Faculty Bibliography

This collective eulogy by colleagues, co-authors and friends is a tribute to the work and life of Rudolf Nieuwenhuys. 'Neurofascination' is an apt label for his scholarly life in the sciences from the start in 1955 until his last days in 2024. In addition, he had a broad interest in Roman and Gothic architecture, the history and politics of the twentieth century, religion and the music of Johann Sebastian Bach. Extensive discussions on one or more of these topics often led to long-lasting friendships, some of which inform the following pages. Rudolf is remembered for his highly didactical and remarkably illustrated presentations and publications, including the three-volume The Central Nervous System of Vertebrates and the four editions of The Human Central Nervous System. His research interests addressed an impressively wide range of topics concerning development and evolutionary neurobiology and a systematic approach to comparative brain structures in vertebrates. His almost endless fascination for neuromorphology included the invertebrates as well. But unfortunately, even his long life was not enough to write the book on the comparative neuroanatomy of invertebrates which he long had in mind. The many years of his career spanned the remarkable histology of the gigantocerebellum of mormyrids to an exploratory synthesis of subdivisions of the human cortex, as originally mapped by the Vogt-Vogt school of cortical architectonics.

BACKGROUND:/calmodulin-dependent protein kinase II and selected for probe collection. RESULTS:This approach significantly reduced the amount of FFPE tissue needed for robust single population RNA-seq. We demonstrate ~20 identified L3 or L5 pyramidal neurons or one lamina-specific cortical ribbon from a single 5µm thick section is sufficient to generate robust RNA-seq reads. Bioinformatic analysis of neurons and ribbons showed notable similarities and differences reflective of the single neuron and multiple admixed cell types within the former and latter, respectively. Comparison with existing methods Protocols exist for DSP of postmortem human FFPE brain tissue. However, this new approach enables profiling small groups of ~14-21 pyramidal neurons using the GeoMx DSP platform. CONCLUSIONS:This optimized DSP assay provides high resolution RNA-seq data demonstrating utility and versatility of the GeoMx platform for individually characterized neurons and isolated cortical ribbons within postmortem FFPE human brain tissue for downstream analyses.

OBJECTIVES/UNASSIGNED:To review the different analgesic modalities and benefits of non-opioid pain management options as well as their evidence-based, established superiority, compared to opioid medications. MATERIALS/UNASSIGNED:We review the updated literature about pain management of renal colic, a prevalent and painful urologic condition. Prescribers must know the efficacy, safety and possible ramifications of analgesic selections. RESULTS/UNASSIGNED:Commonly prescribed medications in the United States (US) include non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioids. In the context of the current epidemic of death from overdoses of opioids in the US, the frequency of opioid prescribing for renal colic is likely excessive, problematic and potentially remediable. We also present analgesic modalities revolving around interventions with peri-procedural pain management for ureteroscopy and percutaneous nephrolithotomy. After touching on the implications of misguided opioid use, especially in the context of kidney stone disease, and despite the evidence and consensus guidelines supporting NSAIDs in renal colic, current evidence has shown that many clinicians continue to prescribe opioids as first-line treatment. Finally, we highlight current efforts targeted at the reduction of opioid use and prescription in the setting of provider education and decision aids in curbing misguided opioid use in renal colic. CONCLUSIONS/UNASSIGNED:While the evidence against treating kidney stones with opioids is clear, more work is needed to shift current practices to reflect that renal colic is a non-opioid-requiring condition.

The value of preclinical diffusion MRI (dMRI) is substantial. While dMRI enables in vivo non-invasive characterization of tissue, ex vivo dMRI is increasingly being used to probe tissue microstructure and brain connectivity. Ex vivo dMRI has several experimental advantages including higher SNR and spatial resolution compared to in vivo studies, and enabling more advanced diffusion contrasts for improved microstructure and connectivity characterization. Another major advantage of ex vivo dMRI is the direct comparison with histological data, as a crucial methodological validation. However, there are a number of considerations that must be made when performing ex vivo experiments. The steps from tissue preparation, image acquisition and processing, and interpretation of results are complex, with many decisions that not only differ dramatically from in vivo imaging of small animals, but ultimately affect what questions can be answered using the data. This work represents "Part 2" of a three-part series of recommendations and considerations for preclinical dMRI. We describe best practices for dMRI of ex vivo tissue, with a focus on the value that ex vivo imaging adds to the field of dMRI and considerations in ex vivo image acquisition. We first give general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in specimens and models and discuss why some may be more or less appropriate for different studies. We then give guidelines for ex vivo protocols, including tissue fixation, sample preparation, and MR scanning. In each section, we attempt to provide guidelines and recommendations, but also highlight areas for which no guidelines exist (and why), and where future work should lie. An overarching goal herein is to enhance the rigor and reproducibility of ex vivo dMRI acquisitions and analyses, and thereby advance biomedical knowledge.

RATIONALE & OBJECTIVE/OBJECTIVE:Despite national efforts, the uptake of home dialysis (peritoneal dialysis or home hemodialysis) remains low. Characteristics of the built environment may differentially impact home dialysis use. STUDY DESIGN/METHODS:Retrospective cohort study (2010-2019). SETTING & PARTICIPANTS/METHODS:1,103,695 adults (aged≥18 years) initiating dialysis in the US Renal Data System. EXPOSURE/METHODS:We examined 3 built environment domains based on residential ZIP code: (1) medically underserved areas (MUAs), defined as neighborhoods with limited primary care access; (2) distance to the nearest dialysis facility; and (3) distribution of housing characteristics (structure and overcrowding). OUTCOME/RESULTS:Uptake of home dialysis modalities at dialysis initiation. ANALYTICAL APPROACH/METHODS:We quantified associations between built environment characteristics and home dialysis initiation using multilevel logistic regression stratified by urbanicity type (urban, suburban, small-town, and rural). RESULTS:Among adults initiating dialysis, 40.8% lived in MUAs. Across ZIP codes, the mean percentage of overcrowded housing was 4.2% (SD, 4.7%), and the percentage of detached housing was 61.1% (SD, 21.1%); mean distance to the nearest dialysis facility was 5.5km (SD, 9.1km). Living in MUAs was associated with reduced home dialysis use only in urban (OR, 0.94; 95% CI, 0.91-0.96) and suburban (OR, 0.92; 95% CI, 0.89-0.94) areas. Similarly, housing overcrowding was associated with decreased home dialysis use only in urban (OR, 0.88; 95% CI, 0.86-0.89) and suburban (OR, 0.91; 95% CI, 0.90-0.93) areas. Longer distance to a dialysis facility was the most salient neighborhood factor associated with increased home dialysis use in small towns (OR, 1.14; 95% CI, 1.12-1.16) and rural areas (OR, 1.17; 95% CI, 1.15-1.19). LIMITATIONS/CONCLUSIONS:Housing characteristics were measured at the ZIP code level. CONCLUSIONS:Built environment characteristics associated with home dialysis uptake vary by urbanicity. Policies should address built environment barriers that are specific to urbanicity level. For example, increasing the frequency of dialysate delivery schedules could address housing space constraints in urban and suburban areas, and promoting home dialysis might be more effective for patients living far from dialysis centers in small-town and rural areas.

BACKGROUND:Despite evidence supporting the efficacy of culturally tailored interventions in reducing stigma, such approaches are lacking for women living with HIV/AIDS (WLWHAs) in China. We conducted this study to determine the efficacy of the culturally tailored Helping Overcome Perceived Stigma (HOPES) intervention in reducing perceived stigma among WLWHAs in China. METHODS:A single-blinded, two-arm parallel-group randomized clinical trial was conducted from 2023 to 2024 in South and Southwest China. WLWHAs from four hospitals were assigned using a WeChat-embedded randomization application to the control group (usual care) or the HOPES intervention. Data analysts remained blinded. Interventions were conducted virtually using Leave No One Behind (LNOB) platform for 3 months. The primary outcome, perceived stigma score, was assessed at baseline, immediately after the intervention and at 3 months post-intervention using 7 items from the HIV/AIDS Stigma Experience Questionnaire (HASEQ), with data analyzed through repeated measures analysis. RESULTS:Of 136 WLWHAs screened, we randomized 101 WLWHAs (50 HOPES; 51 controls). The HOPES group demonstrated a statistically significant reduction in perceived stigma scores immediately after the intervention (-3.86 points, 95 % CI: 5.34 to -2.38, P < .001) and at three months post-intervention (-5.83 points, 95 % CI: 7.20 to -4.47, P < .001) compared to the control group. CONCLUSION/CONCLUSIONS:The findings demonstrate HOPES' efficacy in reducing perceived stigma in WLWHA. However, the clinical significance of these changes needs further investigation. Future research should focus on defining meaningful patient-reported thresholds, assessing long-term impact, and optimizing delivery methods.

BackgroundRespiratory impairment in neuromuscular disorders (NMDs) is generally assessed using forced vital capacity (FVC). Any improvement in FVC trajectory will delay ventilatory support; however, the change required for patients to perceive a noticeable clinical benefit, the clinically meaningful threshold (CMT), has not been defined in NMDs.ObjectiveTo derive the within-person and between-group CMTs for FVC (% predicted) in patients with late-onset Pompe disease (LOPD).MethodsThis analysis leverages data from the Phase 3 COMET trial (NCT02782741, registered 25 May 2016), which assessed the efficacy of avalglucosidase alfa (AVA) versus alglucosidase alfa (ALG) on upright FVC (% predicted) in LOPD. Anchor- and distribution-based methods were used to estimate the within-person and between-group CMTs for FVC at Weeks 49 and 97.ResultsCOMET enrolled 99 participants aged ≥18 years (52% male; mean age 48.0 years). The within-person CMT for absolute change in FVC expressed as % predicted was estimated as 3.0% [95% confidence interval (CI) 2.3, 3.8]. The proportion of patients with a meaningful increase in FVC was higher in the AVA versus ALG group across the CI of the estimated CMT (odds ratios: 2.3-2.6; nominal p-values: 0.026-0.058). The between-group CMT, needed to evaluate differences between treatment groups, was estimated as 2.1% predicted [95% CI 1.1, 3.1].ConclusionsWe identified a narrow range of within-person and between-group CMTs for upright FVC (% predicted) in LOPD. Post hoc application of these thresholds to COMET showed that a greater proportion of patients in the AVA group had clinically meaningful improvement in FVC versus ALG. These findings may aid in interpretation of data from studies in other NMDs.

Around 40% of the US population and 1 in 6 individuals worldwide have obesity, with the incidence surging globally^1,2. Various dietary interventions, including carbohydrate, fat and, more recently, amino acid restriction, have been explored to combat this epidemic^3-6. Here we investigated the impact of removing individual amino acids on the weight profiles of mice. We show that conditional cysteine restriction resulted in the most substantial weight loss when compared to essential amino acid restriction, amounting to 30% within 1 week, which was readily reversed. We found that cysteine deficiency activated the integrated stress response and oxidative stress response, which amplify each other, leading to the induction of GDF15 and FGF21, partly explaining the phenotype^7-9. Notably, we observed lower levels of tissue coenzyme A (CoA), which has been considered to be extremely stable¹⁰, resulting in reduced mitochondrial functionality and metabolic rewiring. This results in energetically inefficient anaerobic glycolysis and defective tricarboxylic acid cycle, with sustained urinary excretion of pyruvate, orotate, citrate, α-ketoglutarate, nitrogen-rich compounds and amino acids. In summary, our investigation reveals that cysteine restriction, by depleting GSH and CoA, exerts a maximal impact on weight loss, metabolism and stress signalling compared with other amino acid restrictions. These findings suggest strategies for addressing a range of metabolic diseases and the growing obesity crisis.

BACKGROUND:Hyperexcitability in Alzheimer's disease (AD) is proposed to emerge early and contribute to disease progression. The dentate gyrus (DG) and its primary cell type, granule cells (GCs) are implicated in hyperexcitability in AD. Hence, we hypothesized that mossy cells (MCs), important regulators of GC excitability, contribute to early hyperexcitability in AD. Indeed, MCs and GCs are linked to hyperexcitability in epilepsy. METHODS:Using the Tg2576 model of AD and WT mice (~ 1 month-old), we compared MCs and GCs electrophysiologically and morphologically, assessed the activity marker c-Fos, Aβ expression and a hippocampal- and MC-dependent memory task that is impaired at 3-4 months of age in Tg2576 mice. RESULTS:Tg2576 MCs had increased spontaneous excitatory events (sEPSP/Cs) and decreased spontaneous inhibitory currents (sIPSCs), increasing the excitation/inhibition ratio. Additionally, Tg2576 MC intrinsic excitability was enhanced. Consistent with in vitro results, Tg2576 MCs showed enhanced c-Fos protein expression. Tg2576 MCs had increased intracellular Aβ expression, suggesting a reason for increased excitability. GCs showed increased excitatory and inhibitory input without changes in intrinsic properties, consistent with effects of increased MC activity. In support, increased GC activity was normalized by an antagonist of MC input to GCs. Also in support, Tg2576 MC axons showed sprouting to the area of GC dendrites. These effects occurred before an impairment in the memory task, suggesting they are extremely early alterations. CONCLUSIONS:Alterations in Tg2576 MCs and GCs early in life suggest an early role for MCs in increased GC excitability. MCs may be a novel target to intervene in AD pathophysiology at early stages.

BACKGROUND:), can be self- or caregiver-administered at home with fixed-dosing for patients ≥ 12 years of age. This real-world study aimed to understand treatment preferences among individuals with PH1, highlighting challenges in administration of current treatments. METHODS:A cross-sectional web-based survey was conducted among U.S.-based adults (aged ≥ 18) diagnosed with PH1. The survey consisted of a 20-25 min questionnaire and was conducted from October to December 2023. RESULTS:The study participants (N = 39) included both male (N = 26) and female (N = 13) adults with PH1. Participants came from a range of community settings, including urban (46%), rural (39%), and suburban (15%); and were full- or part-time workers (56%) or students (41%). Most participants were on lumasiran therapy (95%) for an average of 1 year (range: 0.3-1.8 years). The survey revealed that the commonly reported factors important for treatment selection among participants living with PH1 were frequency of administration, treatment administrator, time required for treatment, and place of administration. The ability to self-administer was ranked as the top choice by most participants. Over half (56%) found quarterly injections easy or very easy. Similarly, 56-59% found home administration, whether self- or healthcare provider (HCP)-administered, easy or very easy. Nearly half (46%) considered injections at medical facilities challenging or very challenging. The majority indicated traveling > 15 min for injections would be burdensome (57%) and arranging appointments problematic (54%). When comparing administration methods, 72% preferred self-injection over HCP-administered injections. Regarding treatment regimens, 57% found it easy or very easy to receive monthly injections initially, before switching to quarterly. Additionally, 64% preferred a medication dosage that is not weight-based. While participants expressed a preference for less frequent treatments, 67% preferred self-injection at home over medical facility injections, and 67% preferred monthly injections at home over quarterly injections at a medical facility. CONCLUSIONS:This study shows that patients with PH1 value treatments that are convenient and fit their lifestyle.