Cytosolic dsRNA improves neonatal innate immune responses to adjuvants in use in pediatric vaccines.

Pattern recognition receptors (PRRs) of the innate immune system represent the critical front-line defense against pathogens, and new vaccine formulations target these PRR pathways to boost vaccine responses, through activation of cellular/Th1 immunity. The majority of pediatric vaccines contain aluminum (ALUM) or monophosphoryl lipid A (MPLA) as adjuvants to encourage immune activation. Evidence suggests that elements of the innate immune system, currently being targeted for vaccine adjuvanticity do not fully develop until puberty and it is likely that effective adjuvants for the neonatal and pediatric populations are being overlooked due to modeling of responses in adult systems. We recently reported that the activity of the cytosolic nucleic acid (CNA) sensing family of PRRs is strong in cord blood and peripheral blood of young children. This study investigates the function of CNA sensors in subsets of neonatal innate immune cells and shows that myeloid cells from cord blood can be activated to express T cell costimulatory markers, and also to produce Th1 promoting cytokines. CD80 and CD86 were consistently up-regulated in response to cytosolic Poly(I:C) stimulation in all cell types examined and CNA activation also induced robust Type I IFN and low levels of TNFα in monocytes, monocyte-derived macrophages, and monocyte-derived dendritic cells. We have compared CNA activation to adjuvants currently in use (MPLA or ALUM), either alone or in combination and found that cytosolic Poly(I:C) in combination with MPLA or ALUM can improve expression of activation marker levels above those observed with either adjuvant alone. This may prove particularly promising in the context of improving the efficacy of existing ALUM- or MPLA-containing vaccines, through activation of T cell-mediated immunity.

The impact of the CervicalCheck controversy on provision of colposcopy services in Ireland: A cohort study.

OBJECTIVES: In 2018, an inquiry into the Irish Cervical Cancer screening programme (CervicalCheck) was initiated, following publicised cases of non-disclosure regarding internal audit results of cytology screening in women diagnosed with cervical cancer. The inquiry attracted widespread media coverage and the government offered women free, out of programme screening. We investigated whether the controversy led to an increase in referrals based on clinical suspicion and the impact on waiting times for abnormal cytology. STUDY DESIGN: A retrospective cross-sectional analysis was performed, including all colposcopy referrals to The National Maternity Hospital, Dublin, before (March 2016-2018) and after (March 2018-2020) the media coverage. Chi-squared (χ2) and independent one-tailed t-tests were used to perform between-group analyses. RESULTS: Post-controversy, suspicious cervix referrals increased (10.1 %-14.2 %; p = 0.037 × 10-27), as did colposcopic impression of CIN (p = 0.000000016). While an increase in CIN1 histology (18.5 %-30.3 %) was diagnosed, a decrease in high-risk CIN2 (10 % to 8.6 %), CIN3 (6.2 % to 2.9 %), AIS (1.2 % to 0.3 %) and invasive cancer (2.8 % to 1.2 %; p = 0.0058 × 10-9) were diagnosed. Across all grades of cytological abnormality, significantly fewer patients were reviewed in the recommended waiting time post-controversy. Half of delayed abnormal cytology referrals had high-grade changes. CONCLUSIONS: This study highlights the profound impact that the CervicalCheck Controversy had on the women attending colposcopy and clinicians performing the screening tests, and the direct impact on women with confirmed cytological abnormalities. The increase in suspicious cervix referrals reflects a lack of confidence in both clinical practice and screening test results. The importance of public trust in the effective delivery of screening services cannot be ignored. Increased resources are required to ensure all women are seen within recommended time frames. Heightened anxiety and increased surveillance does not necessarily lead to better clinical outcomes for patients but can result in unnecessary distress for low-risk patients and delays to diagnosis for high-risk patients with concerning abnormalities.

White matter alterations in patients with MRI-negative temporal lobe epilepsy and their asymptomatic siblings.

OBJECTIVE: The identification of "endophenotypes"-measurable variations along the pathways between genes and distal disease state-may help deconstruct focal epilepsies into more sensitive phenomena and improve future efforts to map the genetic underpinnings of the disorder. In this study, we set out to determine if diffusion tensor imaging (DTI)-inferred white matter (WM) alterations represent a suitable structural endophenotype for focal epilepsy. METHODS: We recruited 25 patients with sporadic mesial temporal lobe epilepsy (MTLE) with normal magnetic resonance imaging (MRI) findings, 25 of their gender-matched, asymptomatic siblings, and 60 control subjects. Whole-brain, voxelwise statistics were conducted to identify regions of microstructural degeneration in patients with MTLE and/or their asymptomatic siblings. WM tracts exhibiting evidence of microstructural disruption were then reconstructed using deterministic tractography. Diffusion metrics including fractional anisotropy (FA) and mean diffusivity (MD) were compared across groups using a series of one-way multivariate analyses of covariance (MANCOVAs). RESULTS: Voxelwise statistics revealed significant FA reductions in the corpus callosum (CC), bilateral superior longitudinal fasciculi (SLF), bilateral inferior longitudinal fasciculi (ILF), and left corticospinal tract (CST) in MTLE patients only. MD increases were observed in MTLE patients and their asymptomatic siblings in the left SLF and left CST. Deterministic tractography supported the voxelwise results, revealing significant FA alterations in the left SLF and CST in patients only and significant MD alterations in MTLE patients and their unaffected siblings. The diffusion scalars of MTLE patients and their asymptomatic siblings were highly correlated in the SLF and CST ipsilateral to patients' sides of seizure onset. SIGNIFICANCE: These findings confirm the presence of microstructural WM alterations in patients with MRI-negative MTLE and provide preliminary support for a diffusion-based endophenotype in the disorder. Further studies of narrow-sense heritability in larger cohorts of first-degree relatives of MTLE patients are required to confirm these results.

Default mode network connectivity distinguishes chemotherapy-treated breast cancer survivors from controls.

Breast cancer (BC) chemotherapy is associated with cognitive changes including persistent deficits in some individuals. We tested the accuracy of default mode network (DMN) resting state functional connectivity patterns in discriminating chemotherapy treated (C+) from non-chemotherapy (C-) treated BC survivors and healthy controls (HC). We also examined the relationship between DMN connectivity patterns and cognitive function. Multivariate pattern analysis was used to classify 30 C+, 27 C-, and 24 HC, which showed significant accuracy for discriminating C+ from C- (91.23%, P < 0.0001) and C+ from HC (90.74%, P < 0.0001). The C- group did not differ significantly from HC (47.06%, P = 0.60). Lower subjective memory function was correlated (P < 0.002) with greater hyperplane distance (distance from the linear decision function that optimally separates the groups). Disrupted DMN connectivity may help explain long-term cognitive difficulties following BC chemotherapy.

Understanding and meeting the needs of the older population: a global challenge.

BACKGROUND: In the past century, there has been a significant rise in life expectancy in almost all regions of the world, contributing to an increasingly older population. The aging of the population, in conjunction with urbanization and industrialization, has resulted in an important epidemiological transition marked by a widespread increase in the prevalence of chronic diseases and their sequelae. Current trends suggest that the transition will have a greater impact on developing countries compared to developed countries. An adequate response to the transition requires a strong emphasis on primary prevention and adequate resource allocation.