Physical activity and sedentary behaviour and their associations with clinical measures in axial spondyloarthritis

Engaging in physical activity (PA) is a key aspect in the management of axial spondyloarthritis (axial SpA), however, its relationship with clinical measures is unknown. Previous research has mainly focused on subjective methods of measuring PA and sedentary behaviour (SB). The aim of this study was to explore the associations between objectively measured PA and SB with clinical measures in people with established axial SpA. Fifty participants were recruited from secondary-care rheumatology outpatient services in Glasgow, UK. Clinical measures collected included; Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), Ankylosing Spondylitis Quality of Life (ASQOL) and the Six Minute Walk Test (6MWT). PA and SB were measured using the activPAL3 tri-axial accelerometer. Data from forty-five participants were included (23 males, average age 49 ± 12 years). Participants accumulated an average of 93.2 ± 41.5 min/day walking with an average of 7200 ± 3397 steps/day. The majority of the day (65%) was spent sitting, accumulated in prolonged bouts. Walking time and steps taken/day were associated with better BASFI (r = − 0.395, p = 0.007 and r = − 0.404, p = 0.006), ASQOL (r = − 0.375, p = 0.011 and r = − 0.361, p = 0.015) and 6MWT (r = 0.396, p = 0.007 and r = 0.421, p = 0.004); while longer walking events were associated with better BASMI (rho = − 0.352, p = 0.018), BASFI (rho = − 0.316, p = 0.034) and 6MWT (rho = 0.404, p = 0.006). SB was associated with worse ASQOL (r = 0.380, p = 0.010) and 6MWT (6MWT, r = − 0.357, p = 0.016). In people with axial SpA PA is associated with better function, exercise capacity and spinal mobility, while SB is associated with lower exercise capacity and poor quality of life. These findings support the promotion of PA and reduction of SB in people with axial SpA

Level of, and factors affecting adherence to prescribed exercise in people with spondyloarthritis

Background: Spondyloarthritis is a group of chronic inflammatory musculoskeletal diseases for which exercise is considered an essential part of their management. Adherence is a primary determinant of the effectiveness of any intervention and can be influenced by multiple factors. The World Health Organisation proposes that when studying adherence, an approach where adherence is determined by interplay of factors relating to five construct; socioeconomic, healthcare, condition, treatment and patient-related can be used. Currently the level of adherence and factors affecting adherence to prescribed physiotherapy programmes in people with SpA is unknown. Objectives: The aim of the research within this thesis was to investigate the level of, and factors affecting, adherence in people with SpA. Methods: Three studies were undertaken. Firstly, a systematic review of the current literature investigating adherence to prescribed exercise in SpA. Secondly a cohort study to investigate the level of, and factors affecting, adherence to a web-based physiotherapy programme in patients with axial SpA (axSpA), the prototypic SpA condition. Finally, a survey of physiotherapists in the United Kingdom (UK) delivering prescribed exercise programmes to people with SpA, investigating the factors they perceive as affecting adherence and barriers to adopting methods to improve adherence. Results: The systematic review identified and included ten studies with a total of 690 participants. Rates of adherence ranged from 51% to 95%, and in the main were poorly reported. The interventions and measurement of adherence varied across studies, making comparisons difficult. Two studies identified that adherence was improved following educational programmes and one study identified that higher disease severity and longer diagnostic delays were associated with higher adherence rates. One study indicated supervised group exercise increased adherence to HEP whilst another found no difference. Three linked studies by the same authors with the same participants demonstrated that adherence reduced over time. No study within the systematic review measured adherence to a web-based physiotherapy programme. The cohort study found adherence to web-based physiotherapy exercise in people with axSpA was 27.6% of all sessions for all participants over 12-months. When participants started a session, they were likely to complete all the individual exercises within the session (74% versus 26% of the time). Adherence reduced over the course of the intervention. No quantitative factors were found to influence adherence, however participant interviews found that disease symptoms, getting into a routine and support have an important role in influencing adherence. The online survey identified that physiotherapists believe that adherence to prescribed exercises can be low. There were high levels of agreement of the factors affecting adherence to exercise. Within the WHO-proposed healthcare- related construct, good access to physiotherapy and effective medication for symptom control were perceived to improve adherence. Within the disease- related construct, concurrent mental health problems, high disease symptoms and multiple co-morbidities were considered to reduce adherence. Within the socio-economic domain, support increased adherence, while social deprivation reduced adherence. Within the person related construct, the belief the exercise would help and being physically active improved adherence, whilst lack time, interest or confidence and low self-efficacy reduced adherence. Within the treatment related construct, several strategies such as individualising the intervention, including goal setting, providing patient education, could increase adherence. Time was the most common barrier to physiotherapists implementing strategies to improve adherence. Conclusions: This thesis has provided data that adherence to prescribed exercise in people with SpA can be variable, often low and reduces over the course of interventions. This thesis has identified multiple interacting factors within the five constructs suggested by the WHO adherence model which may influence adherence. When prescribing exercise, physiotherapists should consider which factors are potentially affecting adherence within each WHO domain and address key modifiable factors in order to optimise adherence for that individual. Further research is required to compare rates of adherence across different modes of programmes, identifying which factors are most important in influencing adherence on a group level. Finally improving and standardising the measurement of adherence is crucial to facilitate progress and comparisons in this field

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin

Enhanced Maternal Origin of the 22q11.2 Deletion in Velocardiofacial and DiGeorge Syndromes

Velocardiofacial and DiGeorge syndromes, also known as 22q11.2 deletion syndrome (22q11DS), are congenital-anomaly disorders caused by a de novo hemizygous 22q11.2 deletion mediated by meiotic nonallelic homologous recombination events between low-copy repeats, also known as segmental duplications. Although previous studies exist, each was of small size, and it remains to be determined whether there are parent-of-origin biases for the de novo 22q11.2 deletion. To address this question, we genotyped a total of 389 DNA samples from 22q11DS-affected families. A total of 219 (56%) individuals with 22q11DS had maternal origin and 170 (44%) had paternal origin of the de novo deletion, which represents a statistically significant bias for maternal origin (p = 0.0151). Combined with many smaller, previous studies, 465 (57%) individuals had maternal origin and 345 (43%) had paternal origin, amounting to a ratio of 1.35 or a 35% increase in maternal compared to paternal origin (p = 0.000028). Among 1,892 probands with the de novo 22q11.2 deletion, the average maternal age at time of conception was 29.5, and this is similar to data for the general population in individual countries. Of interest, the female recombination rate in the 22q11.2 region was about 1.6–1.7 times greater than that for males, suggesting that for this region in the genome, enhanced meiotic recombination rates, as well as other as-of-yet undefined 22q11.2-specific features, could be responsible for the observed excess in maternal origin

Neurocognitive profiles of 22q11.2 and 16p11.2 deletions and duplications

Rare recurrent copy number variants (CNVs) at chromosomal loci 22q11.2 and 16p11.2 are genetic disorders with lifespan risk for neuropsychiatric disorders. Microdeletions and duplications are associated with neurocognitive deficits, yet few studies compared these groups using the same measures to address confounding measurement differences. We report a prospective international collaboration applying the same computerized neurocognitive assessment, the Penn Computerized Neurocognitive Battery (CNB), administered in a multi-site study on rare genomic disorders: 22q11.2 deletions (n = 492); 22q11.2 duplications (n = 106); 16p11.2 deletion (n = 117); and 16p11.2 duplications (n = 46). Domains examined include executive functions, episodic memory, complex cognition, social cognition, and psychomotor speed. Accuracy and speed for each domain were included as dependent measures in a mixed-model repeated measures analysis. Locus (22q11.2, 16p11.2) and Copy number (deletion/duplication) were grouping factors and Measure (accuracy, speed) and neurocognitive domain were repeated measures factors, with Sex and Site as covariates. We also examined correlation with IQ. We found a significant Locus × Copy number × Domain × Measure interaction (p = 0.0004). 22q11.2 deletions were associated with greater performance accuracy deficits than 22q11.2 duplications, while 16p11.2 duplications were associated with greater specific deficits than 16p11.2 deletions. Duplications at both loci were associated with reduced speed compared to deletions. Performance profiles differed among the groups with particularly poor memory performance of the 22q11.2 deletion group while the 16p11.2 duplication group had greatest deficits in complex cognition. Average accuracy on the CNB was moderately correlated with Full Scale IQ. Deletions and duplications of 22q11.2 and 16p11.2 have differential effects on accuracy and speed of neurocognition indicating locus specificity of performance profiles. These profile differences can help inform mechanistic substrates to heterogeneity in presentation and outcome, and can only be established in large-scale international consortia using the same neurocognitive assessment. Future studies could aim to link performance profiles to clinical features and brain function

Mapping genomic loci implicates genes and synaptic biology in schizophrenia

Schizophrenia has a heritability of 60-80%1, much of which is attributable to common risk alleles. Here, in a two-stage genome-wide association study of up to 76,755 individuals with schizophrenia and 243,649 control individuals, we report common variant associations at 287 distinct genomic loci. Associations were concentrated in genes that are expressed in excitatory and inhibitory neurons of the central nervous system, but not in other tissues or cell types. Using fine-mapping and functional genomic data, we identify 120 genes (106 protein-coding) that are likely to underpin associations at some of these loci, including 16 genes with credible causal non-synonymous or untranslated region variation. We also implicate fundamental processes related to neuronal function, including synaptic organization, differentiation and transmission. Fine-mapped candidates were enriched for genes associated with rare disruptive coding variants in people with schizophrenia, including the glutamate receptor subunit GRIN2A and transcription factor SP4, and were also enriched for genes implicated by such variants in neurodevelopmental disorders. We identify biological processes relevant to schizophrenia pathophysiology; show convergence of common and rare variant associations in schizophrenia and neurodevelopmental disorders; and provide a resource of prioritized genes and variants to advance mechanistic studies