Nucleic acid cytokine responses in obese children and infants of obese mothers

Almost a third of Irish children are now overweight and the country ranks 58th out of 200 countries for its proportion of overweight youths. With the rising obesity epidemic, and the impaired immune responses of this population, it is vital to understand the effects that obesity has on the immune system and to design future therapeutics, adjuvants and vaccines with overweight and obese populations in mind. Many current vaccines use adjuvants that have been found to be less effective at stimulating the immune response in children compared with adults and there is now substantial effort to design paediatric-focused adjuvants. Additionally, vaccine responses have been shown to be less effective in obese populations indicating that this is a particularly vulnerable population. We have recently identified cytosolic nucleic acids (CNAs), as novel candidate adjuvants for childhood vaccines. Here we investigated whether immune responses to these candidate adjuvants were adversely affected in infants born to overweight or obese mothers, and in overweight and obese children. Type I Interferon (IFN) and proinflammatory cytokines such as Tumor Necrosis Factor α (TNFα) are vital for driving innate and adaptive immune responses. We found that childhood obesity conferred no significant adverse effect on CNA-induced Type I IFN responses when compared with lean children. Similarly, Type I IFN responses were intact in the cord blood of babies delivered from overweight and obese mothers, when compared with lean mothers. There was also no significant impact of obesity on CNA-induced TNFα responses in children or from cord blood of infants born to overweight/obese mothers. In all cases, there was a tendency towards decreased production of innate cytokine Type I Interferon and TNFα, however there was no significant negative correlation. Interestingly, high maternal BMI showed weak and moderate positive correlation with IL-12p70 and IFNγ, respectively, in response to CNA stimulation. This study demonstrates that future adjuvants can be tailored for these populations through the use of activators of CNA sensors

Validation of online delivery of the Australian Pelvic Floor Questionnaire in an Irish obstetric population

Introduction and hypothesis: Childbirth remains an important risk factor for the development of pelvic floor disorders, regardless of the mode of delivery. To accurately assess these symptoms, accurate, woman-centric assessments are needed. Online versions of these assessments may be especially useful in the COVID-19 era. Women may potentially answer questions differently in an online format, and this study aimed to validate an online version of the paper-based self-administered Australian Pelvic Floor Questionnaire (APFQ). Methods: The questionnaire was completed antenatally and at 3 months postpartum by 647 and 481 women respectively. Test- validity was assessed in subgroups of 61 and 57 women in each period, using intraclass correlation coefficients and Cohen's kappa. Sensitivity to change was assessed by comparing responses during pregnancy to those at 3 months postpartum. Internal consistency was assessed using Cronbach's alpha. Construct validity was assessed by comparing women with and without subjective bothersomeness. Results: Intraclass correlation coefficients were above 0.9 for all domains and the overall questionnaire. Cohen's kappa for individual questions ranged from 0.71-1.00 across the antenatal and postnatal questionnaires. Cronbach's alpha was acceptable for all domains except the prolapse domain. The APFQ was sensitive to changes occurring between antenatal recruitment and 3 months postpartum. Effect sizes ranged from 0.83-7.99. Conclusions: This online version of the APFQ is valid for assessing pelvic floor disorders in an Irish obstetric population. The APFQ is reproducible and responsive to change occurring with childbirth, and can be used to research longitudinal changes in pelvic floor disorders. As an online tool, this questionnaire may be useful in increasing response rates to clinical research.</p

Antenatal urinary retention: risk factors, treatment, and effect on pelvic floor dysfunction

Objective: Physiological changes to the urinary tract begin early in the first trimester and continue throughout pregnancy. Bladder symptoms vary throughout pregnancy and can remain after the puerperium. Antenatal urinary retention is a severe form of pelvic floor dysfunction and research into this topic is sparse. Little is known about the longer-term effects of antenatal urinary retention on pelvic floor dysfunction. This study aimed to establish the incidence of and risk factors for antenatal urinary retention in our population, and whether this had any impact on pelvic floor dysfunction. Study design: This was a cross-sectional study. Women were included if they were currently pregnant when they required catheterisation-either indwelling, intermittent self-catheterisation or both. The Australian Pelvic Floor Questionnaire was posted to all women. No follow-up reminders were sent and any woman who did not return their questionnaire was recorded as a non-responder. Results: From January 2016 to December 2020, 41 women were identified as needing some form of catheterisation for treatment of antenatal urinary retention. During the same period, 44,646 women attended the National Maternity Hospital, giving an incidence of antenatal urinary retention of 0.92/1000 pregnancies. Questionnaire results were available for 25 women. One woman did not respond to one question, giving 99.9% complete data. The median (range) total pelvic floor score was 4.6 (0.2-10.7). Risk factors for antenatal urinary retention were identified in ten women. Most women denied any specific bladder symptoms, including difficulty in voiding and a feeling of incomplete emptying. Conclusions: Antenatal urinary retention is an uncommon form of pelvic floor dysfunction and occurs in 1-in-1000 pregnancies. Most women with antenatal urinary retention can be treated with an indwelling catheter for a short period, with only one in four women requiring intermittent self-catheterisation. Retention typically occurs in the late first and early second trimester, and while some risk factors have been identified, most women appear to have an uncomplicated pregnancy before developing acute urinary retention. Reassuringly, long-term pelvic floor dysfunction is minimal in women who experience antenatal urinary retention.</p

The efficacy and complications of retropubic tension-free vaginal tapes after 20 years: a prospective observational study

Objective: Long-term data regarding risks associated with tension-free vaginal tapes (TVT) are sparse, and where available are limited to small numbers. We analyse patient-reported outcomes of TVT after 16–24 years.  Design: Prospective observational study.  Setting: Single-centre study in a tertiary referral urogynaecology unit.  Population: A cohort of 350 women who had a TVT inserted between 1999 and 2004, in which 96% had urodynamically proven stress incontinence.  Methods: Postal questionnaire survey using the International Consultation on Incontinence Questionnaire, a visual analogue scale and a yes/no question as to whether they would have the procedure again.  Main outcome measures: The primary outcome was cure of stress urinary incontinence, which was assessed using the ICIQ-FLUTS questionnaire. Secondary outcomes included overactive bladder symptoms, pain, sexual dysfunction, and patient satisfaction with the procedure.  Results: A total of 183/350 (52%) responses were received. The median age of women at follow up was 67 years (range 53–93 years) and the median follow up was 20 years (17–24 years). Stress urinary incontinence was denied by 39.3% of women. Urgency was reported by 42.1%. Bladder pain was reported either ‘never’ or ‘occasionally’ by 92.3% of women. The median satisfaction rate was 98/100 and 92.4% said they would have the TVT procedure again.  Conclusions: Tension-free vaginal tape has high levels of satisfaction and cure up to 24 years after placement. Pain was uncommon and its impact on quality of life was low. Symptoms of urgency were prevalent but may be related to age. TVT is an effective treatment for SUI more than 20 years after initial placement.</p

Type 1 IFN Induction by Cytosolic Nucleic Acid Is Intact in Neonatal Mononuclear Cells, Contrasting Starkly with Neonatal Hyporesponsiveness to TLR Ligation Due to Independence from Endosome-Mediated IRF3 Activation

Two million infants die each year from infectious diseases before they reach 12 mo; many of these diseases are vaccine preventable in older populations. Pattern recognition receptors represent the critical front-line defense against pathogens. Evidence suggests that the innate immune system does not fully develop until puberty, contributing to impaired response to infection and impaired vaccine responses in neonates, infants, and children. The activity of the pattern recognition receptor family of cytosolic nucleic acid (CNA) sensors in this pediatric population has not been reported. We show that in direct contrast to weak TLR-induced type I IFN in human cord blood mononuclear cells, cord blood mononuclear cells are capable of initiating a potent response to CNA, inducing both antiviral type I IFN and, unexpectedly, proinflammatory TNF-a. A deficiency in Rab11-GTPase endosome formation and consequent lack of IRF3 activation in neonatal monocytes is at least in part responsible for the marked disparity in TLR-induced IFN production between neonatal and adult monocytes. CNA receptors do not rely on endosome formation, and therefore, these responses remain intact in neonates. Heightened neonatal responses to CNA challenge are maintained in children up to 2 y of age and, in marked contrast to TLR4/9 agonists, result in IL-12p70 and IFN-g generation. CNA sensors induce robust antiviral and proinflammatory pathways in neonates and children and possess great potential for use as immunostimulants or vaccine adjuvants for targeted neonatal and pediatric populations to promote cell-mediated immunity against invasive infectious disease