Concord Hospital

Abstract Charcot-Marie-Tooth (CMT) neuropathy is a clinically and genetically heterogeneous group of diseases characterised by the length dependent axonal degeneration of peripheral nerves. We previously mapped a rare form of X-linked CMT, CMTX3, to a 5.7-Mb interval on chromosome Xq26.3-q27.1 and excluded the coding region of all known genes in the linkage interval for mutations. Whole genome sequencing subsequently identified a 78-kb region of chromosome 8q24.3, that had been duplicated and inserted into the CMTX3 locus between the genes HAPSTR2 and SOX3 . The 78-kb insertion, which contains a partial transcript of ARHGAP39 , fully segregated in families with CMTX3 and was absent in neurologically normal controls. To retain the CMTX3 insertion and investigate its consequences in appropriate neuronal tissue, we generated induced pluripotent stem cells (iPSC) from CMTX3 fibroblasts. Using bulk RNA sequencing of patient-derived spinal motor neurons, ARHGAP39 was deemed non-pathogenic by excluding both the formation of novel fusion transcripts and dosage effects from the partial duplication. Subsequent NanoString expression analyses of candidate genes within the CMTX3 locus, across different stages of neuronal differentiation, identified spatiotemporal dysregulation of SOX3. NanoString showed reduced SOX3 expression in patient iPSC. RNA sequencing detected SOX3 downregulation in CMTX3 neuroepithelial progenitor cells, which was further confirmed by quantitative proteomics. Given the early onset and relatively rapid progression of CMTX3, these data prioritise SOX3 as a leading candidate gene, consistent with its role as one of the earliest transcription factors expressed in the developing nervous system and a key regulator of neuronal fate.

To compare the ALGO Smart Pump (ALGO), operating in Adaptive Pulsatile Aspiration (APA™) and Static modes, with the Penumbra ENGINE during in-vitro mechanical thrombectomy, and to determine whether adaptive pulsatile aspiration improves complete clot ingestion (CCI) and reduces aspiration time across catheters sizes and catheter-to-artery (C/A) ratios. Apre-specified integrative analysis of two previously completed in-vitro thrombectomy studies was conducted using astandardized middle cerebral artery occlusion model. Atotal of 720 thrombectomy procedures were performed by two experienced operators using twelve commercial catheters (six small-bore, six large-bore). Three aspiration modalities were tested: ALGO APA™, ALGO Static, and Penumbra ENGINE continuous aspiration (n = 30 per catheter-pump pairing). The primary endpoint was CCI; secondary endpoint was aspiration time. Outcome analysis included two-way ANOVA and Chi-squared tests, with catheter, operator, and C/A ratio terms. The ALGO demonstrated ahigher median CCI rate than Penumbra (81.4% vs. 56.1%, χ2(1) = 52.364, p < 0.001). Aspiration times were significantly shorter with ALGO, particularly in APA™ mode (43.8 s vs. 60.6 s, p < 0.001). Two-way ANOVA demonstrated significant interaction between catheter size and pump type (p < 0.001), with ALGO notably improving small-bore catheter performance. CCI correlated positively with catheter-to-artery (C/A) ratio across both systems, with ALGO maintaining higher success across all ratios. Adaptive pulsatile aspiration enhances clot ingestion efficiency and reduces aspiration time in an in-vitro thrombectomy model, particularly for smaller catheters. These findings support further translational studies on optimizing aspiration dynamics to enhance first-pass success in endovascular stroke therapy.

Atopic dermatitis (AD) and hidradenitis (HS) are both chronic inflammatory skin diseases with relapsing courses. Concomitant AD and HS have been noted in the literature, suggesting that a paradox may exist, allowing the 2 conditions to persist in one patient. Here, we present the case of an 11-year-old white female patient diagnosed with AD and HS, whose conditions improved after treatment with dupilumab. We discuss unique clinical considerations for these diagnoses and treatment response for this patient population.

Abstract Background JAK inhibitors (JAKi) are small molecules that cross the placenta from early pregnancy.1 Evidence on the safety of in utero JAKi exposure remains limited, particularly regarding pregnancy outcomes, infant infections, vaccine responses, and early development.2, 3 Methods We conducted a multicenter retrospective study within the ECCO CONFER network, including pregnant women with inflammatory bowel disease (IBD) exposed to tofacitinib (TOFA), upadacitinib (UPA), or filgotinib (FILGO). Data were collected from 22 centers across 16 countries and included maternal characteristics, disease activity, medication patterns, and pregnancy and infant outcomes. Results Among 55 JAKi exposed pregnancies, 21 (38.2%) were unplanned and 30 (54.6%) had active disease. Nine women (16.4%) initiated JAKi during pregnancy. Overall, 38 (69.1%) received TOFA, 15 (27.3%) UPA, and 2 (3.6%) FILGO; 39 (70.9%) continued treatment throughout pregnancy. JAKi discontinuation in 1st-2nd trimester led to disease activity in 9/16 cases (56.3%). Maternal complication risk was low: no DVT or (pre) eclampsia occurred; three cases of premature rupture of membranes (GA 34–37) and four required hospitalizations due to infection or other complications. A total of 10 abortions occurred - five spontaneous (9.1%) and five induced (9.1%), including three due to concern about JAKi exposure. Among 45 live births, two infants (3.6%) were preterm, four (7.3%) small for gestational age, and two (3.6%) had Apgar &amp;lt;7 at 5 minutes. No congenital abnormalities were reported. Infant follow-up findings are summarized in Table 1. One-third of breastfeeding women continued JAKi postpartum. A high adherence rate to the national immunization schedule was seen. Eight (19.5%) received the live BCG-vaccine within the first 30 days of life. No adverse events followed live or inactivated vaccines, and no malignancies were observed. Conclusion In this global cohort of JAKi-exposed pregnancies in women with IBD, maternal complication rates were low, and no increased risk of adverse outcomes among live births was identified. While disease activity was common, particularly following discontinuation of JAKi, infant outcomes - including development, infection risk, and vaccine response - were reassuring. These findings provide important preliminary safety data to inform decision-making regarding JAKi use in pregnancy, though prospective studies are needed to confirm long-term safety.

Abstract Background Geographic variation in advanced therapy use for inflammatory bowel disease (IBD) has been reported across Europe (1) and North America (2), where higher latitudes consistently show greater prescribing and disease prevalence. However, comparable evidence from the Southern Hemisphere is lacking. Australia’s wide north-south span and universal health system provide a unique setting to examine whether such gradients persist within a single country. Methods Nationwide Pharmaceutical Benefits Scheme data (2007-2025) on advanced therapies, capturing 100% of subsidied prescriptions nationwide, were analysed by state and territory. Prescriptions were standardised per 1,000 IBD patients. Regression analyses were done to examine associations with latitude, ultraviolet (UV) index, and temperature, among other environmental, demographic, healthcare access, and health and lifestyle modifiers. Results More than 2.2 million prescriptions were supplied during the 18-year study period, with rapid growth after 2015 driven by newer agents. Disparities among states and territories were observed, with prescription numbers lowest in the Northern Territory (404/1,000 IBD patients) and highest in Tasmania (1,004/1,000) (Figure 1). Prescription use increased with latitude, where every 10o further south corresponded to an increase in fold-difference of ∼0.5 (95% CI 0.35-0.68, p = 0.0004). This translates to nearly 2.5-fold higher rates in Tasmania (∼43 oS) compared with the NT (∼15 oS). Latitude accounted for most of the variation in prescribing between states (R2=0.89). Prescription numbers were also inversely related to mean temperature (R2=0.92) and peak UV index (R2=0.86). Other demographic, healthcare, and lifestyle modifiers were non-significant (Figure 2). Conclusion For the first time in any Southern Hemisphere country, this nationwide analysis demonstrates a clear north-south gradient in advanced IBD therapy prescribing. These findings suggest an environmental signal linked to latitude, UV exposure and ambient temperature. Although traditionally attributed to vitamin D synthesis, the persistence of this gradient despite negative vitamin D intervention trials implies alternative UV-mediated mechanisms, such as effects on mucosal immunity, microbial composition or systemic immune regulation. These findings provide novel evidence of a latitude-dependent gradient within a single national health system and highlight potential environmental determinants of IBD care in Australia.

Not available.

ABSTRACTDiabetic wounds are characterized by chronic inflammation, partly due to the persistent accumulation of pro‐inflammatory M1 macrophages. Asiaticoside (AS), a triterpenoid extracted from Centella asiatica, has known anti‐inflammatory effects in several diseases, but the underlying mechanisms in diabetic wounds are still unclear. This study reveals that AS alleviates inflammation in diabetic wounds by activating ferroptosis of M1 macrophages. In vitro, AS reduces the number of M1 macrophages in a high glucose microenvironment and their secretion of proinflammatory cytokines with concurrent induction of ferroptosis. Further investigation shows that AS‐activated ferroptosis is attributed to the downregulation of ferroportin 1 (FPN1) and ferritinophagy‐induced degradation of ferritin heavy chain 1 (FTH1), which together increase the amount of intracellular free ferrous ions (Fe2+). In vivo, AS‐encapsulated gelatin‐methacryloyl hydrogels accelerates diabetic wound healing and shortens the inflammatory period by activating ferroptosis of M1 macrophages with the reduced expression of FPN1 and FTH1. These results suggest a promising AS‐based strategy for treating inflammatory diseases associated with excessive activation of M1 macrophages.

Inflammatory bowel diseases (IBD) are chronic and recurrent conditions of the gastrointestinal tract. IBD is often challenging to manage due to the complex etiology and involvement of multiple dysregulated immune pathways. Current treatments, including biologics and immunosuppressants, are associated with significant risks and side effects, highlighting the need for safer alternatives. Human milk oligosaccharides (HMOs), a group of bioactive carbohydrates found in human breast milk, play a crucial role in shaping the infant gut microbiome, modulating microbial metabolism and immune responses, and reducing inflammation. Notably, HMOs have no nutritional value for the infant and travel undigested through the upper gastrointestinal tract, serving as selective substrates for beneficial gut bacteria and supporting intestinal epithelial health. Among these, 2′-fucosyllactose (2′-FL) is the most abundant and well-studied HMO, functioning as a trisaccharide prebiotic. Emerging evidence suggests that the benefits of HMOs extend beyond infancy, with potential therapeutic applications in modulating immune responses, promoting epithelial health, and reducing inflammation in IBD. This review summarizes current research on the role of 2′-FL in inflammation and colitis, exploring its potential role in treating IBD.