Rhombomere-specific analysis reveals the repertoire of genetic cues expressed across the developing hindbrain

<p>Abstract</p> <p>Background</p> <p>The Hox family of homeodomain transcription factors comprises pivotal regulators of cell specification and identity during animal development. However, despite their well-defined roles in the establishment of anteroposterior pattern and considerable research into their mechanism of action, relatively few target genes have been identified in the downstream regulatory network. We have sought to investigate this issue, focussing on the developing hindbrain and the cranial motor neurons that arise from this region. The reiterated anteroposterior compartments of the developing hindbrain (rhombomeres (r)) are normally patterned by the combinatorial action of distinct Hox genes. Alteration in the normal pattern of Hox cues in this region results in a transformation of cellular identity to match the remaining Hox profile, similar to that observed in <it>Drosophila </it>homeotic transformations.</p> <p>Results</p> <p>To define the repertoire of genes regulated in each rhombomere, we have analysed the transcriptome of each rhombomere from wild-type mouse embryos and not those where pattern is perturbed by gain or loss of Hox gene function. Using microarray and bioinformatic methodologies in conjunction with other confirmatory techniques, we report here a detailed and comprehensive set of potential Hox target genes in r2, r3, r4 and r5. We have demonstrated that the data produced are both fully reflective and predictive of rhombomere identity and, thus, may represent some the of Hox targets. These data have been interrogated to generate a list of candidate genes whose function may contribute to the generation of neuronal subtypes characteristic of each rhombomere. Interestingly, the data can also be classified into genetic motifs that are predicted by the specific combinations of Hox genes and other regulators of hindbrain anteroposterior identity. The sets of genes described in each or combinations of rhombomeres span a wide functional range and suggest that the Hox genes, as well as other regulatory inputs, exert their influence across the full spectrum of molecular machinery.</p> <p>Conclusion</p> <p>We have performed a systematic survey of the transcriptional status of individual segments of the developing mouse hindbrain and identified hundreds of previously undescribed genes expressed in this region. The functional range of the potential candidate effectors or upstream modulators of Hox activity suggest multiple unexplored mechanisms. In particular, we present evidence of a potential new retinoic acid signalling system in ventral r4 and propose a model for the refinement of identity in this region. Furthermore, the rhombomeres demonstrate a molecular relationship to each other that is consistent with known observations about neurogenesis in the hindbrain. These findings give the first genome-wide insight into the complexity of gene expression during patterning of the developing hindbrain.</p

Occurrence and outcomes of possible superadded infections in older adults with COVID-19—cohort study

Purpose: Current guidance discourages use of antibiotics in COVID-19. However, in older adults, superadded infection may be common and require treatment. Our aim was to investigate the occurrence and outcomes from possible superadded infections, occurring within 2 weeks of hospitalization, in older adults with COVID-19. Methods: This was a single centre, observational cohort study. We collected data from patients admitted to older adult wards who had tested positive for the Sars-CoV-2 virus on viral PCR between 1st October and 1st December 2020. The primary outcome was inpatient death occurring within 90 days of COVID-19 diagnosis. The secondary outcome was length of stay in hospital. Associations were described using univariable and multivariable models, and time to event data. Results: Of 266 patients with COVID-19, 43% (115) had evidence of superadded infections (91 with positive bacterial cultures and 36 instances of radiological lobar consolidation). Patients with superadded infections were more likely to die (45.2 versus 30.7%, p = 0.020) and had an increased length of stay (23 versus 18 days, p = 0.026). Conclusions: Recommendations to avoid antibiotics in COVID-19 may not be applicable to an older adult population. Assessing for possible superadded infections is warranted in this group

Ulipristal acetate versus levonorgestrel-releasing intrauterine system for heavy menstrual bleeding (UCON) : a randomised controlled phase III trial

Acknowledgments This project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership (grant 12/206/52). Medical Research Council (MRC) Centre grants to the Centre for Reproductive Health (CRH) (G1002033 and MR/N022556/1) are also gratefully acknowledged. The views expressed in this publication are those of the authors and not necessarily those of the Medical Research Council, National Institute for Health Research, or Department of Health and Social Care. We thank our Collaborative Group (listed in the Supplementary Material) for their contribution to recruitment, randomisation and collection of data, and to our Trial Steering and Data Monitoring Committees (members listed in Supplementary Material).Peer reviewedPublisher PD

'Why don't you block them?' Police officers' constructions of the ideal victim when responding to reports of interpersonal cybercrime

This chapter explores police officers' responses to reports of interpersonal cybercrime by considering their construction of the 'ideal victim'. It contributes to knowledge on police officers' perceptions of cybercrime and their support for victims. The discussion draws on Nils Christie's (1986) concept of the 'ideal victim' to explore which individuals police officers most readily give the legitimate status of victim to. Three themes are discussed including: police officers' constructions of the 'ideal victim'; their attitudes towards victims in relation to prevention of cybercrime (i.e. 'block them') and; negotiations over responsibility for dealing with the emerging issue of cybercrime. The chapter argues that police forces must advance beyond an approach which entails victim-blaming and instead recognise the centrality of social media and online spaces in individuals' lives

Effects on heavy menstrual bleeding and pregnancy of uterine artery embolization (UAE) or myomectomy for women with uterine fibroids wishing to avoid hysterectomy: the FEMME randomized controlled trial

Objective: To determine treatment options (myomectomy vs uterine artery embolization [UAE]) for women wishing to avoid hysterectomy. Methods: A multicenter randomized controlled trial was conducted on 254 women and data were collected on fibroid-specific quality of life (UFS-QOL), loss of menstrual blood, and pregnancy. Results: At 4 years, the mean difference in the UFS-QOL was 5.0 points (95% confidence interval [CI] −1.4 to 11.5; P=0.13) in favor of myomectomy. This was not statistically significant as it was at 2 years. There were no differences in bleeding scores, rates of amenorrhea, or heavy bleeding. Of those who were still menstruating, the majority reported regular or fairly regular periods: 36 of 48 (75%) in the UAE group and 30 of 39 (77%) in the myomectomy group. Twelve women after UAE and six women after myomectomy became pregnant (4 years) with seven and five live births, respectively (hazard ratio 0.48, 95% CI 0.18–1.28). There was no difference between the levels of hormones associated with the uterine reserve in each group. Conclusion: Leiomyoma are common in reproductive-aged women, causing heavy menses and subfertility. Among women with uterine fibroids, myomectomy resulted in better fibroid-related quality of life at 4 years, compared with UAE but the treatments decreased menstrual bleeding equally. There was also no significant difference in the impact of treatment on ovarian reserve

Uterine artery embolization or myomectomy for women with uterine fibroids: Four-year follow-up of a randomised controlled trial

Objective: To examine the quality of life experienced by women with symptomatic uterine fibroids who had been treated with UAE in comparison to myomectomy. We report the four-year follow-up of the FEMME randomised trial. Two-year follow-up data has been previously reported. Study Design: Premenopausal women who had symptomatic uterine fibroids amenable to myomectomy or uterine artery embolization were recruited from 29 UK hospitals. Women were excluded if they had significant adenomyosis, any malignancy, pelvic inflammatory disease or had had a previous open myomectomy or uterine artery embolization. Participants were randomised to myomectomy or embolization in a 1:1 ratio using a minimisation algorithm. Myomectomy could be open abdominal, laparoscopic or hysteroscopic, according to clinician preference. Embolization of the uterine arteries was performed according to local practice, under fluoroscopic guidance. The primary outcome measure was the Uterine Fibroid Symptom Quality of Life questionnaire, adjusted for baseline score and reported here at four years post-randomisation. Subsequent procedures for fibroids, pregnancy and outcome were amongst secondary outcomes. Trial registration ISRCTN70772394 https://doi.org/10.1186/ISRCTN70772394 Results: 254 women were randomized, 127 to myomectomy (105 underwent myomectomy) and 127 to uterine artery embolization (98 underwent embolization). At four years, 67 (53%) and 81 (64%) completed UFS-QoL quality of life scores. Mean difference in the UFS-QoL at 4 years was 5.0 points (95% CI −1.4 to 11.5; p = 0.13) in favour of myomectomy. There were 15 pregnancies in the UAE group and 7 in the myomectomy group, with a cumulative pregnancy rate to four years of 15% and 6% respectively (hazard ratio: 0.48; 95% CI 0.18–1.28). The cumulative repeat procedure rate to four years was 24% in the UAE group and 13% in the myomectomy group (hazard ratio: 0.53; 95% CI 0.27–1.05). Conclusions: Myomectomy resulted in greater improvement in quality of life compared with uterine artery embolization, although by four years, this difference was not statistically significant. Missing data may limit the generalisability of this result. The numbers of women becoming pregnant were too small draw a conclusion on the effect of the procedures on fertility

A Randomized Trial of Progesterone in Women with Bleeding in Early Pregnancy

BACKGROUND Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. RESULTS A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P=0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P=0.08). The incidence of adverse events did not differ significantly between the groups. CONCLUSIONS Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439. opens in new tab.

Extensive Genetic Diversity, Unique Population Structure and Evidence of Genetic Exchange in the Sexually Transmitted Parasite Trichomonas vaginalis

The human parasite Trichomonas vaginalis causes trichomoniasis, the world's most common non-viral sexually transmitted infection. Research on T. vaginalis genetic diversity has been limited by a lack of appropriate genotyping tools. To address this problem, we recently published a panel of T. vaginalis-specific genetic markers; here we use these markers to genotype isolates collected from ten regions around the globe. We detect high levels of genetic diversity, infer a two-type population structure, identify clinically relevant differences between the two types, and uncover evidence of genetic exchange in what was believed to be a clonal organism. Together, these results greatly improve our understanding of the population genetics of T. vaginalis and provide insights into the possibility of genetic exchange in the parasite, with implications for the epidemiology and control of the disease. By taking into account the existence of different types and their unique characteristics, we can improve understanding of the wide range of symptoms that patients manifest and better implement appropriate drug treatment. In addition, by recognizing the possibility of genetic exchange, we are more equipped to address the growing concern of drug resistance and the mechanisms by which it may spread within parasite populations