Preoperative prediction model for risk of readmission after total joint replacement surgery: a random forest approach leveraging NLP and unfairness mitigation for improved patient care and cost-effectiveness.

BACKGROUND: The Center for Medicare and Medicaid Services (CMS) imposes payment penalties for readmissions following total joint replacement surgeries. This study focuses on total hip, knee, and shoulder arthroplasty procedures as they account for most joint replacement surgeries. Apart from being a burden to healthcare systems, readmissions are also troublesome for patients. There are several studies which only utilized structured data from Electronic Health Records (EHR) without considering any gender and payor bias adjustments. METHODS: For this study, dataset of 38,581 total knee, hip, and shoulder replacement surgeries performed from 2015 to 2021 at Novant Health was gathered. This data was used to train a random forest machine learning model to predict the combined endpoint of emergency department (ED) visit or unplanned readmissions within 30 days of discharge or discharge to Skilled Nursing Facility (SNF) following the surgery. 98 features of laboratory results, diagnoses, vitals, medications, and utilization history were extracted. A natural language processing (NLP) model finetuned from Clinical BERT was used to generate an NLP risk score feature for each patient based on their clinical notes. To address societal biases, a feature bias analysis was performed in conjunction with propensity score matching. A threshold optimization algorithm from the Fairlearn toolkit was used to mitigate gender and payor biases to promote fairness in predictions. RESULTS: The model achieved an Area Under the Receiver Operating characteristic Curve (AUROC) of 0.738 (95% confidence interval, 0.724 to 0.754) and an Area Under the Precision-Recall Curve (AUPRC) of 0.406 (95% confidence interval, 0.384 to 0.433). Considering an outcome prevalence of 16%, these metrics indicate the model's ability to accurately discriminate between readmission and non-readmission cases within the context of total arthroplasty surgeries while adjusting patient scores in the model to mitigate bias based on patient gender and payor. CONCLUSION: This work culminated in a model that identifies the most predictive and protective features associated with the combined endpoint. This model serves as a tool to empower healthcare providers to proactively intervene based on these influential factors without introducing bias towards protected patient classes, effectively mitigating the risk of negative outcomes and ultimately improving quality of care regardless of socioeconomic factors.

Effect of Electronic Portal Messaging With Embedded Asynchronous Care on Physician-Assisted Smoking Cessation Attempts: A Randomized Clinical Trial.

IMPORTANCE: Despite the substantial health and financial burdens of smoking and the availability of effective, evidence-based interventions in primary care settings, few smokers and physicians use these strategies for smoking cessation. OBJECTIVE: To evaluate whether electronic outreach to smokers with embedded asynchronous care increases the number of quit attempts and explore the roles of the message sender (ie, primary care physician [PCP] vs health care system) and patient-related characteristics. DESIGN, SETTING, AND PARTICIPANTS: This quality improvement randomized clinical trial was designed to measure 2 factors: (1) electronic outreach messaging with and without a survey link to asynchronous care and (2) messaging by a personal PCP or health system. The study was conducted within the electronic health record and portal messaging platform of a large health system in the South Central US. Participants were adult patients 18 years or older who were designated as smokers in their electronic health records. Data were collected from January 13 to February 24, 2020, with participating PCPs surveyed in July 2020. INTERVENTIONS: Portal messages encouraging a quit attempt and offering physician assistance were sent to smokers who were randomly selected and assigned to 1 of 4 conditions (message with or without embedded asynchronous care and PCP or system as sender). Half of the messages contained an invitation to come to clinics and the other half contained a link to access asynchronous care. MAIN OUTCOMES AND MEASURES: The primary outcome was electronic health record-documented quit attempts (1 indicates quit attempt; 0, no quit attempt), which were tracked 30 days after the electronic outreach. Secondary outcomes included physician perceptions of the electronic outreach intervention, using a 5-point scale to assess perceptions of workload, comfort with providing medication from survey information, and further interest in the program 6 months after the intervention. RESULTS: A total of 188 participants (99 women [52.4%] and 89 men [47.3%]) with mean (SD) age of 55.2 (13.9) years were randomized to 1 of 4 conditions. Group 1 (n = 46) received a message from the PCP without a link to the survey; group 2 (n = 48) received a message from the PCP with a link to asynchronous care in the form of the survey. Group 3 (n = 47) received a message from the health system without a link to the survey; group 4 (n = 47) received a message from the health system with a link to the survey. No statistically significant difference in documented quite attempts was found among the 4 study groups. There was also no statistically significant difference in quit attempts between the group that received the asynchronous care survey link and the group that did not (odds ratio, 2.50 [95% CI, 0.72-8.72]). However, the quit attempt rate for those with asynchronous care offered (9 of 95 [9.5%]) was more than double the quit attempt rate for those with in-person care offered (4 of 93 [4.3%]). CONCLUSIONS AND RELEVANCE: This quality improvement randomized clinical trial did not find a statistically significant difference in physician-assisted quit attempts among patients who received electronic with asynchronous care vs those who received outreach alone, regardless of whether the message source was a PCP or a health system. However, the program engaged patients in difficult-to-reach rural areas as well as younger patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05172219.

A Bioengineered Neuregulin-Hydrogel Therapy Reduces Scar Size and Enhances Post-Infarct Ventricular Contractility in an Ovine Large Animal Model.

The clinical efficacy of neuregulin (NRG) in the treatment of heart failure is hindered by off-target exposure due to systemic delivery. We previously encapsulated neuregulin in a hydrogel (HG) for targeted and sustained myocardial delivery, demonstrating significant induction of cardiomyocyte proliferation and preservation of post-infarct cardiac function in a murine myocardial infarction (MI) model. Here, we performed a focused evaluation of our hydrogel-encapsulated neuregulin (NRG-HG) therapy's potential to enhance cardiac function in an ovine large animal MI model. Adult male Dorset sheep (n = 21) underwent surgical induction of MI by coronary artery ligation. The sheep were randomized to receive an intramyocardial injection of saline, HG only, NRG only, or NRG-HG circumferentially around the infarct borderzone. Eight weeks after MI, closed-chest intracardiac pressure-volume hemodynamics were assessed, followed by heart explant for infarct size analysis. Compared to each of the control groups, NRG-HG significantly augmented left ventricular ejection fraction (p = 0.006) and contractility based on the slope of the end-systolic pressure-volume relationship (p = 0.006). NRG-HG also significantly reduced infarct scar size (p = 0.002). Overall, using a bioengineered hydrogel delivery system, a one-time dose of NRG delivered intramyocardially to the infarct borderzone at the time of MI in adult sheep significantly reduces scar size and enhances ventricular contractility at 8 weeks after MI.

Diverse human VH antibody fragments with bio-therapeutic properties from the Crescendo Mouse.

We describe the 'Crescendo Mouse', a human VH transgenic platform combining an engineered heavy chain locus with diverse human heavy chain V, D and J genes, a modified mouse Cγ1 gene and complete 3' regulatory region, in a triple knock-out (TKO) mouse background devoid of endogenous immunoglobulin expression. The addition of the engineered heavy chain locus to the TKO mouse restored B cell development, giving rise to functional B cells that responded to immunization with a diverse response that comprised entirely 'heavy chain only' antibodies. Heavy chain variable (VH) domain libraries were rapidly mined using phage display technology, yielding diverse high-affinity human VH that had undergone somatic hypermutation, lacked aggregation and showed enhanced expression in E. coli. The Crescendo Mouse produces human VH fragments, or Humabody® VH, with excellent bio-therapeutic potential, as exemplified here by the generation of antagonistic Humabody® VH specific for human IL17A and IL17RA.

Selecting response anchors with equal intervals for summated rating scales.

Summated rating scales are ubiquitous in organizational research, and there are well-delineated guidelines for scale development (e.g., Hinkin, 1998). Nevertheless, there has been less research on the explicit selection of the response anchors. Constructing survey questions with equal-interval properties (i.e., interval or ratio data) is important if researchers plan to analyze their data using parametric statistics. As such, the primary objectives of the current study were to (a) determine the most common contexts in which summated rating scales are used (e.g., agreement, similarity, frequency, amount, and judgment), (b) determine the most commonly used anchors (e.g., strongly disagree, often, very good), and (c) provide empirical data on the conceptual distance between these anchors. We present the mean and standard deviation of scores for estimates of each anchor and the percentage of distribution overlap between the anchors. Our results provide researchers with data that can be used to guide the selection of verbal anchors with equal-interval properties so as to reduce measurement error and improve confidence in the results of subsequent analyses. We also conducted multiple empirical studies to examine the consequences of measuring constructs with unequal-interval anchors. A clear pattern of results is that correlations involving unequal-interval anchors are consistently weaker than correlations involving equal-interval anchors. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Ex Vivo Biomechanical Study of Apical Versus Papillary Neochord Anchoring for Mitral Regurgitation.

BACKGROUND: Neochordoplasty is an important repair technique, but optimal anchoring position is unknown. Although typically anchored at papillary muscles, new percutaneous devices anchor the neochordae at or near the ventricular apex, which may have an effect on chordal forces and the long-term durability of the repair. METHODS: Porcine mitral valves (n = 6) were mounted in a left heart simulator that generates physiologic pressure and flow through the valves, and chordal forces were measured with Fiber Bragg Grating strain gauge sensors. Isolated mitral regurgitation was induced by cutting P2 primary chordae, and the regurgitant valve was repaired with polytetrafluoroethylene neochord with apical anchoring, followed by papillary muscle fixation for comparison. In both situations, the neochord was anchored to a customized force-sensing post positioned to mimic the relevant in vivo placement. RESULTS: Echocardiographic and hemodynamic data confirmed that the repairs restored physiologic hemodynamics. Forces on the chordae and neochord were lower for papillary fixation than for the apical fixation (p = 0.003). In addition, the maximum rate of change of force on the chordae and neochordae was higher for apical fixation than for papillary fixation (p = 0.028). CONCLUSIONS: Apical neochord anchoring results in effective repair of mitral regurgitation, albeit with somewhat higher forces on the chordae and neochord suture, as well as an increased rate of loading on the neochord compared with the papillary muscle fixation. These results may guide strategies to reduce stresses on neochordae as well as aid optimal patient selection.

Cranial Nerve Foramina: Part II - A Review of the Anatomy and Pathology of Cranial Nerve Foramina of the Posterior Cranial Fossa.

Cranial nerve foramina are integral exits from the confines of the skull. Despite their significance in cranial nerve pathologies, there has been no comprehensive anatomical review of these structures. Owing to the extensive nature of this topic we have divided our review into two parts; Part II, presented here, focuses on the foramina of the posterior cranial fossa and discusses each foramen's shape, orientation, size, surrounding structures, and structures that pass through it. Furthermore, by comparing foramen sizes against the cross-sectional areas of their contents, we determine the amount of free space available within each. We also review lesions that can obstruct each foramen and discuss the clinical consequences.

Cranial Nerve Foramina Part I: A Review of the Anatomy and Pathology of Cranial Nerve Foramina of the Anterior and Middle Fossa.

Cranial nerve foramina are integral exits from the confines of the skull. Despite their significance in cranial nerve pathologies, there has been no comprehensive anatomical review of these structures. Owing to the extensive nature of this topic, Part I of our review, presented here, focuses on the foramina of the anterior and middle cranial fossae, discussing each foramen's shape, orientation, size, surrounding structures, and structures that traverse them. Furthermore, by comparing the size of each foramen against the cross-sectional areas of its contents, we estimate the amount of free space in each. We also review lesions that can obstruct the foramina and discuss their clinical consequences.

SDF 1-alpha Attenuates Myocardial Injury Without Altering the Direct Contribution of Circulating Cells.

Stromal cell-derived factor 1-alpha (SDF) is a potent bone marrow chemokine capable of recruiting circulating progenitor populations to injured tissue. SDF has known angiogenic capabilities, but bone marrow-derived cellular contributions to tissue regeneration remain controversial. Bone marrow from DsRed-transgenic donors was transplanted into recipients to lineage-trace circulating cells after myocardial infarction (MI). SDF was delivered post-MI, and hearts were evaluated for recruitment and plasticity of bone marrow-derived populations. SDF treatment improved ventricular function, border zone vessel density, and CD31+ cell frequency post-MI. Bone marrow-derived endothelial cells were observed; these cells arose through both cell fusion and transdifferentiation. Circulating cells also adopted cardiomyocyte fates, but such events were exceedingly rare and almost exclusively resulted from cell fusion. SDF did not significantly alter the proportion of circulating cells that adopted non-hematopoietic fates. Mechanistic insight into the governance of circulating cells is essential to realizing the full potential of cytokine therapies.

Angiogenesis precedes cardiomyocyte migration in regenerating mammalian hearts.

OBJECTIVE: Although the mammalian heart's ability to fully regenerate is debated, its potential to extensively repair itself is gaining support. We hypothesized that heart regeneration relies on rapid angiogenesis to support myocardial regrowth and sought to characterize the timeline for angiogenesis and cell proliferation in regeneration. METHODS: One-day-old CD-1 mice (P1, N = 60) underwent apical resection or sham surgery. Hearts were explanted at serial time points from 0 to 30 days postresection and analyzed with immunohistochemistry to visualize vessel ingrowth and cardiomyocyte migration into the resected region. Proliferating cells were labeled with 5-ethynyl-2'-deoxyuridine injections 12 hours before explant. 5-Ethynyl-2'-deoxyuridine-positive cells were counted in both the apex and remote areas of the heart. Masson's trichrome was used to assess fibrosis. RESULTS: By 30 days postresection, hearts regenerated with minimal fibrosis. Compared with sham surgery, apical resection stimulated a significant increase in proliferation of preexisting cardiomyocytes between 3 and 11 days after injury. Capillary migration into the apical thrombus was detected as early as 2 days postresection, with development of mature arteries by 5 days postresection. New vessels became perfused by 5 days postresection as evidenced by lectin injection. Vessel density and diameter significantly increased within the resected area over 21 days, and vessel ingrowth always preceded cardiomyocyte migration, with coalignment of most migrating cardiomyocytes with ingrowing vessels. CONCLUSIONS: Endothelial cells migrate into the apical thrombus early after resection, develop into functional arteries, and precede cardiomyocyte ingrowth during mammalian heart regeneration. This endogenous neonatal response emphasizes the importance of expeditious angiogenesis required for neomyogenesis.

Small-Format Drug Conjugates: A Viable Alternative to ADCs for Solid Tumours?

Antibody-Drug Conjugates (ADCs) have been through multiple cycles of technological innovation since the concept was first practically demonstrated ~40 years ago. Current technology is focusing on large, whole immunoglobulin formats (of which there are approaching 100 in clinical development), many with site-specifically conjugated payloads numbering 2 or 4. Despite the success of trastuzumab-emtansine in breast cancer, ADCs have generally failed to have an impact in solid tumours, leading many to explore alternative, smaller formats which have better penetrating properties as well as more rapid pharmacokinetics (PK). This review describes research and development progress over the last ~10 years obtained from the primary literature or conferences covering over a dozen different smaller format-drug conjugates from 80 kDa to around 1 kDa in total size. In general, these agents are potent in vitro, particularly more recent ones incorporating ultra-potent payloads such as auristatins or maytansinoids, but this potency profile changes when testing in vivo due to the more rapid clearance. Strategies to manipulate the PK properties, whilst retaining the more effective tumour penetrating properties could at last make small-format drug conjugates viable alternative therapeutics to the more established ADCs.

Structure and characterization of a high affinity C5a monoclonal antibody that blocks binding to C5aR1 and C5aR2 receptors.

C5a is a potent anaphylatoxin that modulates inflammation through the C5aR1 and C5aR2 receptors. The molecular interactions between C5a-C5aR1 receptor are well defined, whereas C5a-C5aR2 receptor interactions are poorly understood. Here, we describe the generation of a human antibody, MEDI7814, that neutralizes C5a and C5adesArg binding to the C5aR1 and C5aR2 receptors, without affecting complement-mediated bacterial cell killing. Unlike other anti-C5a mAbs described, this antibody has been shown to inhibit the effects of C5a by blocking C5a binding to both C5aR1 and C5aR2 receptors. The crystal structure of the antibody in complex with human C5a reveals a discontinuous epitope of 22 amino acids. This is the first time the epitope for an antibody that blocks C5aR1 and C5aR2 receptors has been described, and this work provides a basis for molecular studies aimed at further understanding the C5a-C5aR2 receptor interaction. MEDI7814 has therapeutic potential for the treatment of acute inflammatory conditions in which both C5a receptors may mediate inflammation, such as sepsis or renal ischemia-reperfusion injury.

Supernumerary Abducens Nerves: A Comprehensive Review.

BACKGROUND: Branching and/or replication of the abducens nerve is not an uncommon occurrence. Although numerous variations have been documented, the rarest forms are duplicated or triplicated nerves, where multiple nerve roots originate from the brainstem, travel intracranially, and attach to the lateral rectus as separate entities. METHODS: We conducted a systematic literature search on the topic of supernumerary abducens nerve, using PubMed and Google Scholar. RESULTS: After screening, 16 studies were included: 11 cadaveric studies and 6 case reports. CONCLUSIONS: In this paper, we review the literature on variations found, discuss current hypotheses and clinical relevance, and propose future studies. Neurosurgeons should be aware of such nerve variants when viewing imaging or operating in the regions traversed by the abducens nerve.

Tissue-engineered smooth muscle cell and endothelial progenitor cell bi-level cell sheets prevent progression of cardiac dysfunction, microvascular dysfunction, and interstitial fibrosis in a rodent model of type 1 diabetes-induced cardiomyopathy.

BACKGROUND: Diabetes mellitus is a risk factor for coronary artery disease and diabetic cardiomyopathy, and adversely impacts outcomes following coronary artery bypass grafting. Current treatments focus on macro-revascularization and neglect the microvascular disease typical of diabetes mellitus-induced cardiomyopathy (DMCM). We hypothesized that engineered smooth muscle cell (SMC)-endothelial progenitor cell (EPC) bi-level cell sheets could improve ventricular dysfunction in DMCM. METHODS: Primary mesenchymal stem cells (MSCs) and EPCs were isolated from the bone marrow of Wistar rats, and MSCs were differentiated into SMCs by culturing on a fibronectin-coated dish. SMCs topped with EPCs were detached from a temperature-responsive culture dish to create an SMC-EPC bi-level cell sheet. A DMCM model was induced by intraperitoneal streptozotocin injection. Four weeks after induction, rats were randomized into 3 groups: control (no DMCM induction), untreated DMCM, and treated DMCM (cell sheet transplant covering the anterior surface of the left ventricle). RESULTS: SMC-EPC cell sheet therapy preserved cardiac function and halted adverse ventricular remodeling, as demonstrated by echocardiography and cardiac magnetic resonance imaging at 8 weeks after DMCM induction. Myocardial contrast echocardiography demonstrated that myocardial perfusion and microvascular function were preserved in the treatment group compared with untreated animals. Histological analysis demonstrated decreased interstitial fibrosis and increased microvascular density in the SMC-EPC cell sheet-treated group. CONCLUSIONS: Treatment of DMCM with tissue-engineered SMC-EPC bi-level cell sheets prevented cardiac dysfunction and microvascular disease associated with DMCM. This multi-lineage cellular therapy is a novel, translatable approach to improve microvascular disease and prevent heart failure in diabetic patients.

Johann Gaspar Spurzheim: A Life Dedicated to Phrenology.

Loved for his empathetic nature but admired for his analytical mind, Gaspar Spurzheim (1776-1832) was a prominent contributor to phrenology, a field of neuroscience focused on studying the shapes of the skulls in relation to the activity levels of certain functional areas of the brain. This curiosity about the connection between physical characteristics and brain function was seeded in the young mind of Spurzheim when he observed that classmates with seemingly superb memories also appeared to have bright eyes. It launched Spurzheim on a journey to study the shape and function of the brain, which eventually led him to his mentor Franz Gall. Together, they classified many functional areas of the brain while touring Europe, describing their findings to audiences that filled lecture theaters to the brim. During their lectures, Gall focused on explaining findings while Spurzheim focused on dissections and demonstrations. After spending significant time with his mentor, captivating audiences and spreading the ideas of phrenology through several books and journal publications, Spurzheim left their fruitful partnership and started lecturing on his own. He toured the UK, giving lectures and dissections in London and Edinburgh, gaining universal respect for his dissection methods, writing several books and publishing articles in what were then major journals. With the aid of his wife's artistic skills in painting and sketching many of dissections, Spurzheim's popularity extended beyond the phrenological community. It eventually led him to Boston, where he opened this field of science in America before his death in 1832. Although phrenology has lost its popularity, Spurzheim's contributions to our anatomical understanding of the brain survive.

More Than Meets the Eye: The Contributions of John Dalrymple (1803-1852).

Having authored two major ophthalmology textbooks and honored with the eponym, the "Dalrymple sign," many are familiar with the works of Dr. John Dalrymple when it comes to the eye. However, few are aware of his other, numerous and wide-ranging contributions to the fields of science and medicine. In this article, we discuss the life and work of a man dedicated to the pursuit and advancement of knowledge and education.

Hiding Within the Cracks: Case Report of Rare Sutural Bone Found at the Nasion.

Pathology such as skull fractures can be misdiagnosed in the presence of anatomical variations. One variant that has had little description in the literature are the sutural bones associated with the nasal bones. Herein, we describe a case of a rare sutural bone at the nasion, between the bones of the right nasal, frontal, and maxillary frontal process. To our knowledge, this is the first report of such a variant bone in this location, and such it should be considered by clinicians when evaluating patients for pathology in this region.

Extremely large sinus pericranii with involvement of the torcular and associated with Crouzon's syndrome.

INTRODUCTION: Sinus pericranii is a rare vascular malformation that connects the intracranial dural sinuses to the extracranial venous drainage system and is caused by either trauma or congenital defects. Although the majority of these vascular structures are due to trauma, some are congenital. CASE REPORT: Herein, we report a 5-month-old patient with a very large and fluctuating subcutaneous mass over the occiput and the diagnosis of Crouzon's syndrome. The child presented with a large midline mass that on imaging, connected to the underlying torcular and was diagnosed as a sinus pericranii. At long-term follow-up and without operative intervention, the sinus pericranii resolved. This uncommon relationship is reviewed. CONCLUSION: Premature closure of posterior fossa sutures as part of Crouzon's syndrome can present with large sinus pericranii. Such subcutaneous swellings might resolve spontaneously.

An innovative biologic system for photon-powered myocardium in the ischemic heart.

Coronary artery disease is one of the most common causes of death and disability, afflicting more than 15 million Americans. Although pharmacological advances and revascularization techniques have decreased mortality, many survivors will eventually succumb to heart failure secondary to the residual microvascular perfusion deficit that remains after revascularization. We present a novel system that rescues the myocardium from acute ischemia, using photosynthesis through intramyocardial delivery of the cyanobacterium Synechococcus elongatus. By using light rather than blood flow as a source of energy, photosynthetic therapy increases tissue oxygenation, maintains myocardial metabolism, and yields durable improvements in cardiac function during and after induction of ischemia. By circumventing blood flow entirely to provide tissue with oxygen and nutrients, this system has the potential to create a paradigm shift in the way ischemic heart disease is treated.

A novel protein-engineered hepatocyte growth factor analog released via a shear-thinning injectable hydrogel enhances post-infarction ventricular function.

In the last decade, numerous growth factors and biomaterials have been explored for the treatment of myocardial infarction (MI). While pre-clinical studies have demonstrated promising results, clinical trials have been disappointing and inconsistent, likely due to poor translatability. In the present study, we investigate a potential myocardial regenerative therapy consisting of a protein-engineered dimeric fragment of hepatocyte growth factor (HGFdf) encapsulated in a shear-thinning, self-healing, bioengineered hydrogel (SHIELD). We hypothesized that SHIELD would facilitate targeted, sustained intramyocardial delivery of HGFdf thereby attenuating myocardial injury and post-infarction remodeling. Adult male Wistar rats (n = 45) underwent sham surgery or induction of MI followed by injection of phosphate buffered saline (PBS), 10 µg HGFdf alone, SHIELD alone, or SHIELD encapsulating 10 µg HGFdf. Ventricular function, infarct size, and angiogenic response were assessed 4 weeks post-infarction. Treatment with SHIELD + HGFdf significantly reduced infarct size and increased both ejection fraction and borderzone arteriole density compared to the controls. Thus, sustained delivery of HGFdf via SHIELD limits post-infarction adverse ventricular remodeling by increasing angiogenesis and reducing fibrosis. Encapsulation of HGFdf in SHIELD improves clinical translatability by enabling minimally-invasive delivery and subsequent retention and sustained administration of this novel, potent angiogenic protein analog. Biotechnol. Bioeng. 2017;114: 2379-2389. © 2017 Wiley Periodicals, Inc.