Faculty Bibliography

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'^1-3, with a proposed role in contributing to human bipedalism^4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene^7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans¹⁰. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.

BACKGROUND:There are knowledge gaps about factors associated with acute kidney injury (AKI) among COVID-19 patients. To examine AKI predictors among COVID-19 patients, a retrospective longitudinal cohort study was conducted between January 2020 and December 2022. Logistic regression models were used to examine predictors of AKI, and survival analysis was performed to examine mortality in COVID-19 patients. RESULTS:A total of 742,799 veterans diagnosed with COVID-19 were included and 95,573 were hospitalized within 60 days following COVID-19 diagnosis. A total of 45,754 developed AKI and 28,573 AKI patients were hospitalized. Use of vasopressors (OR = 14.73; 95% CL 13.96-15.53), history of AKI (OR = 2.22; CL 2.15-2.29), male gender (OR = 1.90; CL 1.75-2.05), Black race (OR = 1.62; CL 1.57-1.65), and age 65+ (OR = 1.57; CL 1.50-1.63) were associated with AKI. Patients who were vaccinated twice and boosted were least likely to develop AKI (OR = 0.51; CL 0.49-0.53) compared to unvaccinated COVID-19 patients. Patients receiving two doses (OR = 0.77; CL = 0.72-0.81), or a single dose (OR = 0.88; CL = 0.81-0.95) were also less likely to develop AKI compared to the unvaccinated. AKI patients exhibited four times higher mortality compared to those without AKI (HR = 4.35; CL 4.23-4.50). Vaccinated and boosted patients had the lowest mortality risk compared to the unvaccinated (HR = 0.30; CL 0.28-0.31). CONCLUSION/CONCLUSIONS:Use of vasopressors, being unvaccinated, older age, male gender, and Black race were associated with post COVID-19 AKI. Whether COVID-19 vaccination, including boosters, decreases the risk of developing AKI warrants additional studies.

Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic contexts. Long-read, high fidelity genome sequencing (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal and graph genomes. We leverage standard reference genomes, public assemblies (n = 94) and a large collection of HiFi-GS data from a rare disease program (Genomic Answers for Kids, GA4K, n = 574 assemblies) to build a graph genome representing a unified SV callset in GA4K, identify common variation and prioritize SVs that are more likely to cause genetic disease (MAF < 0.01). Using graphs, we obtain a higher level of reproducibility than the standard reference approach. We observe over 200,000 SV alleles unique to GA4K, including nearly 1000 rare variants that impact coding sequence. With improved specificity for rare SVs, we isolate 30 candidate SVs in phenotypically prioritized genes, including known disease SVs. We isolate a novel diagnostic SV in KMT2E, demonstrating use of personal assemblies coupled with pangenome graphs for rare disease genomics. The community may interrogate our pangenome with additional assemblies to discover new SVs within the allele frequency spectrum relevant to genetic diseases.

BACKGROUND:Mastectomies are commonly performed and strongly associated with chronic postsurgical pain (CPSP), more specifically termed postmastectomy pain syndrome (PMPS), with 25-60% of patients reporting pain 3 months after surgery. PMPS interferes with function, recovery, and compliance with adjuvant therapy. Importantly, it is associated with chronic opioid use, as a recent study showed that 1 in 10 patients continue to use opioids at least 3 months after curative surgery. The majority of PMPS patients are women, and, over the past 10 years, women have outpaced men in the rate of growth in opioid dependence. Standard perioperative multimodal analgesia is only modestly effective in prevention of CPSP. Thus, interventions to reduce CPSP and PMPS are urgently needed. Ketamine is well known to improve pain and reduce opioid use in the acute postoperative period. Additionally, ketamine has been shown to control mood in studies of anxiety and depression. By targeting acute pain and improving mood in the perioperative period, ketamine may be able to prevent the development of CPSP. METHODS:Ketamine analgesia for long-lasting pain relief after surgery (KALPAS) is a phase 3, multicenter, randomized, placebo-controlled, double-blind trial to study the effectiveness of ketamine in reducing PMPS. The study compares continuous perioperative ketamine infusion vs single-dose ketamine in the postanesthesia care unit vs placebo for reducing PMPS. Participants are followed for 1 year after surgery. The primary outcome is pain at the surgical site at 3 months after the index surgery as assessed with the Brief Pain Inventory-short form pain severity subscale. DISCUSSION/CONCLUSIONS:This project is part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, a nationwide effort to address the opioid public health crisis. This study can substantially impact perioperative pain management and can contribute significantly to combatting the opioid epidemic. TRIAL REGISTRATION/BACKGROUND:ClinicalTrials.gov NCT05037123. Registered on September 8, 2021.

BACKGROUND:Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. METHODS:All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant's response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses ("win ratio"), with ties excluded. RESULTS:In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30-4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13-3.62, p = 0.018). CONCLUSION/CONCLUSIONS:The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Distributed hypothalamic-midbrain neural circuits orchestrate complex behavioral responses during social interactions. How population-averaged neural activity measured by multi-fiber photometry (MFP) for calcium fluorescence signals correlates with social behaviors is a fundamental question. We propose a state-space analysis framework to characterize mouse MFP data based on dynamic latent variable models, which include continuous-state linear dynamical system (LDS) and discrete-state hidden semi-Markov model (HSMM). We validate these models on extensive MFP recordings during aggressive and mating behaviors in male-male and male-female interactions, respectively. Our results show that these models are capable of capturing both temporal behavioral structure and associated neural states. Overall, these analysis approaches provide an unbiased strategy to examine neural dynamics underlying social behaviors and reveals mechanistic insights into the relevant networks.

Astrocytes play crucial roles in regulating neural circuit function by forming a dense network of synapse-associated membrane specializations, but signaling pathways regulating astrocyte morphogenesis remain poorly defined. Here, we show the Drosophila lipid-binding G protein-coupled receptor (GPCR) Tre1 is required for astrocytes to establish their intricate morphology in vivo. The lipid phosphate phosphatases Wunen/Wunen2 also regulate astrocyte morphology and, via Tre1, mediate astrocyte-astrocyte competition for growth-promoting lipids. Loss of s1pr1, the functional analog of Tre1 in zebrafish, disrupts astrocyte process elaboration, and live imaging and pharmacology demonstrate that S1pr1 balances proper astrocyte process extension/retraction dynamics during growth. Loss of Tre1 in flies or S1pr1 in zebrafish results in defects in simple assays of motor behavior. Tre1 and S1pr1 are thus potent evolutionarily conserved regulators of the elaboration of astrocyte morphological complexity and, ultimately, astrocyte control of behavior.

PURPOSE OF REVIEW/OBJECTIVE:Kidney stones affect an increasing proportion of the population. We suggest that these trends are in part influenced by exposure to higher temperatures as a result of climate change and urbanization. The changing epidemiology of kidney stones is a topic worthy of discussion due to the economic and healthcare burden the condition poses as well as the quality-of-life disruption faced by individuals with kidney stones. RECENT FINDINGS/RESULTS:The relationship between heat and kidney stones is well supported. Exposure to high temperatures has been shown to increase risk for stone development within a short time frame. Effects are modified by factors such as sex, comorbid conditions, and population vulnerability and adaptability. Urban heat islands (UHIs) likely exaggerate the effect of increasing global surface temperature. The concentration of UHIs often coincides with historic redlining practices in the United States, potentially contributing to observed disparities in kidney health among minoritized populations. As global surface temperature increases and urbanization trends continue, a greater proportion of the world's population is exposed to significant temperature extremes each year, leading to the expectation that kidney stone prevalence will continue to increase. SUMMARY/CONCLUSIONS:This work describes the effect of increasing global surface temperature as a result of climate change on kidney stone disease and kidney health. These effects may result in further perpetuation of significant kidney stone related social disparities. We suggest strategies to mitigate the effects of heat exposure on stone formation.