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Background: Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain.Methods: We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation.Results: A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events.Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.). [ABSTRACT FROM AUTHOR]

Background: Pregnant women with their infants are considered at higher risk for influenza-associated complications, and the World Health Organization (WHO) recommends influenza vaccination during pregnancy to protect them, including their infants (0-6 months). There are limited data on the influenza burden among pregnant women and their infants (0-6 months), and there are no routine influenza vaccinations in Bangladesh., Methods: Five annual cohorts (2013-2017) of pregnant women were enrolled from the eight sub-districts of Bangladesh before the influenza season (May-September); they were contacted weekly to identify new onset of influenza-like illness (ILI) (subjective or measured fever and cough) and acute respiratory illness (ARI) (at least two of these symptoms: cough, rhinorrhea, or difficulty in breathing) among their infants from birth to 6 months of age. We collected nasopharyngeal swabs from ILI and ARI cases, tested by real-time reverse transcription polymerase chain reaction (rRT-PCR) for influenza virus (including types and subtypes) and estimated influenza incidence (95% CI)/10000 pregnant women-months or infant-months, respectively., Results: We enrolled 9020 pregnant women, followed for 26,709 pregnancy-months, and detected 1241 ILI episodes. We also followed 8963 infants for 51,518 infant-months and identified 5116 ARI episodes. Influenza positivity was 23% for ILI and 3% for ARI cases. The overall incidence (2013-2017) of influenza among pregnant women was 158.5/10000 pregnant women-months (95% CI: 141.4-177.6) and that among infants was 21.9/10000 infant-months (95% CI: 18.2-26.5)., Conclusions: Although the data was collected more than 5 years ago, as the only baseline data, our findings illustrate evidence of influenza burden among pregnant women and infants (0-6 months), which may support preventive policy decisions in Bangladesh., Competing Interests: The authors have no competing interest to declare., (© 2023 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Importance: Associations between prenatal SARS-CoV-2 exposure and neurodevelopmental outcomes have substantial public health relevance. A previous study found no association between prenatal SARS-CoV-2 infection and parent-reported infant neurodevelopmental outcomes, but standardized observational assessments are needed to confirm this finding., Objective: To assess whether mild or asymptomatic maternal SARS-CoV-2 infection vs no infection during pregnancy is associated with infant neurodevelopmental differences at ages 5 to 11 months., Design, Setting, and Participants: This cohort study included infants of mothers from a single-site prospective cross-sectional study (COVID-19 Mother Baby Outcomes [COMBO] Initiative) of mother-infant dyads and a multisite prospective cohort study (Epidemiology of Severe Acute Respiratory Syndrome Coronavirus 2 in Pregnancy and Infancy [ESPI]) of pregnant individuals. A subset of ESPI participants was subsequently enrolled in the ESPI COMBO substudy. Participants in the ongoing COMBO study were enrolled beginning on May 26, 2020; participants in the ESPI study were enrolled from May 7 to November 3, 2021; and participants in the ESPI COMBO substudy were enrolled from August 2020 to March 2021. For the current analysis, infant neurodevelopment was assessed between March 2021 and June 2022. A total of 407 infants born to 403 mothers were enrolled (204 from Columbia University Irving Medical Center in New York, New York; 167 from the University of Utah in Salt Lake City; and 36 from the University of Alabama in Birmingham). Mothers of unexposed infants were approached for participation based on similar infant gestational age at birth, date of birth, sex, and mode of delivery to exposed infants., Exposures: Maternal symptomatic or asymptomatic SARS-CoV-2 infection., Main Outcomes and Measures: Infant neurodevelopment was assessed using the Developmental Assessment of Young Children, second edition (DAYC-2), adapted for telehealth assessment. The primary outcome was age-adjusted standard scores on 5 DAYC-2 subdomains: cognitive, gross motor, fine motor, expressive language, and receptive language., Results: Among 403 mothers, the mean (SD) maternal age at delivery was 32.1 (5.4) years; most mothers were of White race (240 [59.6%]) and non-Hispanic ethnicity (253 [62.8%]). Among 407 infants, 367 (90.2%) were born full term and 212 (52.1%) were male. Overall, 258 infants (63.4%) had no documented prenatal exposure to SARS-CoV-2 infection, 112 (27.5%) had confirmed prenatal exposure, and 37 (9.1%) had exposure before pregnancy or at an indeterminate time. In adjusted models, maternal SARS-CoV-2 infection during pregnancy was not associated with differences in cognitive (β = 0.31; 95% CI, -2.97 to 3.58), gross motor (β = 0.82; 95% CI, -1.34 to 2.99), fine motor (β = 0.36; 95% CI, -0.74 to 1.47), expressive language (β = -1.00; 95% CI, -4.02 to 2.02), or receptive language (β = 0.45; 95% CI, -2.15 to 3.04) DAYC-2 subdomain scores. Trimester of exposure and maternal symptom status were not associated with DAYC-2 subdomain scores., Conclusions and Relevance: In this study, results of a novel telehealth-adapted observational neurodevelopmental assessment extended a previous finding of no association between prenatal exposure to maternal SARS-CoV-2 infection and infant neurodevelopment. Given the widespread and continued high prevalence of COVID-19, these data offer information that may be helpful for pregnant individuals who experience asymptomatic or mild SARS-CoV-2 infections.

Accurate patient disease classification and detection through deep-learning (DL) models are increasingly contributing to the area of biomedical imaging. The most frequent gastrointestinal (GI) tract ailments are peptic ulcers and stomach cancer. Conventional endoscopy is a painful and hectic procedure for the patient while Wireless Capsule Endoscopy (WCE) is a useful technology for diagnosing GI problems and doing painless gut imaging. However, there is still a challenge to investigate thousands of images captured during the WCE procedure accurately and efficiently because existing deep models are not scored with significant accuracy on WCE image analysis. So, to prevent emergency conditions among patients, we need an efficient and accurate DL model for real-time analysis. In this study, we propose a reliable and efficient approach for classifying GI tract abnormalities using WCE images by applying a deep Convolutional Neural Network (CNN). For this purpose, we propose a custom CNN architecture named GI Disease-Detection Network (GIDD-Net) that is designed from scratch with relatively few parameters to detect GI tract disorders more accurately and efficiently at a low computational cost. Moreover, our model successfully distinguishes GI disorders by visualizing class activation patterns in the stomach bowls as a heat map. The Kvasir-Capsule image dataset has a significant class imbalance problem, we exploited a synthetic oversampling technique BORDERLINE SMOTE (BL-SMOTE) to evenly distribute the image among the classes to prevent the problem of class imbalance. The proposed model is evaluated against various metrics and achieved the following values for evaluation metrics: 98.9%, 99.8%, 98.9%, 98.9%, 98.8%, and 0.0474 for accuracy, AUC, F1-score, precision, recall, and loss, respectively. From the simulation results, it is noted that the proposed model outperforms other state-of-the-art models in all the evaluation metrics.

Background: There are limited data on influenza vaccine effectiveness (IVE) in preventing laboratory-confirmed influenza illness among healthcare personnel (HCP)., Methods: HCP with direct patient contact working full-time in hospitals were followed during three influenza seasons in Israel (2016-2017 to 2018-2019) and Peru (2016 to 2018). Trivalent influenza vaccines were available at all sites, except during 2018-2019 when Israel used quadrivalent vaccines; vaccination was documented by electronic medical records, vaccine registries, and/or self-report (for vaccinations outside the hospital). Twice-weekly active surveillance identified acute respiratory symptoms or febrile illness (ARFI); self-collected respiratory specimens were tested by real-time reverse transcription polymerase chain reaction (PCR) assay. IVE was 100 × 1-hazard ratio (adjusted for sex, age, occupation, and hospital)., Results: Among 5,489 HCP who contributed 10,041 person-seasons, influenza vaccination coverage was 47% in Israel and 32% in Peru. Of 3,056 ARFIs in Israel and 3,538 in Peru, A or B influenza virus infections were identified in 205 (7%) in Israel and 87 (2.5%) in Peru. IVE against all viruses across seasons was 1% (95% confidence interval [CI] = -30%, 25%) in Israel and 12% (95% CI = -61%, 52%) in Peru., Conclusion: Estimates of IVE were null using person-time models during six study seasons in Israel and Peru., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Ltd.)

Background: Cardiac hypertrophy is a key biological response to injurious stresses such as pressure overload and, when excessive, can lead to heart failure. Innate immune activation by danger signals, through intracellular pattern recognition receptors such as nucleotide-binding oligomerization domain 1 (Nod1) and its adaptor receptor-interacting protein 2 (RIP2), might play a major role in cardiac remodeling and progression to heart failure. We hypothesize that Nod1/RIP2 are major contributors to cardiac hypertrophy, but may not be sufficient to fully express the phenotype alone., Methods: To elucidate the contribution of Nod1/RIP2 signaling to cardiac hypertrophy, we randomized Nod1 -/- , RIP2 -/- , or wild-type mice to transverse aortic constriction or sham operations. Cardiac hypertrophy, fibrosis, and cardiac function were examined in these mice., Results: Nod1 and RIP2 proteins were upregulated in the heart after transverse aortic constriction, and this was paralleled by increased expression of mitochondrial proteins, including mitochondrial antiviral signaling protein (MAVS). Nod1 -/- and RIP2 -/- mice subjected to transverse aortic constriction exhibited better survival, improved cardiac function, and decreased cardiac hypertrophy. Downstream signal transduction pathways that regulate inflammation and fibrosis, including NF (nuclear factor) κB and MAPK (mitogen-activated protein kinase)-GATA4/p300, were reduced in both Nod1 -/- and RIP2 -/- mice after transverse aortic constriction compared with wild-type mice. Coimmunoprecipitation of extracted cardiac proteins and confocal immunofluorescence microscopy showed that Nod1/RIP2 interaction was robust and that this complex also included MAVS as an essential component. Suppression of MAVS expression attenuated the complex formation, NF κB signaling, and myocyte hypertrophy. Interrogation of mitochondrial function compared in the presence or ablation of MAVS revealed that MAVS serves to suppress mitochondrial energy output and mediate fission/fusion related dynamic changes. The latter is possibly linked to mitophagy during cardiomyocytes stress, which may provide an intriguing link between innate immune activation and mitochondrial energy balance under stress or injury conditions., Conclusions: We have identified that innate immune Nod1/RIP2 signaling is a major contributor to cardiac remodeling after stress. This process is critically joined by and regulated through the mitochondrial danger signal adapter MAVS. This novel complex coordinates remodeling, inflammatory response, and mitochondrial energy metabolism in stressed cardiomyocytes. Thus, Nod1/RIP2/MAVS signaling complex may represent an attractive new therapeutic approach toward heart failure.

Background: Audiologists, globally, are generally challenged when assessing and creating intervention plans to help patients suffering from tinnitus. Tinnitus is very common among individuals and may significantly affect one's quality of life, especially if not addressed by health care professionals. In South Africa, there seems to be limited published studies regarding the current practices of tinnitus management by audiologists. This is mainly because of limited training and a lack of guidelines and strategies for the management of tinnitus. In particular, some participants reported being unfamiliar on how to approach the identification of tinnitus and difficulty is also encountered when counselling tinnitus patients., Aim: The aim of this study was to describe the preparedness, perspectives and practices of audiologists who manage adult patients with tinnitus., Method: Two hundred and forty-three registered Health Professions Council of South Africa (HPCSA) participants were involved in the study by responding to an electronic questionnaire survey. Data were collected online from Survey Monkey and were exported to Statistical Packages for the Social Sciences (SPSS) (Version 23) for statistical analysis. Data were analysed using descriptive and inferential statistics. Closed-ended questions were analysed within a quantitative framework and thematic analysis for open-ended questions that were descriptively quantified., Results: The results of the study are presented according to the objectives. Approximately 44% of participants (44.3%) disagreed that the undergraduate university training had sufficiently prepared them to manage adult patients with tinnitus. Very few (12.3%) had the opportunity to attend specialist training on how to assess patients with tinnitus. Similarly, only 11.6% received any specialist training with regard to tinnitus intervention. With regard to its overall management, 49.4% felt adequately informed in the assessment of patients with tinnitus, while a further 39.2% rated their experience as being limited with regard to tinnitus intervention. There is no statistical significance relationship between participants' years of experience and tinnitus intervention (p = 0.075). Most participants did not follow any standard guidelines for its management. Some participants (26.8%) reported that further education and training are required in the overall management of patients with tinnitus, while a further 17.7% required training in all areas of tinnitus., Conclusion: The feedback relating to the study suggests that overall management of tinnitus seems to be a challenge among South African audiologists, irrespective of their years of experience. Audiologists in the study perceived that tinnitus services are limited mainly because of a lack of or limited knowledge, training and guidelines, these being affected by contextual restraints.

Background: Human immunodeficiency virus (HIV)-infected persons are at a higher risk of severe influenza. Although we have shown that a standard-dose intradermal influenza vaccine versus a standard-dose intramuscular influenza vaccine does not result in differences in hemagglutination-inhibition titers in this population, a comprehensive examination of cell-mediated immune responses remains lacking., Methods: Serological, antigen-specific B-cell, and interleukin 2-, interferon γ-, and tumor necrosis factor α-secreting T-cell responses were assessed in 79 HIV-infected men and 79 HIV-uninfected men., Results: The route of vaccination did not affect the immunoglobulin A and immunoglobulin G (IgG) plasmablast or memory B-cell response, although these were severely impaired in the group with a CD4+ T-cell count of <200 cells/μL. The frequencies of IgG memory B cells measured on day 28 after vaccination were highest in the HIV-uninfected group, followed by the group with a CD4+ T-cell count of ≥200 cells/μL and the group with a CD4+ T-cell count of <200 cells/μL. The route of vaccination did not affect the CD4+ or CD8+ T-cell responses measured at various times after vaccination., Conclusions: The route of vaccination had no effect on antibody responses, antibody avidity, T-cell responses, or B-cell responses in HIV-infected or HIV-uninfected subjects. With the serological and cellular immune responses to influenza vaccination being impaired in HIV-infected individuals with a CD4+ T-cell count of <200 cells/μL, passive immunization strategies need to be explored to protect this population., Clinical Trials Registration: NCT01538940., (Published by Oxford University Press for the Infectious Diseases Society of America 2019.)

People high in negative affect (anxiety or depression) show cognitive distortions, specific thinking errors which contribute to the maintenance of their condition. It is thought that weak attentional control is a risk factor for negative affect and emotional disorders, because weak attentional control exaggerates the expression of attentional bias, another cognitive feature of emotional disorders. We wondered whether weak attentional control might similarly exaggerate the expression of cognitive distortions. In two samples of students from Turkey and the UK, we found that weak attentional control was indeed related to cognitive distortions, but this relationship was explained by both variables' relationships with negative affect. This suggests that weak attentional control, while related to negative affect, does not necessarily exaggerate all of its cognitive features. There seems to be a limit on the affective consequences of poor attentional control, which may limit its clinical usefulness as a risk factor for emotional disorders., Competing Interests: The authors have declared that no competing interests exist.

Objective: To estimate the incidence of caesarean scar pregnancy (CSP) and to describe the management outcomes associated with this condition., Design: A national cohort study using the UK Early Pregnancy Surveillance Service (UKEPSS)., Setting: 86 participating Early Pregnancy Units., Population: All women diagnosed in the participating units with CSP between November 2013 and January 2015., Methods: Cohort study of women identified through the UKEPSS monthly mailing system., Main Outcome Measures: Incidence, clinical outcomes and complications., Results: 102 cases of CSP were reported, with an estimated incidence of 1.5 per 10 000 (95% CI 1.1-1.9) maternities. Full outcome data were available for 92 women. Management was expectant in 21/92 (23%), medical in 15/92 (16%) and surgical in 56/92 (61%). The success rates of expectant, medical and surgical management were 43% (9/21), 46% (7/15) and 96% (54/56), respectively. The complication rates were 15/21 (71%) with expectant, 9/15 (60%) with medical and 20/56 (36%) with surgical management. Discharge from care (median number of days) was 82 (range 37-174) with expectant, 21 (range 10-31) with medical and 11 (range 4-49) with surgical management., Conclusions: Surgical management appears to be associated with a high success rate, low complication rate and short post-treatment follow up., Tweetable Abstract: Surgery for CSP appears to be successful, with low complication rates and short post-treatment follow up., (© 2018 Royal College of Obstetricians and Gynaecologists.)

Dip-pen nanolithography (DPN) is used to precisely position core/thick-shell ("giant") quantum dots (gQDs; ≥10 nm in diameter) exclusively on top of silicon nanodisk antennas (≈500 nm diameter pillars with a height of ≈200 nm), resulting in periodic arrays of hybrid nanostructures and demonstrating a facile integration strategy toward next-generation quantum light sources. A three-step reading-inking-writing approach is employed, where atomic force microscopy (AFM) images of the pre-patterned substrate topography are used as maps to direct accurate placement of nanocrystals. The DPN "ink" comprises gQDs suspended in a non-aqueous carrier solvent, o-dichlorobenzene. Systematic analyses of factors influencing deposition rate for this non-conventional DPN ink are described for flat substrates and used to establish the conditions required to achieve small (sub-500 nm) feature sizes, namely: dwell time, ink-substrate contact angle and ink volume. Finally, it is shown that the rate of solvent transport controls the feature size in which gQDs are found on the substrate, but also that the number and consistency of nanocrystals deposited depends on the stability of the gQD suspension. Overall, the results lay the groundwork for expanded use of nanocrystal liquid inks and DPN for fabrication of multi-component nanostructures that are challenging to create using traditional lithographic techniques., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Imitation learning through self-exploration is essential in developing sensorimotor skills. Most developmental theories emphasize that social interactions, especially understanding of observed actions, could be first achieved through imitation, yet the discussion on the origin of primitive imitative abilities is often neglected, referring instead to the possibility of its innateness. This paper presents a developmental model of imitation learning based on the hypothesis that humanoid robot acquires imitative abilities as induced by sensorimotor associative learning through self-exploration. In designing such learning system, several key issues will be addressed: automatic segmentation of the observed actions into motion primitives using raw images acquired from the camera without requiring any kinematic model; incremental learning of spatio-temporal motion sequences to dynamically generates a topological structure in a self-stabilizing manner; organization of the learned data for easy and efficient retrieval using a dynamic associative memory; and utilizing segmented motion primitives to generate complex behavior by the combining these motion primitives. In our experiment, the self-posture is acquired through observing the image of its own body posture while performing the action in front of a mirror through body babbling. The complete architecture was evaluated by simulation and real robot experiments performed on DARwIn-OP humanoid robot.

Adaptive Resonance Theory (ART) is one of the successful approaches to resolving "the plasticity-stability dilemma" in neural networks, and its supervised learning model called ARTMAP is a powerful tool for classification. Among several improvements, such as Fuzzy or Gaussian based models, the state of art model is Bayesian based one, while solving the drawbacks of others. However, it is known that the Bayesian approach for the high dimensional and a large number of data requires high computational cost, and the covariance matrix in likelihood becomes unstable. This paper introduces Kernel Bayesian ART (KBA) and ARTMAP (KBAM) by integrating Kernel Bayes' Rule (KBR) and Correntropy Induced Metric (CIM) to Bayesian ART (BA) and ARTMAP (BAM), respectively, while maintaining the properties of BA and BAM. The kernel frameworks in KBA and KBAM are able to avoid the curse of dimensionality. In addition, the covariance-free Bayesian computation by KBR provides the efficient and stable computational capability to KBA and KBAM. Furthermore, Correntropy-based similarity measurement allows improving the noise reduction ability even in the high dimensional space. The simulation experiments show that KBA performs an outstanding self-organizing capability than BA, and KBAM provides the superior classification ability than BAM, respectively., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Thyroid disorders have been associated with recurrent miscarriage. Little evidence is available on the influence of subclinical hypothyroidism on live birth rates. In this cohort study, women who had experienced miscarriage and subclinical hypothyroidism (defined as thyroid-stimulating hormone >97.5th percentile mU/l with a normal thyroxine level) were investigated; the control group included women who had experienced recurrent miscarriage and normal thyroid function. Multivariable logistic regression was used to investigate the association of subclinical hypothyroidism. Data were available for 848 women; 20 (2.4%) had subclinical hypothyroidism; 818 women (96%) had euthyroidism; and 10 (1.2%) had overt hypothyroidism. The live birth rate was 45% in women with subclinical hypothyroidism and 52% in euthyroid women (OR 0.69, 95% CI 0.28 to 1.71). The ongoing pregnancy rate was 65% versus 69% (OR 0.82, 95% CI 0.32 to 2.10) and the miscarriage rate was 35% versus 28% (OR 1.43, 95% CI 0.56 to 3.68), respectively. No differences were found when thyroid stimulating hormone 2.5 mU/l was used as cut-off level to define subclinical hypothyroidism. In women with unexplained miscarriage, no differences were found in live birth, ongoing pregnancy and miscarriage rates between women with subclinical hypothyroidism and euthyroid women., (Copyright © 2016. Published by Elsevier Ltd.)

Background and Objectives: Progesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted., Design and Setting: A randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites)., Participants and Interventions: Women with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan(®), Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks)., Main Outcome Measures: Live birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6-8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use., Methods: Participants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth., Results: A total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15; p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence's threshold of £20,000-30,000 per quality-adjusted life-year as between 0.7145 and 0.7341., Conclusions: There is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM., Limitations: This study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle., Future Work: Future research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM., Trial Registration: Current Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44., Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Objective: Transabdominal cerclage (TAC) is an effective intervention to prevent spontaneous mid-trimester loss and preterm delivery when a transvaginal cerclage has failed. A TAC may be inserted during the first trimester of pregnancy or preconceptually. The objective of this study was to determine whether or not preconceptual transabdominal cerclage (TAC) confers any benefit over first trimester TAC insertion in terms of associated surgical and pregnancy-related morbidity and subsequent pregnancy outcome., Study Design: This was a retrospective and prospective cohort study of 161 consecutive women who underwent preconceptual (PC) TAC versus first trimester (T1) TAC over a 22-year period from January 1993 to January 2015 at a tertiary referral miscarriage clinic. Data was obtained from case note review retrospectively from 1993 to 2006 and prospectively between 2006 and 2015. Inclusion criteria comprised a history of at least one previous spontaneous mid-trimester loss coupled with at least one failed transvaginal cerclage and screening for antiphospholipid syndrome and bacterial vaginosis. Of 144 patients who conceived, 121 had complete pregnancy outcomes; 62 in the preconceptual group and 59 in the first trimester group. Both groups had similar previous pregnancy losses and previous transvaginal cerclage history., Results: Successful pregnancies >24 weeks occurred in 97% of PC TACs compared to 93% in the T1 group. Furthermore, a successful pregnancy >34 weeks occurred in 90% (56/62) in the PC group compared to 74% (44/59) in the T1 group (OR 3.18; CI 1.14-8.8). Significantly fewer patients needed emergency caesarean section for preterm delivery in the PC group (7/62 (12%) versus 21/59 (36%); OR 4.34; CI 1.68-11.32). All 6 failures before 24 weeks gestation (T1=4, PC=2) were associated with antiphospholipid syndrome or bacterial vaginosis. In the T1 group 3/65 (5%) of patients suffered serious surgical complications and haemorrhage >500mls occurred in 32/65(50%) of cases whereas no surgical complications occurred in the PC group., Conclusions: Preconceptual TAC is more successful in preventing repeat spontaneous mid-trimester loss and preterm labour, and is associated with less surgical and pregnancy-related morbidity compared to first trimester TAC insertion., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Mirror neurons are visuo-motor neurons found in primates and thought to be significant for imitation learning. The proposition that mirror neurons result from associative learning while the neonate observes his own actions has received noteworthy empirical support. Self-exploration is regarded as a procedure by which infants become perceptually observant to their own body and engage in a perceptual communication with themselves. We assume that crude sense of self is the prerequisite for social interaction. However, the contribution of mirror neurons in encoding the perspective from which the motor acts of others are seen have not been addressed in relation to humanoid robots. In this paper we present a computational model for development of mirror neuron system for humanoid based on the hypothesis that infants acquire MNS by sensorimotor associative learning through self-exploration capable of sustaining early imitation skills. The purpose of our proposed model is to take into account the view-dependency of neurons as a probable outcome of the associative connectivity between motor and visual information. In our experiment, a humanoid robot stands in front of a mirror (represented through self-image using camera) in order to obtain the associative relationship between his own motor generated actions and his own visual body-image. In the learning process the network first forms mapping from each motor representation onto visual representation from the self-exploratory perspective. Afterwards, the representation of the motor commands is learned to be associated with all possible visual perspectives. The complete architecture was evaluated by simulation experiments performed on DARwIn-OP humanoid robot.

Importance: Bradycardia has been associated with lower cardiovascular disease (CVD) risk in selected populations. There is a paucity of information available about heart rate (HR) less than 50 beats per minute (bpm) among middle-aged or older adults., Objective: To determine whether asymptomatic bradycardia was associated with a lower cardiovascular risk profile, less subclinical atherosclerosis, and decreased incident CVD and mortality., Design, Setting, and Participants: This retrospective analysis includes 6733 participants of the Multi-Ethnic Study of Atherosclerosis, which recruited men and women free of clinical cardiovascular disease ages 45 to 84 years from 2000 to 2002 and followed them over 10 years for incident CVD events and mortality. The HR was measured by baseline electrocardiogram. The analysis was performed in June 2014., Main Outcomes and Measures: The association between HR categories with CVD events and all-cause mortality were examined using Cox proportional hazards models adjusted for potential confounders and mediators., Results: The 6733 participants had a mean (SD) age of 62 (10.2) years; 47% were male. The mean (SD) HR was 63 (9.5) bpm among the 5831 participants not taking an HR-modifying drug; 5.3% had an HR lower than 50 bpm. Preliminary results revealed significant interaction for HR categories according to use of HR-modifying drugs for mortality (P = .002); thus, all further analyses were stratified. An HR of less than 50 bpm was not associated with incident CVD in either subgroup (participants taking or not taking HR-modifying drugs). Among participants not taking HR-modifying drugs, the fully adjusted mortality risk was not different for an HR less than 50 bpm (hazard ratio, 0.71 [95% CI, 0.41-1.09]; P = .12) and increased among those with an HR greater than 80 bpm (hazard ratio, 1.49 [95% CI, 1.08-2.05]; P = .01) (reference HR, 60-69 bpm). Among the 902 participants taking HR-modifying drugs there was an elevated mortality risk associated with an HR less than 50 bpm (hazard ratio, 2.42 [95% CI, 1.39-4.20]; P = .002) and with an HR greater than 80 bpm (hazard ratio, 3.55 [95% CI, 1.65-7.65]; P = .001) (reference HR, 60-69 bpm)., Conclusions and Relevance: In a contemporary, community-based cohort, bradycardia was generally not associated with incident CVD or mortality except for a potential adverse association between bradycardia among those taking HR-modifying drugs.

Background: Despite acute respiratory infections being a major cause of death among children in developing countries including India, there is a lack of community-based studies that document its burden and aetiology., Methods: A dynamic cohort of children aged 0-10 years was established in four villages in a north Indian state of Haryana from August 2012 onwards. Trained health workers conducted weekly home visits to screen children for acute respiratory infection (ARI) defined as one of the following: cough, sore throat, nasal congestion, earache/discharge, or breathing difficulty. Nurses clinically assessed these children to grade disease severity based on standard age-specific guidelines into acute upper or lower respiratory infection (AURI or ALRI) and collected nasal/throat swabs for pathogen testing., Results: Our first year results show that ARI incidence in 0-10 years of age was 5.9 (5.8-6.0) per child-year with minimal gender difference, the ALRI incidence in the under-five age group was higher among boys (0.43; 0.39-0.49) as compared to girls (0.31; 0.26-0.35) per child year. Boys had 2.4 times higher ARI-related hospitalization rate as compared to girls., Conclusion: ARI impose a significant burden on the children of this cohort. This study platform aims to provide better evidence for prevention and control of pneumonia in developing countries.

Background: In the general population, the majority of cardiovascular events occur in people at the low to moderate end of population risk distribution. The 2013 American College of Cardiology/American Heart Association guideline on the treatment of blood cholesterol recommends consideration of statin therapy for adults with an estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk ≥7.5% based on traditional risk factors. Whether use of nontraditional risk markers can improve risk assessment in those below this threshold for statin therapy is unclear., Methods and Results: Using data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population sample free of clinical CVD at baseline, we calibrated the Pooled Cohort Equations (cPCE). ASCVD was defined as myocardial infarction, coronary heart disease death, or fatal or nonfatal stroke. Adults with an initial cPCE <7.5% and elevated levels of additional risk markers (abnormal test) whose new calculated risk was ≥7.5% were considered statin eligible: low-density lipoprotein cholesterol ≥160 mg/dL; family history of ASCVD; high-sensitivity C-reactive protein ≥2 mg/dL; coronary artery calcium score ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; and ankle-brachial index <0.9. We compared the absolute and relative ASCVD risks among those with versus without elevated posttest estimated risk. We calculated the number needed to screen to identify 1 person with abnormal test for each risk marker, defined as the number of participants with baseline cPCE risk <7.5% divided by the number with an abnormal test reclassified as statin eligible. Of 5185 participants not taking statins with complete data (age, 45-84 years), 4185 had a cPCE risk <7.5%. During 10 years of follow-up, 57% of the ASCVD events (183 of 320) occurred among adults with a cPCE risk <7.5%. When people with diabetes mellitus were excluded, the coronary artery calcium criterion reclassified 6.8% upward, with an event rate of 13.3%, absolute risk of 10%, relative risk of 4.0 (95% confidence interval [CI], 2.8-5.7), and number needed to screen of 14.7. The corresponding numbers for family history of ASCVD were 4.6%, 15.1%, 12%, 4.3 (95% CI, 3.0-6.4), and 21.8; for high-sensitivity C-reactive protein criteria, 2.6%, 10%, 6%, 2.6 (95% CI, 1.4-4.8), and 39.2; for ankle-brachial index criteria, 0.6%, 9%, 5%, 2.3 (95% CI, 0.6-8.6), and 176.5; and for low-density lipoprotein cholesterol criteria, 0.5%, 5%, 1%, 1.2 (95% CI, 0.2-8.4), and 193.3, respectively. Of the 3882 with <7.5% cPCE risk, 431 (11.1%) were reclassified to ≥7.5% (statin eligible) by at least 1 of the additional risk marker criteria., Conclusions: In this generally low-risk population sample, a large proportion of ASCVD events occurred among adults with a 10-year cPCE risk <7.5%. We found that the coronary artery calcium score, high-sensitivity C-reactive protein, family history of ASCVD, and ankle-brachial index recommendations by the American College of Cardiology/American Heart Association cholesterol guidelines (Class IIB) identify small subgroups of asymptomatic population with a 10-year cPCE risk <7.5% but with observed ASCVD event rates >7.5% who may warrant statin therapy considerations., (© 2015 American Heart Association, Inc.)

Background: Endoplasmic reticulum (ER) resident protein 44 (ERp44) is a member of the protein disulfide isomerase family, is induced during ER stress, and may be involved in regulating Ca(2+) homeostasis. However, the role of ERp44 in cardiac development and function is unknown. The aim of this study was to investigate the role of ERp44 in cardiac development and function in mice, zebrafish, and embryonic stem cell (ESC)-derived cardiomyocytes to determine the underlying role of ERp44., Methods and Results: We generated and characterized ERp44(-/-) mice, ERp44 morphant zebrafish embryos, and ERp44(-/-) ESC-derived cardiomyocytes. Deletion of ERp44 in mouse and zebrafish caused significant embryonic lethality, abnormal heart development, altered Ca(2+) dynamics, reactive oxygen species generation, activated ER stress gene profiles, and apoptotic cell death. We also determined the cardiac phenotype in pressure overloaded, aortic-banded ERp44(+/-) mice: enhanced ER stress activation and increased mortality, as well as diastolic cardiac dysfunction with a significantly lower fractional shortening. Confocal and LacZ histochemical staining showed a significant transmural gradient for ERp44 in the adult heart, in which high expression of ERp44 was observed in the outer subepicardial region of the myocardium., Conclusions: ERp44 plays a critical role in embryonic heart development and is crucial in regulating cardiac cell Ca(2+) signaling, ER stress, ROS-induced oxidative stress, and activation of the intrinsic mitochondrial apoptosis pathway., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

The HECT E3 ubiquitin ligase HACE1 is a tumour suppressor known to regulate Rac1 activity under stress conditions. HACE1 is increased in the serum of patients with heart failure. Here we show that HACE1 protects the heart under pressure stress by controlling protein degradation. Hace1 deficiency in mice results in accelerated heart failure and increased mortality under haemodynamic stress. Hearts from Hace1(-/-) mice display abnormal cardiac hypertrophy, left ventricular dysfunction, accumulation of LC3, p62 and ubiquitinated proteins enriched for cytoskeletal species, indicating impaired autophagy. Our data suggest that HACE1 mediates p62-dependent selective autophagic turnover of ubiquitinated proteins by its ankyrin repeat domain through protein-protein interaction, which is independent of its E3 ligase activity. This would classify HACE1 as a dual-function E3 ligase. Our finding that HACE1 has a protective function in the heart in response to haemodynamic stress suggests that HACE1 may be a potential diagnostic and therapeutic target for heart disease.

Mid-trimester pregnancy loss (MTL) occurs between 12 and 24 weeks' gestation. The true incidence of this pregnancy complication is unknown, because research into MTL in isolation is scarce, although the estimated incidence has been noted to be 2% to 3% of pregnancies. A comprehensive preconceptual screening protocol is recommended, because the cause for an MTL may be present in isolation or combined (dual pathology), and is often heterogeneous. Patients with a history of MTL are at an increased risk of future miscarriage and preterm delivery. This risk is increased further depending on the number of associative factors diagnosed., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Several factors may influence the progression of normal labour. It has been postulated that the routine administration of intravenous fluids to keep women adequately hydrated during labour may reduce the period of contraction and relaxation of the uterine muscle, and may ultimately reduce the duration of the labour. It has also been suggested that intravenous fluids may reduce caesarean sections (CS) for prolonged labour. However, the routine administration of intravenous fluids to labouring women has not been adequately elucidated although it is a widely-adopted policy, and there is no consensus on the type or volume of fluids that are required, or indeed, whether intravenous fluids are at all necessary. Women may be able to adequately hydrate themselves if they were allowed oral fluids during labour.Furthermore, excessive volumes of intravenous fluids may pose risks to both the mother and her newborn and different fluids are associated with different risks., Objectives: To evaluate whether the routine administration of intravenous fluids to low-risk nulliparous labouring women reduces the duration of labour and to evaluate the safety of intravenous fluids on maternal and neonatal health., Search Methods: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (13 February 2013)., Selection Criteria: Randomised controlled trials of intravenous fluid administration to spontaneously labouring low-risk nulliparous women., Data Collection and Analysis: The review authors independently assessed trials for inclusion, trial quality and extracted data., Main Results: We included nine randomised trials with 1781 women. Three trials had more than two treatment arms and were included in more than one comparison.Two trials compared women randomised to receive up to 250 mL/hour of Ringer's lactate solution as well as oral intake versus oral intake only. For women delivering vaginally, there was a reduction in the duration of labour in the Ringer's lactate group (mean difference (MD) -28.86 minutes, 95% confidence interval (CI) -47.41 to -10.30). There was no statistical reduction in the number of CS in the Ringer's lactate group (risk ratio (RR), 0.73 95% CI 0.49 to 1.08).Three trials compared women who received 125 mL/hour versus 250 mL/hour of intravenous fluids with free oral fluids in both groups. Women receiving a greater hourly volume of intravenous fluids (250 mL) had shorter labours than those receiving 125 mL (MD 23.87 minutes, 95% CI 3.72 to 44.02, 256 women). There was no statistically significant reduction in the number of CS in the 250 mL intravenous fluid group (average RR 1.00, 95% CI 0.54 to1.87, three studies, 334 women). In one study the number of assisted vaginal deliveries was lower in the group receiving 125 mL/hour (RR 0.47, 95% CI 0.27 to 0.81).Four trials compared rates of intravenous fluids in women where oral intake was restricted (125 mL/hour versus 250 mL/hour). There was a reduction in the duration of labour in women who received the higher infusion rate (MD 105.61 minutes, 95% CI 53.19 to 158.02); P < 0.0001, however, findings must be interpreted with caution as there was high heterogeneity amongst trials (I(2) = 53%). There was a significant reduction in CS in women receiving the higher rate of intravenous fluid infusion (RR 1.56, 95% CI 1.10 to 2.21; P = 0.01). There was no difference identified in the assisted delivery rate (RR 0.78, 95% CI 0.44 to 1.40). There was no clear difference between groups in the number of babies admitted to the NICU (RR 0.48, 95% CI 0.07 to 3.17).Two trials compared normal saline versus 5% dextrose. Only one reported the mean duration of labour, and there was no strong evidence of a difference between groups (MD -12.00, 95% CI -30.09 to 6.09). A trial reporting the median suggested that the duration was reduced in the dextrose group. There was no significant difference in CS or assisted deliveries (RR 0.77, 95% CI 0.41 to 1.43, two studies, 284 women) and (RR 0.59, 95% CI 0.21 to 1.63, one study, 93 women) respectively. Only one trial reported on maternal hyponatraemia (serum sodium levels < 135 mmol/L ). For neonatal complications, there was no difference in the admission to NICU) or in low Apgar scores, however 33.3% of babies developed hyponatraemia in the dextrose group compared to 13.3 % in the normal saline group (RR 0.40, 95% CI 0.17 to 0.93) (P = 0.03). One trial reported a higher incidence of neonatal hyperbilirubinaemia in the dextrose group of babies. There was no difference in neonatal hypoglycaemic episodes between groups., Authors' Conclusions: Although the administration of intravenous fluids compared with oral intake alone demonstrated a reduction in the duration of labour, this finding emerged from only two trials. The findings of other trials suggest that if a policy of no oral intake is applied, then the duration of labour in nulliparous women may be shortened by the administration of intravenous fluids at a rate of 250 mL/hour rather than 125 mL/hour. However, it may be possible for women to simply increase their oral intake rather than being attached to a drip and we have to consider whether it is justifiable to persist with a policy of 'nil by mouth'. One trial raised concerns about the safety of dextrose and this needs further exploration.None of the trials reported on the evaluation of maternal views of being attached to a drip during their entire labour. Furthermore, there was no objective assessment of dehydration. The evidence from this review does not provide robust evidence to recommend routine administration of intravenous fluids. Interpreting the results from trials was hampered by the low number of trials contributing data and by variation between trials. In trials where oral fluids were not restricted there was considerable variation in the amount of oral fluid consumed by women in different arms of the same trial, and between different trials. In addition, results from trials were not consistent and risk of bias varied. Some important research questions were addressed by single trials only, and important outcomes relating to maternal and infant morbidity were frequently not reported.

Objective: To investigate the relationship between the number and sequence of preceding miscarriages and antiphospholipid syndrome (APS)., Design: Retrospective cohort study., Setting: Recurrent miscarriage (RM) clinic., Patient(s): Women who attended the RM clinic from 1988 to 2006., Intervention(s): None., Main Outcome Measure(s): Number, type, and sequence of previous pregnancies were compared between women with APS and women with unexplained RM., Result(s): A total of 1,719 patients were included; 312 (18%) had APS, and 1,407 (82%) had unexplained RM. The mean maternal age (32.6 years) did not differ between women with and without APS. The median number of miscarriages was three in both groups. A total of 865 women (50%) had a history of at least one live birth, with no difference between the two groups. In both groups, 97% of the women had a history of consecutive miscarriages., Conclusion(s): The number of preceding miscarriage, type and sequence of previous pregnancies, and maternal age were not associated with APS in women with RM. There is no increased diagnostic yield for APS after three miscarriages rather than after two miscarriages and no increased diagnostic yield for APS after consecutive miscarriages rather than after nonconsecutive miscarriages. Therefore, APS testing should be considered for all women with two or more miscarriages., (Copyright © 2013 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To assess case definitions for influenza in a rural community in India., Methods: Residents of the study area who were hospitalized for any acute medical condition for at least one night between May 2009 and April 2011 were enrolled. Respiratory specimens were collected and tested for influenza viruses in a reverse-transcription polymerase chain reaction (PCR). The PCR results were taken as the "gold standard" in evaluating the performance of several case definitions., Findings: Of the 3179 patients included in the final analysis, 21% (665) were PCR-positive for influenza virus, 96% reported fever and 4% reported shortness of breath. The World Health Organization (WHO) case definition for severe acute respiratory illness had a sensitivity of 11% among patients aged < 5 years and of 3% among older patients. When shortness of breath was excluded from the definition, sensitivities increased (to 69% and 70%, respectively) and corresponding specificities of 43% and 53% were recorded. Among patients aged ≥ 5 years, WHO's definition of a case of influenza-like illness had a sensitivity of 70% and a specificity of 53%. The addition of "cough and reported or measured fever" increased sensitivity to 80% but decreased specificity to 42%., Conclusion: The inclusion of shortness of breath in WHO's case definition for severe acute respiratory illness may grossly underestimate the burden posed by influenza in hospitals. The exclusion of shortness of breath from this definition or, alternatively, the inclusion of "cough and measured or reported fever" may improve estimates of the burden.

Purpose of Review: Acquired and inherited thrombophilia is an important research avenue in the recurrent miscarriage field. The optimum treatment for patients with recurrent miscarriage and a confirmed thrombophilia remains a contentious issue. We aim to appraise and explore the latest research in the field of thrombophilia and recurrent miscarriage in this review., Recent Findings: Antiphospholipid syndrome (APS) is the only proven thrombophilia that is associated with adverse pregnancy outcomes. Research involving inherited thrombophilia and recurrent miscarriage is limited to small observational studies with small and heterogeneous populations. Aspirin and heparin therapy are frequently prescribed for APS, yet there is no robust evidence for the most efficacious regime. The combination of inherited hypercoagulability and environmental factors in association with recurrent miscarriage has recently been explored as an aid to identify high-risk individuals., Summary: The cause of recurrent miscarriage is multifactorial and appropriate treatment continues to be a challenge. Laboratory tests need to be standardized and well designed multicentre research trials are essential to expand on the current knowledge base with the aim to produce strong evidence-based medicine.

Early pregnancy loss is the most common pregnancy complication. About 15% of pregnancies result in pregnancy loss and 1% of women experience recurrent miscarriage (more than three consecutive miscarriages). The influence of thrombophilia in pregnancy is a popular research topic in recurrent miscarriage. Both acquired and inherited thrombophilia are associated with a risk of pregnancy failure. Antiphospholipid syndrome is the only thrombophilia known to have a direct adverse effect on pregnancy. Historically, clinical research studying thrombophilia treatment in recurrent miscarriage has been of limited value owing to small participant numbers, poor study design and heterogeneity. The debate on the efficacy of aspirin and heparin has advanced with recently published randomised-controlled trials. Multi-centre collaboration is required to ascertain the effect of thrombophilia on early pregnancy loss and to establish an evidence-based treatment protocol., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

Objective: To assess the extent to which in vitro measurements of myometrial contractility reflect the clinical indication for caesarean section., Design: A prospective, observational hypothesis-generating study., Setting: Women were recruited from Liverpool Women's NHS Foundation Trust and experiments were performed in the Physiology Department at the University of Liverpool., Population: Myometrial samples were taken from women undergoing a caesarean section during labour (n = 50) or from women having a repeat nonlabouring caesarean section (n = 70)., Methods: The demographic characteristics of the women and indications for current and previous caesarean sections were recorded. The force, frequency and duration of spontaneous contractions of myometrial strips, and changes in the intracellular calcium concentration of the strips, were measured. Kruskall-Wallis and post hoc tests were used to assess the significance of differences between groups., Results: Samples from women whose caesarean section was for fetal distress/acidosis (scalp pH <7.2) contracted with more force than those from women whose caesarean section was for delay in the first stage of labour (P < 0.001). For repeat, nonlabouring caesarean sections, samples from women whose first caesarean section was for fetal distress/acidosis also contracted with more force than did samples from women whose first caesarean section was for delay in the first stage of labour (P = 0.03)., Conclusions: These findings suggest that the myometrium contracts with greater force in women who have a caesarean section for fetal distress., (© 2011 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2011 RCOG.)

Objectives: Our objective was to test the hypothesis that there is a significant diurnal variation for the therapeutic benefit of angiotensin-converting enzyme (ACE) inhibitors on pressure-overload cardiovascular hypertrophy., Background: Physiological and molecular processes exhibit diurnal rhythms that may affect efficacy of disease treatment (chronotherapy). Evidence suggests that the heart primarily remodels during sleep. Although a growing body of clinical and epidemiological evidence suggests that the timing of therapy, such as ACE inhibition, alters diurnal blood pressure patterns in patients with hypertension, the benefits of chronotherapy on myocardial and vascular remodeling have not been studied., Methods: We examined the effects of the short-acting ACE inhibitor, captopril, on the structure and function of cardiovascular tissue subjected to pressure overload by transverse aortic constriction (TAC) in mice. Captopril (15 mg/kg intraperitoneally) or placebo was administered at either murine sleep time or wake time for 8 weeks starting 1 week after surgery., Results: TAC mice given captopril at sleep time had improved cardiac function and significantly decreased heart: body weight ratios, myocyte cross-sectional areas, intramyocardial vascular medial wall thickness, and perivascular collagen versus TAC mice given captopril or placebo during wake time. Captopril induced similar drops in blood pressure at sleep or wake time, suggesting that time-of-day differences were not attributable to blood pressure changes. These beneficial effects of captopril were correlated with diurnal changes in ACE mRNA expression in the heart., Conclusions: The ACE inhibitor captopril benefited cardiovascular remodeling only when administered during sleep; wake-time captopril ACE inhibition was identical to that of placebo. These studies support the hypothesis that the heart (and vessels) remodel during sleep time and also illustrate the importance of diurnal timing for some cardiovascular therapies., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Cathepsin-L (CTSL) is a member of the lysozomal cysteine protease family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of CTSL in cardiac remodelling post-infarction., Methods and Results: Experimental myocardial infarction (MI) was created in CTSL-deficient (Ctsl(-/-)) mice (B6 × FSB/GnEi a/a Ctsl(fs)/J) and wild-type littermates (Ctsl(+/+)) by left coronary artery ligation. At days 3, 7, 14, and 28 post-MI, we monitored survival rate and evaluated cardiac function, morphology, and molecular endpoints of repair and remodelling. Survival was 56% in Ctsl(-/-) mice in contrast to 80% (P < 0.05) in Ctsl(+/+) mice post-MI by day 28. The Ctsl(-/-) mice exhibited greater scar dilatation, wall thinning, and worse cardiac dysfunction when compared with Ctsl(+/+) mice. Cardiac matrix metallopeptidase-9 (MMP-9) activity was also diminished, and c-kit-positive cells, natural killer cells, fibrocytes, and monocytes mobilized to peripheral blood and deposited to the infarcted myocardium were significantly decreased in Ctsl(-/-) mice. Furthermore, the local inflammatory response, and granulocyte-colony stimulating factor, stem cell factor (SCF), and stromal cell-derived factor-1 (SDF-1α) expression, as well as cell proliferation, revascularization, and myofibroblast deposition were significantly decreased in Ctsl(-/-) mice compared with Ctsl(+/+) mice., Conclusion: Our data indicate that CTSL regulates cardiac repair and remodelling post-MI through a mechanism with multiple pathways.

Knowledge from early outbreaks is limited regarding the virus detection and illness duration of the 2009 pandemic influenza A (H1N1) infections. During the period from April to May 2009 in Texas, we collected serial nasopharyngeal (NP) and stool specimens from 35 participants, testing by real-time reverse transcriptase-polymerase chain reaction (rRT-PCR) and culture. The participants were aged 2 months to 71 years; 25 (71%) were under 18. The median duration of measured fever was 3.0 days and of virus detection in NP specimens was 4.2 days; however, few specimens were collected between days 5-9. The duration of virus detection (4.2 days) was similar to the duration of fever (3.5 days) (RR, 1.14; 95% CI, .66-1.95; P = .8), but was shorter than the duration of cough (11.0 days) (RR, .41; 95% CI, .24-.68; P < .001). We detected viral RNA in two participants' stools. All cultures were negative. This investigation suggests that the duration of virus detection was likely similar to the seasonal influenza virus.

San Antonio, Texas, was one of the first metropolitan areas where 2009 pandemic influenza A (H1N1) virus (pH1N1) was detected. Identification of laboratory-confirmed pH1N1 in 2 students led to a preemptive 8-day closure of their high school. We assessed transmission of pH1N1 and changes in adoption of nonpharmaceutical interventions (NPIs) within households of students attending the affected school. Household secondary attack rates were 3.7% overall and 9.1% among those 0-4 years of age. Widespread adoption of NPIs was reported among household members. Respondents who viewed pH1N1 as very serious were more likely to adopt certain NPIs than were respondents who viewed pH1N1 as not very serious. NPIs may complement influenza vaccine prevention programs or be the only line of defense when pandemic vaccine is unavailable. The 2009 pandemic provided a unique opportunity to study NPIs, and these real-world experiences provide much-needed data to inform pandemic response policy.

To assess household transmission of pandemic (H1N1) 2009 in San Antonio, Texas, USA, during April 15-May 8, 2009, we investigated 77 households. The index case-patient was defined as the household member with the earliest onset date of symptoms of acute respiratory infection (ARI), influenza-like illness (ILI), or laboratory-confirmed pandemic (H1N1) 2009. Median interval between illness onset in index and secondary case-patients was 4 days (range 1-9 days); the index case-patient was likely to be < or =18 years of age (p = 0.034). The secondary attack rate was 4% for pandemic (H1N1) 2009, 9% for ILI, and 13% for ARI. The secondary attack rate was highest for children <5 years of age (8%-19%) and lowest for adults > or =50 years of age (4%-12%). Early in the outbreak, household transmission primarily occurred from children to other household members and was lower than the transmission rate for seasonal influenza.

The pleiotropic cytokines, transforming growth factor beta1 (TGFbeta1), and tumor necrosis factor (TNF) play critical roles in tissue homeostasis in response to injury and are implicated in multiple human diseases and cancer. We reported that the loss of Timp3 (tissue inhibitor of metalloproteinase 3) leads to abnormal TNF signaling and cardiovascular function. Here we show that parallel deregulation of TGFbeta1 and TNF signaling in Timp3(-/-) mice amplifies their cross-talk at the onset of cardiac response to mechanical stress (pressure overload), resulting in fibrosis and early heart failure. Microarray analysis showed a distinct gene expression profile in Timp3(-/-) hearts, highlighting activation of TGFbeta1 signaling as a potential mechanism underlying fibrosis. Neonatal cardiomyocyte-cardiofibroblast co-cultures were established to measure fibrogenic response to agonists known to be induced following mechanical stress in vivo. A stronger response occurred in neonatal Timp3(-/-) co-cultures, as determined by increased Smad signaling and collagen expression, due to increased TNF processing and precocious proteolytic maturation of TGFbeta1 to its active form. The relationship between TGFbeta1 and TNF was dissected using genetic and pharmacological manipulations. Timp3(-/-)/Tnf(-/-) mice had lower TGFbeta1 than Timp3(-/-), and anti-TGFbeta1 antibody (1D11) negated the abnormal TNF response, indicating their reciprocal stimulatory effects, with each manipulation abolishing fibrosis and improving heart function. Thus, TIMP3 is a common innate regulator of TGFbeta1 and TNF in tissue response to injury. The matrix-bound TIMP3 balances the anti-inflammatory and proinflammatory processes toward constructive tissue remodeling.

Background: The innate immune system greatly contributes to the inflammatory process after myocardial infarction (MI). Interleukin-1 receptor-associated kinase-4 (IRAK-4), downstream of Toll/interleukin-1 receptor signaling, has an essential role in regulating the innate immune response. The present study was designed to determine the mechanism by which IRAK-4 is responsible for the cardiac inflammatory process, which consequently affects left ventricular remodeling after MI., Methods and Results: Experimental MI was created in IRAK-4(-/-) and wild-type mice by left coronary ligation. Mice with a targeted deletion of IRAK-4 had an improved survival rate at 4 weeks after MI. IRAK-4(-/-) mice also demonstrated attenuated cardiac dilation and decreased inflammation in the infarcted myocardium, which was associated with less proinflammatory and Th1 cytokine expression mediated by suppression of nuclear factor-kappaB and c-Jun N-terminal kinase activation. IRAK-4(-/-) mice had fewer infiltrations of CD45+ leukocytes and CD11c+ dendritic cells, inhibition of apoptosis, and reduced fibrosis and nitric oxide production. Cardiac dendritic cells in IRAK-4(-/-) mice were relatively immature or functionally naïve after MI in that they demonstrated less cytokine and costimulatory molecule gene expression. Furthermore, IRAK-4(-/-) dendritic cells have less mobilization capacity. Transfer of wild type-derived bone marrow dendritic cells into IRAK-4(-/-) mice for functional dendritic cell reconstitution negated the survival advantage and reduced the cardiac dilation observed with IRAK-4(-/-) mice at 28 days after MI., Conclusions: Deletion of IRAK-4 has favorable effects on survival and left ventricular remodeling after MI through modification of the host inflammatory process by blunting the detrimental bone marrow dendritic cells mobilization after myocardial ischemia.

Gelsolin, a calcium-regulated actin severing and capping protein, is highly expressed in murine and human hearts after myocardial infarction and is associated with progression of heart failure in humans. The biological role of gelsolin in cardiac remodeling and heart failure progression after injury is not defined. To elucidate the contribution of gelsolin in these processes, we randomly allocated gelsolin knockout mice (GSN(-/-)) and wild-type littermates (GSN(+/+)) to left anterior descending coronary artery ligation or sham surgery. We found that GSN(-/-) mice have a surprisingly lower mortality, markedly reduced hypertrophy, smaller late infarct size, less interstitial fibrosis, and improved cardiac function when compared with GSN(+/+) mice. Gene expression and protein analysis identified significantly lower levels of deoxyribonuclease (DNase) I and reduced nuclear translocation and biological activity of DNase I in GSN(-/-) mice. Absence of gelsolin markedly reduced DNase I-induced apoptosis. The association of hypoxia-inducible factor (HIF)-1alpha with gelsolin and actin filaments cleaved by gelsolin may contribute to the higher activation of DNase. The expression pattern of HIF-1alpha was similar to that of gelsolin, and HIF-1alpha was detected in the gelsolin complex by coprecipitation and HIF-1alpha bound to the promoter of DNase I in both gel-shift and promoter activity assays. Furthermore, the phosphorylation of Akt at Ser473 and expression of Bcl-2 were significantly increased in GSN(-/-) mice, suggesting that gelsolin downregulates prosurvival factors. Our investigation concludes that gelsolin is an important contributor to heart failure progression through novel mechanisms of HIF-1alpha and DNase I activation and downregulation of antiapoptotic survival factors. Gelsolin inhibition may form a novel target for heart failure therapy.

Myocardial infarction (MI) and subsequent adverse remodeling cause heart failure. Previously we demonstrated a role for Kit ligand (KL) in improving cardiac function post-MI. KL has two major isoforms; KL-1 is secreted whereas KL-2 is predominantly membrane bound. We demonstrate here first that KL-2-deficient mice have worse survival and an increased heart/bodyweight ratio post-MI compared to mice with reduced c-Kit receptor expression. Next we synthesized recombinant lentiviral vectors (LVs) that engineered functional expression of murine KL-1 and KL-2. For in vivo analyses, we directly injected these LVs into the left ventricle of membrane-bound KL-deficient Sl/Sl(d) or wild-type (WT) mice undergoing MI. Control LV/enGFP injection led to measurable reporter gene expression in hearts. Injection of LV/KL-2 attenuated adverse left ventricular remodeling and dramatically improved survival post-MI in both Sl/Sl(d) and WT mice (from 12 to 71% and 35 to 73%, respectively, versus controls). With regard toward beginning to understand the possible salutary mechanisms involved in this effect, differential staining patterns of Sca-1 and Ly49 on peripheral blood (PB) cells from therapeutically treated animals was found. Our data show that LV/KL-2 gene therapy is a promising treatment for MI.

The controllable synthesis of semiconductor nanocrystals is important for exploiting their size-dependent properties in a variety of applications. The important wide-bandgap semiconductors ZnS and ZnSe crystallize in both the zincblende (ZB) and wurtzite (WZ) structures. While the ZB polymorphs are most stable, methods exist for synthesizing the WZ-type nanocrystals. However, because of the subtle structural differences between the ZB and WZ structures, subtle synthetic differences can favor one polymorph over the other. It is therefore challenging to predictably generate the WZ polymorphs and understand the factors that play a key role in their formation. Through careful mechanistic studies, we show that ZnO nanoparticles, which adopt the WZ structure, form as intermediates in typical reactions that generate WZ-ZnS. This implies that ZnO nanoparticles can serve as structural templates for the preferential formation of WZ-ZnS nanoparticles, and this is confirmed experimentally. Similar chemistry can be used to preferentially form WZ-ZnSe and ZB-ZnSe.

Chromatin remodeling, particularly histone acetylation, plays a critical role in the progression of pathological cardiac hypertrophy and heart failure. We hypothesized that curcumin, a natural polyphenolic compound abundant in the spice turmeric and a known suppressor of histone acetylation, would suppress cardiac hypertrophy through the disruption of p300 histone acetyltransferase-dependent (p300-HAT-dependent) transcriptional activation. We tested this hypothesis using primary cultured rat cardiac myocytes and fibroblasts as well as two well-established mouse models of cardiac hypertrophy. Curcumin blocked phenylephrin-induced (PE-induced) cardiac hypertrophy in vitro in a dose-dependent manner. Furthermore, curcumin both prevented and reversed mouse cardiac hypertrophy induced by aortic banding (AB) and PE infusion, as assessed by heart weight/BW and lung weight/BW ratios, echocardiographic parameters, and gene expression of hypertrophic markers. Further investigation demonstrated that curcumin abrogated histone acetylation, GATA4 acetylation, and DNA-binding activity through blocking p300-HAT activity. Curcumin also blocked AB-induced inflammation and fibrosis through disrupting p300-HAT-dependent signaling pathways. Our results indicate that curcumin has the potential to protect against cardiac hypertrophy, inflammation, and fibrosis through suppression of p300-HAT activity and downstream GATA4, NF-kappaB, and TGF-beta-Smad signaling pathways.

Apelin constitutes a novel endogenous peptide system suggested to be involved in a broad range of physiological functions, including cardiovascular function, heart development, control of fluid homeostasis, and obesity. Apelin is also a catalytic substrate for angiotensin-converting enzyme 2, the key severe acute respiratory syndrome receptor. The in vivo physiological role of Apelin is still elusive. Here we report the generation of Apelin gene-targeted mice. Apelin mutant mice are viable and fertile, appear healthy, and exhibit normal body weight, water and food intake, heart rates, and heart morphology. Intriguingly, aged Apelin knockout mice developed progressive impairment of cardiac contractility associated with systolic dysfunction in the absence of histological abnormalities. We also report that pressure overload induces upregulation of Apelin expression in the heart. Importantly, in pressure overload-induced heart failure, loss of Apelin did not significantly affect the hypertrophy response, but Apelin mutant mice developed progressive heart failure. Global gene expression arrays and hierarchical clustering of differentially expressed genes in hearts of banded Apelin(-/y) and Apelin(+/y) mice showed concerted upregulation of genes involved in extracellular matrix remodeling and muscle contraction. These genetic data show that the endogenous peptide Apelin is crucial to maintain cardiac contractility in pressure overload and aging.

Day/night rhythms are recognized as important to normal cardiovascular physiology and timing of adverse cardiovascular events; however, their significance in disease has not been determined. We demonstrate that day/night rhythms play a critical role in compensatory remodeling of cardiovascular tissue, and disruption exacerbates disease pathophysiology. We use a murine model of pressure overload cardiac hypertrophy (transverse aortic constriction) in a rhythm-disruptive 20-hour versus 24-hour environment. Echocardiography reveals increased left ventricular end-systolic and -diastolic dimensions and reduced contractility in rhythm-disturbed transverse aortic constriction animals. Furthermore, cardiomyocytes and vascular smooth muscle cells exhibit reduced hypertrophy, despite increased pressure load. Microarray and real-time PCR demonstrate altered gene cycling in transverse aortic constriction myocardium and hypothalamic suprachiasmatic nucleus. With rhythm disturbance, there is a consequent altered cellular clock mechanism (per2 and bmal), whereas key genes in hypertrophic pathways (ANF, BNP, ACE, and collagen) are downregulated paradoxical to the increased pressure. Phenotypic rescue, including reversal/attenuation of abnormal pathology and genes, only occurs when the external rhythm is allowed to correspond with the animals' innate 24-hour internal rhythm. Our study establishes the importance of diurnal rhythm as a vital determinant in heart disease. Disrupted rhythms contribute to progression of organ dysfunction; restoration of normal diurnal schedules appears to be important for effective treatment of disease.

Background: Recombinant lentiviral vectors (LVs) offer the possibility of stable, long-term expression of transgenes even in non-dividing cells. In the present study this vector system was applied to a clinically relevant cardiovascular problem., Methods and Results: Fabry disease results from deficient activity of alpha-galactosidase A (alpha-gal A) and cardiac abnormalities are a common and an important cause of death in patients with the disease. A therapeutic LV that delivers the alpha-gal A cDNA has been synthesized. In vitro studies established efficient transduction of the H9c2 rat cardiomyocytes and showed overexpression of enGFP (control) and alpha-gal A. In in vivo studies, the enGFP cDNA was transferred into C57BL/6 mouse hearts by direct intraventricular injection. Next, in a mouse model of Fabry disease, the recombinant therapeutic construct was delivered analogously. In cardiac tissue, alpha-gal A activity rose to 23% of normal levels at day 7 after LV injection, which is encouraging because levels of correction approximating 5% of normal may be curative for this disorder. There was also a corresponding reduction in globotriaosylceramide accumulation. Other organs assayed showed no detectable changes in alpha-gal A activity levels in injected animals., Conclusion: A localized benefit of directly injecting a therapeutic LV into the heart has been shown, confirming the utility of this delivery system for research and therapy for a variety of cardiovascular disorders.

Inappropriate cardiac remodeling and repair after myocardial infarction (MI) predisposes to heart failure. Studies have reported on the potential for lineage negative, steel factor positive (c-kit+) bone marrow-derived hematopoetic stem/progenitor cells (HSPCs) to repair damaged myocardium through neovascularization and myogenesis. However, the precise contribution of the c-kit signaling pathway to the cardiac repair process has yet to be determined. In this study, we sought to directly elucidate the mechanistic contributions of c-kit+ bone marrow-derived hematopoetic stem/progenitor cells in the maintenance and repair of damaged myocardium after MI. Using c-kit-deficient mice, we demonstrate the importance of c-kit signaling in preventing ventricular dilation and hypertrophy, and the maintenance of cardiac function after MI in c-kit-deficient mice. Furthermore, we show phenotypic rescue of cardiac repair after MI of c-kit-deficient mice by bone marrow transplantation of wild-type HSPCs. The transplanted group also had reduced apoptosis and collagen deposition, along with an increase in neovascularization. To better understand the mechanisms underlying this phenotypic rescue, we investigated the gene expression pattern within the infarcted region by using microarray analysis. This analysis suggested activation of inflammatory pathways, specifically natural killer (NK) cell-mediated mobilization after MI in rescued hearts. This finding was confirmed by immunohistology and by using an NK blocker. Thus, our investigation revealed a previously uncharacterized role for c-kit signaling after infarction by mediating bone marrow-derived NK and angiogenic cell mobilization, which contributes to improved remodeling and cardiac function after MI.

Background: We have recently demonstrated that remote ischemic preconditioning reduces ischemia-reperfusion injury in animal models. The mechanisms by which the remote ischemic preconditioning stimulus exerts its effect remain to be fully defined, and its effect on myocardial gene expression is unknown. We tested the hypothesis that remote ischemic preconditioning modifies myocardial gene expression immediately after the remote ischemic preconditioning stimulus (early phase) and 24 hours later (late phase)., Methods: Twenty male (C57BL/6) 10- to 12-week-old mice were randomized into 4 groups: group 1 (control, early phase; n = 5), group 2 (remote ischemic preconditioning, early phase; n = 5), group 3 (control, late phase; n = 5), and group 4 (remote ischemic preconditioning, late phase; n = 5). Groups 2 and 4 underwent remote ischemic preconditioning induced by 6 cycles of 4 minutes of occlusion and 4 minutes of reperfusion of the femoral artery. Groups 1 and 2 were killed 15 minutes after completion of sham procedure or remote ischemic preconditioning, and the hearts were removed and frozen in liquid nitrogen. Groups 3 and 4 were killed 24 hours after remote ischemic preconditioning, and the hearts were harvested in the same fashion. Gene expression was assessed by using the Affymetrix MG-430A chip (Affymetrix, Santa Clara, Calif)., Results: Data filtering (P < .05, analysis of variance) and hierarchic 2-way clustering identified significant differences in gene expression among the 4 groups. Genes involved in protection against oxidative stress (eg, Hadhsc, Prdx4, and Fabp4) and cytoprotection (Hsp73) were upregulated, whereas many proinflammatory genes (eg, Egr-1 and Dusp 1 and 6) were suppressed., Conclusion: A simple remote ischemic preconditioning stimulus modifies myocardial gene expression by upregulating cardioprotective genes and suppressing genes potentially involved in the pathogenesis of ischemia-reperfusion injury.