Equity analysis audit of access and utilisation of Special Care Dental Services by ethnicity and social demographic markers.

OBJECTIVE: To identify and investigate any differences in utilisation of the, Sussex Community NHSFT, Special Care Dental Service (SCDS) across multiple demographic factors, including ethnicity, socio-economic groups and age in the Crawley area. METHOD: Data were audited for all new patients seen at the Crawley Special Care Dental Centre from November 2020-October 2021. Demographic data were compared to population data from the 2011 Census. Deprivation data, using Index of Multiple Deprivation, were also examined against utilisation and failure to attend appointments. RESULTS: A total of 1250 new patients accessed the Crawley SCDS between November 2020 and October 2021. The data suggests good equity to the service being utilised by the local community; the proportions of patients utilising the service over the course of a year from different ethnic groups reflected the demographic profile of Crawley. The proportion of failed appointments showed no correlation with deprivation decile. There was also no association between ethnic group and proportion of failed appointments. CONCLUSION: Ensuring equal utilisation of healthcare for all population groups has become a priority for healthcare providers. This audit found minimal inequities in utilisation of the Special Care Dental Service at Crawley.

Mental health and wellbeing coordinators in primary schools to support student mental health: protocol for a quasi-experimental cluster study.

BACKGROUND: Half of mental health disorders begin before the age of 14, highlighting the importance of prevention and early-intervention in childhood. Schools have been identified globally by policymakers as a platform to support good child mental health; however, the majority of the research is focused on secondary schools, with primary schools receiving very little attention by comparison. The limited available evidence on mental health initiatives in primary schools is hindered by a lack of rigorous evaluation. This quasi-experimental cluster study aims to examine the implementation and effectiveness of a Mental Health and Wellbeing Co-ordinator role designed to build mental health capacity within primary schools. METHODS: This is a primary (ages 5-12) school-based cluster quasi-experimental study in Victoria, Australia. Before baseline data collection, 16 schools selected by the state education department will be allocated to intervention, and another 16 matched schools will continue as 'Business as Usual'. In intervention schools, a mental health and well-being coordinator will be recruited and trained, and three additional school staff will also be selected to receive components of the mental health training. Surveys will be completed by consenting staff (at 2-, 5-, 10- and 17-months post allocation) and by consenting parents/carers (at 3-, 10- and 17-months post allocation) in both intervention and business as usual schools. The primary objective is to assess the change in teacher's confidence to support student mental health and wellbeing using the School Mental Health Self-Efficacy Teacher Survey. Secondary objectives are to assess the indirect impact on systemic factors (level of support, prioritisation of child mental health), parent and teachers' mental health literacy (stigma, knowledge), care access (school engagement with community-based services), and student mental health outcomes. Implementation outcomes (feasibility, acceptability, and fidelity) and costs will also be evaluated. DISCUSSION: The current study will examine the implementation and effectiveness of having a trained Mental Health and Wellbeing Coordinator within primary schools. If the intervention increases teachers' confidence to support student mental health and wellbeing and builds the capacity of primary schools it will improve student mental health provision and inform large-scale mental health service reform. TRIAL REGISTRATION: The trial was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) on July 6, 2021. The registration number is ACTRN12621000873820 .

Sleep influences on cardio-metabolic health in Indigenous populations.

Indigenous populations continue to be among the world's most marginalized population groups. Studies in Indigenous populations from high income countries (including the United States, Canada, Australia, and New Zealand) indicate increased risk of sleep disorders compared to non-Indigenous populations. Poor sleep, whether it be short sleep duration or fragmented sleep, is a well-established risk factor for cardio-metabolic diseases. Given the implications, targeted improvement of poor sleep may be beneficial for the health and well-being of Indigenous people. In this narrative review, we will: (1) discuss the effects of sleep on the cardio-metabolic processes; (2) examine sleep in Indigenous populations; (3) review the association between sleep and cardio-metabolic risk in Indigenous populations; and (4) review the potential role of sleep in cardiovascular disease risk detection and interventions to improve sleep and cardio-metabolic health in Indigenous people. In particular, this review highlights that the assessment of sleep quality and quantity may be a beneficial step toward identifying Indigenous people at risk of cardio-metabolic diseases and may represent a key intervention target to improve cardio-metabolic outcomes.

Changes in verbal and visuospatial working memory from Grade 1 to Grade 3 of primary school: Population longitudinal study.

BACKGROUND: Adaptive working memory training is being implemented without an adequate understanding of developmental trajectories of working memory. We aimed to quantify from Grade 1 to Grade 3 of primary school (1) changes in verbal and visuospatial working memory and (2) whether low verbal and visuospatial working memory in Grade 1 predicts low working memory in Grade 3. METHOD: The study design includes a population-based longitudinal study of 1,802 children (66% uptake from all 2,747 Grade 1 students) at 44 randomly selected primary schools in Melbourne, Australia. Backwards Digit Recall (verbal working memory) and Mister X (visuospatial working memory) screening measures from the Automated Working Memory Assessment (M = 100; SD = 15) were used to assess Grades 1 and 3 (ages 6-7 and 8-9 years) students. Low working memory was defined as ≥1 standard deviation below the standard score mean. Descriptive statistics addressed Aim 1, and predictive parameters addressed Aim 2. RESULTS: One thousand seventy (59%) of 1802 Grade 1 participants were reassessed in Grade 3. As expected for typically developing children, group mean standard scores were similar in Grades 1 and 3 for verbal, visuospatial, and overall working memory, but group mean raw scores increased markedly. Compared to "not low" children, those classified as having low working memory in Grade 1 showed much larger increases in both standard and raw scores across verbal, visuospatial, and overall working memory. Sensitivity was very low for Grade 1 low working memory predicting Grade 3 low classifications. CONCLUSION: Although mean changes in working memory standard scores between Grades 1 and 3 were minimal, we found that individual development varied widely, with marked natural resolution by Grade 3 in children who initially had low working memory. This may render brain-training interventions ineffective in the early school year ages, particularly if (as population-based programmes usually mandate) selection occurs within a screening paradigm.

Common variant in VEGFA and response to anti-VEGF therapy for neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in aging populations in industrialized countries. Here we investigated whether the genotype of vascular endothelial growth factor A (VEGFA) gene is associated with response to anti-VEGF therapy. 223 eyes with neovascular AMD were treated with intravitreal anti-VEGF therapy. Responders were defined as patients who had an improvement in best corrected visual acuity (BCVA) of at least 5 letters or one line on the EDTRS visual acuity chart along with resolution of intraretinal or subretinal fluid over 12 months. Patients who did not meet the definition of responders were classified as poor-responders. The vision of responders (n = 148) improved while the vision of poor-responders (n = 75) worsened (P<0.001). Responders on average had a decrease in central foveal thickness (CFT), while poor-responders had an increase in CFT (P <0.001). Compared with the responder group, the poor-responder group had a higher frequency of the risk (T) allele (Allelic P = 0.019) and TT genotype (P = 0.002 under a recessive model) for the VEGFA-rs943080 polymorphism. VEGFA expression was 1.8-fold higher in cells with the VEGFA rs943080 TT genotype than in cells with the VEGFA rs943080 CC genotype (P = 0.012). Age, gender, smoking, diabetes mellitus, and hypertension did not play a significant role in treatment response, but BMI was found to be significantly different between responders and poorresponders (P = 0.033). In conclusion, we demonstrated a potential pharmacogenetic relationship between the VEGFA gene and treatment response to anti-VEGF therapy.The studies are registered at ClinicalTrials.gov under the identifiers NCT00474695 (http://clinicaltrials. gov/ct2/show/NCT00474695) and NCT01464723 (http://clinicaltrials.gov/ct2/show/NCT01464723).

Primary healthcare costs associated with sleep problems up to age 7 years: Australian population-based study.

OBJECTIVES: In Australian 0-7-year olds with and without sleep problems, to compare (1) type and costs to government of non-hospital healthcare services and prescription medication in each year of age and (2) the cumulative costs according to persistence of the sleep problem. DESIGN: Cross-sectional and longitudinal data from a longitudinal population study. SETTING: Data from two cohorts participating in the first two waves of the nationally representative Longitudinal Study of Australian Children. PARTICIPANTS: Baby cohort at ages 0-1 and 2-3 (n=5107, 4606) and Kindergarten cohort at ages 4-5 and 6-7 (n=4983, 4460). MEASUREMENTS: Federal Government expenditure on healthcare attendances and prescription medication from birth to 8 years, calculated via linkage to Australian Medicare data, were compared according to parent report of child sleep problems at each of the surveys. RESULTS: At both waves and in both cohorts, over 92% of children had both sleep and Medicare data. The average additional healthcare costs for children with sleep problems ranged from $141 (age 5) to $43 (age 7), falling to $98 (age 5) to $18 (age 7) per child per annum once family socioeconomic position, child gender, global health and special healthcare needs were taken into account. This equates to an estimated additional $27.5 million (95% CI $9.2 to $46.8 million) cost to the Australian federal government every year for all children aged between 0 and 7 years. In both cohorts, costs were higher for persistent than transient sleep problems. CONCLUSIONS: Higher healthcare costs were sustained by infants and children with sleep problems. This supports ongoing economic evaluations of early prevention and intervention services for sleep problems considering impacts not only on the child and family but also on the healthcare system.

Association of LIPC and advanced age-related macular degeneration.

PURPOSE: To determine whether there is an association between hepatic lipase (LIPC) and age-related macular degeneration (AMD) in two independent Caucasian cohorts. METHODS: A discovery cohort of 1626 patients with advanced AMD and 859 normal controls and a replication cohort of 2159 cases and 1150 controls were genotyped for two single-nucleotide polymorphisms (SNPs) in the promoter region of LIPC. The associations between the SNPs and AMD were examined by χ(2) tests. RESULTS: In the discovery cohort, rs493258 and rs10468017 were both associated with advanced AMD (P=9.63E-3 and P=0.048, respectively). The association was corroborated in the replication cohort (P=4.48E-03 for rs493258 and P=0.015 for rs10468017). Combined analysis resulted in even more significant associations (P=1.21E-04 for rs493258 and P=1.67E-03 for rs10468017). CONCLUSION: The LIPC promoter variants rs493258 and rs10468017 were associated with advanced AMD in two independent Caucasian populations, confirming that LIPC polymorphisms may be a genetic risk factor for AMD in the Caucasian population.

Myotonia congenita with strabismus in a large family with a mutation in the SCN4A gene.

BACKGROUND/AIMS: To determine the genetic basis of myotonia congenita (MC) and strabismus in a large Caucasian family. METHODS: Seven patients making up four generations of a family with MC and strabismus were recruited. All patients had at least one standard ophthalmic examination, including best-corrected visual acuity, refraction, and ocular motility measurements. CLCN1 and SCN4A genes were sequenced and analysed for mutations. RESULTS: Five out of the seven family members were diagnosed with MC by clinical history and electromyography. Ophthalmic history and exam revealed eyelid myotonia and strabismus. All patients with MC were diagnosed with strabismus between the ages of 3 and 6 and required surgical restoration of ocular alignment. Sequencing results revealed a c. 1333G>A; p. Val445Met mutation in the SCN4A gene. CONCLUSION: There are few reports describing eyelid myotonia and strabismus in patients diagnosed with MC. We found significant ocular involvement in a family with a mutation in SCN4A. Future studies may confirm that MC with significant ocular involvement can be used to direct genetic analysis.

A novel compound heterozygous mutation in the BEST1 gene causes autosomal recessive Best vitelliform macular dystrophy.

PURPOSE: To determine the genetic basis of early onset autosomal recessive Best vitelliform macular dystrophy (arBVMD) in a family with three affected children. DESIGN: Clinical and family-based genetic study. METHODS: Seven subjects making up a family with three children affected by Best vitelliform macular dystrophy were studied. Standard ophthalmic exam with dilated ophthalmoscopy and imaging were performed in each individual. The eleven exons of BEST1 were directly sequenced. RESULTS: All three affected children have the clinical characteristic features of Best vitelliform macular dystrophy: large macular vitelliform lesions, scattered vitelliform lesions along the arcades and in the peripheral retina, and an accumulation of serous retinal fluid. A novel compound heterozygous mutation in the BEST1 gene was found in the three affected individuals (L41P and I201T). The unaffected parents and children only harbor one heterozygous mutation. CONCLUSION: arBVMD can be caused by the compound heterozygous mutation L41P and I201T in the BEST1 gene.

The osteoprotegerin/receptor activator of nuclear factor kappaB/receptor activator of nuclear factor kappaB ligand system in cartilage.

OBJECTIVE: The receptor activator of nuclear factor kappaB (RANK) is a member of the tumor necrosis factor receptor family. It is activated by the secreted or cell surface-bound RANK ligand (RANKL). Osteoprotegerin (OPG) is a soluble nonsignaling receptor for RANKL and interferes with RANK activation. This receptor-ligand system regulates the differentiation of osteoclasts and dendritic cells. The present study examined human articular cartilage for the expression of these molecules and the role of RANKL in the regulation of chondrocyte function. METHODS: Normal and osteoarthritic (OA) human articular cartilage was used for explant tissue culture or for isolation of chondrocytes and cell culture. Expression of RANK, RANKL, and OPG was analyzed by immunohistochemistry, Western blotting, or reverse transcription-polymerase chain reaction. Recombinant RANKL was added to cartilage or chondrocyte cultures, and gene expression, collagenase and nitric oxide production, and NF-kappaB activation were determined. RESULTS: RANK, RANKL, and OPG messenger RNA (mRNA) were expressed in normal cartilage. By immunohistochemistry, RANK, RANKL, and OPG were detected in the superficial zone of normal cartilage. OA cartilage contained increased levels of OPG mRNA, and expression of the 3 proteins extended into the midzone of OA cartilage. OPG was detected by Western blotting, and was increased in response to interleukin-1beta stimulation. OPG, RANK, and RANKL protein were also detected in cultured chondrocytes. Addition of exogenous RANKL did not activate NF-kappaB, induce expression of genes encoding proinflammatory mediators in chondrocytes, or stimulate the production of collagenase and nitric oxide. CONCLUSION: These results demonstrate the expression of OPG, RANK, and RANKL in cartilage. However, RANKL does not activate human articular chondrocytes.

IL-18 is produced by articular chondrocytes and induces proinflammatory and catabolic responses.

IL-18, a cytokine originally identified as IFN-gamma-inducing factor, is a member of the IL-1 family of proteins. Because IL-1alpha and IL-1beta are important mediators in the pathogenesis of arthritis, the present study addresses the expression of IL-18 and its role in regulating in articular chondrocytes. IL-18 mRNA was induced by IL-1beta in chondrocytes. Chondrocytes produced the IL-18 precursor and in response to IL-1 stimulation secreted the mature form of IL-18. Studies on IL-18 effects on chondrocytes showed that it inhibits TGF-beta-induced proliferation and enhances nitric oxide production. IL-18 stimulated the expression of several genes in normal human articular chondrocytes including inducible nitric oxide synthase, inducible cyclooxygenase, IL-6, and stromelysin. Gene expression was associated with the synthesis of the corresponding proteins. Treatment of normal human articular cartilage with IL-18 increased the release of glycosaminoglycans. These finding identify IL-18 as a cytokine that regulates chondrocyte responses and contributes to cartilage degradation.

Phenylephrine, endothelin, prostaglandin F2alpha' and leukemia inhibitory factor induce different cardiac hypertrophy phenotypes in vitro.

In these studies, we show that endothelin (ET), leukemia inhibitory factor (LIF), phenylephrine (PE), and prostaglandin F2alpha (PGF2alpha), which are all hypertrophic for neonatal rat cardiac myocytes in culture, induce distinct morphological, physiological, and genetic changes after a 48-h treatment. Transmission electron microscopy revealed differences in myofibril organization, with ET-treated cells containing the most mature-looking myofibrils and PGF2alpha- and LIF-treated cells the least. ET- and PE-treated cultures contained the same number of beating cells as control, but LIF and PGF2alpha treatment increased the number of beating cells 180%. Treatment with LIF, PE, and PGF2alpha increased the beat rate to 3.3 times that of control. After exposure to the beta-adrenergic agonist isoproterenol, the beat rate increased 50% for PGF2alpha' 54% for PE, 84% for LIF, and 125% for control. ET treatment did not increase the beat rate, nor did these cells respond to isoproterenol. ET, LIF, and PE increased the production of atrial natriuretic peptide (ANP) by three-fold and PGF2alpha by 18-fold over nontreated cells. Brain natriuretic peptide (BNP) was increased fourfold by ET and PE, 16-fold by LIF, and 29-fold by PGF2alpha. Interestingly, on a pmol/L basis, only LIF induced more BNP than ANP. Treatment with all agents led to a similar pattern of gene induction: increased expression of the embryonic genes for ANP and skeletal alpha-actin, and less than a twofold change in the constitutively expressed gene myosin light chain-2, with the exception that LIF did not induce skeletal alpha-actin. Each agent, however, induced ANP mRNA with a different time-course. We conclude that at least four distinct cardiac myocyte hypertrophy response programs can be induced in vitro. Further studies are necessary to determine whether these correlate to the different types of cardiac hypertrophy seen in vivo.

Interleukin-17-induced gene expression in articular chondrocytes is associated with activation of mitogen-activated protein kinases and NF-kappaB.

This study examines intracellular signaling events associated with the activation of chondrocytes by the cytokine interleukin-17 (IL-17). Stimulation of normal human articular chondrocytes with IL-17 induced nitric oxide (NO) production, concomitant with an increase in transcripts and de novo translation products of the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) genes. Several other genes associated with inflammation and cartilage degradation, such as IL-1beta, IL-6, and stromelysin, were also up-regulated in IL-17-treated chondrocytes. Among signaling events displaying early response to IL-17 in chondrocytes were the mitogen-activated protein (MAP) kinases ERK1, ERK2, JNK, and p38. DNA binding activity of NF-kappaB was also significantly induced. IL-17 effects on NO release, as well as iNOS, COX-2, and IL-6 protein expression, were inhibited by the anti-inflammatory drug dexamethasone. Importantly, dexamethasone blunted IL-17-dependent activation of MAP kinases, suggesting a mechanistic relationship between these activities and the aforementioned gene expression responses. Similar effects of a lesser extent were observed with the p38-specific inhibitor SB203580. These results suggest that IL-17 activation of chondrocytes is associated with and depends at least in part on the activation of MAP kinases and NF-kappaB.

Chondrocyte-derived apoptotic bodies and calcification of articular cartilage.

Chondrocytes exposed to nitric oxide (NO) or antibody to Fas undergo cell death by apoptosis. This study examines structural and functional properties of chondrocyte-derived apoptotic bodies. In NO treated cartilage, the dense pericellular matrix that normally surrounds the cells is degraded and apoptotic bodies accumulate within and in the vicinity of the chondrocyte lacunae. Functional analysis shows that apoptotic bodies isolated from NO-treated chondrocytes or cartilage produce pyrophosphate. The levels of pyrophosphate produced by apoptotic bodies are increased by pretreatment of the chondrocytes with transforming growth factor beta and decreased by interleukin 1. Apoptotic bodies contain alkaline phosphatase and NTP pyrophosphohydrolase activities and can precipitate calcium. These results suggest that chondrocyte-derived apoptotic bodies express functional properties that may contribute to the pathologic cartilage calcification observed in aging and osteoarthritis.

Differential effects of aging on human chondrocyte responses to transforming growth factor beta: increased pyrophosphate production and decreased cell proliferation.

OBJECTIVE: To address the influence of age on inorganic pyrophosphate (PPi) accumulation in human articular chondrocytes. METHODS: Articular cartilage was obtained from men and women in 2 different age groups: ages 15-55 and 56-91. The effects of transforming growth factor beta1 (TGFbeta1) on PPi levels in the media and cell lysates of chondrocytes were investigated. In addition, the effects of TGFbeta on PPi accumulation were compared with chondrocyte proliferation. RESULTS: TGFbeta1 increased PPi levels to a greater extent in chondrocytes from subjects in the older age group compared with those obtained from younger subjects. Treatment of chondrocytes with TGFbeta1 led to a similar increase in total intracellular protein in both age groups. Although TGFbeta increased nucleoside triphosphate pyrophosphohydrolase activity and decreased alkaline phosphatase activity, these effects did not differ between the 2 age groups. Analysis of the same cell preparations showed an age-related decrease in TGFbeta-induced chondrocyte proliferation, whereas these same cells showed an increased response with respect to PPi elaboration. CONCLUSION: These results show that aging differentially affected TGFbeta-induced PPi accumulation versus proliferation in human articular chondrocytes. These differences in TGFbeta response are likely to contribute to the development of age-associated cartilage diseases such as osteoarthritis.

Interleukin 1 beta suppresses transforming growth factor-induced inorganic pyrophosphate (PPi) production and expression of the PPi-generating enzyme PC-1 in human chondrocytes.

Articular cartilage chondrocytes have the unique ability to elaborate large amounts of extracellular pyrophosphate (PPi), and transforming growth factor beta (TGF beta) appears singular among cartilage regulatory factors in stimulating PPi production. TGF beta caused a time and dose-dependent increase in intracellular and extracellular PPi in human articular chondrocyte cultures. TGF beta and interleukin 1 beta (IL-1 beta) antagonistically regulate certain chondrocyte functions. IL-1 beta profoundly inhibited basal and TGF beta-induced PPi elaboration. To address mechanisms involved with the regulation of PPi synthesis by IL-1 beta and TGF beta, we analyzed the activity of the PPi-generating enzyme NTP pyrophosphohydrolase (NTPPPH) and the PPi-hydrolyzing enzyme alkaline phosphatase. Human chondrocyte NTPPPH activity was largely attributable to plasma cell membrane glycoprotein 1, PC-1. Furthermore, TGF beta induced comparable increases in the activity of extracellular PPi, intracellular PPi, and cellular NTPPPH and in the levels of PC-1 protein and mRNA in chondrocytes as well as a decrease in alkaline phosphatase. All of these TGF beta-induced responses were completely blocked by IL-1 beta. Thus, IL-1 beta may be an important regulator of mineralization in chondrocytes by inhibiting TGF beta-induced PPi production and PC-1 expression.