Watch me grow integrated (WMG-I): protocol for a cluster randomised controlled trial of a web-based surveillance approach for developmental screening in primary care settings

Introduction The increasing prevalence of developmental disorders in early childhood poses a significant global health burden. Early detection of developmental problems is vital to ensure timely access to early intervention, and universal developmental surveillance is recommended best practice for identifying issues. Despite this, there is currently considerable variation in developmental surveillance and screening between Australian states and territories and low rates of developmental screening uptake by parents. This study aims to evaluate an innovative web-based developmental surveillance programme and a sustainable approach to referral and care pathways, linking primary care general practice (GP) services that fall under federal policy responsibility and state government-funded child health services. Methods and analysis The proposed study describes a longitudinal cluster randomised controlled trial (c-RCT) comparing a â € Watch Me Grow Integrated' (WMG-I) approach for developmental screening, to Surveillance as Usual (SaU) in GPs. Forty practices will be recruited across New South Wales and Queensland, and randomly allocated into either the (1) WMG-I or (2) SaU group. A cohort of 2000 children will be recruited during their 18-month vaccination visit or opportunistic visit to GP. At the end of the c-RCT, a qualitative study using focus groups/interviews will evaluate parent and practitioner views of the WMG-I programme and inform national and state policy recommendations. Ethics and dissemination The South Western Sydney Local Health District (2020/ETH01625), UNSW Sydney (2020/ETH01625) and University of Queensland (2021/HE000667) Human Research Ethics Committees independently reviewed and approved this study. Findings will be reported to the funding bodies, study institutes and partners; families and peer-reviewed conferences/publications

Relevance of laboratory testing for the diagnosis of primary immunodeficiencies: a review of case-based examples of selected immunodeficiencies

The field of primary immunodeficiencies (PIDs) is one of several in the area of clinical immunology that has not been static, but rather has shown exponential growth due to enhanced physician, scientist and patient education and awareness, leading to identification of new diseases, new molecular diagnoses of existing clinical phenotypes, broadening of the spectrum of clinical and phenotypic presentations associated with a single or related gene defects, increased bioinformatics resources, and utilization of advanced diagnostic technology and methodology for disease diagnosis and management resulting in improved outcomes and survival. There are currently over 200 PIDs with at least 170 associated genetic defects identified, with several of these being reported in recent years. The enormous clinical and immunological heterogeneity in the PIDs makes diagnosis challenging, but there is no doubt that early and accurate diagnosis facilitates prompt intervention leading to decreased morbidity and mortality. Diagnosis of PIDs often requires correlation of data obtained from clinical and radiological findings with laboratory immunological analyses and genetic testing. The field of laboratory diagnostic immunology is also rapidly burgeoning, both in terms of novel technologies and applications, and knowledge of human immunology. Over the years, the classification of PIDs has been primarily based on the immunological defect(s) ("immunophenotype") with the relatively recent addition of genotype, though there are clinical classifications as well. There can be substantial overlap in terms of the broad immunophenotype and clinical features between PIDs, and therefore, it is relevant to refine, at a cellular and molecular level, unique immunological defects that allow for a specific and accurate diagnosis. The diagnostic testing armamentarium for PID includes flow cytometry - phenotyping and functional, cellular and molecular assays, protein analysis, and mutation identification by gene sequencing. The complexity and diversity of the laboratory diagnosis of PIDs necessitates many of the above-mentioned tests being performed in highly specialized reference laboratories. Despite these restrictions, there remains an urgent need for improved standardization and optimization of phenotypic and functional flow cytometry and protein-specific assays. A key component in the interpretation of immunological assays is the comparison of patient data to that obtained in a statistically-robust manner from age and gender-matched healthy donors. This review highlights a few of the laboratory assays available for the diagnostic work-up of broad categories of PIDs, based on immunophenotyping, followed by examples of disease-specific testing

The changing epidemiology of oral cancer: definitions, trends, and risk factors

Objective This review has three objectives, namely: (i) to discuss how oral cancer is and ought to be defined and recorded; (ii) to present up-to-date data on the incidence burden of the disease in the four countries of the UK, and review recent analyses of trends in the disease; and (iii) to summarise recent evidence on risk factors of the disease. Methods Cancer definitions were clarified by the International Classification of Diseases accounting for anatomical and aetiological differences; descriptive epidemiology included international / UK literature review and information requests for incidence data from the UK cancer registries (2000-2016); analytical epidemiology focused on reviewing the findings of the International Head and Neck Cancer Epidemiology (INHANCE) consortium, which has pooled data from multiple case-control studies providing the best estimates of risk factors. Results Emerging evidence of the role played by risk factors in different anatomical sites means that oral cavity cancer and oropharynx cancer should be considered distinct disease entities – and a standardised attribution of anatomical subsites will be helpful in ensuring consistency in how data are presented. In 2016, over 3,700 people were diagnosed with oral cavity cancer and over 3,500 people were diagnosed with oropharyngeal cancer in the UK. Incidence of oropharyngeal cancer is rapidly rising across the UK. Rates of oral cavity cancer are higher in Northern Ireland and higher still (and relatively stable) in Scotland, but rising in England and Wales. INHANCE data show that while the consumption of alcohol and tobacco are the prime risk factors for oral cavity and oropharyngeal cancers, they provide greater certainty in the preventive benefits of reducing these risk factors. The role played by other factors such as low socioeconomic status, genetics, oral health, and human papillomavirus (only for oropharyngeal cancer) have become clearer. Conclusions This epidemiology provides a strong foundation for designing and managing both population and individual oral cavity and oropharyngeal cancer control strategies

Age related endocrine patterns observed in polycystic ovary syndrome patients vs. ovulatory controls: descriptive data from a university based infertility center

ABSTRACT Objective To compare serum anti-Müllerian hormone (AMH) and other endocrine parameters between patients diagnosed with polycystic ovary syndrome (PCOS) and age-matched ovulatory women. Materials and methods AMH, DHEAS, FSH, LH, PRL, TSH and total testosterone (TT) were prospectively measured in oligo-ovulatory PCOS patients (n = 595) and in ovulatory non-PCOS women (n = 157) referred to a tertiary infertility center. Mean BMI was similar across the two study populations and there were no smokers in the sample. Patients in both groups were further classified into three categories by age: < 25 yrs, 25-34 yrs, and &#8805; 35 yrs. Selected clinical and demographic characteristics were tabulated for each group. Results Serum AMH was significantly higher among PCOS patients compared to non-PCOS controls in the non-stratified sample (7.54 ± 5.8 vs. 2.49 ± 2.0 ng/mL, respectively; p < 0.0001), while serum FSH, DHEAS, TSH and prolactin were similar for both groups (p > 0.05). As expected, mean (total) testosterone levels were notably different between PCOS vs. non-PCOS controls (0.84 ± 0.76 vs. 0.43 ± 0.38 ng/mL, respectively; p < 0.001), and mean AMH level was significantly lower in the oldest age category (> 35 yrs) compared to both younger control groups (p < 0.0001). Both DHEAS and total testosterone decreased with age among PCOS patients, although mean serum DHEAS for women age > 35 yrs was significantly lower than DHEAS measured in younger women with PCOS (p < 0.02). For PCOS patients, AMH remained relatively stable irrespective of age. Conclusion Although AMH can serve as a satisfactory marker of ovarian reserve, for PCOS patients the expected decline in AMH associated with reproductive aging appears attenuated despite ovarian senescence. In contrast, mean DHEAS levels were markedly lower among older PCOS women (> 35 yrs) compared to younger PCOS patients

Subependymal giant cell astrocytomas are characterized by mTORC1 hyperactivation, a very low somatic mutation rate, and a unique gene expression profile

Subependymal giant-cell astrocytomas (SEGAs) are slow-growing brain tumors that are a hallmark feature seen in 5–10% of patients with Tuberous Sclerosis Complex (TSC). Though histologically benign, they can cause serious neurologic symptoms, leading to death if untreated. SEGAs consistently show biallelic loss of TSC1 or TSC2. Herein, we aimed to define other somatic events beyond TSC1/TSC2 loss and identify potential transcriptional drivers that contribute to SEGA formation. Paired tumor-normal whole-exome sequencing was performed on 21 resected SEGAs from 20 TSC patients. Pathogenic variants in TSC1/TSC2 were identified in 19/21 (90%) SEGAs. Copy neutral loss of heterozygosity (size range: 2.2–46 Mb) was seen in 76% (16/21) of SEGAs (44% chr9q and 56% chr16p). An average of 1.4 other somatic variants (range 0–7) per tumor were identified, unlikely of pathogenic significance. Whole transcriptome RNA-sequencing analyses revealed 190 common differentially expressed genes in SEGA (n = 16, 13 from a prior study) in pairwise comparison to each of: low grade diffuse gliomas (n = 530) and glioblastoma (n = 171) from The Cancer Genome Atlas (TCGA) consortium, ganglioglioma (n = 10), TSC cortical tubers (n = 15), and multiple normal tissues. Among these, homeobox transcription factors (TFs) HMX3, HMX2, VAX1, SIX3; and TFs IRF6 and EOMES were all expressed >12-fold higher in SEGAs (FDR/q-value < 0.05). Immunohistochemistry supported the specificity of IRF6, VAX1, SIX3 for SEGAs in comparison to other tumor entities and normal brain. We conclude that SEGAs have an extremely low somatic mutation rate, suggesting that TSC1/TSC2 loss is sufficient to drive tumor growth. The unique and highly expressed SEGA-specific TFs likely reflect the neuroepithelial cell of origin, and may also contribute to the transcriptional and epigenetic state that enables SEGA growth following two-hit loss of TSC1 or TSC2 and mTORC1 activation