👤 Margaret R Dunne

Accurate dementia risk prediction is critical for prevention, yet it remains unclear which predictors add meaningful value beyond chronological age. This review evaluates the extent to which multivariable dementia risk models identify modifiable risk factors that enhance prediction value. We systematically reviewed cohort studies reporting both age-only and multivariable dementia prediction models in the same population. Six age-only models across five cohorts were included. Age-only models achieved poor to good discrimination (C-statistics 0.66-0.84). Adding modifiable cardiovascular and lifestyle factors provided consistent, modest improvements of 0.02-0.05 in the UK Biobank, Atherosclerosis Risk in Communities (ARIC), and Rotterdam cohorts. Larger improvements of 0.07-0.12 were observed in models including cognitive testing or genetic factors [e.g., UK Biobank Dementia Risk Score (UKBDRS-APOE)] with the Hanley-McNeil z-test confirming the improvements were significant, indicating genuine improvement rather than random variation. While age is a significant risk factor for dementia, modifiable cardiovascular and lifestyle factors provide incremental predictive value beyond age and represent actionable targets for prevention. Despite modest statistical improvements, these factors offer the most clinically relevant targets for prevention strategies. Future efforts should prioritise interventions addressing these modifiable determinants to reduce dementia risk across populations. Show less

Staphylococcus aureus is an important human commensal which persistently colonizes up to 30% of the human population, predominantly within the nasal cavity. The commensal lifestyle of S. aureus is complex, and the mechanisms underpinning colonization are not fully understood. S. aureus can induce an immunosuppressive environment in the nasal tissue (NT) by driving IL-10 and IL-27 to facilitate nasal colonization, indicating that S. aureus has the capacity to modulate the local immune environment for its commensal habitation. Mounting evidence suggests commensal bacteria drive type 1 interferons (IFN-I) to establish an immunosuppressive environment and whilst S. aureus can induce IFN-I during infection, its role in colonization has not yet been examined. Here, we show that S. aureus preferentially induces IFN signaling in macrophages. This IFN-I in turn upregulates expression of proapoptotic genes within macrophages culminating in caspase-3 cleavage. Importantly, S. aureus was found to drive phagocytic cell apoptosis in the nasal tissue during nasal colonization in an IFN-I dependent manner with colonization significantly reduced under caspase-3 inhibition. Overall, loss of IFN-I signaling significantly diminished S. aureus nasal colonization implicating a pivotal role for IFN-I in controlling S. aureus persistence during colonization through its ability to induce phagocyte apoptosis. Together, this study reveals a novel strategy utilized by S. aureus to circumvent host immunity in the nasal mucosa to facilitate nasal colonization. Show less

The Rehabilitation Strategies Following Esophagogastric cancer (ReStOre) randomized control trial demonstrated a significant improvement in cardiorespiratory fitness of esophagogastric cancer survivors. This follow-up, exploratory study analyzed the biological effect of exercise intervention on levels of 55 serum proteins, encompassing mediators of angiogenesis, inflammation, and vascular injury, from participants on the ReStOre trial. Patients >6 months disease free from esophagogastric cancer were randomized to usual care or the 12-week ReStOre program (exercise training, dietary counselling, and multidisciplinary education). Serum was collected at baseline (T0), post-intervention (T1), and at 3-month follow up (T2). Serum biomarkers were quantified by enzyme-linked immunosorbent assay (ELISA). Thirty-seven patients participated in this study; 17 in the control arm and 20 in the intervention arm. Exercise intervention resulted in significant alterations in the level of expression of serum IP-10 (mean difference (MD): 38.02 (95% CI: 0.69 to 75.35)), IL-27 (MD: 249.48 (95% CI: 22.43 to 476.53)), and the vascular injury biomarkers, ICAM-1 (MD: 1.05 (95% CI: 1.07 to 1.66)), and VCAM-1 (MD: 1.51 (95% CI: 1.04 to 2.14)) at T1. A significant increase in eotaxin-3 (MD: 2.59 (95% CI: 0.23 to 4.96)), IL-15 (MD: 0.27 (95% CI: 0 to 0.54)) and decrease in bFGF (MD: 1.62 (95% CI: -2.99 to 0.26)) expression was observed between control and intervention cohorts at T2 (p<0.05). Exercise intervention significantly altered the expression of a number of serum biomarkers in disease-free patients who had prior treatment for esophagogastric cancer. Exercise rehabilitation causes a significant biological effect on serum biomarkers in esophagogastric cancer survivors. ClinicalTrials.gov (NCT03314311). Show less

Rapsyn, a 43-kDa postsynaptic protein, is essential for anchoring and clustering acetylcholine receptors (AChRs) at the endplate (EP). Mutations in the rapsyn gene have been found to cause a postsynaptic congenital myasthenic syndrome (CMS). We detected six patients with CMS due to mutations in the rapsyn gene (RAPSN). In vitro studies performed in the anconeus muscle biopsies of four patients showed severe reduction of miniature EP potential amplitudes. Electron microscopy revealed various degrees of impaired development of postsynaptic membrane folds. All patients carried the N88K mutation. Three patients were homozygous for N88K and had less severe phenotypes and milder histopathologic abnormalities than the three patients who were heterozygous and carried a second mutation (either L14P, 46insC, or Y269X). Surprisingly, two N88K homozygous patients had one asymptomatic relative each who carried the same genotype, suggesting that additional genetic factors to RAPSN mutations are required for disease expression. Show less

Rapsyn, a complex postsynaptic protein of the striated muscle, assembles acetylcholine receptors (AChR) at high density at the motor endplate (EP). Neuromuscular junctions of mice lacking rapsyn show no clusters of AChRs or other structural postsynaptic proteins such as beta-dystroglycan and utrophin. Humans with mutations in the rapsyn gene ( RAPSN) are affected with a postsynaptic form of congenital myasthenic syndrome (CMS) characterized by impairment of the morphologic development of the postsynaptic region. We have identified four patients from four different families with RAPSNmutations and CMS, confirmed in two cases by microelectrode and electron microscopy studies. The N88K mutation was present in all patients. One patient who was homozygous for N88K was only mildly affected, while the other three patients who were heterozygous for N88K and a second mutation (either L14P, 46insC, or Y269X) were severely affected. Mutations 46insC and Y269X predicts truncation of the protein. L14P predicts a conformational change at the N-terminus that may disrupt membrane association. N88K occurs within the putative leucine zipper motif potentially important for AChR clustering. These findings may explain the severe clinical involvement of compound heterozygous patients. Show less