Diverse clinical features and diagnostic delay in monogenic inborn errors of immunity: A call for access to genetic testing.

Background: Inborn errors of immunity (IEIs) are a group of conditions affecting immune system development and function. Due to their clinical heterogeneity and lack of provider awareness, patients suffer from long diagnostic delays that increase morbidity and mortality. Next-generation sequencing facilitates earlier diagnosis and treatment of IEIs, but too often patients are unable to see the benefit of this technology due to gaps in providers' knowledge regarding which patients to test and barriers to accessing sequencing.

Idiopathic splenomegaly in childhood and the spectrum of RAS-associated lymphoproliferative disease: a case report.

Background: KRAS (KRAS proto-oncogene, GTPase; OMIM: 190,070) encodes one of three small guanosine triphosphatase proteins belonging to the RAS family. This group of proteins is responsible for cell proliferation, differentiation and inhibition of apoptosis. Gain-of-function variants in KRAS are commonly found in human cancers.

Cow's Milk Fat Obesity pRevention Trial (CoMFORT): a primary care embedded randomised controlled trial protocol to determine the effect of cow's milk fat on child adiposity.

Introduction: Cow's milk is a dietary staple for children in North America. Though clinical guidelines suggest children transition from whole (3.25% fat) milk to reduced (1% or 2%) fat milk at age 2 years, recent epidemiological evidence supports a link between whole milk consumption and lower adiposity in children.

Guidance on development and operation of Young Persons' Advisory Groups.

Background: Engaging patients and the public as collaborators in research is increasingly recognised as important as such partnerships can help improve research relevance and acceptability. Young Persons' Advisory Groups (YPAGs) provide a forum for clinical researchers and triallists to engage with children and young people on issues relevant to the design, conduct and translation of paediatric clinical trials. Until fairly recently, there was very little information available to guide the successful development and operation of YPAGs.

The Canadian Rare Diseases Models and Mechanisms (RDMM) Network: Connecting Understudied Genes to Model Organisms.

Advances in genomics have transformed our ability to identify the genetic causes of rare diseases (RDs), yet we have a limited understanding of the mechanistic roles of most genes in health and disease. When a novel RD gene is first discovered, there is minimal insight into its biological function, the pathogenic mechanisms of disease-causing variants, and how therapy might be approached. To address this gap, the Canadian Rare Diseases Models and Mechanisms (RDMM) Network was established to connect clinicians discovering new disease genes with Canadian scientists able to study equivalent genes and pathways in model organisms (MOs).

π-Expanded Thioxanthones - Engineering the Triplet Level of Thioxanthone Sensitizers for Lanthanide-Based Luminescent Probes with Visible Excitation.

Bright lanthanide based probes for optical bioimaging must rely on the antenna principle, where the lanthanide-centred excited state is formed by a complex sensitization process. Efficient sensitization of lanthanide-centred emission occurs via triplet states centred on the sensitizing chromophore. Here, the triplet state of thioxanthone chromophores is modulated by extending the π-system.

π-Expanded Thioxanthones-Engineering the Triplet Level of Thioxanthone Sensitizers for Lanthanide-Based Luminescent Probes with Visible Excitation.

Invited for this month's cover are the collaborating groups of Dr. Thomas Just Sørensen at the University of Copenhagen, Denmark and Dr. Robert Pal at Durham University, United Kingdom.

A Germline Mutation in the C2 Domain of PLCγ2 Associated with Gain-of-Function Expands the Phenotype for PLCG2-Related Diseases.

We report three new cases of a germline heterozygous gain-of-function missense (p.(Met1141Lys)) mutation in the C2 domain of phospholipase C gamma 2 (PLCG2) associated with symptoms consistent with previously described auto-inflammation and phospholipase Cγ2 (PLCγ2)-associated antibody deficiency and immune dysregulation (APLAID) syndrome and pediatric common variable immunodeficiency (CVID). Functional evaluation showed platelet hyper-reactivity, increased B cell receptor-triggered calcium influx and ERK phosphorylation.

Shining light on the excited state energy cascade in kinetically inert Ln(iii) complexes of a coumarin-appended DO3A ligand.

Our understanding of the solution structure of the complexes between a coumarin-appended 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A) ligand and Eu(iii), Gd(iii), Tb(iii) and Y(iii) ions allows us to investigate the excited state energy transfer cascade that result in sensitised lanthanide centred luminescence, and we can do so in unprecedented detail. Spectroscopic data from solutions with ambient oxygen levels, without oxygen and solid solutions at 77 K unequivocally show that the simple model for the antenna principle is not valid. We find that the Tb(iii) complex photophysics is determined by the non-emissive 5D3 state, not the emissive 5D4 state as usually assumed.

Clinical presentation, immunologic features, and hematopoietic stem cell transplant outcomes for IKBKB immune deficiency.

IKBKB immune deficiency is a rare but life-threatening primary immunodeficiency disorder, involving activation defects in adaptive and innate immunity. We present sixteen cases of a homozygous IKBKB mutation (c.1292dupG) in infants characterized by early-onset bacterial, viral, fungal and Mycobacterial infections.

Considerations for adaptive design in pediatric clinical trials: study protocol for a systematic review, mixed-methods study, and integrated knowledge translation plan.

Background: Although children have historically been excluded from clinical trials (CTs), many require medicines tested and approved in CTs, forcing health care providers to treat their pediatric patients based on extrapolated data. Unfortunately, traditional randomized CTs can be slow and resource-intensive, and they often require multi-center collaboration. However, an adaptive design (AD) framework for CTs could be used to increase the efficiency of pediatric CTs by incorporating prospectively planned modifications to CT methods without undermining the integrity or validity of the study.

Genome-wide sequencing in acutely ill infants: genomic medicine's critical application?

Diagnostic genome-wide sequencing (exome or genome sequencing and data analysis for high-penetrance disease-causing variants) in acutely ill infants appears to be clinically useful, but the value of this diagnostic test should be rigorously demonstrated before it is accepted as a standard of care. This white paper was developed by the Paediatric Task Team of the Global Alliance for Genomics and Health's Regulatory and Ethics Work Stream to address the question of how we can determine the clinical value of genome-wide sequencing in infants in an intensive care setting. After reviewing available clinical and ethics literature on this question, we conclude that evaluating diagnostic genome-wide sequencing as a comprehensive scan for major genetic disease (rather than as a large panel of single-gene tests) provides a practical approach to assessing its clinical value in acutely ill infants.

Composed in the f-block: solution structure and function of kinetically inert lanthanide(iii) complexes.

It has been more than 15 years since the last authoritative report on the solution structure of lanthanide complexes made from cylcen derived polydentate ligands. The field has progressed and diversified, and tools have been developed that should enable a step-change in the field in the imminent future. This will only happen if the tools are used, and the results communicated in a form that is consistent within the field and readily accesible to scientists outside the field.

Investigating subtle 4f vs. 5f coordination differences using kinetically inert Eu(iii), Tb(iii), and Cm(iii) complexes of a coumarin-appended 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (DO3A) ligand.

In order to reveal subtle differences between the solution chemistries of trivalent 4f and 5f elements, the physicochemical and photophysical properties of europium(iii), terbium(iii) and curium(iii) complexes formed with a 7-methoxy-coumarin appended 1,4,7,10-tetraazadodecane-1,4,7-triacid (DO3A) ligand were studied. All three complexes were found to be kinetically inert and exhibit stability constants similar to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) equivalents. The Cm(iii) and Eu(iii) complexes feature strong sensitised emission, while the triplet energy of the coumarin prohibits efficient sensitisation of the Tb(iii) analogue.

Shining light on the antenna chromophore in lanthanide based dyes.

Lanthanide based dyes and assays exploit the antenna effect, where a sensitiser-chromophore is used as a light harvesting antenna and subsequent excited state energy transfer populates the emitting lanthanide centred excited state. A rudimentary understanding of the design criteria for designing efficient dyes and assays based on the antenna effect is in place. By preparing kinetically inert lanthanide complexes based on the DO3A scaffold, we are able to study the excited state energy transfer from a 7-methoxy-coumarin antenna chromophore to europium(iii) and terbium(iii) centred excited states.

Rationalizing substituent effects in 1-azathioxanthone photophysics.

The influence of an electron donating substituent on the photophysical properties of 1-azathioxanthone dyes has been investigated using optical spectroscopy and theoretical models. The motivation behind the study is based on the fact that thioxanthones are efficient triplet sensitizers, and thus promising sensitizers for lanthanide centered emission. By adding an aza group to one of the phenyl ring systems, direct coordination to a lanthanide center becomes possible, which makes azathoixanthones great candidates as antenna chromophores in lanthanide(III) based dyes.

LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State.

The low-density lipoprotein receptor-related protein 1, LRP1, interacts with APP and affects its processing. This is assumed to be mostly caused by the impact of LRP1 on APP endocytosis. More recently, also an interaction of APP and LRP1 early in the secretory pathway was reported whereat retention of LRP1 in the ER leads to decreased APP cell surface levels and in turn, to reduced Aβ secretion.

Kinetically Inert Lanthanide Complexes as Reporter Groups for Binding of Potassium by 18-crown-6.

The barcode-like spectrum of lanthanide-centered emission has been used in imaging and to make responsive luminescent reporters. The intensities and the shapes of each line in the luminescence spectrum can also report on the coordination environment of the lanthanide ion. Here, we used lanthanide-centered emission to report on the binding of potassium in an 18-crown-6 binding pocket.

Evaluation of a Novel Mobile Exergame in a School-Based Environment.

Physical inactivity is increasing among children globally and has been directly linked to the growing problems of overweight and obesity. We aim to assess the impact of a new mobile exergame, MobileKids Monster Manor (MKMM), in a school-based setting. MKMM, developed with input from youth to enhance physical activity, is wirelessly connected to an accelerometer-based activity monitor.

IRAK-4 deficiency as a cause for familial fatal invasive infection by Streptococcus pneumoniae.

In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4. The letter also highlights the importance of invasive pneumococcal infection as a critical 'red flag' warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency.

Assessment of a Mobile Game ("MobileKids Monster Manor") to Promote Physical Activity Among Children.

Objective: The majority of children in North America are not meeting current physical activity guidelines. The purpose of this study was to evaluate the impact of a mobile phone game ("MobileKids Monster Manor") as a tool to promote voluntary physical activity among children.

Materials And Methods: The game integrates data from an accelerometer-based activity monitor (Tractivity(®); Kineteks Corp.