A further examination of growth factors, T helper 1 polarization, and the gut microbiome in major depression: Associations with reoccurrence of illness, cognitive functions, suicidal behaviors, and quality of life.

Growth factors, T helper (Th)1 polarization, and the microbiome are involved in the pathophysiology of major depression (MDD). It remains unclear whether the combination of these three pathways could enhance the accuracy of predicting the features of MDD, including recurrence of illness (ROI), suicidal behaviors and the phenome. We measured serum stem cell factor (SCF), stem cell growth factor (SCGF), stromal cell-derived factor-1 (SDF-1), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), macrophage-colony stimulating factor (M-CSF) and vascular endothelial growth factor (VEGF), the ratio of serum Th1/Th2 cytokines (zTh1-zTh2), and the abundances of gut microbiome taxa by analyzing stool samples using 16S rDNA sequencing from 32 MDD patients and 37 healthy controls. The results show that serum SCF is significantly lower and VEGF increased in MDD. Adverse childhood experiences (ACE) and ROI are significantly associated with lowered SCF and increasing VEGF. Lifetime and current suicidal behaviors are strongly predicted (63.5%) by an increased VEGF/SCF ratio, Th1 polarization, a gut microbiome enterotype indicating gut dysbiosis, and lowered abundance of Dorea and Faecalobacterium. Around 80.5% of the variance in the phenome's severity is explained by ROI, ACEs, and lowered Parabacteroides distasonis and Clostridium IV abundances. A large part of the variance in health-related quality of life (54.1%) is explained by the VEGF/SCF ratio, Th1 polarization, ACE, and male sex. In conclusion, key features of MDD are largely predicted by the cumulative effects of ACE, Th1 polarization, aberrations in growth factors and the gut microbiome with increased pathobionts but lowered beneficial symbionts.

Complex Intersections Between Adverse Childhood Experiences and Negative Life Events Impact the Phenome of Major Depression.

Background: There is evidence that adverse childhood experiences (ACEs) and negative life events (NLEs) are associated with major depression (MDD). Purpose: To determine whether ACEs affect all features of mild MDD, including suicidal tendencies, brooding, neuroticism, insomnia, cognitive deficits, severity of depression and anxiety, and cognitive deficits, and whether NLEs mediate these effects. Sample of the Study and Methods: This study examines a cohort of 118 academic students, namely 74 students who satisfied the DSM-5-TR criteria for MDD and 44 normal control students. We assessed brooding, neuroticism, suicidal ideation and attempts, and the severity of depression, anxiety, insomnia, and the Stroop tests. Results: One validated factor could be extracted from brooding, neuroticism, current suicidal behaviors, and the severity of depression, anxiety, and insomnia, labeled the phenome of depression. A large part of the variance in the phenome of depression (55.0%) was explained by the combined effects of self-, relationships, and academic-related NLEs in conjunction with ACEs, including family dysfunction and abuse and neglect (both physical and emotional). The latter ACEs significantly interacted (moderating effect) with NLEs to impact the depression phenome. Although sexual abuse did not have direct effects on the phenome, its effects were mediated by NLEs. We discovered that increased sexual abuse, physical and emotional abuse and neglect, and ACEs related to family dysfunction predicted 22.5% of the variance in NLEs. Up to 18.5% of the variance in the Stroop test scores was explained by sexual abuse and the phenome of depression. The latter mediated the effects of NLEs and abuse, neglect, and family dysfunction on the Stroop test scores. Conclusion: Complex intersections between ACEs and NLEs impact the phenome of depression, which comprises neuroticism, brooding, suicidal tendencies, and the severity of insomnia, anxiety, and depression, while sexual abuse together with other ACEs and NLEs may impact cognitive interference inhibition.

T cell activation and lowered T regulatory cell numbers are key processes in severe major depressive disorder: Effects of recurrence of illness and adverse childhood experiences.

BACKGROUND: Major depressive disorder (MDD) is characterized by increased T helper (Th)1 polarization, T cell activation (e.g., CD71+ and CD40L+), and cannabinoid receptor type 2 bearing CD20+ B cells; and lower T regulatory (Treg) numbers. AIMS: To delineate the effects of adverse childhood experiences (ACEs) and recurrence of illness (ROI) on activated T and CB2-bearing B populations, and Tregs, including FoxP3 + CD152+, FoxP3 + GARP+, and FoxP3 + CB1+ cells. METHODS: We measured ROI, ACEs, the number of activated T cells, Tregs, and CD20 + CB2+ B cells, in 30 MDD patients and 20 healthy controls. RESULTS: A larger part of the variance in the depression phenome (40.8 %) was explained by increased CD20 + CB2+ and activated T cells, and lowered Tregs. ROI and lifetime suicidal behaviors were significantly and positively associated with CD20 + CB2+, CD3 + CD71+, CD3 + CD40L+, CD4 + CD71+, CD4 + CD40L+, and CD4HLADR+ numbers. ROI was significantly correlated with CD8 + CD40L+ numbers. The sum of ACEs was significantly associated with CD20 + CB2+, CD3 + CD40L+, CD4 + 40 L+ numbers, T cell activation (positively) and Treg (inversely) indices. One replicable latent vector could be extracted from activated T cells, lifetime and current suicidal behaviors, number of depressive episodes, and severity of depression, and 48.8 % of its variance was explained by ACEs. CONCLUSIONS: ACE-induced activation of T effector and cytotoxic cells and B cells with autoimmune potential, coupled with lowered Treg numbers are a key component of depression. The findings indicate that increasing ROI, the phenome of depression and suicidal behaviors, are caused by autoimmune processes, which are the consequence of ACEs and increasing sensitization of immune responses.

T cell activation and deficits in T regulatory cells are associated with major depressive disorder and severity of depression.

Major depressive disorder (MDD) is associated with T cell activation, but no studies have examined the combined effects of T cell activation and deficits in T regulatory (Treg) cells on the severity of acute phase MDD. Using flow cytometry, we determined the percentage and median fluorescence intensity of CD69, CD71, CD40L, and HLADR-bearing CD3+, CD4+, and CD8+ cells, and cannabinoid type 1 receptor (CB1), CD152 and GARP (glycoprotein A repetitions predominant)-bearing CD25+ FoxP3 T regulatory (Treg) cells in 30 MDD patients and 20 healthy controls in unstimulated and stimulated (anti-CD3/CD28) conditions. Based on cytokine levels, we assessed M1 macrophage, T helper (Th)-1 cell, immune-inflammatory response system (IRS), T cell growth, and neurotoxicity immune profiles. We found that the immune profiles (including IRS and neurotoxicity) were significantly predicted by decreased numbers of CD152 or GARP-bearing CD25+ FoxP3 cells or CD152 and GARP expression in combination with increases in activated T cells (especially CD8+ CD40L+ percentage and expression). MDD patients showed significantly increased numbers of CD3+ CD71+, CD3+ CD40L+, CD4+ CD71+, CD4+ CD40L+, CD4+ HLADR+, and CD8+ HLADR+ T cells, increased CD3+ CD71+, CD4+ CD71+ and CD4+ HLADR+ expression, and lowered CD25+ FoxP3 expression and CD25+ FoxP+ CB1+ numbers as compared with controls. The Hamilton Depression Rating Scale score was strongly predicted (between 30 and 40% of its variance) by a lower number of CB1 or GARP-bearing Treg cells and one or more activated T cell subtypes (especially CD8+ CD40L+). In conclusion, increased T helper and cytotoxic cell activation along with decreased Treg homeostatic defenses are important parts of MDD that lead to enhanced immune responses and, as a result, neuroimmunotoxicity.

A Comparison of the Fluoride 'Paint- On' vs Tray Application Techniques for Enamel Remineralisation.

BACKGROUND: Fluoride gel treatment is not recommended for children < 6 years old due to its potential toxicity. Hence the aim of this study was to compare the effect of 1.23% acidulated-phosphate fluoride (APF) gel paint-on and the conventional tray application techniques on artificial, deciduous enamel carious lesions embedded on wearable appliances. METHODS: In a randomised crossover study, the volunteer children (n = 29) wore mandibular removable appliances containing embedded tooth specimens with artificial carious lesions. The volunteers had 3 different treatment protocols: (I) 0.4 mL non-fluoride (control) gel, (II) 0.4 mL paint-on 1.23% APF gel or (III) 5 mL 1.23% APF gel, 4 minutes tray application. After 1 hour, the appliances were removed and the specimens underwent an in vitro, 14 days of pH-cycling. The mean percentage reduction in fluorescence (ΔF, %) at baseline (ΔF0) and after the pH-cycling (ΔF1) were determined using quantitative light-induced fluorescence-digital analysis. The mean ΔΔF (ΔF1-ΔF0) was calculated to compare the differences between groups. RESULTS: The mean ΔΔF of groups I to III were -1.42 ± 1.49, 1.06 ± 2.11, and 1.12 ± 3.57 and -1.25 ± 1.44, 1.13 ± 1.84 and 1.44 ± 3.62 for the smooth surface and proximal surface lesions, respectively. The mean ΔΔF in the 2 treatment groups were significantly greater compared with the control group (P < .001). There was no significant difference in ΔΔF between the APF gel tray and paint-on groups either in the smooth surfaces, or the proximal surfaces (P = .629 and P = .613, respectively). CONCLUSION: Our study, for the first time, indicates that the paint-on application of APF gel or the tray application of APF had a similar enamel remineralisation effect. Clinically, this implies that, particularly in younger children, the paint-on application of fluoride is less cumbersome, and possibly more tolerable with a lesser likelihood of fluoride ingestion than the tray application technique. TRIAL REGISTRATION: Thai Clinical Trial Registry (https://www.thaiclinicaltrials.org/show/TCTR20190724001).

Towards a major methodological shift in depression research by assessing continuous scores of recurrence of illness, lifetime and current suicidal behaviors and phenome features.

BACKGROUND: The binary major depressive disorder (MDD) diagnosis is inadequate and should never be used in research. AIMS: The study's objective is to explicate our novel precision nomothetic strategy for constructing depression models based on adverse childhood experiences (ACEs), lifetime and current phenome, and biomarker (atherogenicity indices) scores. METHODS: This study assessed recurrence of illness (ROI: namely recurrence of depressive episodes and suicidal behaviors, SBs), lifetime and current SBs and the phenome of depression, neuroticism, dysthymia, anxiety disorders, and lipid biomarkers including apolipoprotein (Apo)A, ApoB, free cholesterol and cholesteryl esters, triglycerides, high density lipoprotein cholesterol in 67 normal controls and 66 MDD patients. We computed atherogenic and reverse cholesterol transport indices. RESULTS: We were able to extract one factor from a) the lifetime phenome of depression comprising ROI, and traits such as neuroticism, dysthymia and anxiety disorders, and b) the phenome of the acute phase (based on depression, anxiety and quality of life scores). PLS analysis showed that 55.7 % of the variance in the lifetime + current phenome factor was explained by increased atherogenicity, neglect and sexual abuse, while atherogenicity partially mediated the effects of neglect. Cluster analysis generated a cluster of patients with major dysmood disorder, which was externally validated by increased atherogenicity and characterized by increased scores of all clinical features. CONCLUSIONS: The outcome of depression should not be represented as a binary variable (MDD or not), but rather as multiple dimensional scores based on biomarkers, ROI, subclinical depression traits, and lifetime and current phenome scores including SBs.

Bronchoalveolar lavage fluid cytokines and chemokines changes after bronchial thermoplasty in severe asthma.

BACKGROUND: Bronchial thermoplasty (BT) is a non-pharmacological intervention in severe asthma with a well-known mechanism of reducing airway smooth muscle. However, its effect on airway inflammation remains uncertain. OBJECTIVE: To investigate the effect of BT on bronchoalveolar lavage fluid (BALF) cytokines and chemokines in severe asthma patients before BT, after the first BT, and 12 weeks after BT. METHODS: Ten severe asthma patients were recruited, and BALF was obtained from right lower lobe before BT, after the first BT, and 12 weeks after BT. BALF analytes were measured and values were compared among the time points. Lung function, asthma control test (ACT), and asthma quality of life questionnaire (AQLQ) were also measured. RESULTS: Tumor necrosis factor (TNF)-α concentration was significantly decreased after the first BT and significantly increased at 12 weeks after BT. Interleukin-6 (IL-6) and TNF-related apoptosis inducing ligand (TRAIL) concentration were significantly increased at 12 weeks after BT. There were no significant changes in Regulated upon activation, normal T-cell expressed and secreted (RANTES) and transforming growth factor-beta1 (TGF-ß1) concentration over time after BT. At 12 weeks after BT, there were significantly greater improvements in the scores on AQLQ (3.93 ± 0.88 to 5.3 ± 0.99, p = 0.002) and ACT (13.6 ± 3.27 to 19 ± 4.44, p = 0.002). The lung function did not differ significantly between pre- and post-BT. CONCLUSIONS: BT has limited effect on TNF-α, IL-6, TRAIL, RANTES, and TGF- ß1 in BALF suggesting that its clinical benefit is not primarily related to this local airway inflammation. The effect on long-term airway inflammation probably needs further studies.

Role of T and B lymphocyte cannabinoid type 1 and 2 receptors in major depression and suicidal behaviours.

Early flow cytometry studies revealed T cell activation in major depressive disorder (MDD). MDD is characterised by activation of the immune-inflammatory response system (IRS) and the compensatory immunoregulatory system (CIRS), including deficits in T regulatory (Treg) cells. This study examines the number of cannabinoid type 1 (CB1) and type 2 (CB2) receptor-bearing T/B lymphocytes in MDD, and the effects of in vitro cannabidiol (CBD) administration on CB1/CB2-bearing immunocytes. Using flow cytometry, we determined the percentage of CD20+CB2+, CD3+CB2+, CD4+CB2+, CD8+CB2+ and FoxP3+CB1+ cells in 19 healthy controls and 29 MDD patients in 5 conditions: baseline, stimulation with anti-CD3/CD28 with or without 0.1 µg/mL, 1.0 µg/mL, or 10.0 µg/mL CBD. CB2+ was significantly higher in CD20+ than CD3+ and CD4+ and CD 8+ cells. Stimulation with anti-CD3/CD8 increases the number of CB2-bearing CD3+, CD4+ and CD8+ cells, as well as CB1-bearing FoxP3+ cells. There was an inverse association between the number of reduced CD4+ CB2+ and IRS profiles, including M1 macrophage, T helper-(Th)-1 and Th-17 phenotypes. MDD is characterised by lowered basal FoxP3+ CB1+% and higher CD20+ CB2+%. 33.2% of the variance in the depression phenome (including severity of depression, anxiety and current suicidal behaviours) is explained by CD20+ CB2+ % (positively) and CD3+ CB2+% (inversely). All five immune cell populations were significantly increased by 10 µg/mL of CBD administration. Reductions in FoxP3+ CB1+% and CD3+ /CD4+ CB2+% contribute to deficits in immune homoeostasis in MDD, while increased CD20+CB2+% may contribute to the pathophysiology of MDD by activating T-independent humoral immunity.

Lower Nerve Growth Factor Levels in Major Depression and Suicidal Behaviors: Effects of Adverse Childhood Experiences and Recurrence of Illness.

Major depressive disorder (MDD) and its severe subtype, major dysmood disorder (MDMD), are distinguished by activation of inflammatory and growth factor subnetworks, which are associated with recurrence of illness (ROI) and adverse childhood experiences (ACEs). Nerve growth factor (NGF) plays a crucial role in facilitating neuro-immune communications and may regulate the inflammatory response. METHODS: The present study examined the effects of ACEs and ROI on culture supernatant NGF, stem cell factor (SCF), stem cell GF (SCGF), hepatocyte GF (HGF), and macrophage colony-stimulating factor (M-CSF), in relation to a neurotoxicity (NT) cytokine profile. RESULTS: NGF levels are lower in MDD (p = 0.003), particularly MDMD (p < 0.001), as compared with normal controls. ROI and ACE were significantly and inversely associated with NGF (≤0.003) and the NGF/NT ratio (≤0.001), whereas there are no effects of ACEs and ROI on SCF, SCGF, HGF, or M-CSF. Lowered NGF (p = 0.003) and the NGF/NT ratio (p < 0.001) are highly significantly and inversely associated with the severity of the current depression phenome, conceptualized as a latent vector extracted from the current severity of depression, anxiety, and suicidal behaviors. We found that one validated and replicable latent vector could be extracted from NGF, ROI, and the depression phenome, which therefore constitutes a novel ROI-NGF-pathway-phenotype. ACEs explained 59.5% of the variance in the latter pathway phenotype (p < 0.001). CONCLUSIONS: The imbalance between decreased NGF and increased neurotoxic cytokines during the acute phase of severe depression may contribute to decreased neuroprotection, increased neuro-affective toxicity, and chronic mild inflammation.

The effects of adverse childhood experiences on depression and suicidal behaviors are partially mediated by neuroticism: A subclinical manifestation of major depression.

Introduction: Neuroticism, a personality trait, can predict major depressive disorder (MDD). The current study aims to determine whether a) neuroticism is a feature of the acute state of MDD, including suicidal behaviors (SB); and b) adverse childhood experiences (ACEs) are associated with neuroticism in MDD. Methods: This study included 133 participants, 67 healthy controls and 66 MDD patients, and assessed the Big 5 Inventory (BFI), ACEs using the ACE Questionnaire, and the phenome of depression using the Hamilton Depression Rating Scale (HAM-D), Beck Depression Inventory (BDI), The State-Trait Anxiety Inventory (STAI) and Columbia Suicide Severity Rating Scale (C-SSRS) scores to assess current SB. Results: Neuroticism was significantly higher in MDD than controls, and it explained 64.9% of the variance in the depression phenome (a latent vector extracted from HAM-D, BDI, STAI, and current SB scores). The other BFI domains had much less (extraversion, agreeableness) or no effect (openness, conscientiousness). One latent vector could be extracted from the phenome, lifetime dysthymia, lifetime anxiety disorders and neuroticism scores. Neglect (physical and emotional) and abuse (physical, neglect and sexual) account for approximately 30% of the variance in this latent vector. Partial Least Squares analysis showed that the effects of neglect on the phenome were partially mediated by neuroticism, whereas the effects of abuse were completely mediated by neuroticism. Discussion: Neuroticism (trait) and the MDD phenome (state) are both manifestations of the same latent core, with neuroticism being a subclinical manifestation of MDD.

Exploration of the Gut Microbiome in Thai Patients with Major Depressive Disorder Shows a Specific Bacterial Profile with Depletion of the Ruminococcus Genus as a Putative Biomarker.

Maes et al. (2008) published the first paper demonstrating that major depressive disorder (MDD) is accompanied by abnormalities in the microbiota-gut-brain axis, as evidenced by elevated serum IgM/IgA to lipopolysaccharides (LPS) of Gram-negative bacteria, such as Morganella morganii and Klebsiella Pneumoniae. The latter aberrations, which point to increased gut permeability (leaky gut), are linked to activated neuro-immune and oxidative pathways in MDD. To delineate the profile and composition of the gut microbiome in Thai patients with MDD, we examined fecal samples of 32 MDD patients and 37 controls using 16S rDNA sequencing, analyzed α- (Chao1 and Shannon indices) and ß-diversity (Bray-Curtis dissimilarity), and conducted linear discriminant analysis (LDA) effect size (LEfSe) analysis. Neither α- nor ß-diversity differed significantly between MDD and controls. Rhodospirillaceae, Hungatella, Clostridium bolteae, Hungatella hathewayi, and Clostridium propionicum were significantly enriched in MDD, while Gracillibacteraceae family, Lutispora, and Ruminococcus genus, Ruminococcus callidus, Desulfovibrio piger, Coprococcus comes, and Gemmiger were enriched in controls. Contradictory results have been reported for all these taxa, with the exception of Ruminococcus, which is depleted in six different MDD studies (one study showed increased abundance), many medical disorders that show comorbidities with MDD, and animal MDD models. Our results may suggest a specific profile of compositional gut dysbiosis in Thai MDD patients, with increases in some pathobionts and depletion of some beneficial microbiota. The results suggest that depletion of Ruminococcus may be a more universal biomarker of MDD that may contribute to increased enteral LPS load, LPS translocation, and gut-brain axis abnormalities.

Factors affecting sibling bullying and its association with self-esteem and depression in middle school students.

Sibling bullying is an unwanted aggressive behavior of a sibling that is associated with peer bullying and emotional problems. However, the prevalence of sibling bullying, the factors that affect this condition, and its impact on depression and self-esteem are understudied, especially in Thailand. This study aims to examine the prevalence of sibling bullying, factors that affect sibling bullying, and its association with self-esteem and depression during the pandemic. From January to February 2022, a cross-sectional study was conducted in grades 7-9 (age 12-15 years) who had at least one sibling. Demographic characteristics, sibling bullying, self-esteem, and depression were collected using the revised Olweus bully/victim questionnaire, the Rosenberg self-esteem scale, and Patient Health Questionnaire-9, respectively. Binary logistic regression was analyzed to determine associations between sibling bullying and outcomes. Of 352 participants (30.4% female), 92 (26.1%) were victims and 49 (13.9%) were bullies of sibling bullying in the previous 6 months. Factors associated with an increased risk of being victims included female (OR = 2.46; 95%CI 1.34-4.53), peer victimization (OR = 12.99; 95%CI 5.27-32.04), domestic violence (OR = 4.48; 95%CI 1.68-11.95), and perpetrating sibling bullying (OR = 9.81; 95%CI 4.62-20.81). Factors associated with an increased risk of depression were female (OR = 2.59; 95%CI 1.57-4.26), sibling bullying victimization (OR = 2.08; 95%CI 1.22-3.56), physical abuse (OR = 9.50, 95%CI 1.13-79.71) and domestic violence (OR = 3.44; 95%CI 1.40-8.45).  Conclusion: Sibling bullying was not uncommon in Thai young adolescents and was associated with female, peer bullying, domestic violence, and depression. Such associations should be identified early so preventive measures and management could be properly implemented. What is Known: • Sibling bullying increases the risk for engaging in peer bullying, aggressive behaviors, violence, and emotional difficulties during life course trajectories. • Victims of sibling bullying are at increased risk of depression, anxiety, mental distress, self-harm, and decreased well-being. What is New: • The rate of sibling bullying in Thai middle school students, even during the pandemic, was comparable to previous studies of different cultural backgrounds without the pandemic. • Victims of sibling bullying were associated with female sex, peer victimization, domestic violence, perpetrating sibling bullying, and depression. Perpetrating sibling bullying was also associated with bullies in cyberbullying.

Adverse childhood experiences and reoccurrence of illness impact the gut microbiome, which affects suicidal behaviours and the phenome of major depression: towards enterotypic phenotypes.

The first publication demonstrating that major depressive disorder (MDD) is associated with alterations in the gut microbiota appeared in 2008 (Maes et al., 2008). The purpose of the present study is to delineate a) the microbiome signature of the phenome of depression, including suicidal behaviours (SB) and cognitive deficits; the effects of adverse childhood experiences (ACEs) and recurrence of illness index (ROI) on the microbiome; and the microbiome signature of lowered high-density lipoprotein cholesterol (HDLc). We determined isometric log-ratio abundances or prevalences of gut microbiome phyla, genera, and species by analysing stool samples from 37 healthy Thai controls and 32 MDD patients using 16S rDNA sequencing. Six microbiome taxa accounted for 36% of the variance in the depression phenome, namely Hungatella and Fusicatenibacter (positive associations) and Butyricicoccus, Clostridium, Parabacteroides merdae, and Desulfovibrio piger (inverse association). This profile (labelled enterotype 1) indicates compositional dysbiosis, is strongly predicted by ACE and ROI, and is linked to SB. A second enterotype was developed that predicted a decrease in HDLc and an increase in the atherogenic index of plasma (Bifidobacterium, P. merdae, and Romboutsia were positively associated, while Proteobacteria and Clostridium sensu stricto were negatively associated). Together, enterotypes 1 and 2 explained 40.4% of the variance in the depression phenome, and enterotype 1 in conjunction with HDLc explained 39.9% of the variance in current SB. In conclusion, the microimmuneoxysome is a potential new drug target for the treatment of severe depression and SB and possibly for the prevention of future episodes.

Enhanced effectiveness of silver diamine fluoride application with light curing on natural dentin carious lesions: an in vitro study.

This study aimed to compare the mean mineral density difference (mMDD) and surface morphology of 10- and 60-s silver diamine fluoride (SDF)-applied dentin carious lesions and to study the effect of an additional 20-s light curing (LC) on SDF-treated teeth. Forty primary molar blocks with natural dentin carious lesions were measured for baseline lesion depth and mineral density using Image-Pro Plus software. The samples were randomly distributed into 4 groups; 38% SDF applied for 1) 10-s (10SDF), 2) 60-s (60SDF), 3) 10-s + LC (10SDF + LC), 4) 60-s + LC (60SDF + LC) and an additional control group to assess the outcome of pH-cycling only. Then all the groups underwent a 7-d bacterial pH-cycling. The dentin carious lesions' mMDD was determined by digital subtraction radiographic analysis. The surface morphology and elemental profile were assessed by scanning electron microscopy and energy-dispersive X-ray spectroscopy. The mMDD of the dentin lesions was analyzed using two-way ANOVA, generalized linear models analysis. Light curing was the only factor that affected the mMDD (p = 0.007). The mMDD in the 10SDF + LC and 60SDF + LC groups were significantly higher than those without light curing (p = 0.041 and 0.041, respectively). The 60SDF + LC group demonstrated a significantly higher mMDD than the 10SDF group (p = 0.010), while that in the 10SDF + LC group was similar to the 60SDF group (p = 1.00). Scanning electron microscopy revealed denser mineral content layers, which were likely silver and chloride, in the 10SDF + LC and 60SDF + LC groups than in the 10SDF and 60SDF groups, respectively. In conclusion, shortened application time with light curing enhanced SDF remineralization similarly to the conventional method.

Brooding and neuroticism are strongly interrelated manifestations of the phenome of depression.

Introduction: We found that neuroticism may be identified as a subclinical manifestation of the phenome of depression, comprising depressive and anxiety symptoms, and suicidal behaviors. Rumination is positively associated with depression and neuroticism and may mediate the effects of neuroticism on depression. This study aimed to determine whether rumination or its components, including brooding or reflection, mediate the effects of neuroticism on depression or, alternatively, whether both neuroticism and rumination are manifestations of the phenome of depression. Methods: This study recruited 74 depressed subjects and 44 healthy controls. The depression group was split into groups with high versus low brooding scores. We used partial least squares (PLS) to examine mediation effects. Results: We found that brooding and reflection scores are significantly higher in depressed patients than in controls. Patients with higher brooding scores have increased severity of depression, anxiety, insomnia, neuroticism, and current suicidal ideation as compared with patients with lower brooding scores and controls. There is a strong positive association between rumination, and neuroticism, depression, anxiety, and lifetime and current suicidal behaviors. PLS analysis shows that brooding does not mediate the effects of neuroticism on the depression phenome because no discriminant validity could be established between neuroticism and brooding, or between neuroticism and brooding and the depression phenome. We were able to extract one validated latent vector from brooding and neuroticism, insomnia, depression, anxiety, and current suicidal behaviors. Conclusion: Overall, this study supports the theory that rumination and neuroticism are reflective manifestations of the phenome of depression.

Allergic rhinitis and other comorbidities associated with asthma control in Thailand.

Background: Asthma and allergic rhinitis (AR) can coexist and cause disabilities. This study aimed to assess the association between AR, asthma control, asthma-related quality of life, and other comorbidities. Methods: A cross-sectional study was conducted in adults with asthma in six hospitals in Thailand. The outcomes were association of asthma control assessed by the asthma control test (ACT), AR, and asthma comorbidities. Not-well-controlled asthma was defined as ACT scores ≤22. The severity of AR was determined by visual analog scale (VAS). Severe AR was defined as VAS ≥5. Asthma-related quality of life (AQLQ), comorbidities, and total IgE were recorded. Results: A total of 682 asthmatic patients were included. Median (IQR) age was 58.0 (47.0-64.0) years. 69.9% were female. Not-well-controlled asthma was present in 44.7%. The prevalence of AR was 86.1%. Moderate/severe persistent AR was diagnosed in 21.7% and severe AR was diagnosed in 30.2% of the patients. Inhaled corticosteroid-containing regimens were prescribed in 97.7% of patients. Intranasal corticosteroid and antihistamine were prescribed in 65.7 and 31.7%, respectively. Patients with not-well-controlled asthma had higher body mass index, VAS scores, proportions of pollution exposure, aeroallergen sensitization, severe AR, nasal polyp, urticaria, food allergy, gastroesophageal reflux disease, depression and anxiety, peptic ulcer, and asthma exacerbations, but younger age, lower AQLQ scores, and lower FEV1. Correlation was found between AR severity and ACT (r = -0.461, p < 0.001), AQLQ (r = -0.512, p < 0.001), and total IgE (r = 0.246, p < 0.023). Multiple regression analysis revealed that ACT, AQLQ, and percentage of FEV1/FVC were significantly associated with severe AR. Conclusion: Allergic rhinitis is prevalent in Thai asthmatic patients. AR severity is associated with asthma control, quality of life, and pulmonary function. Comprehensive care is essential for patients with uncontrolled asthma, particularly when coexisting with conditions.

Adverse Childhood Experiences Predict the Phenome of Affective Disorders and These Effects Are Mediated by Staging, Neuroimmunotoxic and Growth Factor Profiles.

Adverse childhood experiences (ACEs) enhance pro-inflammatory and pro-oxidant responses. In affective disorders, recent precision nomothetic psychiatry studies disclosed new pathway phenotypes, including an ROI-reoccurrence of illness (ROI)-oxidative stress latent construct. The aim of the present study is to delineate a) whether ACEs sensitize the M1 macrophage, the T helper cells (Th)1, Th2, and Th17, the IRS (immune-inflammatory-responses system), the CIRS (compensatory immunoregulatory system), and the neuroimmunotoxic and growth factor (GF) profiles and whether they are associated with ROI and the phenome of affective disorders and b) the molecular pathways underpinning the effects of the ACEs. We collected supernatants of stimulated (5 µg/mL of PHA and 25 µg/mL of LPS) and unstimulated diluted whole blood in 20 healthy controls and 30 depressed patients and measured a panel of 27 cytokines/GF using a Luminex method. ACEs (comprising mental and physical trauma, mental neglect, domestic violence, family history of mental disease, and parent loss) are accompanied by the increased stimulated, but not unstimulated, production of M1, Th1, Th2, Th17, IRS, neuroimmunotoxic, and GF profiles and are strongly correlated with ROI and the phenome. A latent vector extracted from the ROI features (recurrent episodes and suicidal behaviors) and the IRS/neuroimmunotoxic/GF profiles explains 66.8% of the variance in the phenome and completely mediates the effects of ACEs on the phenome. Enrichment analysis showed that the ACE-associated sensitization of immune/GF profiles involves JAK-STAT, nuclear factor-κB, tumor necrosis factor-α, G-protein coupled receptor, PI3K/Akt/RAS/MAPK, and hypoxia signaling. In summary, the ACE-induced sensitization of immune pathways and secondary immune hits predicts the phenome of affective disorders.

Online positive parenting programme for promoting parenting competencies and skills: randomised controlled trial.

Positive parenting programmes (PPP), albeit effective, are not readily accessible to the general public, particularly during the COVID-19 pandemic. In 103 healthy caregiver-child dyads, we investigated the effectiveness of online PPP on parenting sense of competencies (primary outcome), parenting styles and behavioural concerns of children aged 3-6 years (secondary outcomes) between 2 blinded, parallel groups. After block of 4 randomisations, intervention group (n = 52) attended live, group-based, internet delivered PPP while both intervention and active control group (n = 51) received weekly general education via communication application. Outcomes were measured at baseline, 8 and 14 weeks. Most parents from both groups had high education and household income. From the intervention group, 87.5% of the parents attended live sessions while 8.6% subsequently watched recorded sessions. At 14 weeks, the intervention group reported higher sense of competence (Wald 9.63, p = 0.008); both groups reported using more authoritative parenting style (Wald 15.52, p ≤ 0.001) from Generalised Estimating Equations model. Compared to baseline, both groups had significant reduction of children's emotional problems at 14 weeks (mean change: Intervention = - 0.44, p = 0.033; Control = - 0.30, p = 0.046) and behavioural problems over time (Wald 7.07, p = 0.029). Online PPP offered an easily accessible, primary preventive measure to mitigate behavioural concerns and improve parental competency.Clinical trial registration Thai Clinical Trials Registry; https://www.thaiclinicaltrials.org/ ; TCTR20201030001; October 30, 2020.

In Vitro Effects of Cannabidiol on Activated Immune-Inflammatory Pathways in Major Depressive Patients and Healthy Controls.

Major depressive disorder and major depressive episodes (MDD/MDE) are characterized by the activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). Cannabidiol (CBD) is a phytocannabinoid isolated from the cannabis plant, which is reported to have antidepressant-like and anti-inflammatory effects. The aim of the present study is to examine the effects of CBD on IRS, CIRS, M1, T helper (Th)-1, Th-2, Th-17, T regulatory (Treg) profiles, and growth factors in depression and healthy controls. Culture supernatant of stimulated (5 µg/mL of PHA and 25 µg/mL of LPS) whole blood of 30 depressed patients and 20 controls was assayed for cytokines using the LUMINEX assay. The effects of three CBD concentrations (0.1 µg/mL, 1 µg/mL, and 10 µg/mL) were examined. Depression was characterized by significantly increased PHA + LPS-stimulated Th-1, Th-2, Th-17, Treg, IRS, CIRS, and neurotoxicity profiles. CBD 0.1 µg/mL did not have any immune effects. CBD 1.0 µg/mL decreased CIRS activities but increased growth factor production, while CBD 10.0 µg/mL suppressed Th-1, Th-17, IRS, CIRS, and a neurotoxicity profile and enhanced T cell growth and growth factor production. CBD 1.0 to 10.0 µg/mL dose-dependently decreased sIL-1RA, IL-8, IL-9, IL-10, IL-13, CCL11, G-CSF, IFN-γ, CCL2, CCL4, and CCL5, and increased IL-1ß, IL-4, IL-15, IL-17, GM-CSF, TNF-α, FGF, and VEGF. In summary, in this experiment, there was no beneficial effect of CBD on the activated immune profile of depression and higher CBD concentrations can worsen inflammatory processes.