Alberta Children's Hospital

Hypogammaglobulinemia is a common side effect of rituximab that can result in life-threatening infections. The risk of hypogammaglobulinemia and infections should be weighed against the effectiveness of rituximab for nephrotic syndrome management. Prospero registration: CRD42024536465. •Rituximab, a chimeric anti-CD20 monoclonal antibody, is commonly used for complicated pediatric nephrotic syndrome. •Post-rituximab hypogammaglobulinemia is a recognized adverse effect that may predispose to severe, including fatal, infections; however, the magnitude of risk of poorly understood in pediatric population. •The pooled incidence of hypogammaglobulinemia in children with nephrotic syndrome receiving rituximab was 11.4%. Rituximab exposure was associated with a significantly higher risk of hypogammaglobulinemia compared with children not receiving rituximab (risk ratio 1.81). •In 517 episodes of hypogammaglobulinemia, 93 (18%) infections occurred, four of which were fatal.

Legumain (Lgmn) is a virulence factor found in the protozoan parasites Blastocystis and Trichomonas, which affect both humans and animals. However, its specific targets and cytotoxic mechanisms on host cells are not well understood. Recent findings show that Lgmn cleaves PAR2 at the N30-R31 residue, a site also targeted by L-asparaginase, a vital treatment for acute lymphoblastic leukemia (ALL), a severe hematologic cancer that poses high risks to children. This emphasizes the urgent need for more effective therapeutic strategies. Here, we demonstrate that Lgmn induces ER Ca2+ release via the µ-OR1-Gαi and PAR2-Gαq pathways. In PAR2-knockdown ALL cells, the stimulation of adenylate cyclase (AC) with forskolin or treatment with 8-CPT-cAMP effectively inhibits Lgmn-induced µ-OR1-mediated ER Ca2+ release, indicating that Lgmn's stimulation of µ-OR1 results in the downregulation of AC and a subsequent decrease in cAMP levels. Additionally, the PKA-specific inhibitor 14-22 amide alone triggers ER Ca2+ release, and subsequent treatment with Lgmn does not enhance this effect, suggesting that PKA inhibition plays a role and that the Lgmn-µ-OR1-AC-cAMP axis can be bypassed in µ-OR1-mediated ER Ca2+ release. Furthermore, we observed a corresponding reduction in the phosphorylation of PLCβ3 at Ser1105 and BAD at Ser118, both of which are regulated by PKA. The Lgmn-induced ER Ca2+ release ultimately leads to apoptosis in ALL cells, which can be reversed by blocking ER Ca2+ release. Our results thus provide novel insights into the specific targets of Lgmn secreted from the protozoa and demonstrate how this virulence factor induces cytotoxic effects on host cells, paving the way for innovative therapeutic strategies for patients with ALL.

Abstract Coronary artery disease increases risk of cognitive decline and stroke and is associated with white matter alterations. However, the biological basis of these changes remains unclear. Myelin content and iron deposition are crucial measures of white matter health and can be measured with quantitative MRI. This study investigated whether myelin and iron alterations occur in coronary artery disease, and their relationship with cognition. In this cross-sectional study, 46 individuals with coronary artery disease and 40 healthy controls aged > 50 years, with normal cognition underwent 3T MRI and cognitive assessments. Quantitative MRI metrics (susceptibility, magnetization transfer saturation, R 2 ∗ and R 1 relaxation rates) were calculated in the border zones between adjacent arterial territories (watershed regions) and in the areas outside these borders (non-watershed regions). Relative to controls, the coronary artery disease group showed lower myelin and higher iron content, as measured by lower magnetization transfer saturation and R 1 , and higher susceptibility specifically in watershed regions. Importantly, these microstructural alterations were associated with poorer cognitive performance in the coronary artery disease group with lower magnetization transfer and R 1 related to poorer global cognition and with higher magnetic susceptibility with poorer verbal memory. These findings suggest that coronary artery disease is associated with demyelination and iron deposition in white matter, most prominently in watershed regions, which are known for their susceptibility to stroke. The association of these microstructural alterations with cognition highlights the role of white matter as a key vulnerable region and a promising focus for future mechanistic and therapeutic studies.

Zusammenfassung Das Feld der klinischen und molekularen Genetik bei an Epilepsie erkrankten Personen entwickelt sich rasant weiter. In dieser Übersichtsarbeit bietet das Expertenpanel „Epilepsie und Genetik“ der Deutschen Gesellschaft für Epileptologie (DGfE) einen aktualisierten Überblick über die neuen Entwicklungen, sowohl klinisch etabliert als auch derzeit nur im Forschungskontext durchgeführt. Diese bauen auf der vorherigen Version von 2023 der allgemeinen Empfehlungen auf und ergänzen diese mit speziellen Aspekten. Hervorgehoben werden dabei moderne Ansätze in der Interpretation von Varianten unklarer Signifikanz, das Vorgehen bei ungelösten Fällen anhand von neuartigen Sequenziertechnologien und Omics-Ansätzen, die zunehmende Rolle der prä- und postoperativen Sequenzierung im Rahmen der Epilepsiechirurgie und die Risikostratifizierung anhand von polygenen Scores. Aus diesen Aspekten ergeben sich teils unmittelbar klinisch anwendbare Konsequenzen für alle Teilbereiche der Epileptologie.

Triheptanoin is an anaplerotic agent to provide substrates to the TCA cycle. This novel therapy improved neurodevelopmental outcome in our patient with PDE-ALDH7A1. We think that trihepatonoin should be the part of the current standard therapy to improve neurodevelopmental outcomes in patients with PDE-ALDH7A1.

ABSTRACT Background and Aims The COVID‐19 pandemic disrupted the behaviours and occupations of individuals with inflammatory bowel disease. We studied behavioural changes in persons with inflammatory bowel disease during the pandemic and examined their association with COVID‐19. Methods We surveyed 556 adults diagnosed with inflammatory bowel disease through an online self‐report questionnaire at baseline. A follow‐up questionnaire was completed by a subset of 223 participants. Participants provided demographic, occupational and social behaviour data (e.g., restaurant visits, using public transportation) at three time periods: January–March 2020 (i.e., pre‐pandemic), January–September 2021 (during restrictions) and January–March 2022 (Omicron era). Proportions for high‐frequency behaviours (daily to once per week vs. less than once per week) across the three time periods are reported. Multivariable logistic regression was used to analyse the relationship between behaviours and Omicron‐era COVID‐19 cases. Results Behaviours declined from January–March 2020 to January–September 2021, and increased in January–March 2022 but did not return to pre‐pandemic levels. Restaurant visits decreased from 33.8% pre‐pandemic to 7.2% in the January–September 2021 period ( p < 0.001), before increasing to 19.3% in the January–March 2022 period ( p < 0.001). Dining at restaurants daily to once per week was associated with a 3.24‐fold (95% CI: 1.58, 6.65) increase in the odds of COVID‐19 infection compared to dining less than once per week. Conclusions Restaurant dining was associated with higher COVID‐19 among those with inflammatory bowel disease. Changes in social behaviours throughout the pandemic likely reflect adaptations in response to evolving public health policies and guidelines.

The Attachment and Child Health (ATTACH™) program is a 10-12-week mentalization-based parenting intervention designed to increase parental reflective function (PRF), promote secure attachment, increase parent/child interaction quality, and improve child development outcomes in families at risk of poor health outcomes due to intergenerational stressors such as poverty, domestic violence, substance use and depression. What is the effect of the ATTACH™ program on PRF, parent-child interaction quality, and child development in Indigenous participants who have experienced intergenerational stressors? Secondary analysis was performed on data collected from participating Indigenous dyads (n = 17) who provided complete data on the primary outcome in one of seven pilot trials which consisted of both randomized controlled trial (RCT) and quasi-experimental (QE) studies. This study utilised two-tailed paired t-tests (alpha = 0.05) to compare baseline and post-assessment scores on the Reflective Function Scale (RFS) obtained from transcribed and coded Parent Development Interviews (PDI), Parent-Child Interaction Teaching Scale (PCITS), Ages and Stages Questionnaire (ASQ-3), and Ages and Stages Questionnaire - Social Emotional (ASQ-SE) for all Indigenous participants who received the ATTACH™ program in both the RCT and QE pilots. We found significant improvements in Parental-, Child-, and Total RF scores (p = 0.023, p = 0.024, p = 0.015 respectively). There was also significant improvement in the PCITS clarity of cues (p = 0.040). The ATTACH™ program is a promising intervention that stands to counter the effect of intergenerational stressors on high-risk Indigenous parents' abilities to reflect on their own and their children's thoughts and feelings and may improve parent-child interaction quality.