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In recent years, pragmatic metformin use in pregnancy has stretched to include prediabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, and (most recently) preeclampsia. However, with its expanded use, concerns of unintended harm have been raised. This study developed an experimental primate model and applied ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry for direct quantitation of maternal and fetal tissue metformin levels with detailed fetal biometry and histopathology. Within 30 days of confirmed conception (defined as early pregnancy), 13 time-bred (timed-mated breeding) Rhesus dams with pregnancies designated for fetal necropsy were initiated on twice-daily human dose-equivalent 10 mg/kg metformin or vehicle control. Pregnant dams were maintained as pairs and fed either a control chow or 36% fat Western-style diet. Metformin or placebo vehicle control was delivered in various treats while the animals were separated via a slide. A cesarean delivery was performed at gestational day 145, and amniotic fluid and blood were collected, and the fetus and placenta were delivered. The fetus was immediately necropsied by trained primate center personnel. All fetal organs were dissected, measured, sectioned, and processed per clinical standards. Fluid and tissue metformin levels were assayed using validated ultrahigh performance liquid chromatography coupled to triple-quadrupole mass spectrometry in selected reaction monitoring against standard curves. Among 13 pregnancies at gestational day 145 with fetal necropsy, 1 dam and its fetal tissues had detectable metformin levels despite being allocated to the vehicle control group (>1 μmol metformin/kg maternal weight or fetal or placental tissue), whereas a second fetus allocated to the vehicle control group had severe fetal growth restriction (birthweight of 248.32 g [<1%]) and was suspected of having a fetal congenital condition. After excluding these 2 fetal pregnancies from further analyses, 11 fetuses from dams initiated on either vehicle control (n=4: 3 female and 1 male fetuses) or 10 mg/kg metformin (n=7: 5 female and 2 male fetuses) were available for analyses. Among dams initiated on metformin at gestational day 30 (regardless of maternal diet), significant bioaccumulation within the fetal kidney (0.78–6.06 μmol/kg; mean of 2.48 μmol/kg), liver (0.16–0.73 μmol/kg; mean of 0.38 μmol/kg), fetal gut (0.28–1.22 μmol/kg; mean of 0.70 μmol/kg), amniotic fluid (0.43–3.33 μmol/L; mean of 1.88 μmol/L), placenta (0.16–1.00 μmol/kg; mean of 0.50 μmol/kg), fetal serum (0.00–0.66 μmol/L; mean of 0.23 μmol/L), and fetal urine (4.10–174.10 μmol/L; mean of 38.5 μmol/L) was observed, with fetal levels near biomolar equivalent to maternal levels (maternal serum: 0.18–0.86 μmol/L [mean of 0.46 μmol/L]; maternal urine: 42.60–254.00 μmol/L [mean of 149.30 μmol/L]). Western-style diet feeding neither accelerated nor reduced metformin bioaccumulations in maternal or fetal serum, urine, amniotic fluid, placenta, or fetal tissues. In these 11 animals, fetal bioaccumulation of metformin was associated with less fetal skeletal muscle (57% lower cross-sectional area of gastrocnemius) and decreased liver, heart, and retroperitoneal fat masses (P <.05), collectively driving lower delivery weight (P <.0001) without changing the crown-rump length. Sagittal sections of fetal kidneys demonstrated delayed maturation, with disorganized glomerular generations and increased cortical thickness. This renal dysmorphology was not accompanied by structural or functional changes indicative of renal insufficiency. Our study demonstrates fetal bioaccumulation of metformin with associated fetal growth restriction and renal dysmorphology after maternal initiation of the drug within 30 days of conception in primates. Given these results and the prevalence of metformin use during pregnancy, additional investigation of any potential immediate and enduring effects of prenatal metformin use is warranted. [Display omitted] [ABSTRACT FROM AUTHOR]

Zika virus congenital infection evades double-stranded RNA detection and may persist in the placenta for the duration of pregnancy without accompanying overt histopathologic inflammation. Understanding how viruses can persist and replicate in the placenta without causing overt cellular or tissue damage is fundamental to deciphering mechanisms of maternal-fetal vertical transmission. Placenta-specific microRNAs are believed to be a tenet of viral resistance at the maternal-fetal interface. We aimed to test the hypothesis that the Zika virus functionally disrupts placental microRNAs, enabling viral persistence and fetal pathogenesis. To test this hypothesis, we used orthogonal approaches in human and murine experimental models. In primary human trophoblast cultures (n=5 donor placentae), we performed Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation to identify any significant alterations in the functional loading of microRNAs and their targets onto the RNA-induced silencing complex. Trophoblasts from same-donors were split and infected with a contemporary first-passage Zika virus strain HN16 (multiplicity of infection=1 plaque forming unit per cell) or mock infected. To functionally cross-validate microRNA–messenger RNA interactions, we compared our Argonaute high-throughput sequencing ultraviolet-crosslinking and immunoprecipitation results with an independent analysis of published bulk RNA-sequencing data from human placental disk specimens (n=3 subjects; Zika virus positive in first, second, or third trimester, CD45– cells sorted by flow cytometry) and compared it with uninfected controls (n=2 subjects). To investigate the importance of these microRNA and RNA interference networks in Zika virus pathogenesis, we used a gnotobiotic mouse model uniquely susceptible to the Zika virus. We evaluated if small-molecule enhancement of microRNA and RNA interference pathways with enoxacin influenced Zika virus pathogenesis (n=20 dams total yielding 187 fetal specimens). Lastly, placentae (n=14 total) from this mouse model were analyzed with Visium spatial transcriptomics (9743 spatial transcriptomes) to identify potential Zika virus–associated alterations in immune microenvironments. We found that Zika virus infection of primary human trophoblast cells led to an unexpected disruption of placental microRNA regulation networks. When compared with uninfected controls, Zika virus–infected placentae had significantly altered SLC12A8 , SDK1 , and VLDLR RNA-induced silencing complex loading and transcript levels (–22; adjusted P value <.05; Wald-test with false discovery rate correction q <0.05). In silico microRNA target analyses revealed that 26 of 119 transcripts (22%) in the transforming growth factor-β signaling pathway were targeted by microRNAs that were found to be dysregulated following Zika virus infection in trophoblasts. In gnotobiotic mice, relative to mock controls, Zika virus–associated fetal pathogenesis included fetal growth restriction (P =.036) and viral persistence in placental tissue (P =.011). Moreover, spatial transcriptomics of murine placentae revealed that Zika virus–specific placental niches were defined by significant up-regulation of complement cascade components and coordinated changes in transforming growth factor-β gene expression. Finally, treatment of Zika virus–infected mice with enoxacin abolished placental Zika virus persistence, rescued the associated fetal growth restriction, and the Zika virus–associated transcriptional changes in placental immune microenvironments were no longer observed. These results collectively suggest that (1) Zika virus infection and persistence is associated with functionally perturbed microRNA and RNA interference pathways specifically related to immune regulation in placental microenvironments and (2) enhancement of placental microRNA and RNA interference pathways in mice rescued Zika virus–associated pathogenesis, specifically persistence of viral transcripts in placental microenvironments and fetal growth restriction. [ABSTRACT FROM AUTHOR]

Although the earth's climate has been continuously changing over billions of years, human influence has accelerated that rate of change. While high latitudes suffer the greatest increase in incremental temperature, moderate latitudes are highly vulnerable due to their temperate/tropical rain storms and hurricanes that bring about extreme flooding events. We and others have shown that there is a link between the occurrence and severity of these climate events and risk of adverse perinatal outcomes. In this review, we will discuss the data and consider interacting near and intermediate sequelae of worsening natural disasters–including food scarcity, disrupted or compromised built environments and infrastructure, and loss of communities with human migration. While certainly tackling these and other proximal mediators of adverse perinatal outcomes will benefit maternal and child health, a failure to meaningfully address the root causes of climate change and resultant environmental chemical exposures will be of little long-term benefit. [ABSTRACT FROM AUTHOR]

Zika virus is an emerging mosquito-borne (Aedes genus) arbovirus of the Flaviviridae family. Following epidemics in Micronesia and French Polynesia during the past decade, more recent Zika virus infection outbreaks were first reported in South America as early as May 2013 and spread to now 50 countries throughout the Americas. Although no other flavivirus has previously been known to cause major fetal malformations following perinatal infection, reports of a causal link between Zika virus and microcephaly, brain and ocular malformations, and fetal loss emerged from hard-hit regions of Brazil by October 2015. Among the minority of infected women with symptoms, clinical manifestations of Zika virus infection may include fever, headache, arthralgia, myalgia, and maculopapular rash; however, only 1 of every 4-5 people who are infected have any symptoms. Thus, clinical symptom reporting is an ineffective screening tool for the relative risk assessment of Zika virus infection in the majority of patients. As previously occurred with other largely asymptomatic viral infections posing perinatal transmission risk (such as HIV or cytomegalovirus), we must develop and implement rapid, sensitive, and specific screening and diagnostic testing for both viral detection and estimation of timing of exposure. Unfortunately, despite an unprecedented surge in attempts to rapidly advance perinatal clinical testing for a previously obscure arbovirus, there are several ongoing hindrances to molecular- and sonographic-based screening and diagnosis of congenital Zika virus infection. These include the following: (1) difficulty in estimating the timing of exposure for women living in endemic areas and thus limited interpretability of immunoglobulin M serologies; (2) cross-reaction of immunoglobulin serologies with other endemic flaviruses, such as dengue; (3) persistent viremia and viruria in pregnancy weeks to months after primary exposure; and (4) fetal brain malformations and anomalies preceding the sonographic detection of microcephaly. In this commentary, we discuss screening and diagnostic considerations that are grounded not only in the realities of current obstetrical practice in a largely global population but also in basic immunology and virology. We review recent epidemiological data pertaining to the risk of congenital Zika virus malformations based on trimester of exposure and consider side by side with emerging data demonstrating replication of Zika virus in placental and fetal tissue throughout gestation. We discuss limitations to ultrasound based strategies that rely largely or solely on the detection of microcephaly and provide alternative neurosonographic approaches for the detection of malformations that may precede or occur independent of a small head circumference. This expert review provides information that is of value for the following: (1) obstetrician, maternal-fetal medicine specialist, midwife, patient, and family in cases of suspected Zika virus infection; (2) review of the methodology for laboratory testing to explore the presence of the virus and the immune response; (3) ultrasound-based assessment of the fetus suspected to be exposed to Zika virus with particular emphasis on the central nervous system; and (4) identification of areas ready for development. [ABSTRACT FROM AUTHOR]

Background: Preterm birth (PTB) is a multifactorial disorder, and air pollution has been suggested to increase the risk of occurrence. However, large population studies controlling for multiple exposure measures in high-density settings with established commuter patterns are lacking.Objective: We performed a geospatial analysis with the use of a publicly available database to identify whether residence during pregnancy, specifically with regard to exposure to traffic density and mobility in urban and suburban neighborhoods, may be a contributing risk factor for premature delivery.Study Design: In our cohort study, we analyzed 9004 pregnancies with as many as 4900 distinct clinical and demographic variables from Harris County, Texas. On the basis of primary residency and occupational zip code information, geospatial analysis was conducted. Data on vehicle miles traveled (VMT) and percentages of inhabitants traveling to work were collected at the zip code level and additionally grouped by the three recognized regional commuter loop high-density thoroughfares resulting from two interstate/highway belts (inner, middle, and outer loops). PTB was categorized as late (34 1/7 to 36 6/7 weeks) and early PTB (22 1/7 to 33 6/7 weeks), and unadjusted odds ratios (OR) and adjusted ORs were ascribed.Results: PTB prevalence in our study population was 10.1% (6.8% late and 3.3% early preterm), which is in accordance with our study and other previous studies. Prevalence of early PTB varied significantly between the regional commuter loop thoroughfares [OR for inner vs outer loop: 0.58 (95% confidence interval, 0.39-0.87), OR for middle vs outer loop, 0.74 (0.57-0.96)]. The ORs for PTB and early PTB were shown to be lower in gravidae from neighborhoods with the highest VMT/acre [OR for PTB, 0.82 (0.68-0.98), OR for early PTB, 0.78 (0.62-0.98)]. Conversely, risk of PTB and early PTB among subjects living in neighborhoods with a high percentage of inhabitants traveling to work over a greater distance demonstrated a contrary tendency [OR for PTB, 1.18 (1.03-1.35), OR for early PTB, 1.48 (1.17-1.86)]. In logistic regression models, the described association between PTB and residence withstood and could not be explained by differences in maternal age, gravidity or ethnicity, tobacco use, or history of PTB.Conclusion: While PTB is of multifactorial origin, the present study shows that community-based risk factors (namely urban/suburban location, differences in traffic density exposure, and need for traveling to work along high-vehicle density thoroughfares) may influence risk for PTB. Further research focusing on previously unrecognized community-based risk factors may lead to innovative future prevention measures. [ABSTRACT FROM AUTHOR]

Background: Biopsy surveillance protocols for the assessment of Barrett's esophagus can be subject to sampling errors, resulting in diagnostic uncertainty. Optical coherence tomography is a cross-sectional imaging technique that can be used to conduct volumetric laser endomicroscopy (VLE) of the entire distal esophagus. We have developed a biopsy guidance platform that places endoscopically visible marks at VLE-determined biopsy sites. Objective: The objective of this study was to demonstrate in human participants the safety and feasibility of VLE-guided biopsy in vivo. Design: A pilot feasibility study. Setting: Massachusetts General Hospital. Patients: A total of 22 participants were enrolled from January 2011 to June 2012 with a prior diagnosis of Barrett's esophagus. Twelve participants were used to optimize the laser marking parameters and the system platform. A total of 30 target sites were selected and marked in real-time by using the VLE-guided biopsy platform in the remaining 10 participants. Intervention: Volumetric laser endomicroscopy. Main Outcome Measurements: Endoscopic and VLE visibility, and accuracy of VLE diagnosis of the tissue between the laser cautery marks. Results: There were no adverse events of VLE and laser marking. The optimal laser marking parameters were determined to be 2 seconds at 410 mW, with a mark separation of 6 mm. All marks made with these parameters were visible on endoscopy and VLE. The accuracies for diagnosing tissue in between the laser cautery marks by independent blinded readers for endoscopy were 67% (95% confidence interval [CI], 47%-83%), for VLE intent-to-biopsy images 93% (95% CI, 78%-99%), and for corrected VLE post-marking images 100% when compared with histopathology interpretations. Limitations: This is a single-center feasibility study with a limited number of patients. Conclusion: Our results demonstrate that VLE-guided biopsy of the esophagus is safe and can be used to guide biopsy site selection based on the acquired volumetric optical coherence tomography imaging data. (Clinical trial registration number: NCT01439633.) [Copyright &y& Elsevier]

There is an ever-increasing demand for new imaging methods that can provide additional information about the coronary wall to better characterize and stratify high-risk plaques, and to guide interventional and pharmacologic management of patients with coronary artery disease. While there are a number of imaging modalities that facilitate the assessment of coronary artery pathology, this review paper focuses on intravascular optical imaging modalities that provide information on the microstructural, compositional, biochemical, biomechanical, and molecular features of coronary lesions and stents. The optical imaging modalities discussed include angioscopy, optical coherence tomography, polarization sensitive-optical coherence tomography, laser speckle imaging, near-infrared spectroscopy, time-resolved laser induced fluorescence spectroscopy, Raman spectroscopy, and near-infrared fluorescence molecular imaging. Given the wealth of information that these techniques can provide, optical imaging modalities are poised to play an increasingly significant role in the evaluation of the coronary artery in the future. [Copyright &y& Elsevier]

Abstract: The metabolic pathways used by higher-eukaryotic organisms to deal with potentially carcinogenic xenobiotic compounds from tobacco smoke have been well characterized. Carcinogenic compounds such as polycyclic aromatic hydrocarbons are metabolized sequentially in 2 phases: in phase I, CYP1A1 catalyzes conversion into harmful hydrophilic DNA adducts, whereas in phase II, GSTT1 enables excretion via conjugation into polar electrophiles. In an effort to understand susceptibility to in utero tobacco exposure, we previously characterized known metabolic functional polymorphisms and demonstrated that although deletion of fetal GSTT1 significantly modified birth weight in smokers, no polymorphism fully accounted for fetal growth restriction. Because smoking up-regulates CYP1A1 expression, we hypothesized that nonallelic (epigenetic) dysregulation of placental CYP1A1 expression via alterations in DNA methylation (meCpG) may further modify fetal growth. In the present article, we compared placental expression of multiple CYP family members among gravidae and observed significantly increased CYP1A1 expression among smokers relative to controls (4.4-fold, P < .05). To fully characterize CYP1A1 meCpG status, bisulfite modification and sequencing of the entire proximal 1-kilobase promoter (containing 59 CpG sites) were performed. CpG sites immediately proximal to the 5′-xenobiotic response element transcription factor binding element were significantly hypomethylated among smokers (55.6% vs 45.9% meCpG, P = .027), a finding that uniquely correlated with placental gene expression (r = 0.737, P = .007). Thus, in utero tobacco exposure significantly increases placental CYP1A1 expression in association with differential methylation at a critical xenobiotic response element. [ABSTRACT FROM AUTHOR]

Background: Random biopsy esophageal surveillance can be subject to sampling errors, resulting in diagnostic uncertainty. Optical frequency domain imaging (OFDI) is a high-speed, 3-dimensional endoscopic microscopy technique. When deployed through a balloon-centering catheter, OFDI can automatically image the entire distal esophagus (6.0 cm length) in approximately 2 minutes. Objective: To test a new platform for guided biopsy that allows the operator to select target regions of interest on an OFDI dataset, and then use a laser to mark the esophagus at corresponding locations. The specific goals include determining the optimal laser parameters, testing the accuracy of the laser marking process, evaluating the endoscopic visibility of the laser marks, and assessing the amount of mucosal damage produced by the laser. Design: Experimental study conducted in 5 swine in vivo. Setting: Massachusetts General Hospital. Main Outcome Measurements: Success rate, including endoscopic visibility of laser marks and accuracy of the laser marking process for selected target sites, and extent of the thermal damage caused by the laser marks. Results: All of the laser-induced marks were visible by endoscopy. Target locations were correctly marked with a success rate of 97.07% (95% confidence interval, 89.8%-99.7%). Thermal damage was limited to the superficial layers of the mucosa and was observed to partially heal within 2 days. Limitations: An animal study with artificially placed targets to simulate pathology. Conclusions: The study demonstrates that laser marking of esophageal sites identified in comprehensive OFDI datasets is feasible and can be performed with sufficient accuracy, precision, and visibility to guide biopsy in vivo. [Copyright &y& Elsevier]

Background: Spectrally encoded confocal microscopy (SECM) is a high-speed reflectance confocal microscopy technique that has the potential to be used for acquiring comprehensive images of the entire distal esophagus endoscopically with subcellular resolution. Objective: The goal of this study was to demonstrate large-area SECM in upper GI tissues and to determine whether the images contain microstructural information that is useful for pathologic diagnosis. Design: A feasibility study. Setting: Gastrointestinal Unit, Massachusetts General Hospital. Patients: Fifty biopsy samples from 36 patients undergoing routine EGD were imaged by SECM, in their entirety, immediately after their removal. Results: The microstructure seen in the SECM images was similar to that seen by histopathology. Gastric cardia mucosa was clearly differentiated from squamous mucosa. Gastric fundic/body type mucosa showed more tightly packed glands than gastric cardia mucosa. Fundic gland polyps showed cystically dilated glands lined with cuboidal epithelium. The presence of intraepithelial eosinophils was detected with the cells demonstrating a characteristic bilobed nucleus. Specialized intestinal metaplasia was identified by columnar epithelium and the presence of goblet cells. Barrett''s esophagus (BE) with dysplasia was differentiated from specialized intestinal metaplasia by the loss of nuclear polarity and disorganized glandular architecture. Limitations: Ex vivo, descriptive study. Conclusions: Large-area SECM images of gastroesophageal biopsy samples enabled the visualization of both subcellular and architectural features of various upper GI mucosal types and were similar to the corresponding histopathologic slides. These results suggest that the development of an endoscopic SECM probe is merited. [Copyright &y& Elsevier]

Objectives: We present the first clinical experience with intracoronary optical frequency domain imaging (OFDI) in human patients. Background: Intracoronary optical coherence tomography (OCT) is a catheter-based optical imaging modality that is capable of providing microscopic (∼7-μm axial resolution, ∼30-μm transverse resolution), cross-sectional images of the coronary wall. Although the use of OCT has shown substantial promise for imaging coronary microstructure, blood attenuates the OCT signal, necessitating prolonged, proximal occlusion to screen long arterial segments. OFDI is a second-generation form of OCT that is capable of acquiring images at much higher frame rates. The increased speed of OFDI enables rapid, 3-dimensional imaging of long coronary segments after a brief, nonocclusive saline purge. Methods: Volumetric OFDI images were obtained in 3 patients after intracoronary stent deployment. Imaging was performed in the left anterior descending and right coronary arteries with the use of a nonocclusive saline purge rates ranging from 3 to 4 ml/s and for purge durations of 3 to 4 s. After imaging, the OFDI datasets were segmented using previously documented criteria and volume rendered. Results: Good visualization of the artery wall was obtained in all cases, with clear viewing lengths ranging from 3.0 to 7.0 cm at pullback rates ranging from 5 to 20 mm/s. A diverse range of microscopic features were identified in 2 and 3 dimensions, including thin-capped fibroatheromas, calcium, macrophages, cholesterol crystals, bare stent struts, and stents with neointimal hyperplasia. There were no complications of the OFDI procedure. Conclusions: Our results demonstrate that OFDI is a viable method for imaging the microstructure of long coronary segments in patients. Given its ability to provide microscopic information in a practical manner, this technology may be useful for studying human coronary pathophysiology in vivo and as a clinical tool for guiding the management of coronary artery disease. [Copyright &y& Elsevier]

Background: Optical coherence tomography (OCT) is a cross-sectional, high-resolution imaging modality that has been shown to accurately differentiate esophageal specialized intestinal metaplasia (SIM) from gastric cardia at the squamocolumnar junction (SCJ) and diagnose high-grade dysplasia and intramucosal carcinoma in patients with SIM. The clinical utility of OCT has been limited, however, by its inability to acquire images over large areas. Objective: The aim of this study was to use recently developed high-speed OCT technology, termed optical frequency domain imaging (OFDI), and a new balloon-centering catheter (2.5 cm diameter) to demonstrate the feasibility of large area, comprehensive optical microscopy of the entire distal esophagus (∼6.0 cm) in patients. Design: A pilot feasibility study. Setting: Massachusetts General Hospital. Patients: Twelve patients undergoing routine EGD. Results: Comprehensive microscopy of the distal esophagus was successfully performed in 10 patients with the OFDI system and balloon catheter. There were no complications resulting from the imaging procedure. Volumetric data sets were acquired in less than 2 minutes. OFDI images at the SCJ showed a variety of microscopic features that were consistent with histopathologic findings, including squamous mucosa, cardia, SIM with and without dysplasia, and esophageal erosion. Limitations: Inability to obtain direct correlation of OFDI data and histopathologic diagnoses. Conclusions: Comprehensive volumetric microscopy of the human distal esophagus was successfully demonstrated with OFDI and a balloon-centering catheter, providing a wealth of detailed information about the structure of the esophageal wall. This technique will support future studies to compare OFDI image information with histopathologic diagnoses. [Copyright &y& Elsevier]

Rationale and Objectives: Many imaging modalities and methodologies exist for evaluating the pulmonary airways. Individually, each modality provides insight to the state of the airways; however, alone they do not necessarily provide a comprehensive description. The goal of this work is to integrate complementary medical imaging datasets to form a synergistic description of the airways. Materials and Methods: Two digital bronchoscopic techniques were used to evaluate the pulmonary mucosa. A digital color bronchoscopic system was used to detect mucosal color alterations, and a fluorescence detection system was used to assess the microvasculature of the bronchial mucosa. Study participants were also imaged with a multidetector row computed tomographic (MDCT) scanner. Virtual bronchoscopic and image registration techniques were exploited to combine three-dimensional surface renderings, extracted from the MDCT data, together with the two-dimensional digital bronchoscopic images. Validation of the fusion process was performed on a rubber phantom of an adult airway with 4 embedded metal beads. Results: The fusion of the MDCT extracted airway tree and the digital bronchoscopic datasets were presented for three study participants. In addition, the detected accuracy of the registration method to reliably align the MDCT and bronchoscopic image datasets was determined to be 1.98 mm in the phantom airway model. Conclusion: We have demonstrated that merging of three distinct digital datasets to provide a single synergistic description of the airways is possible. This is a pilot project in the field of eidomics, the process of combining digital image datasets and image-based processes together. We anticipate that in the future eidomics will provide a universal and predictive imaging language that will change health care delivery. [Copyright &y& Elsevier]

Background: Optical coherence tomography (OCT) has been used for high-resolution endoscopic imaging and diagnosis of specialized intestinal metaplasia, dysplasia, and intramucosal carcinoma of the esophagus. However, the relatively slow image-acquisition rate of the present OCT systems inhibits wide-field imaging and limits the clinical utility of OCT for diagnostic imaging in patients with Barrett''s esophagus. Objective: This study describes a new optical imaging technology, optical frequency-domain imaging (OFDI), derived from OCT, that enables comprehensive imaging of large esophageal segments with microscopic resolution. Design: A prototype OFDI system was developed for endoscopic imaging. The system was used in combination with a balloon-centering catheter to comprehensively image the distal esophagus in swine. Results: Volumetric images of the mucosa and portions of the muscularis propria were obtained for 4.5-cm-long segments. Image resolution was 7 μm in depth and 30 μm parallel to the lumen, and provided clear delineation of each mucosal layer. The 3-dimensional data sets were used to create cross-sectional microscopic images, as well as vascular maps of the esophagus. Submucosal vessels and capillaries were visualized by using Doppler-flow processing. Conclusions: Comprehensive microscopic imaging of the distal esophagus in vivo by using OFDI is feasible. The unique capabilities of this technology for obtaining detailed information of tissue microstructure over large mucosal areas may open up new possibilities for improving the management of patients with Barrett''s esophagus. [Copyright &y& Elsevier]

Background: Vertical transmission of Zika virus leads to infection of neuroprogenitor cells and destruction of brain parenchyma. Recent evidence suggests that the timing of infection as well as host factors may affect vertical transmission. As a result, congenital Zika virus infection may only become clinically apparent in the postnatal period.Objective: We sought to develop an outbred mouse model of Zika virus vertical transmission to determine if the timing of gestational Zika virus exposure yields phenotypic differences at birth and through adolescence. We hypothesized that later gestational inoculations would only become apparent in adolescence.Study Design: To better recapitulate human exposures, timed pregnant Swiss-Webster dams (n = 15) were subcutaneously inoculated with 1 × 104 plaque-forming units of first passage contemporary Zika virus HN16 strain or a mock injection on embryonic day 4, 8, or 12 with bioactive antiinterferon alpha receptor antibody administered in days preceding and proceeding inoculation. The antibody was given to prevent the robust type I interferon signaling cascade that make mice inherently resistant to Zika virus infection. At birth and adolescence (6 weeks of age) offspring were assessed for growth, brain weight, and biparietal head diameters, and Zika virus viral levels by reverse transcription-polymerase chain reaction or in situ hybridization.Results: Pups of Zika virus-infected dams infected at embryonic days 4 and 8 but not 12 were growth restricted (P < .003). Brain weights were significantly smaller at birth (P = .01) for embryonic day 8 Zika virus-exposed offspring. At 6 weeks of age, biparietal diameters were smaller for all Zika virus-exposed males and females (P < .05), with embryonic day 8-exposed males smallest by biparietal diameter and growth-restriction measurements (weight >2 SD, P = .0007). All pups and adolescent mice were assessed for Zika virus infection by reverse transcription-polymerase chain reaction. Analysis of all underweight pups reveled 1 to be positive for neuronal Zika virus infection by in situ hybridization, while a second moribund animal was diffusely positive at 8 days of age by Zika virus infectivity throughout the brain, kidneys, and intestine.Conclusion: These findings demonstrate that postnatal effects of infection occurring at single time points continue to be detrimental to offspring in the postnatal period in a subset of littermates and subject to a window of gestational susceptibility coinciding with placentation. This model recapitulates frequently encountered clinical scenarios in nonendemic regions, including the majority of the United States, where travel-related exposure occurs in short and well-defined windows of gestation. Our low rate of infection and relatively rare evidence of congenital Zika syndrome parallels human population-based data. [ABSTRACT FROM AUTHOR]

Background: It is generally assumed that marijuana is one of the more widely used controlled substances during pregnancy. However, there remains a general paucity of population-based data regarding its use and subsequent perinatal morbidity. We hypothesized that direct patient query during pregnancy regarding marijuana, tobacco, and nicotine use would provide crucial initial population-based data on perinatal risk.Objective: Our study sought to examine maternal and neonatal outcomes in pregnancies with reported marijuana exposure, in isolation or in combination with maternal cigarette smoking.Study Design: We applied a retrospective cohort study design to subjects (n = 12,069) with available information on marijuana use and pregnancy outcomes. Since 2011, we have routinely and directly questioned all gravidae regarding use of marijuana, tobacco, and nicotine-containing products. We examined perinatal outcomes in marijuana smokers vs nonsmokers, as well as patients reporting both marijuana and cigarette smoking. Multivariate analysis enabled determination of adjusted odds ratios for maternal and fetal outcomes, adjusting for confounders. Significance was determined with Mann-Whitney U, χ(2), and Fischer exact tests (as appropriate).Results: In all, 106/12,069 reported marijuana use (0.88%), with 48/12,069 (0.4%; or 48/106, 45%) concurrently using cigarettes and marijuana. After controlling for potential confounding variables, while marijuana use alone was not associated with significant adverse outcomes, use in combination with cigarette smoking was significantly associated with increased risk of multiple adverse perinatal outcomes (increased occurrence of maternal asthma [adjusted odds ratio, 2.4; 95% confidence interval, 1.0-5.9]; preterm birth [adjusted odds ratio, 2.6; 95% confidence interval, 1.3-4.9]; decreased [<25th percentile] head circumference [adjusted odds ratio, 2.8; 95% confidence interval, 1.3-4.3]; and decreased [<25th percentile] birthweight [adjusted odds ratio, 2.8; 95% confidence interval, 1.6-5.0]). Maternal pregnancy-related hypertension was not increased in marijuana smokers (adjusted odds ratio, 1.30; 95% confidence interval, 0.681-2.498), or in cigarette smokers (adjusted odds ratio, 1.4; 95%, confidence interval, 0.9-1.9). However, co-users had elevated rates of preeclampsia compared to nonusers (adjusted odds ratio, 2.5; 95% confidence interval, 1.4-5.0).Conclusion: In our initial cohort analysis, after controlling for potential confounders, while marijuana exposure alone was not associated with significant perinatal adverse outcomes, co-use with cigarette smoking rendered increased risk over either alone. Due to observed prevalence of concurrent cigarette and marijuana use, it is of likely importance to counsel patients regarding use in pregnancy. [ABSTRACT FROM AUTHOR]

Background: The H19/IGF2 imprinted loci have attracted recent attention because of their role in cellular differentiation and proliferation, heritable gene regulation, and in utero or early postnatal growth and development. Expression from the imprinted H19/IGF2 locus involves a complex interplay of 3 means of epigenetic regulation: proper establishment of DNA methylation, promoter occupancy of CTCF, and expression of microRNA-675. We have demonstrated previously in a multigenerational rat model of intrauterine growth restriction the epigenetic heritability of adult metabolic syndrome in a F2 generation. We have further demonstrated abrogation of the F2 adult metabolic syndrome phenotype with essential nutrient supplementation of intermediates along the 1-carbon pathway and shown that alterations in the metabolome precede the adult onset of metabolic syndrome. The upstream molecular and epigenomic mediators underlying these observations, however, have yet to be elucidated fully.Objective: In the current study, we sought to characterize the impact of the intrauterine growth-restricted lineage and essential nutrient supplementation on both levels and molecular mediators of H19 and IGF2 gene expression in the F2 generation.Study Design: F2 intrauterine growth-restricted and sham lineages were obtained by exposing P1 (grandmaternal) pregnant dams to bilateral uterine artery ligation or sham surgery at gestational day 19.5. F1 pups were allocated to the essential nutrient supplemented or control diet at postnatal day 21, and bred at 6-7 weeks of age. Hepatic tissues from the resultant F2 offspring at birth and at weaning (day 21) were obtained. Bisulfite modification and sequencing was employed for methylation analysis. H19 and IGF2 expression was measured by quantitative polymerase chain reaction. Promoter occupancy was quantified by the use of chromatin immunoprecipitation, or ChIP, against CTCF insulator proteins.Results: Growth-restricted F2 on control diet demonstrated significant down-regulation in H19 expression compared with sham lineage (0.7831 vs 1.287; P < .05); however, essential nutrient supplementation diet abrogates this difference (4.995 vs 5.100; P > .05). Conversely, Igf2 was up-regulated by essential nutrient supplemented diet on the sham lineage (2.0 fold, P = .01), an effect that was not observed in the growth restricted offspring. A significant differential methylation was observed in the promoter region of region H19 among the intrauterine growth-restricted lineage (18% vs 25%; P < .05) on a control diet, whereas the essential nutrient supplemented diet was alternately associated with hypermethylation in both lineages (sham: 50%; intrauterine growth restriction: 84%, P < .05). Consistent with essential nutrient supplementation impacting the epigenome, a decrease of CTCF promoter occupancy was observed in CTCF4 of the growth restricted lineage (2.45% vs 0.56%; P < .05) on the control diet, an effect that was repressed with essential nutrient supplementation.Conclusion: Heritable growth restriction is associated with changes in H19 gene expression; these changes are reversible with diet supplementation to favorably impact adult metabolic syndrome. [ABSTRACT FROM AUTHOR]