Faculty Bibliography

PURPOSE OF REVIEW/OBJECTIVE:Initiation of hemodialysis treatment with a thrice-weekly prescription is currently the standard of care irrespective of patients' residual kidney function (RKF), comorbidities, and preferences. RECENT FINDINGS/RESULTS:Each year ∼12 000 Veterans with advanced kidney disease progress to end-stage kidney disease (ESKD) requiring dialysis and comprise greater than 10% of the US incident ESKD population. Dialysis is costly and is associated with impaired health-related quality of life (HRQOL) and high mortality risk, especially in the first year of treatment. Evidence suggests an incremental dialysis transition using twice-weekly hemodialysis provides various benefits, including more dialysis-free time, longer RKF preservation, less vascular access damage, and lower patient burden. Pragmatic studies are needed to inform the efficacy and safety of incremental hemodialysis as a personalized dialysis regimen, and could inform its consideration as a conservation strategy during times of supply shortages. Broadly implementing twice-weekly hemodialysis could also potentially allow more Veterans to receive care within VA-based dialysis units. The VA IncHVets Trial is a pragmatic, multicenter, randomized controlled trial comparing the efficacy and safety of twice-weekly incremental vs. thrice-weekly hemodialysis among Veterans transitioning to ESKD. SUMMARY/CONCLUSIONS:Further research is needed to determine whether incremental hemodialysis is well tolerated, effective, and facilitates a more favorable transition to dialysis.

The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell-mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune-related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. HIGHLIGHTS: The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

Acute rheumatic fever (ARF) is an immune-mediated nonsuppurative complication of group A streptococcal (GAS) pharyngitis. Approximately 470,000 new cases of ARF occur annually, with a more significant disease burden in developing countries with higher rates of untreated or inadequately treated GAS infections. Globally, over 275,000 deaths yearly are attributed to rheumatic heart disease (RHD). The most significant contributors to the spread of GAS pharyngitis are household overcrowding, poor sanitation, and inadequate access to healthcare. The pathophysiology of ARF is characterized by an aberrant immune response to GAS infection triggered by molecular mimicry between GAS antigens and self-antigens. This immune response typically manifests 2 to 4 weeks after the initial GAS infection and may lead to the development of carditis, valvulitis, Sydenham chorea, subcutaneous nodules, erythema marginatum, and polyarthritis that is usually migratory. The severity and distribution of these manifestations vary significantly between individuals making the diagnosis of ARF challenging. Early recognition of ARF using the modified Jones criteria is essential in treating acute infection and preventing complications. A major long-term consequence is RHD, which carries significant morbidity and mortality.

The abnormal assembly of tau protein in neurons is a pathological hallmark of multiple neurodegenerative diseases, including Alzheimer's disease (AD). Assembled tau associates with extracellular vesicles (EVs) in the central nervous system of individuals with AD, which is linked to its clearance and prion-like propagation. However, the identities of the assembled tau species and EVs, as well as how they associate, are not known. Here, we combined quantitative mass spectrometry, cryo-electron tomography and single-particle cryo-electron microscopy to study brain EVs from individuals with AD. We found tau filaments composed mainly of truncated tau that were enclosed within EVs enriched in endo-lysosomal proteins. We observed multiple filament interactions, including with molecules that tethered filaments to the EV limiting membrane, suggesting selective packaging. Our findings will guide studies into the molecular mechanisms of EV-mediated secretion of assembled tau and inform the targeting of EV-associated tau as potential therapeutic and biomarker strategies for AD.

For many years, the hilus of the dentate gyrus (DG) was a mystery because anatomical data suggested a bewildering array of cells without clear organization. Moreover, some of the anatomical information led to more questions than answers. For example, it had been identified that one of the major cell types in the hilus, the mossy cell, innervates granule cells (GCs). However, mossy cells also targeted local GABAergic neurons. Furthermore, it was not yet clear if mossy cells were glutamatergic or GABAergic. This led to many debates about the role of mossy cells. However, it was clear that hilar neurons, including mossy cells, were likely to have very important functions because they provided strong input to GCs. Hilar neurons also attracted attention in epilepsy because pathological studies showed that hilar neurons were often lost, but GCs remained. Vulnerability of hilar neurons also occurred after traumatic brain injury and ischemia. These observations fueled an interest to understand hilar neurons and protect them, an interest that continues to this day. This article provides a historical and personal perspective into the ways that I sought to contribute to resolving some of the debates and moving the field forward. Despite several technical challenges the outcomes of the studies have been worth the effort with some surprising findings along the way. Given the growing interest in the hilus, and the advent of multiple techniques to selectively manipulate hilar neurons, there is a great opportunity for future research.

OBJECTIVE:In people with chronic kidney disease (CKD), hyperphosphatemia is a risk factor for mortality. Though unproven, dietary phosphorus control is considered essential in CKD. Although dietary and serum phosphorus are correlated, phosphorus from plant foods rich in phytate is less bioavailable than from animal and processed foods. Yogurt, valued for its low phosphorus and high protein, may be detrimental in CKD due to animal protein content. Plant-based yogurts (PBYs) might offer similar benefits without the downsides of animal protein, but little is known about their phosphorus content. DESIGN AND METHODS/METHODS:Protein contents and phosphorus additives were gathered from nutrition labels of several PBYs, including almond, cashew, oat, coconut, and soy substrates. Phosphorus content was measured via emission spectrometry by Eurofins (Madison, WI), and the phosphorus-to-protein ratio (PPR) was calculated for each PBY. RESULTS:Phosphorus content was highest in Silk Soy Strawberry, Silk Almond Strawberry, and Siggi's Coconut Mixed Berries, while it was lowest in So Delicious Coconut Strawberry, Oatly Oat Strawberry, Forager Cashew Strawberry, and Kite Hill Almond Strawberry. Ingredient labels revealed that Silk Soy Strawberry, Silk Almond Strawberry, and Oatly Oat Strawberry contained phosphorus additives, and Siggi's Coconut Mixed Berries contained pea protein additives. Though from the same substrate class, So Delicious Coconut Strawberry and Siggi's Coconut Mixed Berries showed significant differences in phosphorus and protein contents. All seven PBYs had higher PPR ratios than dairy yogurts like Stonyfield Organic Oikos Strawberry, Chobani Nonfat Strawberry, and Yoplait Greek Strawberry. CONCLUSION/CONCLUSIONS:Low-PPR foods are important for CKD patients. Siggi's Coconut Mixed Berries had the lowest PPR, making it potentially the most desirable for CKD patients. However, there is high variability in PPR among PBYs with the same substrate; therefore, Delicious Coconut Strawberry had the highest PPR, highlighting the importance of product selection for patients with CKD.

Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary DG cell type, granule cells (GCs). Numerous MC synapses are on GC proximal dendrites in the inner molecular layer (IML). However, field recordings of the GC excitatory postsynaptic potential (fEPSPs) have not been used to study this pathway selectively. Here we describe methods to selectively activate MC axons in the IML using mice with Cre recombinase expressed in MCs. Slices were made after injecting adeno-associated virus (AAV) encoding channelrhodopsin (ChR2) in the DG. In these slices, we show that fEPSPs could be recorded reliably in the IML in response to optogenetic stimulation of MC axons. Furthermore, fEPSPs were widespread across the septotemporal axis. However, fEPSPs were relatively weak because they were small in amplitude and did not elicit a significant population spike in GCs. They also showed little paired pulse facilitation. We confirmed the extracellular findings with patch clamp recordings of GCs despite different recording chambers and other differences in methods. Together the results provide a simple method for studying MC activation of GCs and add to the evidence that this input is normally weak but widespread across the GC population.

Making adaptive decisions in complex environments requires appropriately identifying sources of error^1,2. The frontal cortex is critical for adaptive decisions, but its neurons show mixed selectivity to task features³ and their uncertainty estimates⁴, raising the question of how errors are attributed to their most likely causes. Here, by recording neural responses from tree shrews (Tupaia belangeri) performing a hierarchical decision task with rule reversals, we find that the mediodorsal thalamus independently represents cueing and rule uncertainty. This enables the relevant thalamic population to drive prefrontal reconfiguration following a reversal by appropriately attributing errors to an environmental change. Mechanistic dissection of behavioural switching revealed a transthalamic pathway for cingulate cortical error monitoring^5,6 to reconfigure prefrontal executive control⁷. Overall, our work highlights a potential role for the thalamus in demixing cortical signals while providing a low-dimensional pathway for cortico-cortical communication.