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Purpose and scopeThe aim of this position statement is to provide recommendations for clinicians regarding the use of genetic and metabolic investigations for patients with neurodevelopmental disorders (NDDs), specifically, patients with global developmental delay (GDD), intellectual disability (ID) and/or autism spectrum disorder (ASD). This document also provides guidance for primary care and non-genetics specialists caring for these patients while awaiting consultation with a clinical geneticist or metabolic specialist.Methods of statement developmentA multidisciplinary group reviewed existing literature and guidelines on the use of genetic and metabolic investigations for the diagnosis of NDDs and synthesised the evidence to make recommendations relevant to the Canadian context. The statement was circulated for comment to the Canadian College of Medical Geneticists (CCMG) membership-at-large and to the Canadian Pediatric Society (Mental Health and Developmental Disabilities Committee); following incorporation of feedback, it was approved by the CCMG Board of Directors on 1 September 2022.Results and conclusionsChromosomal microarray is recommended as a first-tier test for patients with GDD, ID or ASD. Fragile X testing should also be done as a first-tier test when there are suggestive clinical features or family history. Metabolic investigations should be done if there are clinical features suggestive of an inherited metabolic disease, while the patient awaits consultation with a metabolic physician. Exome sequencing or a comprehensive gene panel is recommended as a second-tier test for patients with GDD or ID. Genetic testing is not recommended for patients with NDDs in the absence of GDD, ID or ASD, unless accompanied by clinical features suggestive of a syndromic aetiology or inherited metabolic disease.

Enteropathy-associated T-cell lymphomas (EATL) are rare and generally aggressive types of peripheral T-cell lymphomas. Rare cases of primary, small intestinal CD4+ T-cell lymphomas with indolent behavior have been described, but are not well characterized. We describe morphologic, phenotypic, genomic and clinical features of 3 cases of indolent primary small intestinal CD4+ T-cell lymphomas. All patients presented with diarrhea and weight loss and were diagnosed with celiac disease refractory to a gluten free diet at referring institutions. Small intestinal biopsies showed crypt hyperplasia, villous atrophy and a dense lamina propria infiltrate of small-sized CD4+ T-cells often with CD7 downregulation or loss. Gastric and colonic involvement was also detected (n = 2 each). Persistent, clonal TCRβ gene rearrangement products were detected at multiple sites. SNP array analysis showed relative genomic stability, early in disease course, and non-recurrent genetic abnormalities, but complex changes were seen at disease transformation (n = 1). Two patients are alive with persistent disease (4.6 and 2.5 years post-diagnosis), despite immunomodulatory therapy; one died due to bowel perforation related to large cell transformation 11 years post-diagnosis. Unique pathobiologic features warrant designation of indolent small intestinal CD4+ T-cell lymphoma as a distinct entity, greater awareness of which would avoid misdiagnosis as EATL or an inflammatory disorder, especially celiac disease.

Patients with villous atrophy (VA) and negative celiac disease (CD) serologies pose a diagnostic and therapeutic dilemma. When a definitive etiology for VA is not determined, patients are characterized as having unclassified sprue (US), the optimal management of which is unknown. We studied adult patients with VA on biopsy and negative celiac serologies, evaluated at our tertiary referral center over a 10-year period. Testing for HLA DQ2/8 alleles, antienterocyte antibodies, giardia stool antigen, bacterial overgrowth, total serum immunoglobulins, and HIV was noted. Treatment, response, and repeat-biopsy findings were recorded. The most common diagnoses of the 72 patients were seronegative CD, medication-related villous atrophy, and US. Of those with US, the majority reported symptomatic improvement with immunosuppressive therapy. Some patients initially labeled as unclassified were found to have VA associated with olmesartan use. The role of medications in the development of VA and the optimal dose and length of immunosuppression for patients with US should be investigated further.

Mental retardation and epilepsy often occur together. They are both heterogeneous conditions with acquired and genetic causes. Where causes are primarily genetic, major advances have been made in unraveling their molecular basis. The human X chromosome alone is estimated to harbor more than 100 genes that, when mutated, cause mental retardation 1 . At least eight autosomal genes involved in idiopathic epilepsy have been identified 2 , and many more have been implicated in conditions where epilepsy is a feature. We have identified mutations in an X chromosome–linked, Aristaless -related, homeobox gene ( ARX ), in nine families with mental retardation (syndromic and nonspecific), various forms of epilepsy, including infantile spasms and myoclonic seizures, and dystonia. Two recurrent mutations, present in seven families, result in expansion of polyalanine tracts of the ARX protein. These probably cause protein aggregation, similar to other polyalanine 3 and polyglutamine 4 disorders. In addition, we have identified a missense mutation within the ARX homeodomain and a truncation mutation. Thus, it would seem that mutation of ARX is a major contributor to X-linked mental retardation and epilepsy.

Tandem DNA repeats vary in the size and sequence of each unit (motif). When expanded, these tandem DNA repeats have been associated with more than 40 monogenic disorders 1 . Their involvement in disorders with complex genetics is largely unknown, as is the extent of their heterogeneity. Here we investigated the genome-wide characteristics of tandem repeats that had motifs with a length of 2–20 base pairs in 17,231 genomes of families containing individuals with autism spectrum disorder (ASD) 2 , 3 and population control individuals 4 . We found extensive polymorphism in the size and sequence of motifs. Many of the tandem repeat loci that we detected correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated expansions of tandem repeats that were rare among population control individuals were significantly more prevalent among individuals with ASD than their siblings without ASD, particularly in exons and near splice junctions, and in genes related to the development of the nervous system and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in children with ASD compared with 20.7% in children without ASD, which suggests that tandem repeat expansions make a collective contribution to the risk of ASD of 2.6%. These rare tandem repeat expansions included previously undescribed ASD-linked expansions in DMPK and FXN , which are associated with neuromuscular conditions, and in previously unknown loci such as FGF14 and CACNB1 . Rare tandem repeat expansions were associated with lower IQ and adaptive ability. Our results show that tandem DNA repeat expansions contribute strongly to the genetic aetiology and phenotypic complexity of ASD. Genome-wide analysis of tandem DNA repeats in the genomes of individuals with autism spectrum disorder and control participants reveals a strong contribution of tandem repeat expansions to the genetic aetiology and phenotypic complexity of autism spectrum disorder.

Introduction The terms coproduction, co‐creation and codesign (called the ‘Three‐Cs’ in this article) are applied to activities that include stakeholders in the design and implementation of health services. This scoping review sought to understand how Three‐Cs approaches have been designed and implemented sustainably in the primary health care context. Methods Three databases (Medline, Embase and CINAHL) were searched for articles published between 2013 and 2024 using key words related to the Three‐Cs and primary health care (Appendix A) and limited to articles available in English. Dual blind review against specific inclusion and exclusion criteria was carried out at both title/ and full text screening stages. The SPICE Framework was used to consider design, implementation, impact and sustainability. An assessment of quality and risk of bias was completed using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist [1]. The Framework to Assess the Impact of Translational (FAIT) health research [2] was used to review and assess the impact of the design and implementation of Three‐Cs approaches in each study. Results Thirty articles were included in this review with 33% (n = 10) providing a clear definition of their Three‐Cs approach: 10% (n = 3) identified their approach as Coproduction, 20% (n = 6) as co‐creation, and 70% (n = 21) as Codesign. Implementation contexts included clinical settings (10%, n = 3), for example prediabetes programs; community settings (50%, n = 15) such as care navigation support; and health systems settings (40%, n = 12) including health service development. Approaches were implemented across metropolitan (37%, n = 11), regional (43%, n = 13), and rural (17%, n = 5) settings. Three‐Cs approaches in primary health care settings were most typically used for health promotion, and to support improved health equity and health access. Key outcomes included novel solutions to problems, improvements to health and health systems, and solutions that met consumer needs. While nine of the 30 studies undertook some form of evaluation, limited evidence on impact and sustainability was found (7%, n = 2), where only two studies assessed whether the change that was implemented using a Three‐Cs approach was maintained in the longer term. Conclusion Three‐Cs approaches have been adopted across a variety of primary health care settings, yet evidence for impact and sustainability is currently limited. More research is needed to evaluate how the Three‐Cs may best be implemented to support the long‐term sustainability of programs designed by such approaches. Future work should focus on developing a primary health care specific framework or guidance for implementing and evaluating Three‐Cs models, particularly in low‐resource settings and in typically underrepresented populations. This study will extend to consider how the FAIT assessment process can help to support the development of much needed implementation guidance.

Background MicroRNAs (miRNAs) are a family of short, non-coding RNAs modulating expression of human protein coding genes (miRNA target genes). Their dysfunction is associated with many human diseases, including neurodevelopmental disorders. It has been recently shown that genomic copy number variations (CNVs) can cause aberrant expression of integral miRNAs and their target genes, and contribute to intellectual disability (ID). Results To better understand the CNV-miRNA relationship in ID, we investigated the prevalence and function of miRNAs and miRNA target genes in five groups of CNVs. Three groups of CNVs were from 213 probands with ID (24 de novo CNVs, 46 familial and 216 common CNVs), one group of CNVs was from a cohort of 32 cognitively normal subjects (67 CNVs) and one group of CNVs represented 40 ID related syndromic regions listed in DECIPHER (30 CNVs) which served as positive controls for CNVs causing or predisposing to ID. Our results show that 1). The number of miRNAs is significantly higher in de novo or DECIPHER CNVs than in familial or common CNV subgroups (P < 0.01). 2). miRNAs with brain related functions are more prevalent in de novo CNV groups compared to common CNV groups. 3). More miRNA target genes are found in de novo , familial and DECIPHER CNVs than in the common CNV subgroup (P < 0.05). 4). The MAPK signaling cascade is found to be enriched among the miRNA target genes from de novo and DECIPHER CNV subgroups. Conclusions Our findings reveal an increase in miRNA and miRNA target gene content in de novo versus common CNVs in subjects with ID. Their expression profile and participation in pathways support a possible role of miRNA copy number change in cognition and/or CNV-mediated developmental delay. Systematic analysis of expression/function of miRNAs in addition to coding genes integral to CNVs could uncover new causes of ID.

Background and AimsCoeliac disease (CD) diagnosis requires the detection of characteristic histological alterations of small bowel mucosa, which are prone to interobserver variability. This study evaluated the agreement in biopsy interpretation between different pathology practice types.MethodsBiopsies from community hospitals (n=46), university hospitals (n=18) and commercial laboratories (n=38) were blindly assessed by a pathologist at our institution for differences in histopathology reporting and agreement in diagnosis of CD and degree of villous atrophy (VA) by κ analysis.ResultsAgreement for primary diagnosis was very good between this institution and university hospitals (κ=0.888), but moderate compared with community hospitals (κ=0.465) or commercial laboratories (κ=0.419). Diagnosis differed in 26 (25%) cases, leading to a 20% increase in CD diagnosis after review. Among those diagnosed with CD by both institutions (n=49), agreement in degree of VA was fair (κ=0.292), with moderate agreement between the authors and commercial laboratories (κ=0.500) and fair with university hospitals (κ=0.290) or community hospitals (κ=0.211). The degree of VA was upgraded in 27% and downgraded in 2%. Within different Marsh score categories, agreement was poor (κ<0.0316) for scores 1 and 2, both missed at other centres, and fair or moderate for scores 3a and 3b. Information regarding degree of VA and intraepithelial lymphocytosis was lacking in 26% and 86% of reports and non-quantifiable descriptors, eg, ‘blunting’ or ‘marked atrophy’ were prevalent.ConclusionsCD-related histological changes are underdiagnosed in community-based hospitals and commercial pathology laboratories. Because incorrect biopsy interpretation can cause underdiagnosis of CD, greater CD awareness and uniformity in small bowel biopsy reporting is required among pathologists.

In 2002/2003, the National Epidemiologic Database for the Study of Autism in Canada started capturing information on children diagnosed with autism in different regions of the country. Based on data collected through 2008 in Newfoundland and Labrador and 2010 in Prince Edward Island and Southeastern Ontario, the estimated average annual percent increases in prevalence among children 2–14 years of age ranged from 9.7 % (95 % CI 7.8–11.6) to 14.6 % (95 % CI 11.3–18.0). Differential in-migration and identification of previously undetected cases may have contributed in part to the increases observed, but we cannot rule out the possibility of a true increase in incidence, particularly given the lack of a leveling-off of prevalence among the 6- to 9-year olds.

Background Integrated care is an increasingly important principle for organising healthcare. Integrated care models show promise in reducing resource wastage and service fragmentation whilst improving the accessibility, patient-centredness and quality of care for patients. Those needing reliable access to the growing research evidence base for integrated care can be frustrated by search challenges reflective of the topic’s complexity. The aim of this study is to report the empirical development and validation of two search filters for rapid and effective retrieval of integrated care evidence in PubMed. One filter is optimised for recall and the other for precision. Methods An Expert Advisory Group comprising international integrated care experts guided the study. A gold standard test set of citations was formed from screening Handbook Integrated Care chapter references for relevance. This set was divided into a Term Identification Set (20%) for determining candidate terms using frequency analysis; a Filter Development Set (40%) for testing performance of term combinations; and a Filter Validation Set (40%) reserved for confirming final filter performance. In developing the high recall filter, recall was steadily increased while maintaining precision at ≥50%. Similarly, the high precision filter sought to maximise precision while keeping recall ≥50%. For each term combination tested, an approximation of precision was obtained by reviewing the first 100 citations retrieved in Medline for relevance. Results The gold standard set comprised 534 citations. The search filter optimised for recall (‘Broad Integrated Care Search’) achieved 86.0–88.3% recall with corresponding low precision (47–53%). The search filter optimised for precise searching (‘Narrow Integrated Care Search’) demonstrated precision of 73–95% with recall reduced to between 55.9 and 59.8%. These filters are now available as one-click URL hyperlinks in the website of International Foundation for Integrated Care. Conclusions The Broad and Narrow Integrated Care Search filters provide potential users, such as policy makers and researchers, seamless, reliable and ongoing access to integrated care evidence for decision making. These filters were developed according to a rigorous and transparent methodology designed to circumvent the challenges of information retrieval posed by this complex, multifaceted topic.