Secondary sex ratio in assisted reproduction: an analysis of 1 376 454 treatment cycles performed in the UK.

STUDY QUESTION: Does ART impact the secondary sex ratio (SSR) when compared to natural conception? SUMMARY ANSWER: IVF and ICSI as well as the stage of embryo transfer does impact the overall SSR. WHAT IS KNOWN ALREADY: The World Health Organization quotes SSR for natural conception to range between 103 and 110 males per 100 female births. STUDY DESIGN SIZE DURATION: A total of 1 376 454 ART cycles were identified, of which 1 002 698 (72.8%) cycles involved IVF or ICSI. Of these, 863 859 (85.2%) were fresh cycles and 124 654 (12.4%) were frozen cycles. Missing data were identified in 14 185 (1.4%) cycles. PARTICIPANTS/MATERIALS SETTING METHODS: All cycles recorded in the anonymized UK Human Fertilisation and Embryology Authority (HFEA) registry database between 1991 and 2016 were analysed. All singleton live births were included, and multiple births were excluded to avoid duplication. MAIN RESULTS AND THE ROLE OF CHANCE: The overall live birth rate per cycle for all IVF and ICSI treatments was 26.2% (n = 262 961), and the singleton live birth rate per cycle was 17.1% (n = 171 399). The overall SSR for this study was 104.0 males per 100 female births (binomial exact 95% CI: 103.1-105.0) for all IVF and ICSI cycles performed in the UK recorded through the HFEA. This was comparable to the overall SSR for England and Wales at 105.3 males per 100 female births (95% CI: 105.2-105.4) from 1991 to 2016 obtained from the Office of National Statistics database. Male predominance was seen with conventional insemination in fresh IVF treatment cycles (SSR 110.0 males per 100 female births; 95% CI: 108.6-111.5) when compared to micro-injection in fresh ICSI treatment cycles (SSR 97.8 males per 100 female births; 95% CI: 96.5-99.2; odds ratio (OR) 1.16, 95% CI 1.12-1.19, P < 0.0001), as well as with blastocyst stage embryo transfers (SSR 104.8 males per 100 female births; 95% CI: 103.5-106.2) when compared to a cleavage stage embryo transfer (SSR 101.2 males per 100 female births; 95% CI: 99.3-103.1; OR 1.03, 95% CI 1.01-1.06, P = 0.011) for all fertilization methods. LIMITATIONS REASONS FOR CAUTION: The quality of the data relies on the reporting system. Furthermore, success rates through ART have improved since 1991, with an increased number of blastocyst stage embryo transfers. WIDER IMPLICATIONS OF THE FINDINGS: This is the largest study to date evaluating the impact of ART on SSR. The results demonstrate that, overall, ART does have an impact on the SSR when assessed according to the method of fertilization (ICSI increased female births while IVF increased males). However, given the ratio of IVF to ICSI cycles at present with 60% of cycles from IVF and 40% from ICSI, the overall SSR for ART closely reflects the population SSR for, largely, natural conceptions in England and Wales. STUDY FUNDING/COMPETING INTERESTS: The study received no funding. C.M.B. is a member of the independent data monitoring group for a clinical endometriosis trial by ObsEva. He is on the scientific advisory board for Myovant and medical advisory board for Flo Health. He has received research grants from Bayer AG, MDNA Life Sciences, Volition Rx and Roche Diagnostics as well as from Wellbeing of Women, Medical Research Council UK, the NIH, the UK National Institute for Health Research and the European Union. He is the current Chair of the Endometriosis Guideline Development Group for ESHRE and was a co-opted member of the Endometriosis Guideline Group by the UK National Institute for Health and Care Excellence (NICE). I.G. has received research grants from Wellbeing of Women, the European Union and Finox. TRIAL REGISTRATION NUMBER: Not applicable

Case Report: Varicella Associated Neuropsychiatric Syndrome (VANS) in Two Pediatric Cases

Background: Viral or bacterial infections can trigger auto-immune inflammatory reactions and conditions in children. Self-reactivity arises due to similarities in molecular structures between pathogenic microorganisms and regular body structures with consequent immune-cross reactions. Reactivation of latent Varicella Zoster Virus (VZV) infections can cause neurological sequalae, including cerebellitis, post-herpetic neuralgias, meningo/encephalitis, vasculopathy and myelopathy. We propose a syndrome caused by auto-immune reactivity triggered by molecular mimicry between VZV and the brain, culminating in a post-infectious psychiatric syndrome with childhood VZV infections. Case presentation: Two individuals, a 6-year-old male and 10-year-old female developed a neuro-psychiatric syndrome 3-6 weeks following a confirmed VZV infection with intrathecal oligoclonal bands. The 6-year-old male presented with a myasthenic syndrome, behavior deterioration and regression in school, he was poorly responsive to IVIG and risperidone, however had a pronounced response to steroid treatment. The 10-year-old female presented with marked insomnia, agitation, and behavioral regression as well as mild bradykinesia. A trial of neuroleptics and sedatives resulted in a mild unsustained reduction in psychomotor agitation and IVIG was also unsuccessful, however the patient was very responsive to steroid therapy. Conclusion: Psychiatric syndromes with evidence of intrathecal inflammation temporally related to VZV infections that are responsive to immune modulation have not been described before. Here we report two cases demonstrating neuro-psychiatric symptoms following VZV infection, with evidence of persistent CNS inflammation following the resolution of infection, and response to immune modulation.info:eu-repo/semantics/publishedVersio

Statistical-Mechanical Measure of Stochastic Spiking Coherence in A Population of Inhibitory Subthreshold Neurons

By varying the noise intensity, we study stochastic spiking coherence (i.e., collective coherence between noise-induced neural spikings) in an inhibitory population of subthreshold neurons (which cannot fire spontaneously without noise). This stochastic spiking coherence may be well visualized in the raster plot of neural spikes. For a coherent case, partially-occupied "stripes" (composed of spikes and indicating collective coherence) are formed in the raster plot. This partial occupation occurs due to "stochastic spike skipping" which is well shown in the multi-peaked interspike interval histogram. The main purpose of our work is to quantitatively measure the degree of stochastic spiking coherence seen in the raster plot. We introduce a new spike-based coherence measure $M_s$ by considering the occupation pattern and the pacing pattern of spikes in the stripes. In particular, the pacing degree between spikes is determined in a statistical-mechanical way by quantifying the average contribution of (microscopic) individual spikes to the (macroscopic) ensemble-averaged global potential. This "statistical-mechanical" measure $M_s$ is in contrast to the conventional measures such as the "thermodynamic" order parameter (which concerns the time-averaged fluctuations of the macroscopic global potential), the "microscopic" correlation-based measure (based on the cross-correlation between the microscopic individual potentials), and the measures of precise spike timing (based on the peri-stimulus time histogram). In terms of $M_s$, we quantitatively characterize the stochastic spiking coherence, and find that $M_s$ reflects the degree of collective spiking coherence seen in the raster plot very well. Hence, the "statistical-mechanical" spike-based measure $M_s$ may be used usefully to quantify the degree of stochastic spiking coherence in a statistical-mechanical way.Comment: 16 pages, 5 figures, to appear in the J. Comput. Neurosc

Clinical relevance and therapeutic potential of angiopoietin-like protein 4 in hepatocellular carcinoma

published_or_final_versio

Suppression of tumorigenesis and metastasis of hepatocellular carcinoma by shRNA interference targeting on homeoprotein Six1

We previously demonstrated that the overexpression of homeoprotein Six1 in hepatocellular carcinoma (HCC) patients is associated with venous infiltration, advanced pathologic tumor metastasis (pTNM) stage and poor overall survival rate (Ng et al. Br J Cancer 2006;95:1050-5). In this study, short hairpin RNA (shRNA) interference approach was used to suppress the expression of Six1 in a metastatic HCC cell line MHCC97L. Stable transfectant MHCC97L-shSix1 carrying Six1-specific shRNA plasmid was established to downregulate Six1 expression to about 40% when compared with MHCC97L-Control. In vitro functional assays demonstrated that the growth rate and proliferation ability of MHCC97L-shSix1 cells were markedly decreased. Moreover, significant decrease of cell motility and invasiveness were observed in MHCC97L-shSix1 cells. Data from in vivo xenograft tumorigenesis model demonstrated that the size of tumor in MHCC97L-shSix1 group was dramatically reduced. Experimental and spontaneous metastasis models indicated that targeting Six1 suppression noticeably reduced the pulmonary metastasis in MHCC97L-shSix1 group. To identify Six1-regulated targets, cDNA microarray was employed to compare the expression profiles of MHCC97L-Control and MHCC97L-shSix1 cells. Twenty-eight downregulated and 24 upregulated genes with known functions were identified in MHCC97L-shSix1. The functions of these target genes are involved in diverse biological activities. Our data suggest that Six1 may be involved in regulation of proliferation and invasiveness of HCC; thus targeting suppression of Six1 is a viable option for treating HCC patients. © 2009 UICC.postprin

The effectiveness of early lens extraction with intraocular lens implantation for the treatment of primary angle-closure glaucoma (EAGLE) : study protocol for a randomized controlled trial

Peer reviewedPublisher PD

Genome-wide saturation mutagenesis of Burkholderia pseudomallei K96243 predicts essential genes and novel targets for antimicrobial development

This is the final version of the article. Available from the publisher via the DOI in this record.Burkholderia pseudomallei is the causative agent of melioidosis, an often fatal infectious disease for which there is no vaccine. B. pseudomallei is listed as a tier 1 select agent, and as current therapeutic options are limited due to its natural resistance to most antibiotics, the development of new antimicrobial therapies is imperative. To identify drug targets and better understand the complex B. pseudomallei genome, we sought a genome-wide approach to identify lethal gene targets. As B. pseudomallei has an unusually large genome spread over two chromosomes, an extensive screen was required to achieve a comprehensive analysis. Here we describe transposon-directed insertion site sequencing (TraDIS) of a library of over 10(6) transposon insertion mutants, which provides the level of genome saturation required to identify essential genes. Using this technique, we have identified a set of 505 genes that are predicted to be essential in B. pseudomallei K96243. To validate our screen, three genes predicted to be essential, pyrH, accA, and sodB, and a gene predicted to be nonessential, bpss0370, were independently investigated through the generation of conditional mutants. The conditional mutants confirmed the TraDIS predictions, showing that we have generated a list of genes predicted to be essential and demonstrating that this technique can be used to analyze complex genomes and thus be more widely applied. IMPORTANCE: Burkholderia pseudomallei is a lethal human pathogen that is considered a potential bioterrorism threat and has limited treatment options due to an unusually high natural resistance to most antibiotics. We have identified a set of genes that are required for bacterial growth and thus are excellent candidates against which to develop potential novel antibiotics. To validate our approach, we constructed four mutants in which gene expression can be turned on and off conditionally to confirm that these genes are required for the bacteria to survive.This work was partially funded by the Defence Science and Technology Laboratories (DSTL)

Suppression of liver tumor growth and metastasis by adiponectin in nude mice through inhibition of tumor angiogenesis and downregulation of rho kinase/IFN-inducible protein 10/matrix metalloproteinase 9 signaling

Purpose: We aimed to investigate the effects of adiponectin on liver cancer growth and metastasis and explore the underlying mechanisms. Experimental Design: An orthotopic liver tumor nude mice model with distant metastatic potential was applied. Either Ad-adiponectin (1 × 10 8; treatment group) or Ad-luciferase (control group) was injected via portal vein after tumor implantation. Tumor growth and metastasis were monitored by Xenogen In vivo Imaging System. Hepatic stellate cell activation by α-smooth muscle actin staining, microvessel density by CD34 staining, macrophage infiltration in tumor tissue, and cell signaling leading to invasion, migration [Rho kinase (ROCK), IFN-inducible protein 10 (IP10), and matrix metalloproteinase 9], and angiogenesis [vascular endothelial growth factor (VEGF) and angiopoietin 1] were also compared. Tumor-nontumor margin was examined under electron microscopy. Direct effects of adiponectin on liver cancer cells and endothelial cells were further investigated by a series of functional studies. Results: Tumor growth was significantly inhibited by adiponectin treatment, accompanied by a lower incidence of lung metastasis. Hepatic stellate cell activation and macrophage infiltration in the liver tumors were suppressed by adiponectin treatment, along with decreased microvessel density. The treatment group had less Ki-67-positive tumor cells and downregulated protein expression of ROCK1, proline-rich tyrosine kinase 2, and VEGF. Tumor vascular endothelial cell damage was found in the treatment group under electron microscopy. In vitro functional study showed that adiponectin not only downregulated the ROCK/IP10/VEGF signaling pathway but also inhibited the formation of lamellipodia, which contribute to cell migration. Conclusion: Adiponectin treatment significantly inhibited liver tumor growth and metastasis by suppression of tumor angiogenesis and downregulation of the ROCK/IP10/matrix metalloproteinase 9 pathway. ©2010 AACR.postprin

Aiding first incident responders using a decision support system based on live drone feeds

In case of a dangerous incident, such as a fire, a collision or an earthquake, a lot of contextual data is available for the first incident responders when handling this incident. Based on this data, a commander on scene or dispatchers need to make split-second decisions to get a good overview on the situation and to avoid further injuries or risks. Therefore, we propose a decision support system that can aid incident responders on scene in prioritizing the rescue efforts that need to be addressed. The system collects relevant data from a custom designed drone by detecting objects such as firefighters, fires, victims, fuel tanks, etc. The drone autonomously observes the incident area, and based on the detected information it proposes a prioritized based action list on e.g. urgency or danger to incident responders

Apolipoprotein ɛ4 is associated with increased risk of fall- and fracture-related hospitalisation: the Perth Longitudinal Study of Ageing Women

Apolipoprotein ɛ4 (APOE ɛ4) may be a genetic risk factor for reduced bone mineral density (BMD) and muscle function, which could have implications for fall and fracture risk. We examined the association between APOE ɛ4 status and long-term fall- and fracture-related hospitalisation risk in older women. 1276 community-dwelling women from the Perth Longitudinal Study of Ageing Women (mean age ± SD = 75.2 ± 2.7 years) were included. At baseline, women underwent APOE genotyping and detailed phenotyping for covariates including prevalent falls and fractures, as well as health and lifestyle factors. The association between APOE ɛ4 with fall-, any fracture-, and hip fracture-related hospitalisations, obtained over 14.5 years from linked health records, were examined using multivariable-adjusted Cox-proportional hazard models. Over 14.5 years, 507 (39.7%) women experienced a fall-related hospitalisation, 360 (28.2%) women experienced a fracture-related hospitalisation, including 143 (11.2%) attributed to a hip fracture. In multivariable-adjusted models, compared to non-carriers, APOE ɛ4 carriers (n=297, 23.3%) had greater risk for a fall- (HR 1.48 95%CI 1.22-1.81), fracture- (HR 1.28, 95%CI 1.01-1.63) or hip fracture-related hospitalisation (HR 1.83 95%CI 1.29-2.61). The estimates remained similar when specific fall and fracture risk factors (fear of falling, plasma 25-hydroxyvitamin D, grip strength, timed-up-and-go, hip BMD, vitamin K status, prevalent diabetes, HbA1c, cholesterol, abbreviated mental test score) were added to the multivariable model. In conclusion, APOE ɛ4 is a potential risk factor for fall- and fracture-related hospitalisation in community-dwelling older women. Screening for APOE ɛ4 could provide clinicians an opportunity to direct higher risk individuals to appropriate intervention strategies