Towards the adoption of quantitative computed tomography in the management of interstitial lung disease.

The shortcomings of qualitative visual assessment have led to the development of computer-based tools to characterise and quantify disease on high-resolution computed tomography (HRCT) in patients with interstitial lung diseases (ILDs). Quantitative CT (QCT) software enables quantification of patterns on HRCT with results that are objective, reproducible, sensitive to change and predictive of disease progression. Applications developed to provide a diagnosis or pattern classification are mainly based on artificial intelligence. Deep learning, which identifies patterns in high-dimensional data and maps them to segmentations or outcomes, can be used to identify the imaging patterns that most accurately predict disease progression. Optimisation of QCT software will require the implementation of protocol standards to generate data of sufficient quality for use in computerised applications and the identification of diagnostic, imaging and physiological features that are robustly associated with mortality for use as anchors in the development of algorithms. Consortia such as the Open Source Imaging Consortium have a key role to play in the collation of imaging and clinical data that can be used to identify digital imaging biomarkers that inform diagnosis, prognosis and response to therapy.

[Formula: see text] Neural and behavioral indicators of cognitive control in preschoolers with and without prenatal opioid exposure.

Prenatal opioid exposure is one consequence of the opioid epidemic, but effects on child development remain poorly understood. There is emerging evidence that children exposed to opioids in utero exhibit elevated emotional and behavioral problems, which may be partially due to alterations in cognitive control. Using multiple methods (i.e., neuropsychological, behavioral, and event-related potential [ERP] assessments), the present study examined differences in emotional, behavioral, and cognitive control difficulties in preschool-aged children with (n = 21) and without (n = 23) prenatal opioid exposure (Mage = 4.30, SD = 0.77 years). Child emotional and behavioral problems were measured with a caregiver questionnaire, indicators of cognitive control were measured using developmentally appropriate behavioral (i.e., delay discounting, Go/No-Go) and neuropsychological (i.e., Statue) tasks, and electroencephalogram was recorded to error and correct responses in a Go/No-Go task. ERP analyses focused on the error-related negativity (ERN), an ERP that reflects error monitoring, and correct-response negativity (CRN), a component reflecting performance monitoring more generally. Opioid exposure was associated with elevated difficulties across domains and a blunted ERN, reflecting altered cognitive control at the neural level, but groups did not significantly differ on behavioral measures of cognitive control. These result replicate prior studies indicating an association between prenatal opioid exposure and behavioral problems in preschool-aged children. Further, our findings suggest these differences may be partially due to children with prenatal opioid exposure exhibiting difficulties with cognitive control at the neural level. The ERN is a potential target for future research and intervention efforts to address the sequelae of prenatal opioid exposure.

Neural reactivity to infant emotion cues during pregnancy: Associations with peripartum anxiety and depressive symptoms.

BACKGROUND: Pregnancy is marked by physiological and psychosocial changes for women, and event-related potentials (ERP) are comfortable and safe for examining brain function across pregnancy. The late positive potential (LPP) ERP, a measure of allocated attention to emotional stimuli, may provide insight into associations between internalizing symptoms and neural processing of infant emotion cues, which may be particularly salient in this life stage. METHODS: We developed a task to examine neural and behavioral responses to infant faces in pregnant women (N = 120, Mage=31.09, SD=4.81), the impact of auditory infant cries on the LPP to faces, and associations between the LPP and anxiety and depressive symptoms. Participants matched distressed, happy, and neutral infant faces and shapes as a comparison condition with interspersed auditory conditions (infant cry sounds vs. white noise) while electroencephalogram data were collected. Participants also completed self-report measures of anxiety and depressive symptoms. RESULTS: Reaction time (RT) was faster for the infant cry vs. white noise condition and when matching shapes vs. infant faces. Depressive symptoms were associated with slower RTs to neutral infant faces. The LPP was enhanced overall to faces vs. shapes, but there was no main effect of auditory condition. Anxiety symptoms were associated with an enhanced LPP to infant distressed faces in the infant cry condition. CONCLUSIONS: Results support these methods for measuring neural and behavioral responses to infant emotional cues in pregnancy and provide evidence that combinations of auditory and visual stimuli may be particularly useful for capturing emotional processes relevant to anxiety.

Prenatal stress exposure and multimodal assessment of amygdala-medial prefrontal cortex connectivity in infants.

Stressful experiences are linked to neurodevelopment. There is growing interest in the role of stress in the connectivity between the amygdala and medial prefrontal cortex (mPFC), a circuit that subserves automatic emotion regulation. However, the specific timing and mechanisms that underlie the association between stress and amygdala-mPFC connectivity are unclear. Many factors, including variations in fetal exposure to maternal stress, appear to affect early developing brain circuitry. However, few studies have examined the associations of stress and amygdala-mPFC connectivity in early life, when the brain is most plastic and sensitive to environmental influence. In this longitudinal pilot study, we characterized the association between prenatal stress and amygdala-mPFC connectivity in young infants (approximately age 5 weeks). A final sample of 33 women who provided data on preconception and prenatal stress during their pregnancy returned with their offspring for a magnetic resonance imaging scan session, which enabled us to characterize amygdala-mPFC structural and functional connectivity as a function of prenatal stress. Increased prenatal stress was associated with decreased functional connectivity and increased structural connectivity between the amygdala and mPFC. These results provide insight into the influence of prenatal maternal stress on the early development of this critical regulatory circuitry.

TLR2 signaling improves immunoregulation to prevent type 1 diabetes.

Signaling through TLR2 promotes inflammation and modulates CD4(+) CD25(+) Tregs. We assessed mechanistically how this molecule would alter immunoregulation in type 1 diabetes (T1D). We also asked whether TLR2 may be involved in our recent discovery that viral infection can protect from autoimmune diabetes by expanding and invigorating Tregs. Treatment of prediabetic mice with a synthetic TLR2 agonist diminished T1D and increased the number and function of CD4(+) CD25(+) Tregs, also conferring DCs with tolerogenic properties. TLR2 ligation also promoted the expansion of Tregs upon culture with DCs and ameliorated their capacity to prevent the disease. Protection from T1D by lymphocytic choriomeningitis virus (LCMV) infection depended on TLR2. LCMV increased the frequency of CD4(+) CD25(+) Tregs and their production of TGF-ß more significantly in WT than TLR2-deficient mice. Furthermore, LCMV infection in vivo or LCMV-infected DCs in vitro rendered, via TLR2, CD4(+) CD25(+) Tregs capable of diminishing T1D. We identify novel mechanisms by which TLR2 promotes immunoregulation and controls autoimmune diabetes in naïve or infected hosts. This work should help understand T1D etiology and develop novel immune-based therapeutic interventions.

Essential role for TLR9 in prime but not prime-boost plasmid DNA vaccination to activate dendritic cells and protect from lethal viral infection.

One of the requirements for efficient vaccination against infection is to achieve the best combination of an adequate adjuvant with the antigenic information to deliver. Although plasmid DNA is a promising tool bearing the unique potential to activate humoral and cellular immunity, an actual challenge is to increase plasmid immunogenicity in human vaccination protocols in which efficacy has proven rather limited. Previous work showed that the bacterial DNA backbone of the plasmid has potent adjuvant properties because it contains CpG motifs that are particular activating nucleotidic sequences. Among TLRs, which are key sensors of microbial products, TLR9 can detect CpG motifs and confer activation of APCs, such as dendritic cells. However, whether the immunogenic properties of plasmid DNA involve TLR9 signaling has not been clearly established. In the current study, we demonstrate that TLR9 determines the effectiveness of vaccination against lethal lymphocytic choriomeningitis virus infection using plasmid DNA in a prime, but not prime-boost, vaccination regimen. Furthermore, we provide evidence that the presence of TLR9 in dendritic cells is necessary for effective and functional priming of virus-specific CD8+ T cells upon plasmid exposure in vitro or single-dose vaccination in vivo. Therefore, at single or low vaccine doses that are often used in human-vaccination protocols, CpG/TLR9 interactions participate in the immunogenicity of plasmid DNA. These results suggest that the TLR9 signaling pathway is involved in the efficacy of plasmid vaccination; therefore, it should remain a focus in the development or amelioration of vaccines to treat infections in humans.

Immunoregulatory mechanisms triggered by viral infections protect from type 1 diabetes in mice.

Type 1 diabetes (T1D) is an autoimmune disease that is caused by the destruction of insulin-producing beta cells. Viral infections induce immune responses that can damage beta cells and promote T1D or on the other hand prevent the development of the disease. However, the opposing roles of viral infections in T1D are not understood mechanistically. We report here that viruses that do not inflict damage on beta cells provided protection from T1D by triggering immunoregulatory mechanisms. Infection of prediabetic NOD mice with Coxsackie virus B3 or lymphocytic choriomeningitis virus (LCMV) delayed diabetes onset and reduced disease incidence. Delayed T1D onset was due to transient upregulation of programmed cell death-1 ligand 1 (PD-L1) on lymphoid cells, which prevented the expansion of diabetogenic CD8+ T cells expressing programmed cell death-1 (PD-1). Reduced T1D incidence was caused by increased numbers of invigorated CD4+CD25+ Tregs, which produced TGF-beta and maintained long-term tolerance. Full protection from T1D resulted from synergy between PD-L1 and CD4+CD25+ Tregs. Our results provide what we believe to be novel mechanistic insight into the role of viruses in T1D and should be valuable for prospective studies in humans.