Convergent dopamine and ALK4 signaling to PCBP1 controls FosB alternative splicing and cocaine behavioral sensitization.

ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown. Here, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine. These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.

Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function.

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell-derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors.

Spanish validation of the short version of the racing and crowded thoughts questionnaire (RCTQ-13).

BACKGROUND: The Racing and Crowded Thoughts Questionnaire (RCTQ-13) is the most widely used specific scale for the measurement of racing thoughts, but there is currently no Spanish version that allow the evaluation in Spanish-speaking patients. The objective of this study is to translate, adapt, and validate the RCTQ-13 in a Colombian population with affective disorders. METHODS: The questionnaire was translated and back-translated, and corrections were implemented following a pilot test to improve comprehensibility. We included patients with Bipolar I Disorder and with Major depressive disorder seen in three centers in the city of Medellín, Colombia. We evaluate structural validity with confirmatory factor analysis, internal consistency, and test-retest reliability. Construct validity was also assessed with the comparison between euthymic, maniac, and depressive episodes and the correlation with worry, rumination, and mania scales. Responsiveness was measured 1 month after the first evaluation. Based on item response theory (IRT), we also estimated item difficulty, discrimination, and fit using a generalized partial credit model. RESULTS: Two hundred fifty subjects were included. Confirmatory factor analysis revealed that the three-factor structure of the scale was appropriate. Internal consistency was adequate for the entire scale (Cronbach's alpha = 0.95, 95% CI: 0.94-0.96) and for each factor. Test-retest reliability was good (intraclass correlation coefficient = 0.82, 95%IC: 0.70-0.88). For construct validity, we observed differences between patients with different types of affective episodes, a moderate positive correlation with the Penn State Worry Scale (r = 0.55) and the Ruminative Response Scale (r = 0.42), and a low negative correlation with the Young Mania Rating Scale (r = - 0.10). Responsiveness was proved to be adequate. Under IRT, the response thresholds for the response options are organized for all items. The infit was adequate for all items and the outfit was acceptable. CONCLUSIONS: The Spanish version of the RCTQ-13 is a reliable, valid, and responsive scale and can be used for the clinical assessment of the construct of racing and crowded thoughts in patients with the spectrum of affective disorders in whom this experience can be expressed with different nuances. Further research is needed to expand the relationship with rumination and worry.

Epidemiology, clinical features, and classification of 3,404 patients with uveitis: Colombian Uveitis Multicenter Study (COL-UVEA).

PURPOSE: To describe the epidemiology, clinical features, and classification of uveitis in a large cohort of Colombian patients. METHODS: Data were collected from seven ophthalmological referral centers in the four main cities in Colombia. The study included patients with a confirmed diagnosis of uveitis from January 2010 to December 2022. Information on demographics, ophthalmic examination findings, uveitis classification, and etiology was recorded. RESULTS: The study reviewed 3,404 clinical records of patients with uveitis. The mean age at diagnosis was 41.1 (SD 19.0) years, and 54.2% of the patients were female. Overall, 1,341(39.4%) were infectious, 626 (18.4%) non-infectious, and four masquerade syndromes (0.1%). The most common types of uveitis were unilateral (66.7%), acute (48.3%), and non-granulomatous (83%). Anterior uveitis was the most common anatomical localization (49.5%), followed by posterior uveitis (22.9%), panuveitis (22.3%), and intermediate uveitis (5.2%). A diagnosis was established in 3,252 (95.5%) cases; idiopathic was the most common cause (27.7%), followed by toxoplasmosis (25.3%) and virus-associated uveitis (6.4%). The age group between 30 and 50 exhibited the highest frequency of uveitis. CONCLUSION: This multicenter study comprehensively describes uveitis characteristics in Colombian patients, providing valuable insights into its demographic and clinical features. The study findings emphasize the need to continue updating the changing patterns of uveitis to improve diagnosis and treatment strategies for diseases associated with intraocular inflammation.

A diet rich in omega-3 fatty acid improves periodontitis and tissue destruction by MMP2- and MMP9-linked inflammation in a murine model.

Periodontitis is an oral-cavity inflammatory disease and is the principal cause associated with tooth loss. Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are important proteases involved in periodontal tissue destruction. The omega-3 polyunsaturated fatty acids (ω-3 PUFA) have been demonstrated to possess immunoregulatory properties in periodontitis. The aim of the study was to investigate the effects of ω-3 PUFA on inflammation and on the expression of MMP-2 and -9 in a murine periodontitis model. Twenty-four male C57BL/6 mice were divided into control mice (Control), control mice treated with ω-3 PUFA (O3), mice with periodontitis (P), and mice with periodontitis treated with ω-3 PUFA (P + O3). ω-3 PUFA were administered orally once a day for 70 days. Periodontitis in mice was induced by Porphyromonas gingivalis-infected ligature placement around the second maxillary molar. The mice were sacrificed, and blood and maxillary samples were collected. Flow cytometry was used to quantify tumor necrosis factor-alpha (TNFα), interleukin (IL)-2, IL-4, IL-5, and interferon-gamma. Histologic analysis and immunohistochemistry for MMP-2 and -9 were performed. The data were statistically evaluated using analysis of variance (ANOVA) and the Tukey post hoc test. Histological analysis showed that ω-3 PUFA supplementation prevented inflammation and tissue destruction and revealed that bone destruction was more extensive in the P group than in the P + O3 group (p < 0.05). Also, it decreased the serum expressions of TNFα and IL-2 and the tissue expression of MMP-2 and -9 in the periodontitis-induced model (p < 0.05). ω-3 PUFA supplementation prevented alveolar bone loss and periodontal destruction, probably by decreasing the expression of MMP-2 and MMP-9 and its immunoregulatory properties.

Moderate intensity aerobic training reduces the signs of peripheral sensitization in a mouse model of type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a global health problem for many reasons including the comorbidities, such as diabetic neuropathy (DPN), which is the most common. It has been suggested that aerobic training can improve metabolic health in individuals with T2DM. Still, the effect of aerobic training on DPN signs and its relationship with serum levels of tumor necrosis tumor alpha (TNF-α), an essential molecule in T2DM development, is unknown. We evaluated the effect of two intensities of aerobic training in adult male C57BL/6 mice divided into six groups: sedentary control (CTRL), control with low-intensity training (CTRL-LI), control with moderate-intensity training (CTRL-MI), T2DM sedentary (T2DM), T2DM with low-intensity training (T2DM-LI), and T2DM with moderate-intensity training (T2DM-MI). We induced the T2DM model by combining a hypercaloric diet and low doses of streptozotocin. We measured serum TNF-α levels and correlated them with peripheral sensitization and the cardinal signs of T2DM in mice. Moderate intensity aerobic training decreased the symptoms of DPN and improved metabolic health in T2DM. Interestingly, decreased TNF-α serum levels correlated with reduced peripheral thermal sensitivity and mechanical sensitivity by aerobic training. Moderate intensity aerobic training counteracts the development and symptoms of DPN and improve metabolic health in T2DM. Decreased TNF-α correlates with reduced peripheral thermal sensitivity and mechanical sensitivity by aerobic training.

Clinical patterns and risk factors in scleritis: a multicentric study in Colombia.

PURPOSE: This study aims to describe the clinical characteristics of scleritis in a large cohort of Colombian patients and identify factors associated with the clinical presentation. METHODS: Retrospective case series of patients with scleritis from 2015 to 2020. Clinical records were obtained from seven uveitis referral centers in Colombia. Patients with a diagnosis of episcleritis were excluded. RESULTS: We evaluated 389 patients with scleritis (509 eyes). There was a female predominance (75.6%) with a mean age of 51 ± 15 years. Most cases were noninfectious (94.8%) and unilateral (69.2%). The most frequent type of inflammation was diffuse anterior scleritis (41.7%), followed by nodular scleritis (31.9%) and necrotizing scleritis (12.3%). Systemic autoimmune diseases were found in 41.3% of patients, the most common being rheumatoid arthritis (18.5%) and granulomatosis with polyangiitis (5.9%). Polyautoimmunity was found in 10.4% of those with a systemic autoimmune disease. The most frequent treatment was systemic steroids (50.9%), followed by systemic NSAIDs (32.4%). Steroid-sparing immunosuppression was required in 49.1% of patients. Systemic autoimmune diseases were more common in patients with necrotizing scleritis and those older than 40 years of age. Best-corrected visual acuity of 20/80 or worse at presentation was more common in necrotizing scleritis and subjects with associated uveitis, ocular hypertension, or who were over 40 years of age. CONCLUSIONS: This is the first study in Colombia and the largest in Latin America describing the clinical characteristics and presentation patterns of scleritis. The most common presentation was in females, with unilateral, anterior diffuse noninfectious scleritis. Systemic autoimmune diseases and polyautoimmunity were frequent, as was the need for steroid-sparing immunosuppression. Age over 40 and necrotizing scleritis were associated with higher odds of having a systemic autoimmune disease and worse visual acuity at presentation.

Associations between ongoing COVID-19 lockdown and the financial and mental health experiences of Australian families.

In 2020, Australia's successful COVID-19 public health restrictions comprised a national "initial lockdown" (March-May) and "ongoing lockdown" (July-November) for metropolitan Victorian residents only. We evaluated associations between ongoing lockdown and family finances and mental health. In the June and September 2020 Royal Children's Hospital National Child Health Polls, caregivers of children in Victoria and New South Wales (NSW) reported the following: job/income loss; material deprivation (inability to pay for essential items); income poverty; mental health (Kessler-6); perceived impact on caregiver/child mental health; and caregiver/child coping. Data from caregivers (N = 1207/902) in June/September were analysed using difference-in-difference modelling (NSW provided the comparator). During Victoria's ongoing lockdown, job/income loss increased by 11% (95%CI: 3%-18%); Kessler-6 poor mental health by 6% (95%CI: -0.3%-12%) and perceived negative mental health impacts by 14% for caregivers (95%CI: 6%-23%) and 12% for children (95%CI: 4%-20%). Female (vs. male) caregivers, metropolitan (vs. regional/rural) families, and families with elementary school-aged children (vs. pre-/high-school) were the most affected. The ongoing lockdown was associated with negative experiences of mental health, employment and income, but not deprivation or poverty, likely because of government income supplements introduced early in the pandemic. Future lockdowns require planned responses to outbreaks and evidence-informed financial and mental health supports.

Role of social support in the relationship between financial hardship and multimorbidity-a causal mediation analysis.

BACKGROUND: Social disadvantage is a key determinant of multimorbidity. Pathways through which social disadvantage leads to multimorbidity are yet undefined. In this study, we first examined the causal effect of moving into financial hardship on multimorbidity among Australian adults, and then the role of social support as a mediator of the relationship between financial hardship and multimorbidity. METHODS: Data were obtained from the Household, Income and Labour Dynamics in Australia (HILDA) Survey (2009-2013). We identified individuals who moved into financial hardship between 2010 and 2011 (n = 5775). Inverse probability treatment weighting with regression adjustment was used to examine the relationship between financial hardship and multimorbidity. Causal mediation analysis was applied to decompose the total effect of financial hardship on multimorbidity into the proportion attributable to social support and the proportion not occurring through measured pathways. We accounted for baseline covariates including age, sex, marital status, educational attainment, employment status, income, country of birth, multimorbidity and social support. Bootstrapping with 1000 replications was used to calculate 95% confidence intervals (CIs). RESULTS: The risk of multimorbidity was higher in those with financial hardship by 19% [relative risk 1.19 (95% CI: 1.02-1.37) and absolute risk difference 0.036 (95% CI: 0.004-0.067)] than those without financial hardship. Social support accounted for 30% of the total effect of financial hardship on multimorbidity, risk difference 0.009 (95% CI: 0.003-0.018). CONCLUSIONS: Financial hardship leads to increased risk of multimorbidity. Interventions directed at increasing social support among those in financial hardship may reduce their risk of multimorbidity.

Fatty acid amide hydrolase inhibition for the symptomatic relief of Parkinson's disease.

Elements of the endocannabinoid system are strongly expressed in the basal ganglia where they suffer profound rearrangements after dopamine depletion. Modulation of the levels of the endocannabinoid 2-arachidonoyl-glycerol by inhibiting monoacylglycerol lipase alters glial phenotypes and provides neuroprotection in a mouse model of Parkinson's disease. In this study, we assessed whether inhibiting fatty acid amide hydrolase could also provide beneficial effects on the time course of this disease. The fatty acid amide hydrolase inhibitor, URB597, was administered chronically to mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTPp) over 5weeks. URB597 (1mg/kg) prevented MPTPp induced motor impairment but it did not preserve the dopamine levels in the nigrostriatal pathway or regulate glial cell activation. The symptomatic relief of URB597 was confirmed in haloperidol-induced catalepsy assays, where its anti-cataleptic effects were both blocked by antagonists of the two cannabinoid receptors (CB1 and CB2), and abolished in animals deficient in these receptors. Other fatty acid amide hydrolase inhibitors, JNJ1661010 and TCF2, also had anti-cataleptic properties. Together, these results demonstrate an effect of fatty acid amide hydrolase inhibition on the motor symptoms of Parkinson's disease in two distinct experimental models that is mediated by cannabinoid receptors.

Efficacy of vitamin D supplementation in reducing body mass index and lipid profile in healthy young adults in Colombia: a pilot randomised controlled clinical trial.

The objective of the present study was to evaluate the efficacy of oral administration of vitamin D supplementation in reducing BMI and lipid profile in adolescents and young adults from a cohort in Bucaramanga, Colombia. One hundred and one young adults were randomly assigned to one of two doses of vitamin D [1000 international units (IU) or 200 IU] administered daily for 15 weeks. The primary outcomes were serum 25(OH)D levels, BMI and lipid profile. The secondary outcomes were waist-hip ratio, skinfolds and fasting blood glucose. We found a mean ± sd plasma concentration of 25-hydroxyvitamin D [25(OH)D] was 25⋅0 ± 7⋅0 ng/ml at baseline, and after 15 weeks, it increased to 31⋅0 ± 10⋅0 ng/ml in the participants who received a daily dose of 1000 IU, (P < 0⋅0001). For the participants in the control group (200 IU), it went from 26⋅0 ± 8⋅0 ng/ml to 29⋅0 ± 8⋅0 ng/ml (P = 0⋅002). There were no differences between groups in body mass index. There was a statistically significant decrease in LDL-cholesterol between the intervention group v. the control group (mean difference -11⋅50 mg/dl (95 % CI -21⋅86 to -1⋅15; P = 0⋅030). The conclusions of the present study were two different doses of vitamin D supplementation (200 IU v. 1000 IU) produced changes in serum 25(OH)D levels over 15 weeks of administration in healthy young adults. No significant changes were found in the body mass index when the effect of the treatments was compared. A significant reduction in LDL-cholesterol was found when comparing the two intervention groups. Trial registration: NCT04377386.

Effects of Physical Exercise on Gross Motor Skills in Children with Autism Spectrum Disorder.

Research shows many positive effects from physical exercise. The present study examined the impact of a structured physical exercise program compared to treatment as usual on the gross motor skills of children diagnosed with autism spectrum disorder (ASD). Participants included 20 children, from 4 to 7 years old, who were assigned to two groups; an experimental group (n = 10) who received a structured physical exercise program for 60-min sessions, three times a week for eight weeks, and a control group (n = 10) who received conventional physiotherapy. Gross motor skills were assessed with the Abbreviated Development Scale -3 before and after the physical exercise program. The experimental group exhibited significant improvements in gross motor skills compared to the control group. This study suggests that structured physical exercise programs can improve gross motor skills in children with ASD.

Immunogenicity of Adalimumab in Patients with Non-Infectious- Uveitis: Systematic Review and Meta-Analysis.

OBJECTIVE: To review the prevalence, incidence, and risk factors for developing anti-drug antibodies (AAA) in patients with non-infectious uveitis (NIU) treated with Adalimumab (ADA). METHODS: A systematic literature search was performed on PubMed, EMBASE, Virtual Health Library, Cochrane, and medRxiv. Meta-analysis was performed using random effects. RESULTS: Nine out of 2,373 studies were included. The prevalence of AAA in NIU patients treated with ADA was 9% (95% CI: 2% to 37%, I2 = 95% with a P<0.01), it was significantly higher in real-life scenarios (observational studies) than in clinical trials. The pooled incidence at 12 months was 27% (CI 95% 16%-42% I2 = 0%). Several factors have been associated with AAA generation in NIU patients, including the non-use of concomitant immunosuppressants, presence of autoimmune systemic disease, female gender, etc. CONCLUSION: This study showed that AAA prevalence is higher in real-life scenarios compared to clinical trials. Further research is needed to elucidate the factors that trigger AAA generation in NIU patients.

AraC interacts with p75NTR transmembrane domain to induce cell death of mature neurons.

Cytosine arabinoside (AraC) is one of the main therapeutic treatments for several types of cancer, including acute myeloid leukaemia. However, after a high-dose AraC chemotherapy regime, patients develop severe neurotoxicity and cell death in the central nervous system leading to cerebellar ataxia, dysarthria, nystagmus, somnolence and drowsiness. AraC induces apoptosis in dividing cells. However, the mechanism by which it leads to neurite degeneration and cell death in mature neurons remains unclear. We hypothesise that the upregulation of the death receptor p75NTR is responsible for AraC-mediated neurodegeneration and cell death in leukaemia patients undergoing AraC treatment. To determine the role of AraC-p75NTR signalling in the cell death of mature neurons, we used mature cerebellar granule neurons' primary cultures from p75NTR knockout and p75NTRCys259 mice. Evaluation of neurite degeneration, cell death and p75NTR signalling was done by immunohistochemistry and immunoblotting. To assess the interaction between AraC and p75NTR, we performed cellular thermal shift and AraTM assays as well as Homo-FRET anisotropy imaging. We show that AraC induces neurite degeneration and programmed cell death of mature cerebellar granule neurons in a p75NTR-dependent manner. Mechanistically, Proline 252 and Cysteine 256 residues facilitate AraC interaction with the transmembrane domain of p75NTR resulting in uncoupling of p75NTR from the NFκB survival pathway. This, in turn, exacerbates the activation of the cell death/JNK pathway by recruitment of TRAF6 to p75NTR. Our findings identify p75NTR as a novel molecular target to develop treatments for counteract AraC-mediated cell death of mature neurons.

Feasibility of linking universal child and family healthcare and financial counselling: findings from the Australian Healthier Wealthier Families (HWF) mixed-methods study.

OBJECTIVES: 'Healthier Wealthier Families' (HWF) seeks to reduce financial hardship in the early years by embedding a referral pathway between Australia's universal child and family health (CFH) services and financial counselling. This pilot study investigated the feasibility and short-term impacts of HWF, adapted from a successful Scottish initiative. METHODS: Setting: CFH services in five sites across two states, coinciding with the COVID-19 pandemic. PARTICIPANTS: Caregivers of children aged 0-5 years experiencing financial hardship (study-designed screen). DESIGN: Mixed methods. With limited progress using a randomised trial (RCT) design in sites 1-3 (March 2020-November 2021), qualitative interviews with service providers identified implementation barriers including stigma, lack of knowledge of financial counselling, low financial literacy, research burden and pandemic disruption. This informed a simplified RCT protocol (site 4) and direct referral model (no randomisation, pre-post evaluation, site 5) (June 2021-May 2022). INTERVENTION: financial counselling; comparator: usual care (sites 1-4). Feasibility measures: proportions of caregivers screened, enrolled, followed up and who accessed financial counselling. Impact measures: finances (quantitative) and other (qualitative) to 6 months post-enrolment. RESULTS: 355/434 caregivers completed the screen (60%-100% across sites). In RCT sites (1-4), 79/365 (19%-41%) reported hardship but less than one-quarter enrolled. In site 5, n=66/69 (96%) caregivers reported hardship and 44/66 (67%) engaged with financial counselling; common issues were utility debts (73%), and obtaining entitlements (43%) or material aid/emergency relief (27%). Per family, financial counselling increased income from government entitlements by an average $A6504 annually plus $A784 from concessions, grants, brokerage and debt waivers. Caregivers described benefits (qualitative) including reduced stress, practical help, increased knowledge and empowerment. CONCLUSIONS: Financial hardship screening via CFH was acceptable to caregivers, direct referral was feasible, but individual randomisation was infeasible. Larger-scale implementation will require careful, staged adaptations where CFH populations and the intervention are well matched and low burden evaluation. TRIAL REGISTRATION NUMBER: ACTRN12620000154909.

The regulatory landscape of retinoblastoma: a pathway analysis perspective.

Retinoblastoma (Rb) is a rare intraocular tumour in early childhood, with an approximate incidence of 1 in 18 000 live births. Experimental studies for Rb are complex due to the challenges associated with obtaining a normal retina to contrast with diseased tissue. In this work, we reanalyse a dataset that contains normal retina samples. We identified the individual genes whose expression is different in Rb in contrast with normal tissue, determined the pathways whose global expression pattern is more distant from the global expression observed in normal tissue, and finally, we identified which transcription factors regulate the highest number of differentially expressed genes (DEGs) and proposed as transcriptional master regulators (TMRs). The enrichment of DEGs in the phototransduction and retrograde endocannabinoid signalling pathways could be associated with abnormal behaviour of the processes leading to cellular differentiation and cellular proliferation. On the other hand, the TMRs nuclear receptor subfamily 5 group A member 2 and hepatocyte nuclear factor 4 gamma are involved in hepatocyte differentiation. Therefore, the enrichment of aberrant expression in these transcription factors could suggest an abnormal retina development that could be involved in Rb origin and progression.

Theoretical explanations for socioeconomic inequalities in multimorbidity: a scoping review.

OBJECTIVE: To document socioepidemiological theories used to explain the relationship between socioeconomic disadvantage and multimorbidity. DESIGN: Scoping review. METHODS: A search strategy was developed and then applied to multiple electronic databases including Medline, Embase, PsychInfo, Web of Science, Scielo, Applied Social Sciences, ERIC, Humanities Index and Sociological Abstracts. After the selection of studies, data were extracted using a data charting plan. The last search was performed on the 28 September 2021. Extracted data included: study design, country, population subgroups, measures of socioeconomic inequality, assessment of multimorbidity and conclusion on the association between socioeconomic variables and multimorbidity. Included studies were further assessed on their use of theory, type of theories used and context of application. Finally, we conducted a meta-narrative synthesis to summarise the results. RESULTS: A total of 64 studies were included in the review. Of these, 33 papers included theories as explanations for the association between socioeconomic position and multimorbidity. Within this group, 16 explicitly stated those theories and five tested at least one theory. Behavioural theories (health behaviours) were the most frequently used, followed by materialist (access to health resources) and psychosocial (stress pathways) theories. Most studies used theories as post hoc explanations for their findings or for study rationale. Supportive evidence was found for the role of material, behavioural and life course theories in explaining the relationship between social inequalities and multimorbidity. CONCLUSION: Given the widely reported social inequalities in multimorbidity and its increasing public health burden, there is a critical gap in evidence on pathways from socioeconomic disadvantage to multimorbidity. Generating evidence of these pathways will guide the development of intervention and public policies to prevent multimorbidity among people living in social disadvantage. Material, behavioural and life course pathways can be targeted to reduce the negative effect of low socioeconomic position on multimorbidity.

Aerobic training improves bone fragility by reducing the inflammatory microenvironment in bone tissue in type 2 diabetes.

Aerobic training (AT) is indicated in type 2 diabetes mellitus (T2DM) to control hyperglycaemia and inflammation. AT improves bone microarchitecture and resistance to fracture. The intensity of AT and the mechanisms that lead to the improvement in bone quality are still unknown. Using a mouse model of T2DM, we evaluated the effects of two intensities of forced AT. We divided mice into: sedentary (SED), T2DM-SED, low runners (LOW), T2DM-LOW, high runners (HIGH) and T2DM-HIGH. The AT for low was 8 m/minute (m/min); 5° slope or high 18 m/min; 15° slope for 2 months. We measured metabolic parameters, the serum cytokines concentration, lipocalin-2 (LCN-2) and adiponectin; and the tibial concentrations of LCN-2, tumour necrosis factor alpha (TNF-α) and protein carbonylation (CO). We evaluated femur morphometry and biomechanical properties. We performed multiple correlation analysis. The T2DM-LOW versus T2DM-SED group, shown an increase of interleukin (IL)-10 (417 ± 90 vs 102 ± 25 pg/mL) and improved trabecular bone (BV/TV: 31.8 ± 2.3 vs 19.25 ± 1.4%; Tb.Sp.: 1.62 ± 0.02 vs 2.0 ± 0.07 mm), by a decrease bone CO (3.4 ± 0.1 vs 6.0 ± 0.5 nmol/mg), bone TNF-α (84 ± 4 vs 239 ± 13 pg/mL) and LCN-2 (2887 ± 23 vs 3418 ± 105 pg/mL). The T2DM-HIGH versus T2DM-SED group showed a greater hypoglycaemic effect (228 ± 10 vs 408 ± 5 mg/dL), with improved cortical bone density (0.26 ± 0.012 vs 0.21 ± 0.007 mm) and fracture resistance (102 ± 8 vs 78 ± 5 MPa), by a reduction of bone TNF-α (77 ± 34 vs 239 ± 13 pg/mL); LCN-2 (2768 ± 20 vs 3418 ± 105 pg/mL) and CO (4.8 ± 0.5 vs 6.0 ± 0.5 nmol/mg). In conclusion, AT improves bone morphometry and biomechanical properties by reducing the bone inflammatory microenvironment.

Connecting Healthcare with Income Maximisation Services: A Systematic Review on the Health, Wellbeing and Financial Impacts for Families with Young Children.

Financial counselling and income-maximisation services have the potential to reduce financial hardship and its associated burdens on health and wellbeing in High Income Countries. However, referrals to financial counselling services are not systematically integrated into existing health service platforms, thus limiting our ability to identify and link families who might be experiencing financial hardship. Review evidence on this is scarce. The purpose of this study is to review "healthcare-income maximisation" models of care in high-income countries for families of children aged between 0 and 5 years experiencing financial difficulties, and their impacts on family finances and the health and wellbeing of parent(s)/caregiver(s) or children. A systematic review of the MEDLINE, EMBase, PsycInfo, CINAHL, ProQuest, Family & Society Studies Worldwide, Cochrane Library, and Informit Online databases was conducted according to the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) statement. A total of six studies (five unique samples) met inclusion criteria, which reported a total of 11,603 families exposed to a healthcare-income maximisation model. An average annual gain per person of £1661 and £1919 was reported in two studies reporting one Scottish before-after study, whereby health visitors/midwives referred 4805 clients to money advice services. In another UK before-after study, financial counsellors were attached to urban primary healthcare centres and reported an average annual gain per person of £1058. The randomized controlled trial included in the review reported no evidence of impacts on financial or non-financial outcomes, or maternal health outcomes, but did observe small to moderate effects on child health and well-being. Small to moderate benefits were seen in areas relating to child health, preschool education, parenting, child abuse, and early behavioral adjustment. There was a high level of bias in most studies, and insufficient evidence to evaluate the effectiveness of healthcare-income maximisation models of care. Rigorous (RCT-level) studies with clear evaluations are needed to assess efficacy and effectiveness.

Principles and Procedures for Assessment of Acute Toxicity Incorporating In Silico Methods.

Acute toxicity in silico models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an in silico analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed. This framework combines results from different sources including in silico methods and in vitro or in vivo experiments. In silico methods that can assist the prediction of in vivo outcomes (i.e., LD50) are analyzed concluding that predictions obtained using in silico approaches are now well-suited for reliably supporting assessment of LD50-based acute toxicity for the purpose of GHS classification. A general overview is provided of the endpoints from in vitro studies commonly evaluated for predicting acute toxicity (e.g., cytotoxicity/cytolethality as well as assays targeting specific mechanisms). The increased understanding of pathways and key triggering mechanisms underlying toxicity and the increased availability of in vitro data allow for a shift away from assessments solely based on endpoints such as LD50, to mechanism-based endpoints that can be accurately assessed in vitro or by using in silico prediction models. This paper also highlights the importance of an expert review of all available information using weight-of-evidence considerations and illustrates, using a series of diverse practical use cases, how in silico approaches support the assessment of acute toxicity.