Oligohydramnios or Anhydramnios and Ultrasonically Normal Renal Echotexture Secondary to Autosomal Recessive Renal Tubular Dysgenesis: An Important Consideration in the Prenatal Setting.

INTRODUCTION: Autosomal recessive renal tubular dysgenesis (ARRTD) is a rare disorder of renal tubular development. ARRTD is a severe condition with high risk of fetal demise and early neonatal death, with only limited case reports of survival over 2 years [Clin Kidney J. 2012 Feb 1;5(1):56-8]. Prenatal diagnosis of ARRTD is challenging, and diagnosis has only previously been confirmed after postnatal or post-mortem investigation. CASE: To the best of our knowledge, we describe the first reported case of utilizing targeted genetic testing on the chorionic villous sample (CVS) to identify a homozygous variant in the angiotensinogen (AGT) gene. DISCUSSION: By substantiating the diagnosis of ARRTD prenatally, we allow timely and appropriate counseling during pregnancy.

Recurrent TTN metatranscript-only c.39974-11T>G splice variant associated with autosomal recessive arthrogryposis multiplex congenita and myopathy.

We present eight families with arthrogryposis multiplex congenita and myopathy bearing a TTN intron 213 extended splice-site variant (NM_001267550.1:c.39974-11T>G), inherited in trans with a second pathogenic TTN variant. Muscle-derived RNA studies of three individuals confirmed mis-splicing induced by the c.39974-11T>G variant; in-frame exon 214 skipping or use of a cryptic 3' splice-site effecting a frameshift. Confounding interpretation of pathogenicity is the absence of exons 213-217 within the described skeletal muscle TTN N2A isoform. However, RNA-sequencing from 365 adult human gastrocnemius samples revealed that 56% specimens predominantly include exons 213-217 in TTN transcripts (inclusion rate ≥66%). Further, RNA-sequencing of five fetal muscle samples confirmed that 4/5 specimens predominantly include exons 213-217 (fifth sample inclusion rate 57%). Contractures improved significantly with age for four individuals, which may be linked to decreased expression of pathogenic fetal transcripts. Our study extends emerging evidence supporting a vital developmental role for TTN isoforms containing metatranscript-only exons.

Conversion of the Liver into a Biofactory for DNaseI Using Adeno-Associated Virus Vector Gene Transfer Reduces Neutrophil Extracellular Traps in a Model of Systemic Lupus Erythematosus.

Adeno-associated virus (AAV) vectors are proving to be clinically transformative tools in the treatment of monogenic genetic disease. Rapid ongoing development of this technology promises to not only increase the number of monogenic disorders amenable to this approach but also to bring diseases with complex multigenic and nongenetic etiologies within therapeutic reach. In this study, we explore the broader paradigm of converting the liver into a biofactory for systemic output of therapeutic molecules using AAV-mediated delivery of the endonuclease DNaseI as an exemplar. DNaseI can clear neutrophil extracellular traps (NETs), which are nuclear-protein structures possessing antimicrobial action, also involved in the pathophysiology of clinically troubling immune-mediated diseases. However, a translational challenge is short half-life of the enzyme in vivo (<5 h). This study demonstrates that AAV-mediated liver-targeted gene transfer stably induces serum DNaseI activity to >190-fold above physiological levels. In lupus-prone mice (NZBWF1), the activity was maintained for longer than 6 months, the latest time point tested, and resulted in a clear functional effect with reduced renal presence of neutrophils, NETs, IgG, and complement C3. However, treatment in this complex disease model did not extend lifespan, improve serological endpoints, or preserve renal function, indicating there are elements of pathophysiology not accessible to DNaseI in the NZBWF1 model. We conclude that a translational solution to the challenge of short half-life of DNaseI is AAV-mediated gene delivery and that this may be efficacious in treating disease where NETs are a dominant pathological mechanism.

Adeno-Associated Virus Vector Gene Delivery Elevates Factor I Levels and Downregulates the Complement Alternative Pathway In Vivo.

The complement system is a key component of innate immunity, but impaired regulation influences disease susceptibility, including age-related macular degeneration and some kidney diseases. While complete complement inhibition has been used successfully to treat acute kidney disease, key unresolved challenges include strategies to modulate rather than completely inhibit the system and to deliver therapy potentially over decades. Elevating concentrations of complement factor I (CFI) restricts complement activation in vitro and this approach was extended in the current study to modulate complement activation in vivo. Sustained increases in CFI levels were achieved using an adeno-associated virus (AAV) vector to target the liver, inducing a 4- to 5-fold increase in circulating CFI levels. This led to decreased activity of the alternative pathway as demonstrated by a reduction in the rate of inactive C3b (iC3b) deposition and more rapid formation of C3 degradation products. In addition, vector application in a mouse model of systemic lupus erythematosus (NZBWF1), where tissue injury is, in part, complement dependent, resulted in reduced complement C3 and IgG renal deposition. Collectively, these data demonstrate that sustained elevation of CFI reduces complement activation in vivo providing proof-of-principle support for the therapeutic application of AAV gene delivery to modulate complement activation.

Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the emerging role of genomic analysis.

Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of 'oligodendroglioma-like' appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.

Developing and implementing a targeted health-focused climate communications campaign in Ontario-#MakeItBetter.

SETTING: Public health practitioners are called to effectively communicate with the public on climate change. The climate crisis requires swift action that starts with public awareness of climate-related health impacts and leads to public support for individual, community and systemic actions to mitigate and adapt to climate change. INTERVENTION: This paper discusses learnings about public opinion research and communication strategies and how a health-focused climate communication campaign-#MakeItBetter-could help to increase awareness and engage new audiences, including public health partners, in conversations about climate change in order to reduce climate-related health impacts for current and future generations. The #MakeItBetter campaign was grounded in evidence-informed messaging, being sensitive to health inequities. Emerging research and pre-campaign testing suggest that framing climate change as a health issue is a promising practice. OUTCOMES: The #MakeItBetter campaign appeals to parents/caregivers to learn more about climate-related health impacts, take protective action for children and support multi-level climate action. The campaign launch secured 89 news stories, including multicultural media coverage. Longer-term evaluation is required to determine the campaign's effectiveness in building public support for climate action. IMPLICATIONS: An innovative approach to climate communication that draws on the intersections between behavioural and climate sciences and engages in multi-sectoral collaboration can spur both climate action and health protection, aiding public health practitioners and partners in effectively communicating the urgency for climate action. More work is needed to support communication on climate change as an inequity multiplier and promote climate action and community resilience for health equity co-benefits.

RéSUMé: LIEU: Les praticiens de la santé publique sont appelés à transmettre à la population des messages efficaces sur le changement climatique. La crise climatique nécessite une action rapide qui commence par la sensibilisation du public aux incidences du climat sur la santé et mène à l'aide publique aux actions individuelles, collectives et systémiques pour atténuer le changement climatique et s'y adapter. INTERVENTION: Notre article porte sur les enseignements de la recherche sur l'opinion publique et des stratégies de communication et sur le moyen pour une campagne d'information axée sur les effets du climat sur la santé, #MakeItBetter, de favoriser une prise de conscience et de toucher de nouveaux publics, notamment les partenaires de la santé publique, en nouant un dialogue sur le changement climatique afin de réduire les incidences du climat sur la santé des générations actuelles et futures. Fondée sur des messages factuels, la campagne #MakeItBetter est sensible aux inégalités de santé. Selon la recherche émergente et les essais menés avant la campagne, la pratique qui consiste à présenter le changement climatique comme une question de santé est prometteuse. RéSULTATS: La campagne #MakeItBetter demande aux parents/proches aidants de s'informer des incidences du climat sur la santé, de prendre des mesures pour protéger leurs enfants et d'appuyer une action climatique à plusieurs niveaux. Le lancement de la campagne a été mentionné dans 89 articles, y compris dans la presse multiculturelle. Une évaluation à plus long terme est nécessaire pour déterminer dans quelle mesure la campagne a réussi à convaincre le public d'appuyer l'action climatique. CONSéQUENCES: Une démarche de communication novatrice qui mise sur les liens entre les sciences du comportement et du climat et sur la collaboration multisectorielle peut stimuler à la fois l'action climatique et la protection de la santé, aidant ainsi les praticiens de la santé publique et leurs partenaires à communiquer efficacement l'urgence de l'action climatique. Il faut poursuivre les efforts pour faire comprendre que le changement climatique multiplie les inégalités, et promouvoir l'action climatique et la résilience des populations afin de réaliser des gains connexes sur le plan de l'équité en santé.

Developing a harmonized heat warning and information system for Ontario: a case study in collaboration.

BACKGROUND: Heat wave early warning systems help alert decision-makers and the public to prepare for hot weather and implement preventive actions to protect health. Prior to harmonization, public health units across Ontario either used independent systems with varying methodologies for triggering and issuing public heat warnings or did not use any system. The federal government also issued heat warnings based on different criteria. During heat events, adjacent public health units in Ontario and the federal government would routinely call heat warnings at different times with separate public messages, leading to confusion. This article describes the collaborative process and key steps in developing a harmonized Heat Warning and Information System (HWIS) for Ontario. SETTING: Public health units across Ontario, Canada, collaborated with the federal and provincial government to develop the harmonized HWIS for Ontario. INTERVENTION: In 2011, stakeholders identified the need to develop a harmonized system across Ontario to improve heat warning services, warning criteria, and health messaging. Through a 5-year process facilitated by a non-governmental organization, the three levels of government collaborated to establish the Ontario HWIS. OUTCOMES: The province-wide HWIS was implemented in 2016 with the Ontario Ministry of Health and Long-Term Care's release of the harmonized HWIS Standard Operating Practice, which outlined the notification and warning process. IMPLICATIONS: The lessons learned could help spur action in other provinces and jurisdictions internationally in the development of similar health evidence-based warning systems, including in particular those for protecting public health during extreme heat events.

Case Report of Spontaneous Resolution of a Congenital Glioblastoma.

Glioblastoma multiforme (GBM) is a rare, highly aggressive brain tumor associated with a poor outcome in both children and adults. Treatment usually involves a combination of surgical resection, chemotherapy, and radiotherapy, but ultimately it is incurable. Evidence suggests that congenital GBM may have a better prognosis with improved survival compared with GBM in older children. We describe the first known report of spontaneous resolution of a congenital GBM without any systemic therapy. A limited debulking procedure was performed at diagnosis, and the residual tumor underwent spontaneous resolution over the following 21 months. The patient remains in remission, with no tumor recurrence after 5 years of follow-up. Despite the tumor regressing, the patient has had an adverse neurologic outcome, with severe developmental delay and seizures. This case suggests that congenital GBM may be a separate biological entity much like neuroblastomas in infants, and therefore associated with better outcomes and even spontaneous resolution.