The DO-KB Knowledgebase: a 20-year journey developing the disease open science ecosystem.

In 2003, the Human Disease Ontology (DO, https://disease-ontology.org/) was established at Northwestern University. In the intervening 20 years, the DO has expanded to become a highly-utilized disease knowledge resource. Serving as the nomenclature and classification standard for human diseases, the DO provides a stable, etiology-based structure integrating mechanistic drivers of human disease. Over the past two decades the DO has grown from a collection of clinical vocabularies, into an expertly curated semantic resource of over 11300 common and rare diseases linking disease concepts through more than 37000 vocabulary cross mappings (v2023-08-08). Here, we introduce the recently launched DO Knowledgebase (DO-KB), which expands the DO's representation of the diseaseome and enhances the findability, accessibility, interoperability and reusability (FAIR) of disease data through a new SPARQL service and new Faceted Search Interface. The DO-KB is an integrated data system, built upon the DO's semantic disease knowledge backbone, with resources that expose and connect the DO's semantic knowledge with disease-related data across Open Linked Data resources. This update includes descriptions of efforts to assess the DO's global impact and improvements to data quality and content, with emphasis on changes in the last two years.

Pharmacokinetic Effects of Different Models of Nonalcoholic Fatty Liver Disease in Transgenic Humanized OATP1B Mice.

Organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 (collectively, OATP1B) transporters encoded by the solute carrier organic anion transporter (SLCO) genes mediate uptake of multiple pharmaceutical compounds. Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease (NAFLD), decreases OATP1B abundance. This research characterized the pathologic and pharmacokinetics effects of three diet- and one chemical-induced NAFLD model in male and female humanized OATP1B mice, which comprises knock-out of rodent Oatp orthologs and insertion of human SLCO1B1 and SLCO1B3. Histopathology scoring demonstrated elevated steatosis and inflammation scores for all NAFLD-treatment groups. Female mice had minor changes in SLCO1B1 expression in two of the four NAFLD treatment groups, and pitavastatin (PIT) area under the concentration-time curve (AUC) increased in female mice in only one of the diet-induced models. OATP1B3 expression decreased in male and female mice in the chemical-induced NAFLD model, with a coinciding increase in PIT AUC, indicating the chemical-induced model may better replicate changes in OATP1B3 expression and OATP substrate disposition observed in NASH patients. This research also tested a reported multifactorial pharmacokinetic interaction between NAFLD and silymarin, an extract from milk thistle seeds with notable OATP-inhibitory effects. Males showed no change in PIT AUC, whereas female PIT AUC increased 1.55-fold from the diet alone and the 1.88-fold from the combination of diet with silymarin, suggesting that female mice are more sensitive to pharmacokinetic changes than male mice. Overall, the humanized OATP1B model should be used with caution for modeling NAFLD and multifactorial pharmacokinetic interactions. SIGNIFICANCE STATEMENT: Advanced stages of NAFLD cause decreased hepatic OATP1B abundance and increase systemic exposure to OATP substrates in human patients. The humanized OATP1B mouse strain may provide a clinically relevant model to recapitulate these observations and predict pharmacokinetic interactions in NAFLD. This research characterized three diet-induced and one drug-induced NAFLD model in a humanized OATP1B mouse model. Additionally, a multifactorial pharmacokinetic interaction was observed between silymarin and NAFLD.

Rifampin- and Silymarin-Mediated Pharmacokinetic Interactions of Exogenous and Endogenous Substrates in a Transgenic OATP1B Mouse Model.

Organic anion-transporting polypeptides (OATP) 1B1 and OATP1B3, encoded by the SLCO gene family of the solute carrier superfamily, are involved in the disposition of many exogenous and endogenous compounds. Preclinical rodent models help assess risks of pharmacokinetic interactions, but interspecies differences in transporter orthologs and expression limit direct clinical translation. An OATP1B transgenic mouse model comprising a rodent Slco1a/1b gene cluster knockout and human SLCO1B1 and SLCO1B3 gene insertions provides a potential physiologically relevant preclinical tool to predict pharmacokinetic interactions. Pharmacokinetics of exogenous probe substrates, pitavastatin and pravastatin, and endogenous OATP1B biomarkers, coproporphyrin-I and coproporphyrin-III, were determined in the presence and absence of known OATP/Oatp inhibitors, rifampin or silymarin (an extract of milk thistle [Silybum marianum]), in wild-type FVB mice and humanized OATP1B mice. Rifampin increased exposure of pitavastatin (4.6- and 2.8-fold), pravastatin (3.6- and 2.2-fold), and coproporphyrin-III (1.6- and 2.1-fold) in FVB and OATP1B mice, respectively, but increased coproporphyrin-I AUC0-24h only (1.8-fold) in the OATP1B mice. Silymarin did not significantly affect substrate AUC, likely because the silymarin flavonolignan concentrations were at or below their reported IC50 values for the relevant OATPs/Oatps. Silymarin increased the Cmax of pitavastatin 2.7-fold and pravastatin 1.9-fold in the OATP1B mice. The data of the OATP1B mice were similar to those of the pitavastatin and pravastatin clinical data; however, the FVB mice data more closely recapitulated pitavastatin clinical data than the data of the OATP1B mice, suggesting that the OATP1B mice are a reasonable, though costly, preclinical strain for predicting pharmacokinetic interactions when doses are optimized to achieve clinically relevant plasma concentrations.

Green Tea Catechins Decrease Solubility of Raloxifene In Vitro and Its Systemic Exposure in Mice.

PURPOSE: Green tea is a widely consumed beverage. A recent clinical study reported green tea decreased systemic exposure of raloxifene and its glucuronide metabolites by 34-43%. However, the underlying mechanism(s) remains unknown. This study investigated a change in raloxifene's solubility as the responsible mechanism. METHODS: The effects of green tea extract, (-)-epigallocatechin gallate (EGCG), and (-)-epigallocatechin (EGC) on raloxifene's solubility were assessed in fasted state simulated intestinal fluids (FaSSIF) and fed state simulated intestinal fluids (FeSSIF). EGCG and EGC represent green tea's main bioactive constituents, flavan-3-gallate and flavan-3-ol catechins respectively, and the tested concentrations (mM) match the µg/mg of each compound in the extract. Our mouse study (n = 5/time point) evaluated the effect of green tea extract and EGCG on the systemic exposure of raloxifene. RESULTS: EGCG (1 mM) and EGC (1.27 mM) decreased raloxifene's solubility in FaSSIF by 78% and 13%, respectively. Micelle size in FaSSIF increased with increasing EGCG concentrations (> 1000% at 1 mM), whereas EGC (1.27 mM) did not change micelle size. We observed 3.4-fold higher raloxifene solubility in FeSSIF compared to FaSSIF, and neither green tea extract nor EGCG significantly affected raloxifene solubility or micelle size in FeSSIF. The mice study showed that green tea extract significantly decreased raloxifene Cmax by 44%, whereas EGCG had no effect. Green tea extract and EGCG did not affect the AUC0-24 h of raloxifene or the metabolite-to-parent AUC ratio. CONCLUSIONS: This study demonstrated flavan-3-gallate catechins may decrease solubility of poorly water-soluble drugs such as raloxifene, particularly in the fasted state.

The Human Disease Ontology 2022 update.

The Human Disease Ontology (DO) (www.disease-ontology.org) database, has significantly expanded the disease content and enhanced our userbase and website since the DO's 2018 Nucleic Acids Research DATABASE issue paper. Conservatively, based on available resource statistics, terms from the DO have been annotated to over 1.5 million biomedical data elements and citations, a 10× increase in the past 5 years. The DO, funded as a NHGRI Genomic Resource, plays a key role in disease knowledge organization, representation, and standardization, serving as a reference framework for multiscale biomedical data integration and analysis across thousands of clinical, biomedical and computational research projects and genomic resources around the world. This update reports on the addition of 1,793 new disease terms, a 14% increase of textual definitions and the integration of 22 137 new SubClassOf axioms defining disease to disease connections representing the DO's complex disease classification. The DO's updated website provides multifaceted etiology searching, enhanced documentation and educational resources.

Modeling the enigma of complex disease etiology.

BACKGROUND: Complex diseases often present as a diagnosis riddle, further complicated by the combination of multiple phenotypes and diseases as features of other diseases. With the aim of enhancing the determination of key etiological factors, we developed and tested a complex disease model that encompasses diverse factors that in combination result in complex diseases. This model was developed to address the challenges of classifying complex diseases given the evolving nature of understanding of disease and interaction and contributions of genetic, environmental, and social factors. METHODS: Here we present a new approach for modeling complex diseases that integrates the multiple contributing genetic, epigenetic, environmental, host and social pathogenic effects causing disease. The model was developed to provide a guide for capturing diverse mechanisms of complex diseases. Assessment of disease drivers for asthma, diabetes and fetal alcohol syndrome tested the model. RESULTS: We provide a detailed rationale for a model representing the classification of complex disease using three test conditions of asthma, diabetes and fetal alcohol syndrome. Model assessment resulted in the reassessment of the three complex disease classifications and identified driving factors, thus improving the model. The model is robust and flexible to capture new information as the understanding of complex disease improves. CONCLUSIONS: The Human Disease Ontology's Complex Disease model offers a mechanism for defining more accurate disease classification as a tool for more precise clinical diagnosis. This broader representation of complex disease, therefore, has implications for clinicians and researchers who are tasked with creating evidence-based and consensus-based recommendations and for public health tracking of complex disease. The new model facilitates the comparison of etiological factors between complex, common and rare diseases and is available at the Human Disease Ontology website.

Goldenseal-Mediated Inhibition of Intestinal Uptake Transporters Decreases Metformin Systemic Exposure in Mice.

Goldenseal is a perennial plant native to eastern North America. A recent clinical study reported goldenseal decreased metformin Cmax and area under the blood concentration versus time curve (AUC) by 27% and 23%, respectively, but half-life and renal clearance were unchanged. These observations suggested goldenseal altered processes involved in metformin absorption. The underlying mechanism(s) remain(s) unknown. One mechanism for the decreased metformin systemic exposure is inhibition by goldenseal of intestinal uptake transporters involved in metformin absorption. Goldenseal extract and three goldenseal alkaloids (berberine, (-)-ß-hydrastine, hydrastinine) were tested as inhibitors of organic cation transporter (OCT) 3, plasma membrane monoamine transporter (PMAT), and thiamine transporter (THTR) 2 using human embryonic kidney 293 cells overexpressing each transporter. The goldenseal extract, normalized to berberine content, was the strongest inhibitor of each transporter (IC50: 4.9, 13.1, and 5.8 µM for OCT3, PMAT, and THTR2, respectively). A pharmacokinetic study in mice compared the effects of berberine, (-)-ß-hydrastine, goldenseal extract, and imatinib (OCT inhibitor) on orally administered metformin. Goldenseal extract and imatinib significantly decreased metformin Cmax by 31% and 25%, respectively, and had no effect on half-life. Berberine and (-)-ß-hydrastine had no effect on metformin pharmacokinetics, indicating neither alkaloid alone precipitated the interaction in vivo. A follow-up murine study involving intravenous metformin and oral inhibitors examined the contributions of basolateral enteric/hepatic uptake transporters to the goldenseal-metformin interaction. Goldenseal extract and imatinib had no effect on metformin AUC and half-life, suggesting lack of inhibition of basolateral enteric/hepatic uptake transporters. Results may have implications for patients taking goldenseal with drugs that are substrates for OCT3 and THTR2. SIGNIFICANCE STATEMENT: Goldenseal is used to self-treat respiratory infections and digestive disorders. We investigated potential mechanisms for the clinical pharmacokinetic interaction observed between goldenseal and metformin, specifically inhibition by goldenseal of intestinal uptake transporters (OCT3, PMAT, THTR2) involved in metformin absorption. Goldenseal extract inhibited all three transporters in vitro and decreased metformin systemic exposure in mice. These data may have broader implications for patients co-consuming goldenseal with other drugs that are substrates for these transporters.

Hyperbaric effects on cold stored whole blood following a military dive mission profile.

BACKGROUND: Whole blood (WB) is carried by special operations forces as part of a remote damage control resuscitation strategy. The effects of an underwater mission on the quality and coagulation profile of WB were simulated by exposure to hyperbaric pressures in a chamber. METHODS: WB units collected in CPDA-1 were exposed to three different combinations of hyperbaric pressure and duration of exposure: Group A 153.52 kPa (15.24 msw; 1.52 atm) for 4 h; n = 9, Group B 506.63 kPa (50.29 msw; 5.00 atm) for 1 h; n = 9, Group C 153.52 kPa (15.24 msw; 1.52 atm) for 1 h; n = 7. The following parameters were measured on each unit: prothrombin time/international normalized ratio, activated partial thromboplastin time, thromboelastography and concentration determinations of platelets, lactate, fibrinogen, and lactate dehydrogenase. Each sample underwent baseline, prepressurization, immediate postpressurization, and 6 h postpressurization laboratory testing. RESULTS: Six hours following hyperbaric exposure, the lactate concentration in group C was higher than prepressurization measurement and the platelet concentration in Group A was lower than prepressurization measurement. There were no changes in any of the other analyzed biochemical, coagulation and thromboelastogram parameters following exposure to hyperbaric stress. DISCUSSION: These data suggest that pressurization of WB up to 5 atm did not impact parameters tested. Changes observed in lactate and platelet count need further study, as well as complementary testing of red blood cell integrity. Further investigation of the hyperbaric extremes is necessary to determine if there is a damage inducing pressure to which WB should not be exposed.

Viral internet challenges scale in preadolescents: An exploratory study.

In recent years, viral challenges on the Internet have become a very frequent phenomenon. These allude to the actions that are proposed to Internet users to record themselves performing a challenge and disseminate it on different online platforms so that other users will also perform it. Despite its rapid expansion, there is no evidence of any validated assessment tool of this phenomenon. To meet this need, the Viral Internet Challenges Scale (VICH-S) was designed. The main objective of this study was to establish the psychometric properties of this scale, the prevalence of different types of challenges (social, solidary, and dangerous), as well as the single or conjoint performance of these types of challenges using the VICH-S. Furthermore, the construct validity of the scale was tested with these variables: Fear of Missing Out, Loss of Connection (nomophobia), Self-Online, and Emotional Attention Online. Participants were 417 preadolescents (41.2% boys) with age ranging from 10 to 14 years. Exploratory factor analysis of the VICH-S scale revealed the existence of two factors: Challenge Satisfaction and Social Motivation. Convergent validity indicators showed positive and significant correlations between these two dimensions and the Fear of Missing Out, Loss of Connection (nomophobia), Self-Online, and Emotional Attention Online. The most frequent challenges were social challenges (80.3%), followed by solidary (20.6%) and dangerous challenges (7.7%). This study has relevant implications, as the VICH-S presents adequate psychometric properties to evaluate this barely explored and growing phenomenon of viral challenges on the Internet in preadolescence.

Early neurological deterioration following thrombolysis for minor stroke with isolated internal carotid artery occlusion.

BACKGROUND AND PURPOSE: Better understanding the incidence, predictors and mechanisms of early neurological deterioration (END) following intravenous thrombolysis (IVT) for acute stroke with mild symptoms and isolated internal carotid artery occlusion (iICAo) may inform therapeutic decisions. METHODS: From a multicenter retrospective database, we extracted all patients with both National Institutes of Health Stroke Scale (NIHSS) score <6 and iICAo (i.e. not involving the Willis circle) on admission imaging, intended for IVT alone. END was defined as ≥4 NIHSS points increase within 24 h. END and no-END patients were compared for (i) pre-treatment clinical and imaging variables and (ii) occurrence of intracranial occlusion, carotid recanalization and parenchymal hemorrhage on follow-up imaging. RESULTS: Seventy-four patients were included, amongst whom 22 (30%) patients experienced END. Amongst pre-treatment variables, suprabulbar carotid occlusion was the only admission predictor of END following stepwise variable selection (odds ratio = 4.0, 95% confidence interval: 1.3-12.2; P = 0.015). On follow-up imaging, there was no instance of parenchymal hemorrhage, but an intracranial occlusion was now present in 76% vs. 0% of END and no-END patients, respectively (P < 0.001), and there was a trend toward higher carotid recanalization rate in END patients (29% vs. 9%, P = 0.07). As compared to no-END, END was strongly associated with a poor 3-month outcome. CONCLUSIONS: Early neurological deterioration is a frequent and highly deleterious event after IVT for minor stroke with iICAo, and is of thromboembolic origin in three out of four patients. The strong association with iICAo site-largely a function of underlying stroke etiology-may point to a different response of the thrombus to IVT. These findings suggest END may be preventable in this setting.

Cross-reactivity of the IDEXX Legiolert method with other Gram-negative bacteria and waterborne pathogens leads to false-positive assay results.

Legionella species are the causative agent of Legionnaires' disease, a potentially fatal bacterial pneumonia. New regulations and standards have prioritized the development of water safety plans to minimize the growth and spread of Legionella species in buildings. To determine the presence and type of Legionella in a water system, microbiological culturing is the gold standard method. However, recently new methodologies have been developed that claim to be sensitive and specific for Legionella at the genus or L. pneumophila at the species level. Published and anecdotal reports suggest that one of these newer culture-based, enzyme-substrate methods, the IDEXX Legiolert test, may exhibit false positivity with other microbes common to water sources. We experimentally evaluated the IDEXX Legiolert method using these other waterborne bacteria including Elizabethkingia meningoseptica, Pseudomonas aeruginosa, Proteus mirabilis and Serratia marcescens at real-world environmental concentrations. We saw false-positive results for the Legiolert test with several of these organisms, at sample concentrations as low as 60 CFU per ml. False-positive Legionella results can trigger costly remediation and water-use restrictions, that may be implemented while waiting for additional, confirmatory microbiological testing that could, in this case, yield no L. pneumophila.

Hepatic organic anion transporting polypeptides mediate disposition of milk thistle flavonolignans and pharmacokinetic silymarin-drug interactions.

Silybum marianum (L.) Gaertn. (Asteraceae), commonly known as milk thistle, is a botanical natural product used to self-treat multiple diseases such as Type 2 diabetes mellitus and nonalcoholic steatohepatitis (NASH). An extract from milk thistle seeds (achenes), termed silymarin, is comprised primarily of several flavonolignans. Systemic concentrations of these flavonolignans can influence the potential biologic effects of silymarin and the risk for pharmacokinetic silymarin-drug interactions. The aims of this research were to determine the roles of organic anion transporting polypeptides (OATPs/Oatps) in silymarin flavonolignan disposition and in pharmacokinetic silymarin-drug interactions. The seven major flavonolignans from silymarin were determined to be substrates for OATP1B1, OATP1B3, and OATP2B1. Sprague Dawley rats were fed either a control diet or a NASH-inducing diet and administered pitavastatin (OATP/Oatp probe substrate), followed by silymarin via oral gavage. Decreased protein expression of Oatp1b2 and Oatp1a4 in NASH animals increased flavonolignan area under the plasma concentration-time curve (AUC) and maximum plasma concentration. The combination of silymarin inhibition of Oatps and NASH-associated decrease in Oatp expression caused an additive increase in plasma pitavastatin AUC in the animals. These data indicate that OATPs/Oatps contribute to flavonolignan cellular uptake and mediate the interaction between silymarin and NASH on pitavastatin systemic exposure.

Four-year follow-up of two patients on maintenance therapy with fondaparinux and mycophenolate mofetil for microthrombotic antiphospholipid syndrome.

OBJECTIVES: We discuss two patients with antiphospholipid syndrome (APS) who presented with critical ischemia of both lower extremities due to arterial microthrombi. They received multimodality therapy emergently: anticoagulation, immunosuppression, and therapeutic plasma exchange (TPE). Then they were maintained on anticoagulation with fondaparinux and immunosuppression with mycophenolate mofetil (MMF), and were followed for 4 years. METHODS: Two patients with APS with ischemia and necrosis of their distal lower extremities were treated emergently with anticoagulation (intravenous heparin), immunosuppression (prednisone), and TPE. They were maintained on anticoagulation with fondaparinux and immunosuppression with MMF. RESULTS: Neither patient had recurrent microthrombotic disease during a 4-year follow-up. CONCLUSIONS: As described in our small cohort, patients with APS who suffer from microthrombotic arterial disease may benefit from maintenance therapy of anticoagulation with fondaparinux and immunosuppression with MMF, an approach which may be worthy of further trial. Fondaparinux does not require attention to diet, monitoring, and cumbersome bridging that is typical of warfarin therapy. MMF provides immunosuppression while sparing the side effects of steroid treatment.

JAK1/3 inhibition preserves epidermal morphology in full-thickness 3D skin models of atopic dermatitis and psoriasis.

BACKGROUND: Janus kinase (JAK) inhibition may be a promising new treatment modality for inflammatory (skin) diseases. However, little is known about direct effects of kinase inhibitors on keratinocyte differentiation and function as well as skin barrier formation. OBJECTIVE: Our aim was to address the direct impact of kinase inhibition of the JAK1/3 pathways by tofacitinib on keratinocyte immune function and barrier formation in atopic dermatitis (AD) and psoriasis. METHODS: 3D skin equivalents of both diseases were developed and concurrently pretreated with tofacitinib. To induce AD, 3D skin equivalents were stimulated with recombinant human IL-4 and IL-13. Psoriasis-like conditions were induced by incubation with IL-17A, IL-22 and tumour necrosis factor α (TNFα). The activation of signal transducer and activator of transcription (STAT)1, STAT3 and STAT6 was assessed by Western blot analysis. Microarray analysis and quantitative real-time PCR were used for gene expression analysis. RESULTS: Tofacitinib pretreatment preserved epidermal morphology and reduced STAT3 and STAT6 phosphorylation of AD-like and STAT3 phosphorylation of psoriasis-like culture conditions in 3D skin models compared to sham-controls. Filaggrin expression was fully maintained in the AD-like models, but only partially in psoriasis-like conditions after pretreatment with tofacitinib. In addition, tofacitinib upregulated DSC1, FLG and KRT1. Using gene expression analysis, downregulation of POSTN and IL24 was observed in AD-like conditions, whereas downregulation of IL20 and IL1B was observed in psoriasis-like conditions. CONCLUSION: JAK1/3 inhibition counteracted cytokine-induced AD- and psoriasis-like epidermal morphology and enhanced keratinocyte differentiation in 3D skin models. This effect was more pronounced in the AD-like models compared to the psoriasis-like 3D skin models.

Enfermedad periodontal como factor de riesgo adicional asociado con nacimiento pretérmino en México: un estudio de casos y controles.

INTRODUCTION: Substances related to microorganisms involved in periodontal disease can reach the maternal-fetal interface via the hematogenous route and stimulate uterine contractility. OBJECTIVE: To determine the association between periodontal disease and preterm birth. METHOD: Case-control study in 343 preterm and 686 full-term pregnant women. Gestational age was calculated based on the date of the last menstrual period and confirmed with Capurro and Ballard methods. Periodontal disease was diagnosed according to the depth of the space between the tooth root and the gum. The association was measured with logistic regression. RESULTS: Maternal age of the cases was 23.8 ± 6.7 years, and 23.2 ± 6.7 in the controls. Periodontal disease was present in 66.8% of cases and 40.5% of controls. The factors associated with preterm birth were periodontal disease (Odds ratio [OR] = 2.26), history of preterm birth (OR = 4.96), unplanned pregnancy (OR = 2.15) poor prenatal control (OR = 2.53), urinary tract infection (OR = 2.22), preeclampsia (OR = 4.49), premature rupture of membranes (OR = 2.59) and caesarean section delivery (OR = 9.15). CONCLUSION: Periodontal disease in pregnancy was an independent risk factor for preterm birth.

INTRODUCCIÓN: Las sustancias relacionadas con los microorganismos involucrados en la enfermedad periodontal puedan llegar a la interfaz materno-fetal por vía hematógena y estimular la contractilidad uterina. OBJETIVO: Determinar la asociación entre enfermedad periodontal con nacimiento pretérmino. MÉTODO: Estudio de casos y controles de 343 embarazadas pretérmino y 686 de término. Se calculó la edad gestacional por fecha de último periodo menstrual y se confirmó con los métodos de Capurro y Ballard. La enfermedad periodontal se diagnosticó por la profundidad del espacio entre la raíz dental y la encía. La asociación fue medida con regresión logística. RESULTADOS: La edad de las madres en los casos fue de 23.8 ± 6.7 años y en los controles de 23.2 ± 6.7 años. La enfermedad periodontal estuvo presente en 66.8 % de los casos y 40.5 % de los controles. Los factores asociados con nacimiento pretérmino fueron enfermedad periodontal (RM = 2.26), antecedente de nacimiento pretérmino (RM = 4.96), embarazo no planeado (RM = 2.15), control prenatal deficiente (RM = 2.53), infección de vías urinarias (RM = 2.22), preeclampsia (RM = 4.49), ruptura prematura de membranas amnióticas (RM = 2.59) y nacer por cesárea (RM = 9.15). CONCLUSIÓN: La enfermedad periodontal en el embarazo constituyó un factor de riesgo independiente para nacimiento pretérmino.

Risk of basal cell carcinoma in a randomized clinical trial of aspirin and folic acid for the prevention of colorectal adenomas.

BACKGROUND: Aspirin may reduce the risk of several types of cancer. OBJECTIVES: To evaluate if folic acid is associated with risk of basal cell carcinoma (BCC). METHODS: BCC incidence was evaluated in a randomized, double-blind, placebo-controlled clinical trial of aspirin (81 mg daily or 325 mg daily for ~3 years) and/or folic acid (1 mg daily for ~6 years) for the prevention of colorectal adenomas among 1121 participants with a previous adenoma. BCC was confirmed by blinded review of pathology reports. RESULTS: One hundred and four of 958 non-Hispanic white participants were diagnosed with BCC over a median follow-up of 13·5 years. Cumulative incidence of BCC was 12% [95% confidence interval (CI) 7-17] for placebo, 16% (95% CI 11-21) for 81 mg aspirin daily and 15% (95% CI 10-20) for 325 mg aspirin daily [hazard ratio (HR) for any aspirin 1·45 (95% CI 0·93-2·26); HR for 81 mg daily 1·57 (95% CI 0·96-2·56); HR for 325 mg daily 1·33 (95% CI 0·80-2·20)]. BCC risk was higher with aspirin use in those without previous skin cancer but lower with aspirin use in those with previous skin cancer (Pinteraction = 0·02 for 81 mg aspirin daily; Pinteraction = 0·03 for 325 mg aspirin daily). Folic acid supplementation was unrelated to BCC incidence (HR 0·85; 95% CI 0·57-1·27). CONCLUSIONS: Neither aspirin nor folic acid treatment had a statistically significant effect on risk of BCC. Subgroup analysis suggested that chemopreventive effects of nonsteroidal anti-inflammatory drugs may be specific to those at high risk for BCC.

Similarities and differences between doxycycline and minocycline: clinical and antimicrobial stewardship considerations.

Doxycycline and, to a lesser extent, minocycline, have been used for decades to treat various serious systemic infections, but many physicians remain unfamiliar with their spectrum, interpretation of susceptibility results, pharmacokinetic/pharmacodynamic (PK/PD) properties, optimal dosing regimens, and their activity against MRSA, VRE, and multidrug-resistant (MDR) Gram-negative bacilli, e.g., Acinetobacter sp. This article reviews the optimal use of doxycycline and minocycline to treat a variety of infections and when minocycline is preferred instead of doxycycline.

Sliding sign in third-trimester sonographic evaluation of intra-abdominal adhesions in women undergoing repeat Cesarean section: a novel technique.

OBJECTIVE: Intra-abdominal adhesions are associated with an increased risk of complications during repeat Cesarean section (CS), such as bladder and bowel injury, hemorrhage, infection and hysterectomy. We present a simple sonographic marker, the 'sliding sign' of the uterus, for the prediction of intra-abdominal adhesions in the third trimester of pregnancy in women undergoing repeat CS. METHODS: This was a prospective observational study of pregnant women with a history of at least one Cesarean delivery evaluated by transabdominal ultrasound during the third trimester of an ongoing pregnancy. In order to diagnose intra-abdominal adhesions, we assessed a sonographic sign, the sliding of the uterus under the inner part of the fascia of the abdominal muscles during deep breathing. Women were considered to be at high risk for severe adhesions if uterine sliding was absent and at low risk in the presence of obvious or moderate uterine sliding. A comparison between sonographic findings and intra-abdominal adhesions observed during surgery was performed. RESULTS: Of the 63 patients with one or more previous CS examined, 59 completed the study and underwent CS at our institution. In 16 of the 19 cases assigned to the high-risk group for severe adhesions due to absence of sliding of the uterus, the suspicion was confirmed at surgery. The prediction of low risk for adhesions was confirmed in 35 out of 40 patients. The sensitivity and specificity of the sliding sign in predicting presence of intra-abdominal adhesions in women undergoing repeat CS were 76.2% and 92.1%, respectively. Inter- and intraobserver correlation using Cohen's kappa coefficient were 0.52 and 0.77, respectively. CONCLUSION: Our data show that a simple sonographic sign might be able to discriminate between high and low risk for intra-abdominal adhesions in patients with a history of Cesarean delivery. This technique may aid clinical decisions in patients undergoing repeat CS. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Direct biological effects of fractional ultrapulsed CO2 laser irradiation on keratinocytes and fibroblasts in human organotypic full-thickness 3D skin models.

Molecular effects of various ablative and non-ablative laser treatments on human skin cells-especially primary effects on epidermal keratinocytes and dermal fibroblasts-are not yet fully understood. We present the first study addressing molecular effects of fractional non-sequential ultrapulsed CO2 laser treatment using a 3D skin model that allows standardized investigations of time-dependent molecular changes ex vivo. While histological examination was performed to assess morphological changes, we utilized gene expression profiling using microarray and qRT-PCR analyses to identify molecular effects of laser treatment. Irradiated models exhibited dose-dependent morphological changes resulting in an almost complete recovery of the epidermis 5 days after irradiation. On day 5 after laser injury with a laser fluence of 100 mJ/cm2, gene array analysis identified an upregulation of genes associated with tissue remodeling and wound healing (e.g., COL12A1 and FGF7), genes that are involved in the immune response (e.g., CXCL12 and CCL8) as well as members of the heat shock protein family (e.g., HSPB3). On the other hand, we detected a downregulation of matrix metalloproteinases (e.g., MMP3), differentiation markers (e.g., LOR and S100A7), and the pro-inflammatory cytokine IL1α.Overall, our findings substantiate the understanding of time-dependent molecular changes after CO2 laser treatment. The utilized 3D skin model system proved to be a reliable, accurate, and reproducible tool to explore the effects of various laser settings both on skin morphology and gene expression during wound healing.

BRF1 mutations in a family with growth failure, markedly delayed bone age, and central nervous system anomalies.

Linear growth failure can be caused by many different genetic abnormalities. In many cases, the genetic defect affects not only the growth plate, causing short stature but also other organs/tissues causing additional clinical abnormalities. A 10-year old boy was evaluated for impaired postnatal linear growth (height 113.3 cm, -4.6 SDS), a bone age that was delayed by 5 years, dysmorphic facies, cognitive impairment, and central nervous system anomalies. His younger brother, presented only with growth failure at 10 months of age. Exome sequencing identified compound heterozygous variants in the gene encoding RNA polymerase III transcription initiation factor 90 kDa subunit (BRF1) in both affected siblings: a missense mutation (c.875 C > G:p.P292R) and a frameshift mutation (c.551delG:p.C184Sfs). The frameshift mutation is expected to lead to nonsense-mediated mRNA decay (NMD) and/or to protein truncation. Expression of BRF1 with the P292R missense mutation failed to rescue yeast lacking BRF1. The findings confirm a previous report showing that biallelic mutations in BRF1 cause cerebellar-facial-dental syndrome. Our findings also help define the growth phenotype, indicating that the linear growth failure can become clinically evident before the neurological abnormalities and that a severely delayed bone age may serve as a diagnostic clue.