Explore the vast range of titles available.

Importance Although pathological demand avoidance (PDA; also known as “extreme” or “persistent” demand avoidance and persistent drive for autonomy) was first described in 1980 as a distinct behavioral profile among a subgroup of children with autism spectrum disorder, there is limited scientific evidence to support children with PDA or their parents/guardians. Objective To establish the feasibility and acceptability of the Paradigm Shift Program®, a 12‐week educational and training program for parents and guardians of children with PDA. Methods Seventy‐six parents/guardians of children with PDA were enrolled in the study. Prior to the start of the program, the parents/guardians completed a baseline assessment (demographic questions, program expectations, and several patient‐reported outcomes [PROs] and proxy measures). At the end of the program, parents/guardians repeated the PROs and proxy measures, and completed a feasibility and acceptability questionnaire and anchor items. Results A total of 71 parents/guardians completed the pre‐program assessment, and 60 (85%) completed the end‐of‐program assessment. Among those with both assessments, program acceptability was high, and parents/guardians were generally satisfied with the different program elements (level of agreement >70% for agreed or strongly agreed). Parents/guardians reported significant improvement in health‐related quality of life (HRQOL) in 10 of the 13 PROs (all P < 0.05). Parent/guardian proxy reports also indicated significant improvements in demand characteristics (P < 0.05), as well as a trend for significant improvement in conduct problems (P = 0.08), total difficulties (P = 0.05), and externalizing behavior (P = 0.05), in their child with PDA. Interpretation The paradigm shift program was both feasible and acceptable. Furthermore, there was evidence that this program improved the HRQOL of parents/guardians as well as the behavior of children with PDA. The Paradigm Shift Program, a comprehensive training program for parents of neurodivergent children with pathological demand avoidance (PDA), was feasible and acceptable, and there were significant improvements in parents’ well‐being following program completion. As the first examination of a parent‐focused intervention for PDA, results suggest a promising alternative to traditional programs.

Age-related macular degeneration (AMD) is a leading cause of blindness. Genetic variants at the chromosome 1q31.3 encompassing the complement factor H ( CFH , FH) and CFH related genes ( CFHR1-5 ) are major determinants of AMD susceptibility, but their molecular consequences remain unclear. Here we demonstrate that FHR-4 plays a prominent role in AMD pathogenesis. We show that systemic FHR-4 levels are elevated in AMD ( P -value = 7.1 × 10 −6 ), whereas no difference is seen for FH. Furthermore, FHR-4 accumulates in the choriocapillaris, Bruch’s membrane and drusen, and can compete with FH/FHL-1 for C3b binding, preventing FI-mediated C3b cleavage. Critically, the protective allele of the strongest AMD-associated CFH locus variant rs10922109 has the highest association with reduced FHR-4 levels ( P -value = 2.2 × 10 −56 ), independently of the AMD-protective CFHR1–3 deletion, and even in those individuals that carry the high-risk allele of rs1061170 (Y402H). Our findings identify FHR-4 as a key molecular player contributing to complement dysregulation in AMD. A locus on chromosome 1 encompassing the CFHR genes is highly associated with AMD risk. Here, Cipriani and colleagues investigate the role of CFHR4 , encoding FHR-4, and demonstrate a relationship between AMD risk, circulating FHR-4 levels and genetic variants at this locus.

Genome-wide association studies (GWAS) for late stage age-related macular degeneration (AMD) have identified 52 independent genetic variants with genome-wide significance at 34 genomic loci. Typically, such an approach rarely results in the identification of functional variants implicating a defined gene in the disease process. We now performed a transcriptome-wide association study (TWAS) allowing the prediction of effects of AMD-associated genetic variants on gene expression. The TWAS was based on the genotypes of 16,144 late-stage AMD cases and 17,832 healthy controls, and gene expression was imputed for 27 different human tissues which were obtained from 134 to 421 individuals. A linear regression model including each individuals imputed gene expression data and the respective AMD status identified 106 genes significantly associated to AMD variants in at least one tissue (Q-value < 0.001). Gene enrichment analysis highlighted rather systemic than tissue- or cell-specific processes. Remarkably, 31 of the 106 genes overlapped with significant GWAS signals of other complex traits and diseases, such as neurological or autoimmune conditions. Taken together, our study highlights the fact that expression of genes associated with AMD is not restricted to retinal tissue as could be expected for an eye disease of the posterior pole, but instead is rather ubiquitous suggesting processes underlying AMD pathology to be of systemic nature.

Raised intraocular pressure (IOP) is the most important risk factor for developing glaucoma, the second commonest cause of blindness globally. Understanding associations with IOP and variations in IOP between countries may teach us about mechanisms underlying glaucoma. We examined cross-sectional associations with IOP in 43,500 European adults from 12 cohort studies belonging to the European Eye Epidemiology (E³) consortium. Each study conducted multivariable linear regression with IOP as the outcome variable and results were pooled using random effects meta-analysis. The association of standardized study IOP with latitude was tested using meta-regression. Higher IOP was observed in men (0.18 mmHg; 95 % CI 0.06, 0.31; P = 0.004) and with higher body mass index (0.21 mmHg per 5 kg/m²; 95 % CI 0.14, 0.28; P < 0.001), shorter height (–0.17 mmHg per 10 cm; 95 % CI –0.25, –0.08; P < 0.001), higher systolic blood pressure (0.17 mmHg per 10 mmHg; 95 % CI 0.12, 0.22; P < 0.001) and more myopic refraction (0.06 mmHg per Dioptre; 95 % CI 0.03, 0.09; P < 0.001). An inverted U-shaped trend was observed between age and IOP, with IOP increasing up to the age of 60 and decreasing in participants older than 70 years. We found no significant association between standardized IOP and study location latitude (P = 0.76). Novel findings of our study include the association of lower IOP in taller people and an inverted-U shaped association of IOP with age. We found no evidence of significant variation in IOP across Europe. Despite the limited range of latitude amongst included studies, this finding is in favour of collaborative pooling of data from studies examining environmental and genetic determinants of IOP in Europeans.