cost-effective SARS-CoV-2 antigens is critical. We report the bacterial production of the peptide S-RBDN318-V510, which contains the receptor-binding domain of the SARS-CoV-2 spike protein (region of 193 amino acid residues from asparagine-318 to valine-510) of the SARS-CoV-2 spike protein. We purified this peptide using a straightforward approach involving bacterial lysis, his-tag-mediated affinity chromatography, and imidazole-assisted refolding. The antigen performances of S-RBDN318-V510 and a commercial full-length spike protein were compared in ELISAs. In direct ELISAs, where the antigen was directly bound to the ELISA surface, both antigens discriminated sera from non-exposed and exposed individuals. However, the discriminating resolution was better in ELISAs that used the full-spike antigen than the S-RBDN318-V510. Attachment of the antigens to the ELISA surface using a layer of anti-histidine antibodies gave equivalent resolution for both S-RBDN318-V510 and the full-length spike protein. Results demonstrate that ELISA-functional SARS-CoV-2 antigens can be produced in bacterial cultures, and that S-RBDN318-V510 may represent a cost-effective alternative to the use of structurally more complex antigens in serological COVID-19 testing.

Background and Aims FLT3-ITD mutations in acute myeloid leukemia (AML) are associated with a poor prognosis. In Latin America, little epidemiological data exist about these mutations and their influence on clinical evolution and prognosis. Standardization and well-established clinical correlation make FLT3 mutational analysis by molecular methods an invaluable tool to decide among treatment options and to determine AML prognosis. Methods We assessed the prevalence of FLT3-ITD mutations in 138 patients with AML at four hematology referral centers from Mexico and Colombia. Molecular methods based on polymerase chain reaction (PCR) were employed for determining FLT3-ITD status. Results Mutations were present in 28 patients indicating a prevalence of 20.28%. Median age was 47 years (5–96). The FLT3 mutation positive group was older, had higher WBC and hemoglobin values and lower platelet counts but without statistical significance. A not previously described mutation in the FLT3 gene was found in one patient involving a nucleotide exchange of timine for cytosine at the 66608 position. A high mortality was found in the FLT3-mutated group, 67.8 vs. 42.72% in the non-mutated group and median survival was 4.9 months vs. 20.4 months, p = 0.009. A mutated FLT3 did not confer poor prognosis to those with M3 AML. The mutated FLT3 population had poor overall survival (OS) despite hematoprogenitor stem cell transplantation (HSCT). Conclusion Prevalence of FLT3-ITD mutation in AML was present in a proportion comparable to other populations and, when present, was associated with a very poor prognosis.

Introduction Radiographic contrast administration is a major cause of acute kidney injury (AKI), worldwide. Currently, contrast induced acute kidney injury (CI-AKI) is the third leading cause of hospital acquired renal failure in the United States. Over 50% of these cases are the result of contrast exposure during cardiac catheterization. The predictive risk factors for and clinical impact of AKI following coronary procedures have been extensively studied and documented in the literature. Similar data, however, are lacking for AKI following angiography or endovascular interventions for lower extremity peripheral artery disease (PAD). Methods The present review examined the published data available for AKI in patients undergoing peripheral procedures using MEDLINE searches. Specific data on number of peripheral cases, subject characteristics, hydration strategies, and AKI incidence rates was recorded. Results The systematic review resulted in 50 potentially relevant studies and ultimately 15 studies were selected for detailed analysis that included AKI incidence data on patients undergoing peripheral angiography or interventions. The summated studies included 11,311 patients and 10,316 peripheral procedures. The median incidence of AKI in the studies was 10%. The retrieved publications demonstrated significant variations in patient risk factors, definitions of AKI, and specificity of description of endovascular therapies. Conclusions The incidence, risk factors, and outcomes related to AKI in the context of peripheral angiography or endovascular therapy remain poorly described in the literature and warrant further study in a prospective, systematic fashion. © 2016 Wiley Periodicals, Inc.