Indiana University School of Medicine

Sickle cell disease (SCD) is a genetic blood disorder characterized by the production of abnormal hemoglobin known as hemoglobin S, which leads to reduced oxygen-carrying capacity of the blood. This reduced blood oxygenation can trigger cerebrovascular remodeling, leading to a higher risk of cerebrovascular disease and cognitive impairment. Despite growing evidence of the importance of cerebrovascular health in managing SCD, the lack of specific diagnostic tools makes this area an underutilized target in clinical care. In this cross-sectional study, we aimed to investigate the hemodynamic mechanisms of SCD through functional magnetic resonance imaging (fMRI) and their relationship with hematological parameters. In this pioneering study, we utilized the patterns of systemic low-frequency oscillations within the blood oxygen level-dependent fMRI signal to discern oxygen levels in the brain and characterize distinct blood flow patterns in patients with SCD. We formulated a unique model that revealed two blood flow patterns in SCD patients: firstly, an abnormal rapid flow pattern through arterio-venous shunting, where highly oxygenated blood reaches the superior sagittal sinus prematurely, circumventing most capillaries; secondly, a normal flow pattern, wherein normally oxygenated blood reaches the superior sagittal sinus after traversing through the capillaries. Our findings indicate that both flow patterns coexist in SCD patients, but in those with more severe blood abnormalities, the rapid flow pattern predominates. This study marks the first instance of employing fMRI to investigate the rich hemodynamic information in SCD patients. The results hold significant potential for the development of non-invasive hemodynamic biomarkers to gauge cerebrovascular health in SCD.

The connectome, a map of the structural and/or functional connections in the brain, provides a complex representation of the neurobiological phenotypes on which it supervenes. This information-rich data modality has the potential to transform our understanding of the relationship between patterns in brain connectivity and neurological processes, disorders, and diseases. However, existing computational techniques used to analyze connectomes are often insufficient for interrogating multi-subject connectomics datasets: many current methods are either solely designed to analyze single connectomes or leverage heuristic graph statistics that are unable to capture the complete topology of multiscale connections between brain regions. To enable more rigorous connectomics analysis, we introduce a set of robust and interpretable statistical hypothesis tests motivated by recent theoretical advances in random graph models. These tests facilitate simultaneous analysis of multiple connectomes across different scales of network topology, enabling the robust and reproducible discovery of hierarchical brain structures that vary in relation to phenotypic profiles. In addition to explaining the theoretical foundations and guarantees of our algorithms, we demonstrate their superiority over current state-of-the-art connectomics methods through extensive simulation studies and real-data experiments. Using a set of high-resolution connectomes obtained from genetically distinct mouse strains (including the BTBR mouse—a standard model of autism—and three behavioral wild-types), we illustrate how our methods successfully uncover latent information in multi-subject connectomics data and yield valuable insights into the connective correlates of neurological phenotypes that other methods do not capture. The data and code necessary to reproduce the analyses, simulations, and figures presented in this work are available at https://github.com/neurodata/MCC.

Fluctuations in cerebral blood volume (CBV) are a dominant mechanism aiding cerebrospinal fluid (CSF) movement in the brain during wakefulness and non-rapid eye movement (NREM) sleep. However, it is unclear if the amplitudes of CBV oscillations also change in proportion to the changes in amplitude of CSF movement across specific NREM sleep states. It is also not known if the coupling strength between them varies between NREM sleep states. To investigate these relationships, we measured cerebral hemodynamics and craniad CSF movement at the fourth ventricle simultaneously during wakefulness and NREM sleep states using concurrent Electroencephalography and functional Magnetic Resonance Imaging. We found that the amplitude fluctuations of cerebral hemodynamics and CSF oscillations desynchronize from one another only during deep NREM3 state, despite the strong mechanical coupling between CBV changes and CSF movement, which was consistent across all states. This suggests the existence of a different mechanism, linked to the cortical interstitial volume/resistance change, that regulates the NREM3 CSF inflow into the brain.

Apurinic/apyrimidinic endonuclease I (APE1) acts as both an endonuclease and a redox factor to ensure cell survival. The two activities require different conformations of APE1. As an endonuclease, APE1 is fully folded. As a redox factor, APE1 must be partially unfolded to expose the buried residue Cys65, which reduces transcription factors including AP‐1, NF‐κB, and HIF‐1α and thereby enables them to bind DNA. To determine a molecular basis for partial unfolding associated with APE1's redox activity, we characterized specific interactions of a known redox inhibitor APX3330 with APE1 through waterLOGSY and ¹H–¹⁵N HSQC NMR approaches using ethanol and acetonitrile as co‐solvents. We find that APX3330 binds to the endonuclease active site in both co‐solvents and to a distant small pocket in acetonitrile. Prolonged exposure of APE1 with APX3330 in acetonitrile resulted in a time‐dependent loss of ¹H–¹⁵N HSQC chemical shifts (~35%), consistent with partial unfolding. Regions that are partially unfolded include adjacent N‐ and C‐terminal beta strands within one of the two sheets comprising the core, which converge within the small binding pocket defined by the CSPs. Removal of APX3330 via dialysis resulted in a slow reappearance of the ¹H–¹⁵N HSQC chemical shifts suggesting that the effect of APX3330 is reversible. APX3330 significantly decreases the melting temperature of APE1 but has no effect on endonuclease activity using a standard assay in either co‐solvent. Our results provide insights on reversible partial unfolding of APE1 relevant for its redox function as well as the mechanism of redox inhibition by APX3330.

Background Systemic artery-to-pulmonary artery (SA-PA) shunts provide effective palliation for complex congenital heart disease (CHD) but carry a risk for morbidity and mortality. We aimed to comprehensively analyze our experience with SA-PA shunts. Methods Our institutional Society of Thoracic Surgeons (STS) database was queried to identify patients who underwent SA-PA shunts from 2009 to 2022, excluding those who underwent the Norwood procedure, right ventricle-PA shunt, or fenestrated patch. Definitions from the STS Congenital Heart Surgery Database Specifications were used. Shunt failure included dysfunction secondary to thrombosis, obstruction, stenosis, or outgrowth requiring intervention. Results A total of 287 patients met inclusion criteria. Shunts were placed at a median of 15.0 days (interquartile range 7.0-39.5). A thoracotomy approach was used in 178 out of 287 patients (62.0%), and cardiopulmonary bypass was employed in only 46 of 287 cases (16.0%). Survival to the next stage was 89.5% (246/275), with in-hospital mortality of 6.3% (18/287) and interstage mortality of 4.2% (12/287). Shunt failure occurred in 54/287 (18.8%), and 77/287 (26.8%) required reintervention for shunt-related complications. On multivariable analysis, poorer shunt failure-free survival was associated with any syndrome, left-sided arch vessel shunt origin, concurrent complex repairs, competitive flow from a patent ductus arteriosus, and delayed antiplatelet initiation. The thoracotomy approach was protective. Risk factors for worse survival to the next stage included shunt thrombosis and perioperative platelet transfusion. Conclusions While complications remain common, our contemporary results demonstrate that SA-PA shunts remain a reliable palliation for CHD with insufficient pulmonary blood flow. Risk reduction may involve careful management of competitive pulmonary blood flow and prompt initiation of antiplatelet therapy.

Purpose To evaluate the effectiveness of laser prophylaxis in preventing retinal detachment (RD) in patients with Stickler syndrome. Methods A literature search was performed to identify studies that compared RD rates between eyes that received laser prophylaxis and eyes that received no laser prophylaxis in patients with Stickler syndrome. Data sets from the included studies were pooled and analysed. Individual eyes that presented with RD and eyes without RD with <6 months of follow‐up were excluded. The primary outcome was the rate of RD. The study was conducted in accordance with the PRISMA guideline 2020 for systematic reviews. Results There were 6 articles included in the meta‐analysis, including 400 eyes of 225 patients. RD rate was 6.6% (19 of 289) in eyes with laser compared to 36.0% (40 of 111) in eyes with no laser ( p < 0.00001, chi‐square) with a mean follow‐up interval of 6.3 years for eyes with laser and 4.0 years for eyes with no laser. The pooled risk ratio for retinal detachment after laser prophylaxis was 0.23 (95% CI: 0.13–0.41). Conclusion Prophylactic laser therapy was associated with a significantly lower risk of RD in patients with Stickler syndrome compared to no laser prophylaxis.

We present a model-free phase I/II clinical trial design, referred to as the UFO design, to optimize the dose of immunotherapy by jointly modeling toxicity, efficacy, and immune response outcomes. Instead of relying on complex parametric modeling approaches, we propose a model-free approach that uses the inherent correlations among different types of outcomes in immunotherapy and the constrained dose-outcome order to facilitate information sharing across different doses. This approach ensures the efficiency and transparency of the UFO design to be implemented in clinical practice. The UFO design is also extended to accommodate the delayed outcomes. It demonstrates favorable operating characteristics through simulation studies. The R Shniy app for simulation and trial implementation using the UFO design is also provided at iusccc.shinyapps.io/smartdesign .

The use and misuse of opioids has surged in the past decade, with nearly half of the users being female. Although opioid use is lower among pregnant women, trends mirror the general population. While pediatric exposures largely occur through prescriptions. This review presents a novel landscape analysis of pharmacology knowledge gaps in opioids in the maternal and pediatric populations. We queried PubMed for studies on 27 opioids, focusing on pharmacokinetics (PK), and pharmacoepidemiology (PE) or clinical trials (CT) in maternal and pediatric populations. English‐language publications were included, and data were synthesized to identify gaps. Additionally, MarketScan claims data and United States Food and Drug Administration (FDA) drug labels were analyzed to compare scientific evidence, opioid prescriptions/orders, and FDA recommendations. Morphine, fentanyl, methadone, and buprenorphine are the most researched opioids in PK and PE/CT literature in both populations, but hydrocodone, oxycodone, and codeine are the most prescribed. Nine opioids lack FDA labels, and four of the 18 labeled drugs lack any human data. Hydrocodone, oxycodone, and codeine labels include lactation‐focused PK information, with some pediatric clinical data for the latter two. Seven opioids lack PK and PE/CT studies in the maternal population, and PK research is absent for seven opioids, and PE/CT data is lacking for eight opioids in the pediatric population. PK studies often focus on labor, delivery, and lactation accompanied by neonatal data, whereas pregnancy research mainly occurs in PE studies. In pediatric populations, study types are evenly distributed among children, but PE studies focus more on adolescents. Drug concentration is the most reported parameter in PK studies, and neonatal opioid withdrawal syndrome (NOWS) is a key outcome in both PK and PE studies. NOWS is also researched more using real‐world data, whereas neurodevelopmental outcomes are often captured in prospective observational studies. There is substantial disparity between the most commonly researched and prescribed opioids. In particular, the opioid pharmacology knowledge gaps are larger in pregnant women and for the highly prescribed opioids hydrocodone and oxycodone. The limited human data in FDA labels underscores the need for additional studies. Studies using real‐world data can potentially help address these gaps.

In an era of predicted emerging pandemics, the production of effective vaccines may require an in-depth understanding of the biology of human naive B (B N ) cells. Here we provide evidence that the majority of B N cells expressed CD73, an ecto-5’-nucleotidase often associated with immune cell suppression, and demonstrated features of anergy, including an IgM low IgD ⁺ surface phenotype, reduced calcium flux in response to IgM crosslinking, and increased PTEN expression. Analysis of antibody sequences encoded by the inherently autoreactive V H 4-34 heavy chain produced by plasmablasts seven days following influenza vaccination showed that in younger but not in older individuals, anergic B N cells provided a reservoir of B cells capable of responding to vaccination by somatic mutation, resulting in diversification and loss of autoreactivity. These results suggest that effective human vaccines may require the ability to awaken or ‘redeem’ anergic B N cells that can be repurposed to participate in pathogen-specific responses.

Background Suprascapular neuropathy is an uncommon but treatable cause of shoulder pain and dysfunction. The tortuous course of the suprascapular nerve puts it at risk for entrapment, particularly at the suprascapular and spinoglenoid notches. This video presents a reproducible method for suprascapular nerve decompression at the suprascapular notch. Indications Massive rotator cuff tears, compressive masses, or ligament hypertrophy warrants prompt intervention to prevent subsequent denervation in the face of suprascapular neuropathy. In the absence of these pathologies, a trial of conservative management is advised. Patients who have unsuccessful conservative management and evidence of worsening weakness, atrophy, and denervation by electromyography are indicated for surgical intervention. Technique Description Standard posterior, anterior, lateral, and anterolateral portals are established. The subdeltoid space is dissected following the coracoacromial (CA) ligament to the base of the coracoid to identify the transverse scapular ligament. In the presented case, the CA ligament has been debrided from a previous surgery, so an intra-articular approach was employed, opening the rotator interval to reach the base of the coracoid. A Neviaser portal is made for blunt dissection around the suprascapular notch, with care taken to protect the neurovasculature. A second medial Neviaser portal is used to pass a Kerrison to release the transverse scapular ligament. Nerve adhesions are then gently released with a probe. Results A systematic review of 276 suprascapular nerve decompressions demonstrated good outcomes in terms of pain relief and function, and all athletes in the review returned to sport. A case series of 112 arthroscopic decompressions at the suprascapular notch found that patients achieved significant improvement in pain and strength, and none resulted in serious complications. These outcome studies support a level 4 video publication level of evidence. Discussion/Conclusion The presented arthroscopic decompression technique treats suprascapular nerve entrapment at the suprascapular notch. Patients can expect to achieve a satisfactory outcome. Patient Consent Disclosure Statement The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication.

Background Higher prevalence of sleep disorders is seen in persons with psoriasis (PsO). However, the extent to which sleep conditions are linked to PsO severity, particularly across diverse populations, remains unknown. Bridging this knowledge gap is vital for developing comprehensive, equitable and personalized care strategies. Objectives We aimed to quantify the extent to which psoriasis severity correlates with the risk of developing specific sleep disorders, and to identify how these associations vary by racial/ethnic group, using robust covariate adjustments. Methods Health records for 7743 adults with psoriasis were obtained from the All of Us sample—an NIH database initiative that oversamples underrepresented populations. Cases were selectively matched 1:4 to age‐, sex‐, and race/ethnicity‐matched controls, and differences were interrogated by multivariable regression. Results Mild PsO was significantly associated with restless leg syndrome, insomnia and obstructive sleep apnoea after adjusting for sociodemographic variables and comorbidities. Moderate‐to‐severe PsO demonstrated greater magnitudes of association. We additionally observed a magnified sleep disorder risk in non‐White patients, particularly for insomnia and OSA. Conclusions Both mild and moderate‐to‐severe psoriasis is significantly associated with an increased risk of sleep disorders, with notable variations across different racial/ethnic groups.

The incorporation of humanism through exploration of pathology in gross anatomy allows students to develop a deeper appreciation of the pathological basis of disease and to explore the impacts of pathology on donors' lives through clinicopathologic correlation of their findings. The purpose of this short communication was to describe and evaluate a pilot intervention that integrated histopathology into an existing humanism thread, First Patient Project (FPP), in an undergraduate, dissection‐based gross anatomy course. Five reflections were collected from each student (n = 18 students, 90 reflections) and a post‐course questionnaire collected data on student perceptions of the FPP and integrations of histopathology. Content analysis was used to analyze reflection and survey free response data, and descriptive statistics were performed on Likert‐style items using Excel. The questionnaire was completed by six students (33%) and five themes comprise the perceived impacts of the integration of histopathology into the FPP: pathology deepens anatomy knowledge, promotes career exploration, novice medical professionals, reflections of donor pathology and lifestyle, and general feedback on histopathology integration. Student reflections demonstrated that the histopathology component of the FPP improved clinical understanding of pathology, helped facilitate feelings of belonging in the medical profession, and allowed them to reflect on their own humanity as well as that of the donors. This ultimately demonstrated that histology and particular histopathology from anatomic donors were feasible and provided an avenue for curricular integration and adding another layer of appreciation of the donors' clinical history.

In a United States claims database, 1,358 persons with familial hypophosphatemia who began treatment with burosumab were identified. Prior to treatment, high rates of several morbidities were coded including osteoarthritis, fractures, enthesopathy, spinal stenosis, hypertension, depression and opioid use, which generally increased with age, emphasizing disease burden throughout the lifespan. Purpose To examine the characteristics and disease history of real-world patients with X-linked hypophosphatemia (XLH) in the United States, prior to initiating burosumab. Methods This retrospective cohort study used Komodo Health’s Healthcare Map™, a de-identified patient-level claims database. Included patients had ≥ 1 claim for familial hypophosphatemia between 01-Jan-2015 and 30-Jun-2022 (the study period) and ≥ 1 claim for burosumab between 01-Apr-2018 and 30-Jun-2022. The index date was the date of first burosumab claim. Patient demographics were measured at index; disease history was measured over the pre-index period and stratified by age. All variables were evaluated descriptively. Results 1,358 patients were included (mean age 23.5 ± 19.1 years, 847 [62%] female); 720 patients (53%) were aged < 18 years. Prior to index, patients had high levels of XLH-related morbidities. Most XLH-related morbidities appeared in the youngest age groups, and the prevalence was generally greater among the older age groups. For example, arthralgia was found in 57 patients (12%) aged ≤ 11 years and 123 patients (69%) aged ≥ 50 years. Opioid use increased with age (173 patients [24%] aged < 18 years; 328 [51%] ≥ 18 years). Physical therapy use was observed across age groups (126 patients [18%] aged < 18 years; 253 [40%] ≥ 18 years). Conclusions At initiation of burosumab, over half of patients with XLH were < 18 years of age. Claims indicated a high prevalence of XLH-related morbidities, which began at a young age and increased over time.

Objectives To describe PSMA PET/CT characteristics of patients with high‐risk BCR. Subjects/patients and methods This was a retrospective analysis of patients with high‐risk BCR prostate cancer (PSA ≥ 2 ng/ml above nadir after radiation therapy [RT] or ≥1 ng/ml after radical prostatectomy [RP] +/− RT) who underwent PET/CT from July 2021–March 2023. Patients with prior cytotoxic chemotherapy, androgen deprivation therapy (ADT) initiated >3 months prior to PET/CT or positive conventional imaging within 3 months of PET/CT were excluded. Neoadjuvant/adjuvant ADT completed ≥9 months prior was allowed. Logistic regression, Pearson's Chi‐squared, Wilcoxon rank sum and Fisher's exact tests were used for analysis. Results A total of 113 of 145 (77%) included patients in the analysis had ≥1 lesion on PSMA PET/CT. There was no difference in PSMA PET/CT positivity based on age, race, Gleason Grade at initial biopsy or PSA. Overall, 29 (20%) patients had lesions in the prostate/prostate bed only, 31 (21%) had lesions consistent with N1M0 disease and 53 (37%) had lesions consistent with M1 disease. For M1 patients, 21/53 (40%) had oligometastatic disease (1–3 lesions), and 32/53 (60%) had a higher burden (>3 lesions). Local recurrence was more common with RT and nodal recurrence with RP, with no difference in distant metastasis by initial treatment. Conclusion Nearly 80% of patients with high‐risk BCR after local treatment for prostate cancer with RP and/or RT will have positive findings on PSMA PET/CT. In addition to intensified systemic therapy, up to 55% of the patients may have benefitted from salvage local therapy, nodal pelvic radiation or metastasis‐directed therapies for oligometastatic disease.

P2Y 12 inhibitor selection involves numerous factors, including CYP2C19 genetics, since evidence demonstrates reduced clopidogrel efficacy in patients with decreased or no function CYP2C19 variants. In 2020, Indiana University health embedded interruptive clinical decision support ( CDS ) alerts in the electronic health record ( EHR ) to recommend alternative P2Y 12 inhibitors for patients with decreased CYP2C19 function who had undergone percutaneous coronary intervention ( PCI ). The objective of this study was to evaluate prescriber response to these CDS alerts. Utilizing alert response data and P2Y 12 inhibitor prescriptions from October 2020 to December 2023, we evaluated prescriber response for 362 patients who had a mean of 2.2 (SD: 1.7) CYP2C19 ‐clopidogrel alerts fire post‐PCI. Alert recommendations were accepted 24.5% ± 36.8% (mean ± SD) of the time. Alternative (i.e., non‐clopidogrel) P2Y 12 inhibitors were prescribed for 22.4% ± 36.8% of days during the year following PCI. Alerts were accepted more for CYP2C19 poor metabolizers than for intermediate metabolizers ( P = 0.03). Each year after 2020 was associated with a 4.6% increase in the days prescribed alternative P2Y 12 inhibitors. In contrast, increasing age was associated with decreased alert acceptance and decreased percentage of days prescribed alternatives, and concomitant oral anticoagulant use was associated with decreased percentage of days prescribed alternatives. Provider clinical judgment was the most common alert override reason, accounting for 68% of clinician responses. Our findings demonstrate that CYP2C19 ‐clopidogrel CDS alerts promoted genotype‐guided P2Y 12 inhibitor prescribing in some cases (~22% of study days). Future research should better determine prescriber reasons for rejecting alert recommendations and establish best implementation practices to complement CDS alerts.

Studies support the role of hexamethylene bis‐acetamide [HMBA] induced protein 1 (HEXIM1) as a tumor suppressor. We previously reported that the histone demethylase, KDM5B, inhibits the expression of HEXIM1, and KDM5B inhibitors (KDM5Bi) upregulate HEXIM1 expression. As a consequence, KDM5Bi inhibited cell proliferation, induced differentiation, potentiated sensitivity to cancer chemotherapy, and inhibited breast tumor metastasis. HEXIM1 is crucial for the regulation of triple‐negative breast cancer (TNBC) phenotype by KDM5Bi. Type I Interferon (IFN‐I) employs the immune system in the tumor microenvironment to restrict tumor growth. Moreover, therapeutic approaches (including mainstay chemotherapy) engage IFN‐I signaling. We report herein that HEXIM1 and KDM5Bi induce IFN‐I in TNBC. HEXIM1 and KDM5Bi downregulate the expression of polyribonucleotide nucleotidyltransferase 1 (PNPT1) resulting in the release of mitochondrial dsRNA (mt‐dsRNA) into the cytoplasm. HEXIM1 also upregulates melanoma differentiation‐associated protein 5 (MDA5), a cytoplasmic viral RNA receptor in the innate immune system. MDA5 is required for HEXIM1 and KDM5Bi to induce IFN‐I and downstream signaling factors. We observed the augmentation of DNA damage response to Doxorubicin in the presence of KDM5Bi, and this action is a contributing factor in KDM5Bi‐induced IFN‐I. These actions of HEXIM1 and KDM5Bi occur independently of Cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (cGAS/STING), a major DNA sensing pathway and inducer of innate immunity. Via the upregulation of HEXIM1, KDM5Bi represent pharmacologically induced and tumor intrinsic IFN‐I production that is cGAS/STING independent. This is critical because cGAS/STING induce an inflammatory response that promotes the survival of cancer cells, and STING is often impaired in malignant cancers.

While most people believe that women (vs. men) experience more discriminatory treatment at work, especially in male-dominated professions, relatively few women report experiencing such treatment themselves. These low levels of reporting may arise either because discriminatory treatment has declined, even while laypeople’s assumptions of widespread discrimination persist, or because it is difficult for individuals to know when they are experiencing discriminatory treatment, leading to underreporting. In investigating this puzzle, we theorized four types of nonsexual workplace experiences that may target women and accumulate to harm well-being, yet may be difficult to recognize as discrimination. To test our predictions, we conducted a longitudinal, multisite experience-sampling study of surgeons, capturing workplace experiences over 5 mo. This approach addresses methodological limitations of past research, which include recall biases, demand characteristics, and low external validity. Consistent with hypotheses, female (vs. male) surgeons had more experiences in which their role was challenged or their authority questioned. Moreover, the frequency and severity of these experiences predicted increased burnout over time and decreased intentions to persist in surgery, regardless of whether participants attributed their experiences to their gender. Contrary to hypotheses, female surgeons did not encounter more presumptions of their helpfulness. Female surgeons also received more positive feedback, especially from other women, which yielded increases in professional efficacy and intentions to persist in surgery. Thus, while difficult to detect, workplace discriminatory treatment continues to harm women’s well-being and career opportunities, impede organizations’ efforts to recruit and retain women professionals, and exacerbate burnout among health care providers.