Faculty Bibliography

OBJECTIVES/OBJECTIVE:To determine the most common reason for 30-day readmission following hospitalization for hip fractures. METHODS:Design: A retrospective review. SETTING/METHODS:Single academic medical center that includes a Level 1 Trauma Center. PATIENT SELECTION CRITERIA/UNASSIGNED:Included were all patients operatively treated for hip fractures (OTA 31) between October 2014 and November 2023. Patients that died during their initial admission were excluded. OUTCOME MEASURES AND COMPARISONS/UNASSIGNED:Patient demographics, hospital quality measures, outcomes and readmission within 30-days following discharge for each patient were reviewed. 30-day readmission reason was recorded and correlation analysis was performed. RESULTS:A total of 3,032 patients were identified with a mean age of 82.1 years and 70.5% of patients being female. The 30-day readmission cohort was 2.6 years older (p<0.001) and 8.8% more male patients (p=0.027), had 0.5 higher CCI (p<0.001), 0.3 higher ASA class (p<0.001) and were 9.2% less independent at the time of admission (p= 0.003). Hemiarthroplasty procedure (32.7% vs. 24.1%) was associated with higher 30-day readmission compared to closed percutaneous screw fixation (4.5% vs. 8.8%) and cephalomedullary nail fixation (52.2% vs. 54.4%, p<0.001). Those readmitted by 30-days developed more major (16.7% vs. 8.0%) (p<0.001) and minor (50.5% vs. 36.4%) (p<0.001) complications during their initial hospitalization and had a 1.5 day longer LOS during their first admission (p<0.001). Those discharged home were less likely to be readmitted within 30-days (20.7% vs. 27.6%, (p=0.008). Multivariate regression revealed increasing ASA class (O.R. 1.47, p=0.002) and pre-injury ambulatory status (O.R. 1.42, p=0.007) were most associated with increased 30-day readmission. The most common reason for readmission was pulmonary complications (17.1% of complications) including acute respiratory failure, COPD exacerbation and pneumonia. CONCLUSION/CONCLUSIONS:Thirty-day readmission following hip fracture was associated with older, sicker patients with decreased pre-injury ambulation status. Hemiarthroplasty for femoral neck fracture was also associated with readmission. The most common reason for 30-day readmission following hip fracture was pulmonary complications. LEVEL OF EVIDENCE/METHODS:Prognostic Level III.

Our brains integrate sensory, cognitive and internal state information with memories to extract behavioral relevance. Cortico-hippocampal interactions likely mediate this interplay, but underlying circuit mechanisms remain elusive. Unlike the entorhinal cortex-to-hippocampus pathway, we know little about the organization and function of the hippocampus-to-cortex feedback circuit. Here we report in mice, two functionally distinct parallel hippocampus-to-entorhinal cortex feedback pathways: the canonical disynaptic route via layer 5 and a novel monosynaptic input to layer 2/3. Circuit mapping reveals that hippocampal input predominantly drives excitation in layer 5 but feed-forward inhibition in layer 2/3. Upon repetitive pairing with cortical layer 1 inputs, hippocampal inputs undergo homosynaptic potentiation in layer 5, but induce heterosynaptic plasticity and spike output in layer 2/3. Behaviorally, hippocampal inputs to layer 5 and layer 2/3 support object memory encoding versus recall, respectively. Two-photon imaging during navigation reveals hippocampal suppression reduces spatially tuned cortical axonal activity. We present a model, where hippocampal feedback could iteratively shape ongoing cortical processing.

Aging populations worldwide face an increasing burden of age-related chronic conditions, necessitating a deeper understanding of the underlying mechanisms. Purine metabolism has emerged as a crucial player in the pathophysiology of aging, affecting various tissues and organs. Dysregulation of purine metabolism, particularly alterations in extracellular adenosine levels and adenosine receptor signaling, contributes to age-related musculoskeletal problems, cardiovascular diseases, inflammation, and impaired immune responses. Changes in purine metabolism are associated with diminished tissue repair and regeneration, altered bone density, and impaired muscle regeneration. Mechanistically, age-related alterations in purine metabolism involve reductions in extracellular adenosine production, impaired autocrine signaling, and dysregulated expression of CD73 and CD39. Targeting adenosine receptors, such as A_2A and A_2B receptors, emerges as a promising therapeutic approach to mitigate age-related conditions, including sarcopenia, obesity, osteoarthritis, and impaired wound healing. Since we cannot reverse time, understanding the intricate molecular interplay between purine metabolism and aging-related pathologies holds significant potential for developing novel therapeutic strategies to improve the health and quality of life of aging populations. In this review, we compile the findings related to purine metabolism during aging in several tissues and organs and provide insights into how these signals can be manipulated to circumvent the deleterious effects of the passage of time on our body.

Astrocytes are a highly abundant glial cell type and perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogeneous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of the brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: myocilin (Myoc). We show that glia limitans superficialis astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from zebrafish, rodents, and non-human primates to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.

Microsporidia are divergent fungal pathogens that employ a unique harpoon-like apparatus called the polar tube (PT) to invade host cells. The long PT is fired out of the microsporidian spore over the course of just a few hundred milliseconds. Once fired, the PT is thought to pierce the plasma membrane of a target cell and act as a conduit for the transfer of the parasite into the host cell, which initiates infection. The PT architecture and its association with neighboring organelles within the parasite cell remain poorly understood. Here, we use cryoelectron tomography to investigate the structural cell biology of the PT in dormant spores from the human-infecting microsporidian species, Encephalitozoon intestinalis. Segmentation and subtomogram averaging of the PT reveal at least four layers: two protein-based layers surrounded by a membrane layer and filled with a dense core. Regularly spaced protein filaments form the structural skeleton of the PT. Combining cryoelectron tomography with cellular modeling, we propose a model for the three-dimensional organization of the polaroplast, an organelle that surrounds the PT and is continuous with the outermost, membranous layer of the PT. Our results reveal the ultrastructure of the microsporidian invasion apparatus in situ, laying the foundation for understanding infection mechanisms.

Glaucomatous optic neuropathy, or glaucoma, is the world's primary cause of irreversible blindness. Glaucoma is comorbid with other neurodegenerative diseases, but how it might impact the environment of the full central nervous system to increase neurodegenerative vulnerability is unknown. Two neurodegenerative events occur early in the optic nerve, the structural link between the retina and brain: loss of anterograde transport in retinal ganglion cell (RGC) axons and early alterations in astrocyte structure and function. Here, we used whole-mount tissue clearing of full mouse brains to image RGC anterograde transport function and astrocyte responses across retinorecipient regions early in a unilateral microbead occlusion model of glaucoma. Using light sheet imaging, we found that RGC projections terminating specifically in the accessory optic tract are the first to lose transport function. Although degeneration was induced in one retina, astrocytes in both brain hemispheres responded to transport loss in a retinotopic pattern that mirrored the degenerating RGCs. A subpopulation of these astrocytes in contact with large descending blood vessels were immunopositive for LCN2, a marker associated with astrocyte reactivity. Together, these data suggest that even early stages of unilateral glaucoma have broad impacts on the health of astrocytes across both hemispheres of the brain, implying a glial mechanism behind neurodegenerative comorbidity in glaucoma.

INTRODUCTION/UNASSIGNED:Alkyl nitrites ("poppers") are used recreationally for sexual enhancement, muscle relaxation, and euphoria. However, they can be toxic and cause adverse reactions such as methemoglobinemia. While inhalation is the typical route of usage, the New York City Poison Center has noted an increase in calls related to ingestion. Given the uncertainty of usage instructions at the point of sale, our study aimed to assess instructions provided to consumers about alkyl nitrite use and to evaluate the proximity and co-sale of alkyl nitrites with similarly appearing energy drink shots. METHODS/UNASSIGNED:We conducted a cross-sectional convenience sample survey of smoke shops, cannabis dispensaries, and exotic shops within the catchment area of an urban poison center. Plain clothes "investigators" (i.e., the researchers) visited these retailers and followed a predetermined protocol and script to request information regarding the availability and usage of alkyl nitrites. Additionally, the researchers attempted to visually assess the proximity of alkyl nitrites to similarly appearing energy drink shots during their visit. RESULTS/UNASSIGNED:drinks and alkyl nitrites were located near these energy drink shots in twenty (39%) of these fifty-one stores. DISCUSSION/UNASSIGNED:Many commercial alkyl nitrite retailers in our survey area lack knowledge or provide potentially inaccurate information regarding the use of alkyl nitrites. Additionally, alkyl nitrites are often sold alongside commercial energy drinks, potentially increasing the risk of incidental ingestion. CONCLUSIONS/UNASSIGNED:Further research is necessary to determine the impact of these patterns of sale and potential misinformation. Discussing preliminary results of our survey with the New York City Department of Health led to the rapid creation of an informational poster and local outreach. Clinicians should report cases of alkyl nitrite use to their regional poison center to allow for more targeted and timely public health intervention.

Embryonic development in many species, including case reports in humans, can be temporarily halted before implantation during a process called diapause. Facultative diapause occurs under conditions of maternal metabolic stress such as nursing. While molecular mechanisms of diapause have been studied, a natural inducing factor has yet to be identified. Here, we show that oxytocin induces embryonic diapause in mice. We show that gestational delays were triggered during nursing or optogenetic stimulation of oxytocin neurons simulating nursing patterns. Mouse blastocysts express oxytocin receptors, and oxytocin induced delayed implantation-like dispersion in cultured embryos. Last, oxytocin receptor-knockout embryos transferred into wild-type surrogates had low survival rates during diapause. Our results indicate that oxytocin coordinates timing of embryonic development with uterine progression through pregnancy, providing an evolutionarily conserved mechanism for ensuring successful reproduction.

The discovery of long non-coding RNAs (lncRNAs) has provided a new perspective on the centrality of RNA in gene regulation and genome organization. Here, we screened for lncRNAs with putative functions in the host response to single-stranded RNA respiratory viruses. We identify CARINH as a conserved cis-acting lncRNA up-regulated in three respiratory diseases to control the expression of its antisense gene IRF1, a key transcriptional regulator of the antiviral response. CARINH and IRF1 are coordinately increased in the circulation of patients infected with human metapneumovirus, influenza A virus, or SARS-CoV-2, and in macrophages in response to viral infection or TLR3 agonist treatment. Targeted depletion of CARINH or its mouse ortholog Carinh in macrophages reduces the expression of IRF1/Irf1 and their associated target gene networks, increasing susceptibility to viral infection. Accordingly, CRISPR-mediated deletion of Carinh in mice reduces antiviral immunity, increasing viral burden upon sublethal challenge with influenza A virus. Together, these findings identify a conserved role of lncRNA CARINH in coordinating interferon-stimulated genes and antiviral immune responses.

The field of cardio-oncology has traditionally focused on the impact of cancer and its therapies on cardiovascular health. Mounting clinical and preclinical evidence, however, indicates that the reverse may also be true: cardiovascular disease can itself influence tumor growth and metastasis. Numerous epidemiological studies have reported that individuals with prevalent cardiovascular disease have an increased incidence of cancer. In parallel, studies using preclinical mouse models of myocardial infarction, heart failure, and cardiac remodeling support the notion that cardiovascular disorders accelerate the growth of solid tumors and metastases. These findings have ushered in a new and burgeoning field termed reverse cardio-oncology that investigates the impact of cardiovascular disease pathophysiology on cancer emergence and progression. Recent studies have begun to illuminate the mechanisms driving this relationship, including shared risk factors, reprogramming of immune responses, changes in gene expression, and the release of cardiac factors that result in selective advantages for tumor cells or their local milieu, thus exacerbating cancer pathology. Here, we review the evidence supporting the relationship between cardiovascular disease and cancer, the mechanistic pathways enabling this connection, and the implications of these findings for patient care.