Targets For Early Intervention Research Articles

A systematic review and meta-analysis of loss-of-control eating in relation to cardiometabolic health components and inflammatory markers.

Loss-of-control (LOC) eating, or the subjective experience of being unable to stop eating, is a hallmark feature of binge-eating episodes, which are also characterized by consuming an unusually large amount of food. However, regardless of the size of eating episode, LOC-eating may be a risk factor for adverse health outcomes. This systematic review and meta-analysis comprehensively examine the relationship of LOC-eating with cardiometabolic health components and inflammatory markers. Search procedures were conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines in six electronic databases. Studies of adult or youth samples published in English from the year 2000 onward were included. Given heterogeneity in age groups and adjustment for body mass index across studies, these factors were included as meta-regression moderators. Fifty-eight studies were identified through the literature search. Among individuals with (versus without) LOC-eating, relative risk ratios provided evidence of a greater relative risk for metabolic syndrome, hypertension, and dyslipidemia; standardized mean differences also provided evidence of higher waist circumference and impaired levels of fasting plasma glucose, high-density lipoprotein (HDL)-cholesterol, and triglycerides, but not blood pressure. Age group did not impact cardiometabolic health components. Body mass index differences moderated the effect on waist circumference. A narrative review of inflammatory markers revealed mixed findings linking inflammatory markers to LOC-eating. Overall, evidence for the relationship between LOC-eating and impaired cardiometabolic health underscores LOC-eating as an important early intervention target for prevention of serious adverse health outcomes.

Lateral Thinking: Pathway Specific Neurodegeneration of the Cortical Cholinergic System in Alzheimer's Disease.

Atrophy of the nucleus basalis of Meynert (NBM) is an early indicator of Alzheimer's disease (AD). However, reduced integrity of the NBM white matter tracts may be more relevant for cognitive impairment and progression to dementia than NBM volume. Research is needed to compare differences in NBM volume and integrity of the lateral and medial NBM tracts across early and later stages of AD progression. 187 participants were included in this study who were either healthy controls (HC; n=50) or had early mild cognitive impairment (EMCI; n=50), late MCI (LMCI; n=37), or AD (n=50). NBM volume was calculated using voxel-based morphometry and mean diffusivity (MD) of the lateral and medial NBM tracts were extracted using probabilistic tractography. Between group differences in NBM volume and tract MD were compared using linear mixed models controlling for age, sex, and either total intracranial volume or MD of a control mask, respectively. Associations between NBM volume and tract MD with executive function, memory, language, and visuospatial function were also analysed. NBM volume was smallest in AD followed by LMCI (p<0.0001), with no difference between EMCI and HC. AD had highest MD for both tracts compared to all other groups (p<0.001). Both MCI groups had higher lateral tract MD compared to HC (p<0.05). Medial tract MD was higher in LMCI (p=0.008), but not EMCI (p=0.09) compared to HC. Higher lateral tract MD was associated with executive function (p=0.001) and language (p=0.02). Integrity of the lateral NBM tract is most sensitive to the earliest stages of AD and should be considered an important therapeutic target for early detection and intervention.

Gene Coexpression and miRNA Regulation: A Path to Early Intervention in Colorectal Cancer.

Early diagnosis and intervention are pivotal in reducing colorectal cancer (CRC) incidence and enhancing patient outcomes. In this study, we focused on three genes, AQP8, GUCA2B, and SPIB, which exhibit high coexpression and play crucial roles in suppressing early-stage CRC. Our objective was to identify key miRNAs that can mitigate CRC tumorigenesis and modulate the coexpression network involving these genes. We conducted a comprehensive analysis using large-scale tissue mRNA data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus to validate the coexpression of AQP8, GUCA2B, and SPIB, and to assess their diagnostic and prognostic significance in CRC. The mRNA-miRNA interactions were examined using MiRNet and the Encyclopedia of RNA Interactomes. Furthermore, using various molecular techniques, we conducted miRNA inhibitor transfection experiments in HCT116 cells to evaluate their effects on cell growth, migration, and gene/protein expression. Our findings revealed that, compared with normal tissues, AQP8, GUCA2B, and SPIB exhibited high coexpression and were downregulated in CRC, particularly during tumorigenesis. OncoMirs, hsa-miR-182-5p, and hsa-miR-27a-3p, were predicted to regulate these genes. MiRNA inhibition experiments in HCT116 cells demonstrated the inhibitory effects of miR-27a-3p and miR-182-5p on GUCA2B mRNA and protein expression. These miRNAs promoted the proliferation of CRC cells, possibly through their involvement in the GUCA2B-GUCY2C axis, which is known to promote tumor growth. While the expressions of AQP8 and SPIB were barely detectable, their regulatory relationship with hsa-miR-182-5p remained inconclusive. Our study confirms that hsa-miR-27a-3p and hsa-miR-182-5p are oncomiRs in CRC. These miRNAs may contribute to GUCY2C dysregulation by downregulating GUCA2B, which encodes uroguanylin. Consequently, hsa-miR-182-5p and hsa-miR-27a-3p show promise as potential targets for early intervention and treatment in the early stages of CRC.

Osteocalcin: A novel biomarker of adolescent psychopathology

Osteocalcin is a bone-derived hormone implicated in the acute stress response and recently linked to adult depression. Yet it is unclear whether osteocalcin is a biomarker of other forms of psychopathology and whether osteocalcin-psychopathology associations emerge during developmentally sensitive periods earlier in life. Thus, in the current pilot study we examined salivary osteocalcin and psychiatric symptoms and disorders among 48 early adolescents during a period of stress. A logistic regression indicated lower osteocalcin was associated with meeting criteria for a psychiatric disorder, OR = 0.43, 95% CI [.002,.924], and showed moderate-to-large cross-sectional associations with a range of elevated psychopathology symptoms, Bs ≥ |-3.44|, ps ≤.034. Multilevel linear growth models indicated that low osteocalcin prospectively predicted an even greater range of psychopathology symptoms at one-year follow-up as well as increases in some symptoms over time, Bs ≥ |-1.83|, ps ≤.021. Findings introduce osteocalcin as a biomarker of diverse forms of psychopathology in youth. Osteocalcin is a potential transdiagnostic mechanism through which dysregulated responses to stress could cause or exacerbate various types of psychopathology, highlighting a promising target for clinical assessment and early intervention.

NHANES 2011-2014: Objective Physical Activity is the Strongest Predictor of All-Cause Mortality.

Objectively measured physical activity (PA) is a modifiable risk factor for mortality. Understanding the predictive performance of PA is essential to establish potential targets for early intervention to reduce mortality among older adults. The study used a subset of the National Health and Nutrition Examination Survey (NHANES) 2011-2014 data consisting of participants aged 50 to 80 years old (n = 3653, 24297.5 person-years of follow-up, 416 deaths). Eight accelerometry derived features and 14 traditional predictors of all-cause mortality were compared and ranked in terms of their individual and combined predictive performance using the 10-fold cross-validated Concordance (C) from Cox regression. The top three predictors of mortality in univariate analysis were PA related: average MIMS in the 10 most active hours (C = 0.697), total MIMS per day (C = 0.686), and average log transformed MIMS in the most 10 active hours of the day (C = 0.684), outperforming age (C = 0.676) and other traditional predictors of mortality. In multivariate regression, adding objectively measured PA to the top performing model without PA variables increased concordance from C = 0.776 to C = 0.790 (p < 0.001). These findings highlight the importance of PA as a risk marker of mortality and are consistent with prior studies, confirming the importance of accelerometer-derived activity measures beyond total volume.

Association of Clinical Factors with the Development of GDM in the Hoosier Mom’s Cohort

Introduction: Gestational diabetes mellitus (GDM) develops during pregnancy, raising the risk of adverse perinatal outcomes. The objective of this study was to investigate potential therapeutic targets for prepregnancy and early pregnancy interventions to decrease the impact of GDM on health during and after pregnancy. Methods: The Hoosier Mom’s Cohort was a prospective pregnancy cohort designed to assess for predictors of GDM. Inclusion criteria were gestational age &lt;20 weeks, a singleton pregnancy, and being at least 18 years old. Individuals with a pregestational diabetes diagnosis, HbA1c at screening of ≥6.5, or abnormal 3-hour oral glucose tolerance test before 20 weeks of gestation were excluded. Study visits with survey completion and biospecimen collection occurred, one at enrollment, and one in the early third trimester. All participants were given a Garmin activity tracker to collect objective physical activity and sleep data. Sociodemographic, medical, behavioral, and psychosocial characteristics were obtained, and obstetric outcomes were abstracted after delivery by certified chart abstractors. The primary outcome was development of GDM. Associations between categorical variables and GDM were made with Chi-square testing, and those between continuous variables and GDM were done with t-test. Results: Of 411 participants recruited into the Hoosier Moms Cohort, complete data was available for 391 (95.1%). Participants had a mean age of 30 years, a BMI of 28, and 17% were of Hispanic ethnicity. Study participants self-identified mostly as White (71%) or Black (16%). 66% of participants were nulliparous. Additionally, 54% reported a family history of diabetes, with 4% of patients also reporting a prior history of GDM. A total of 39 participants (10.0%) developed GDM. Participants who developed GDM had significantly higher BMI at study entry (31.6 ±8.5 vs 27.2 ±6.5, p=0.003), lower probability of being nulliparous (15.38% vs 33.61%, p=0.02), higher baseline HbA1c values (5.24 ±0.3 vs 5.07 ±0.3, p&lt;0.001), higher triglycerides levels (156.85 ±62 vs 134.16 ±54.5, p=0.022), and higher blood glucose values (85.90 ±14.4 vs 79.96 ±17.7, p=0.025) at first study visit. Additionally, 28% of participants who developed GDM had a prior history of GDM, compared to 2% of participants who did not (p&lt;0.0001). Those who developed GDM had higher rates of chronic hypertension (12.82% vs 1.96%, p=0.0034) and higher insomnia scores (9.62 ±5.1 vs 7.80 ±4.7, p=0.028). Conclusion/ Implications: Multiple clinical factors were found to be statistically associated with the development of GDM. These characteristics will be utilized in a comprehensive predictive model using machine learning methodologies to guide clinical decisions early in pregnancy.

Autophagy activated by GR/miR-421-3p/mTOR pathway as a compensatory mechanism participates in chondrodysplasia induced by prenatal caffeine exposure in male fetal rats

Autophagy has been implicated in the developmental toxicity of multiple organs in offspring caused by adverse environmental conditions during pregnancy. We have previously found that prenatal caffeine exposure (PCE) can cause fetal overexposure to maternal glucocorticoids, leading to chondrodysplasia. However, whether autophagy is involved and what role it plays has not been reported. In this study, a PCE rat model was established by gavage of caffeine (120mg/kg.d) on gestational day 9-20. The results showed that reduced cartilage matrix synthesis in male fetal rats in the PCE group was accompanied by increased autophagy compared to the control group. Furthermore, the expression of mTOR, miR-421-3p, and glucocorticoid receptor (GR) in male fetal rat cartilage of PCE group was increased. At the cellular level, we confirmed that corticosterone inhibited matrix synthesis in fetal chondrocytes while increasing autophagic flux. However, administration of autophagy enhancer (rapamycin) or inhibitor (bafilomycin A1 or 3-methyladenine) partially increased or further decreased aggrecan expression respectively. At the same time, we found that corticosterone could increase the expression of miR-421-3p through GR and target to inhibit the expression of mTOR, thereby enhancing autophagy. In conclusion, PCE can cause chondrodysplasia and autophagy enhancement in male fetal rats. Intrauterine high corticosterone activates GR/miR-421-3p signaling and down-regulates mTOR signaling in fetal chondrocytes, resulting in enhanced autophagy, which can partially compensate for corticosterone-induced fetal chondrodysplasia. This study confirmed the compensatory protective effect of autophagy on the developmental toxicity of fetal cartilage induced by PCE and its epigenetic mechanism, providing novel insights for exploring the early intervention and therapeutic target of fetal-originated osteoarthritis.

Post-transcriptional dysregulation in autism, schizophrenia, and bipolar disorder.

The alteration of gene expression is not restricted to transcriptional regulation but includes a variety of post-transcriptional mechanisms, however, the role of the latter underlying many diseases remains relatively unknown. By utilizing an RNA-Seq dataset of 1510 brain samples from individuals with autism spectrum disorder (ASD), bipolar disorder (BD), schizophrenia (SCZ), and controls, we assessed the contribution of post-transcriptional dysregulation and identified top perturbators accountable for transcriptomic changes of expression in neuropsychiatric disorders. Around 30% of the variability in expression can be attributed to post-transcriptional dysregulation. Interestingly, RNA stability tended to decrease in SCZ and BD, leading to the inhibition of neurogenesis and neural differentiation, while the increase in ASD, resulted in enhanced activity of apoptosis. This finding implicated contrasting pathologies involving RNA stability among neuropsychiatric disorders. An RNA binding protein (RBP)-ELAVL3 - is predicted to be significantly involved in the disruption of RNA stability in all three disorders. To validate, we knocked down its expression in cerebral organoids. Not only differentially expressed genes in ELAVL3-knockdown covered a considerable proportion of predicted targets in three disorders, we also found neurogenesis was significantly affected, given the diminished proliferation and consequently the reduced size of the organoids. Our study extends the current understanding of the link between post-transcriptional regulation and neuropsychiatric disorders and provides new therapeutic targets for early intervention.

Identification of blood exosomal metabolomic profiling for high-altitude cerebral edema

High-altitude cerebral edema (HACE) is a severe neurological condition that can occur at high altitudes. It is characterized by the accumulation of fluid in the brain, leading to a range of symptoms, including severe headache, confusion, loss of coordination, and even coma and death. Exosomes play a crucial role in intercellular communication, and their contents have been found to change in various diseases. This study analyzed the metabolomic characteristics of blood exosomes from HACE patients compared to those from healthy controls (HCs) with the aim of identifying specific metabolites or metabolic pathways associated with the development of HACE conditions. A total of 21 HACE patients and 21 healthy controls were recruited for this study. Comprehensive metabolomic profiling of the serum exosome samples was conducted using ultraperformance liquid chromatography–tandem mass spectrometry (UPLC‒MS/MS). Additionally, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was performed to identify the metabolic pathways affected in HACE patients. Twenty-six metabolites, including ( +)-camphoric acid, choline, adenosine, adenosine 5′-monophosphate, deoxyguanosine 5′-monophosphate, guanosine, and hypoxanthine-9-β-D-arabinofuranoside, among others, exhibited significant changes in expression in HACE patients compared to HCs. Additionally, these differentially abundant metabolites were confirmed to be potential biomarkers for HACE. KEGG pathway enrichment analysis revealed several pathways that significantly affect energy metabolism regulation (such as purine metabolism, thermogenesis, and nucleotide metabolism), estrogen-related pathways (the estrogen signaling pathway, GnRH signaling pathway, and GnRH pathway), cyclic nucleotide signaling pathways (the cGMP-PKG signaling pathway and cAMP signaling pathway), and hormone synthesis and secretion pathways (renin secretion, parathyroid hormone synthesis, secretion and action, and aldosterone synthesis and secretion). In patients with HACE, adenosine, guanosine, and hypoxanthine-9-β-D-arabinofuranoside were negatively correlated with height. Deoxyguanosine 5′-monophosphate is negatively correlated with weight and BMI. Additionally, LPE (18:2/0:0) and pregnanetriol were positively correlated with age. This study identified potential biomarkers for HACE and provided valuable insights into the underlying metabolic mechanisms of this disease. These findings may lead to potential targets for early diagnosis and therapeutic intervention in HACE patients.

Multiomics approach towards characterization of tumor cell plasticity and its significance in precision and personalized medicine.

Cellular plasticity refers to the ability of cells to change their identity or behavior, which can be advantageous in some cases (e.g., tissue regeneration) but detrimental in others (e.g., cancer metastasis). With a better understanding of cellular plasticity, the complexity of cancer cells, their heterogeneity, and their role in metastasis is being unraveled. The plasticity of the cells could also prove as a nemesis to their characterization. In this review, we have attempted to highlight the possibilities and benefits of using multiomics approach in characterizing the plastic nature of cancer cells. There is a need to integrate fragmented evidence at different levels of cellular organization (DNA, RNA, protein, metabolite, epigenetics, etc.) to facilitate the characterization of different forms of plasticity and cell types. We have discussed the role of cellular plasticity in generating intra-tumor heterogeneity. Different omics level evidence is being provided to highlight the variety of molecular determinants discovered using different techniques. Attempts have been made to integrate some of this information to provide a quantitative assessment and scoring of the plastic nature of the cells. However, there is a huge gap in our understanding of mechanisms that lead to the observed heterogeneity. Understanding of these mechanism(s) is necessary for finding targets for early detection and effective therapeutic interventions in metastasis. Targeting cellular plasticity is akin to neutralizing a moving target. Along with the advancements in precision and personalized medicine, these efforts may translate into better clinical outcomes for cancer patients, especially in metastatic stages.

Amygdala neuronal dyshomeostasis via 5-HT receptors mediates mood and cognitive defects in Alzheimer's disease.

Behavioral changes or neuropsychiatric symptoms (NPSs) are common features in dementia and are associated with accelerated cognitive impairment and earlier deaths. However, how NPSs are intertwined with cognitive decline remains elusive. In this study, we identify that the basolateral amygdala (BLA) is a key brain region that is associated with mood disorders and memory decline in the AD course. During the process from pre- to post-onset in AD, the dysfunction of parvalbumin (PV) interneurons and pyramidal neurons in the amygdala leads to hyperactivity of pyramidal neurons in the basal state and insensitivity to external stimuli. We further demonstrate that serotonin (5-HT) receptors in distinct neurons synergistically regulate the BLA microcircuit of AD rather than 5-HT levels, in which both restrained inhibitory inputs by excessive 5-HT1AR signaling in PV interneurons and depolarized pyramidal neurons via upregulated 5-HT2AR contribute to aberrant neuronal hyperactivity. Downregulation of these two 5-HT receptors simultaneously enables neurons to resist β-amyloid peptides (Aβ) neurotoxicity and ameliorates the mood and cognitive defects. Therefore, our study reveals a crucial role of 5-HT receptors for regulating neuronal homeostasis in AD pathogenesis, and this would provide early intervention and potential targets for AD cognitive decline.

Examining the relationship between emotion regulation, sleep quality, and anxiety disorder diagnosis

Anxiety disorders are highly comorbid with sleep disturbance and have also been associated with deficits in emotion regulation, the ability to control and express emotions. However, the extent to which specific dimensions of sleep disturbance and emotion regulation are associated with anxiety diagnosis is not well-explored. This study examined dimensions of emotion regulation and sleep disturbance that may predict greater likelihood of anxiety diagnosis using novel machine learning techniques. Participants (Mean(SD) age= 28.6(11.3) years, 62.7% female) with primary anxiety disorders (n = 257), including generalized anxiety disorder (n = 122) and social anxiety disorder (n = 135), and healthy controls (n = 89) completed the Difficulties in Emotion Regulation Scale and Pittsburgh Sleep Quality Index. A conditional inference tree was fit to classify likelihood of current anxiety diagnosis based on predictors. The best model fit included 4 split nodes and 5 terminal nodes. Worse scores on two emotion regulation subscales, strategies directed to manage negative emotions and nonacceptance of negative emotions, were the best predictors of current anxiety diagnosis (99.3% probability of diagnosis). For those with better emotion regulation, poor sleep quality and worse daytime functioning due to sleep were important predictors of anxiety diagnosis. Good emotion regulation and non-disturbed sleep predicted high likelihood of being a non-psychiatric control (88.2%). Limitations include cross-sectional design precluding designating directionality of effects of sleep and emotion regulation on anxiety onset; limited sample size; and self-reported sleep. Facets of emotion regulation and sleep disturbance may be important early targets for brief intervention for anxiety disorders.

Early childhood trauma exposure and neurocognitive and emotional processes: Associations in young children in a partial hospital program.

Early childhood trauma has been linked to neurocognitive and emotional processing deficits in older children, yet much less is known about these associations in young children. Early childhood is an important developmental period in which to examine relations between trauma and executive functioning/emotion reactivity, given that these capacities are rapidly developing and are potential transdiagnostic factors implicated in the development of psychopathology. This cross-sectional study examined associations between cumulative trauma, interpersonal trauma, and components of executive functioning, episodic memory, and emotion reactivity, conceptualized using the RDoC framework and assessed with observational and performance-based measures, in a sample of 90 children (ages 4-7) admitted to a partial hospital program. Children who had experienced two or more categories of trauma had lower scores in episodic memory, global cognition, and inhibitory control as measured in a relational (but not computerized) task, when compared to children with less or no trauma. Interpersonal trauma was similarly associated with global cognition and relational inhibitory control. Family contextual factors did not moderate associations. Findings support examining inhibitory control in both relationally significant and decontextualized paradigms in early childhood, and underscore the importance of investigating multiple neurocognitive and emotional processes simultaneously to identify potential targets for early intervention.

Rapid online assessment of reading and phonological awareness (ROAR-PA)

Phonological awareness (PA) is at the foundation of reading development: PA is introduced before formal reading instruction, predicts reading development, is a target for early intervention, and is a core mechanism in dyslexia. Conventional approaches to assessing PA are time-consuming and resource intensive: assessments are individually administered and scoring verbal responses is challenging and subjective. Therefore, we introduce a rapid, automated, online measure of PA—The Rapid Online Assessment of Reading—Phonological Awareness—that can be implemented at scale without a test administrator. We explored whether this gamified, online task is an accurate and reliable measure of PA and predicts reading development. We found high correlations with standardized measures of PA (CTOPP-2, r = .80) for children from Pre-K through fourth grade and exceptional reliability (α = .96). Validation in 50 first and second grade classrooms showed reliable implementation in a public school setting with predictive value of future reading development.

A Membrane-Targeting Aggregation-Induced Emission Probe for Monitoring Lipid Droplet Dynamics in Ischemia/Reperfusion-Induced Cardiomyocyte Ferroptosis.

Myocardial ischemia/reperfusion injury (MIRI) is the leading cause of irreversible myocardial damage. A pivotal pathogenic factor is ischemia/reperfusion (I/R)-induced cardiomyocyte ferroptosis, marked by iron overload and lipid peroxidation. However, the impact of lipid droplet (LD) changes on I/R-induced cardiomyocyte ferroptosis is unclear. In this study, an aggregation-induced emission probe, TPABTBP is developed that is used for imaging dynamic changes in LD during myocardial I/R-induced ferroptosis. TPABTBP exhibits excellent LD-specificity, superior capability for monitoring lipophagy, and remarkable photostability. Molecular dynamics (MD) simulation and super-resolution fluorescence imaging demonstrate that the TPABTBP is specifically localized to the phospholipid monolayer membrane of LDs. Imaging LDs in cardiomyocytes and myocardial tissue in model mice with MIRI reveals that the LD accumulation level increase in the early reperfusion stage (0-9h) but decrease in the late reperfusion stage (>24h) via lipophagy. The inhibition of LD breakdown significantly reduces the lipid peroxidation level in cardiomyocytes. Furthermore, it is demonstrated that chloroquine (CQ), an FDA-approved autophagy modulator, can inhibit ferroptosis, thereby attenuating MIRI in mice. This study describes the dynamic changes in LD during myocardial ischemia injury and suggests a potential therapeutic target for early MIRI intervention.

Contractile pericyte-mediated cerebrovascular deficits in a mouse model of CADASIL

Small vessel disease (SVD) of the brain underlies 25% of stroke cases and is the most common cause of vascular cognitive impairment. The most common monogenic form of SVD is CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy), caused by mutations of the NOTCH3 protein which is widely expressed in mural cells (vascular smooth muscle cells [SMCs] and pericytes). Cerebral blood flow (CBF) deficits present early in CADASIL, attributable in part to NOTCH3-mediated extracellular matrix dysregulation, which alters heparin-binding epidermal growth factor-like (HB-EGF) signaling in SMCs and endothelial cells (ECs). Pericytes also robustly express NOTCH3 and are a relatively underexplored cell type in the context of CADASIL. Pericytes proximal to the penetrating arteriole (PA), known as contractile pericytes, express α-smooth muscle actin (αSMA) and can contract to rapidly regulate capillary diameter and thus blood flow in the downstream capillary tree. We conducted two-photon laser scanning microscopy (2PLSM) of blood flow and pericyte contractile responses with CADASIL Notch3R169C transgenic and control mice. Our data indicates that contractile pericyte-mediated control of blood flow is impaired prior to other known CBF deficits, thus raising the tantalizing possibility that these pericytes could be a target for early clinical intervention in CADASIL. While PA responses to stimulation of capillary electrical signaling remain intact, both blood flow as well as capillary diameter of contractile pericyte-covered vessels are diminished. Taken together, this work will establish pericytes as a novel site of dysfunction and provide a new candidate mechanism by which CBF is diminished early in CADASIL pathogenesis for potential therapeutic intervention. 5T32GM008181-33 (AV), 1DP2OD02944801 (TL), 1R01AG066645 (TL), 5R01NS115401 (TL). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Long Non-Coding RNAs as Determinants of Thyroid Cancer Phenotypes: Investigating Differential Gene Expression Patterns and Novel Biomarker Discovery.

Thyroid Cancer (TC) is the most common endocrine malignancy, with increasing incidence globally. Papillary thyroid cancer (PTC), a differentiated form of TC, accounts for approximately 90% of TC and occurs predominantly in women of childbearing age. Although responsive to current treatments, recurrence of PTC by middle age is common and is much more refractive to treatment. Undifferentiated TC, particularly anaplastic thyroid cancer (ATC), is the most aggressive TC subtype, characterized by it being resistant and unresponsive to all therapeutic and surgical interventions. Further, ATC is one of the most aggressive and lethal malignancies across all cancer types. Despite the differences in therapeutic needs in differentiated vs. undifferentiated TC subtypes, there is a critical unmet need for the identification of molecular biomarkers that can aid in early diagnosis, prognosis, and actionable therapeutic targets for intervention. Advances in the field of cancer genomics have enabled for the elucidation of differential gene expression patterns between tumors and healthy tissue. A novel category of molecules, known as non-coding RNAs, can themselves be differentially expressed, and extensively contribute to the up- and downregulation of protein coding genes, serving as master orchestrators of regulated and dysregulated gene expression patterns. These non-coding RNAs have been identified for their roles in driving carcinogenic patterns at various stages of tumor development and have become attractive targets for study. The identification of specific genes that are differentially expressed can give insight into mechanisms that drive carcinogenic patterns, filling the gaps of deciphering molecular and cellular processes that modulate TC subtypes, outside of well-known driver mutations.

Early interventions for emotional regulation in adolescence, where are we?

Adolescence is a vulnerable period for mental health. It is not easy to make a precise diagnosis during this period, as young people may present attenuated forms of psychiatric pathology, or on the contrary, a combination of several types of difficulties. Adopting a transdiagnostic and dimensional approach, based on clinical stages, and thus proposing interventions adapted to the severity of symptoms, is pertinent. As emotional dysregulation lies at the heart of many pathologies, it is a prime target for early intervention. Although interventions for adolescents are still underdeveloped, certain approaches derived from cognitive-behavioral therapies and the psychodynamic current have been adapted for adolescents and appear promising.

Airway epithelium respiratory illnesses and allergy (AERIAL) birth cohort: study protocol.

Recurrent wheezing disorders including asthma are complex and heterogeneous diseases that affect up to 30% of all children, contributing to a major burden on children, their families, and global healthcare systems. It is now recognized that a dysfunctional airway epithelium plays a central role in the pathogenesis of recurrent wheeze, although the underlying mechanisms are still not fully understood. This prospective birth cohort aims to bridge this knowledge gap by investigating the influence of intrinsic epithelial dysfunction on the risk for developing respiratory disorders and the modulation of this risk by maternal morbidities, in utero exposures, and respiratory exposures in the first year of life. The Airway Epithelium Respiratory Illnesses and Allergy (AERIAL) study is nested within the ORIGINS Project and will monitor 400 infants from birth to 5 years. The primary outcome of the AERIAL study will be the identification of epithelial endotypes and exposure variables that influence the development of recurrent wheezing, asthma, and allergic sensitisation. Nasal respiratory epithelium at birth to 6 weeks, 1, 3, and 5 years will be analysed by bulk RNA-seq and DNA methylation sequencing. Maternal morbidities and in utero exposures will be identified on maternal history and their effects measured through transcriptomic and epigenetic analyses of the amnion and newborn epithelium. Exposures within the first year of life will be identified based on infant medical history as well as on background and symptomatic nasal sampling for viral PCR and microbiome analysis. Daily temperatures and symptoms recorded in a study-specific Smartphone App will be used to identify symptomatic respiratory illnesses. The AERIAL study will provide a comprehensive longitudinal assessment of factors influencing the association between epithelial dysfunction and respiratory morbidity in early life, and hopefully identify novel targets for diagnosis and early intervention.

Incidence and predictors of post-stroke cognitive impairment among patients admitted with first stroke at tertiary hospitals in Dodoma, Tanzania: A prospective cohort study.

Stroke survivors develop cognitive impairment, which significantly impacts their quality of life, their families, and the community as a whole but not given attention. This study aims to determine the incidence and predictors of post-stroke cognitive impairment (PSCI) among adult stroke patients admitted to a tertiary hospital in Dodoma, Tanzania. A prospective cohort study was conducted at tertiary hospitals in the Dodoma region, central Tanzania. A sample size of 158 participants with the first stroke confirmed by CT/MRI brain aged ≥ 18 years met the criteria. At baseline, social-demographic, cardiovascular risks and stroke characteristics were acquired, and then at 30 days, participants were evaluated for cognitive functioning using Montreal Cognitive Assessment (MoCA). Key confounders for cognitive impairment, such as depression and apathy, were evaluated using the Personal Health Questionnaire (PHQ-9) and Apathy Evaluation Scale (AES), respectively. Descriptive statistics were used to summarise data; continuous data were reported as Mean (SD) or Median (IQR), and categorical data were summarised using proportions and frequencies. Univariate and multivariable logistic regression analysis was used to determine predictors of PSCI. The median age of the 158 participants was 58.7 years; 57.6% of them were female, and 80.4% of them met the required criteria for post-stroke cognitive impairment. After multivariable logistic regression, left hemisphere stroke (AOR: 5.798, CI: 1.030-32.623, p = 0.046), a unit cm3 increase in infarct volume (AOR: 1.064, 95% CI: 1.018-1.113, p = 0.007), and apathy symptoms (AOR: 12.259, CI: 1.112-89.173, p = 0.041) had a significant association with PSCI. The study revealed a significant prevalence of PSCI; early intervention targeting stroke survivors at risk may improve their outcomes. Future research in the field will serve to dictate policies and initiatives.