Association of Timely Outpatient Follow-Up and Readmission Risk in a Mobile Integrated Health Program.

The objective was to identify medical conditions associated with 30-day readmission, determine patient characteristics for which outpatient follow-up is most associated with reduced readmission, and evaluate how readmission risk changes with time to outpatient follow-up within a mobile integrated health-community paramedicine (MIH-CP) program. This retrospective observational study used data from 1,118 adult patient enrollments in a MIH-CP program operating in Baltimore, Maryland, from May 14, 2018, to December 21, 2021. Bivariate analysis identified chronic disease exacerbations associated with higher 30-day readmission risk. Kaplan-Meier curves and Cox proportional hazard regressions were used to measure how hazard of readmission changes with outpatient follow-up and how that association may vary with other factors. Receiver operating characteristic analysis was used to evaluate how well time to follow-up could predict 30-day readmission. Timely outpatient follow-up was associated with a significant reduction in hazard of readmission for patients aged 50 and younger and for patients with fewer than 5 social determinants of health needs identified. No significant association between readmission and specific chronic disease exacerbations was observed. An optimal follow-up time frame to reduce readmissions could not be identified. Timely outpatient follow-up may be effective for reducing readmissions in younger patients and patients who are less socially complex. Programs and policies aiming to reduce 30-day readmissions may have more success by expanding efforts to include these patients.

Distinct mesenchymal cell states mediate prostate cancer progression.

In the complex tumor microenvironment (TME), mesenchymal cells are key players, yet their specific roles in prostate cancer (PCa) progression remain to be fully deciphered. This study employs single-cell RNA sequencing to delineate molecular changes in tumor stroma that influence PCa progression and metastasis. Analyzing mesenchymal cells from four genetically engineered mouse models (GEMMs) and correlating these findings with human tumors, we identify eight stromal cell populations with distinct transcriptional identities consistent across both species. Notably, stromal signatures in advanced mouse disease reflect those in human bone metastases, highlighting periostin's role in invasion and differentiation. From these insights, we derive a gene signature that predicts metastatic progression in localized disease beyond traditional Gleason scores. Our results illuminate the critical influence of stromal dynamics on PCa progression, suggesting new prognostic tools and therapeutic targets.

Metacarpal fractures.

Metacarpal fractures are common and can be functionally disabling. The majority are managed non-operatively. When surgical intervention is indicated, various methods of fixation are available with the utility of each being based on injury pattern, patient function and surgeon preference. Early mobilization, especially in case of open reduction and internal fixation, is a critical component of treatment to prevent stiffness and restore function. When possible, a fixation construct that can withstand the applied forces of early postoperative motion is chosen. We provide an updated description for diagnosis, treatment options and operative fixation for metacarpal fractures.

The Identification of CELSR3 and Other Potential Cell Surface Targets in Neuroendocrine Prostate Cancer.

Although recent efforts have led to the development of highly effective androgen receptor (AR)-directed therapies for the treatment of advanced prostate cancer, a significant subset of patients will progress with resistant disease including AR-negative tumors that display neuroendocrine features [neuroendocrine prostate cancer (NEPC)]. On the basis of RNA sequencing (RNA-seq) data from a clinical cohort of tissue from benign prostate, locally advanced prostate cancer, metastatic castration-resistant prostate cancer and NEPC, we developed a multi-step bioinformatics pipeline to identify NEPC-specific, overexpressed gene transcripts that encode cell surface proteins. This included the identification of known NEPC surface protein CEACAM5 as well as other potentially targetable proteins (e.g., HMMR and CESLR3). We further showed that cadherin EGF LAG seven-pass G-type receptor 3 (CELSR3) knockdown results in reduced NEPC tumor cell proliferation and migration in vitro. We provide in vivo data including laser capture microdissection followed by RNA-seq data supporting a causal role of CELSR3 in the development and/or maintenance of the phenotype associated with NEPC. Finally, we provide initial data that suggests CELSR3 is a target for T-cell redirection therapeutics. Further work is now needed to fully evaluate the utility of targeting CELSR3 with T-cell redirection or other similar therapeutics as a potential new strategy for patients with NEPC. Significance: The development of effective treatment for patients with NEPC remains an unmet clinical need. We have identified specific surface proteins, including CELSR3, that may serve as novel biomarkers or therapeutic targets for NEPC.

The Impact of Metabolic Syndrome and Obesity on Perioperative Total Joint Arthroplasty Outcomes: The Obesity Paradox and Risk Assessment in Total Joint Arthroplasty.

Background: The relationship between elevated body mass index (BMI) and adverse outcomes in joint arthroplasty is well established in the literature. This paper aims to challenge the conventional thought of excluding patients from a total knee or hip replacement based on BMI alone. Instead, we propose using the metabolic syndrome (MetS) and its defining components to better identify patients at high risk for intraoperative and postoperative complications. Methods: Patients who underwent primary, elective total knee and total hip arthroplasty were identified in the 2015-2020 American College of Surgeons National Surgical Quality Improvement Program database. Several defining components of MetS, such as hypertension, diabetes, and obesity, were compared to a metabolically healthy cohort. Postoperative outcomes assessed included mortality, length of hospital stay, 30-day surgical and medical complications, and discharge. Results: The outcomes of 529,737 patients from the American College of Surgeons National Surgical Quality Improvement Program who underwent total knee and total hip arthroplasty were assessed. MetS is associated with increased complications and increased mortality. Both hypertension and diabetes are associated with increased complications but have no impact on mortality. Interestingly, while obesity was associated with increased complications, there was a significant decrease in mortality. Conclusions: Our results show that the impact of MetS is more than the sum of its constitutive parts. Additionally, obese patients experience a protective effect, with lower mortality than their nonobese counterparts. This study supports moving away from strict BMI cutoffs alone for someone to be eligible for an arthroplasty surgery and offers more granular data for risk stratification and patient selection.

Distinct mesenchymal cell states mediate prostate cancer progression.

Alterations in tumor stroma influence prostate cancer progression and metastatic potential. However, the molecular underpinnings of this stromal-epithelial crosstalk are largely unknown. Here, we compare mesenchymal cells from four genetically engineered mouse models (GEMMs) of prostate cancer representing different stages of the disease to their wild-type (WT) counterparts by single-cell RNA sequencing (scRNA-seq) and, ultimately, to human tumors with comparable genotypes. We identified 8 transcriptionally and functionally distinct stromal populations responsible for common and GEMM-specific transcriptional programs. We show that stromal responses are conserved in mouse models and human prostate cancers with the same genomic alterations. We noted striking similarities between the transcriptional profiles of the stroma of murine models of advanced disease and those of of human prostate cancer bone metastases. These profiles were then used to build a robust gene signature that can predict metastatic progression in prostate cancer patients with localized disease and is also associated with progression-free survival independent of Gleason score. Taken together, this offers new evidence that stromal microenvironment mediates prostate cancer progression, further identifying tissue-based biomarkers and potential therapeutic targets of aggressive and metastatic disease.

Association Between Prosthetic Knee Effusions and Phosphodiesterase Type-5 Enzyme Inhibitor Use After Total Knee Arthroplasty: A Case Report.

CASE: Phosphodiesterase type-5 enzyme (PDE5) inhibitors are well tolerated and used to treat erectile dysfunction. We report a case of prosthetic knee effusions associated with PDE5 inhibitor use in a 65-year-old man after total knee arthroplasty (TKA). PDE5 inhibitor treatment was stopped, and the patient had no further episodes of painful effusions. CONCLUSION: This report describes a previously unknown adverse effect of PDE5 inhibitor use in a prosthetic joint after TKA. We hope to encourage physicians managing patients after joint replacement to be aware of the association between PDE5 inhibitor use and recurrent joint effusions to improve postoperative outcomes.

Defining cellular population dynamics at single-cell resolution during prostate cancer progression.

Advanced prostate malignancies are a leading cause of cancer-related deaths in men, in large part due to our incomplete understanding of cellular drivers of disease progression. We investigate prostate cancer cell dynamics at single-cell resolution from disease onset to the development of androgen independence in an in vivo murine model. We observe an expansion of a castration-resistant intermediate luminal cell type that correlates with treatment resistance and poor prognosis in human patients. Moreover, transformed epithelial cells and associated fibroblasts create a microenvironment conducive to pro-tumorigenic immune infiltration, which is partially androgen responsive. Androgen-independent prostate cancer leads to significant diversification of intermediate luminal cell populations characterized by a range of androgen signaling activity, which is inversely correlated with proliferation and mRNA translation. Accordingly, distinct epithelial populations are exquisitely sensitive to translation inhibition, which leads to epithelial cell death, loss of pro-tumorigenic signaling, and decreased tumor heterogeneity. Our findings reveal a complex tumor environment largely dominated by castration-resistant luminal cells and immunosuppressive infiltrates.

Anteroposterior pacer pad position is better than anterolateral for transcutaneous cardiac pacing.

INTRODUCTION: Transcutaneous cardiac pacing (TCP) is a lifesaving procedure for patients with certain types of unstable bradycardia. We aimed to assess the difference in the pacing thresholds between the anteroposterior (AP) and anterolateral (AL) pacer pad positions. The second aim was to characterize the severity of chest wall muscle contractions during TCP. METHODS: In this prospective crossover trial, we enrolled patients presenting to the electrophysiology laboratory for elective cardioversion. After successful cardioversion, sedated participants were sequentially paced in both positions. The study procedure concluded after successful capture or inability to achieve capture by 140 mA (the pacer's maximum output) in both positions. Pacing thresholds were compared between positions, using a student's paired t-test, assigning a value of 141 mA to any trials with non-capture. RESULTS: Forty-one patients were screened; 20 were enrolled in the study. Seven participants were excluded from the paired analysis (three were prevented from pacing in the second position at the anesthesiologist's discretion, and 4 did not capture in either position). The study population consisted of 14 men and 6 women with a median age of 65 years. The mean pacing threshold was 33 mA lower (P = 0.001, 95% CI 20-45) in the AP (93 mA) versus the AL (126 mA) position. The median contraction severity score was 3 in the AL position versus 4 in the AP position (P = 0.005). CONCLUSIONS: Placing pacer pads in the AP position requires less energy to capture. Major resuscitation guidelines may favor the AP position for TCP. CLINICALTRIALS: gov Identifier: NCT03898050 https://clinicaltrials.gov/ct2/show/NCT03898050.

A novel source of carbon monoxide for suicide attempt.

Carbon monoxide (CO) inhalation is a common method of suicide. The combination of formic acid with sulfuric acid creates carbon monoxide. This novel method is described in readily accessible internet-based resources. We present the case of a 35-year-old woman who developed CO toxicity by using this method. It is important for hyperbaric medicine physicians to be aware of this source of CO toxicity.

Dissociation of a Medial Pivot Polyethylene in a Kinematically Aligned Total Knee Arthroplasty.

An 81-year-old male patient who underwent a Medacta GMK sphere kinematically aligned (KA) total knee arthroplasty (TKA) for end-stage knee osteoarthritis presented with a dislocated medial pivot (MP) tibia polyethylene (PE) insert on routine six-week postoperative x-rays. The patient presented asymptomatic with a normal range of motion. Dissociation of a fixed-bearing (FB) PE implant is an uncommon complication after TKA. There are only a few cases reported in the literature. We report for the first time a case of non-traumatic dissociation of MP PE from the tibial baseplate in a KA TKA in an asymptomatic patient but identified on routine postoperative radiographs.

Extracellular Matrix in Synthetic Hydrogel-Based Prostate Cancer Organoids Regulate Therapeutic Response to EZH2 and DRD2 Inhibitors.

Following treatment with androgen receptor (AR) pathway inhibitors, ≈20% of prostate cancer patients progress by shedding their AR-dependence. These tumors undergo epigenetic reprogramming turning castration-resistant prostate cancer adenocarcinoma (CRPC-Adeno) into neuroendocrine prostate cancer (CRPC-NEPC). No targeted therapies are available for CRPC-NEPCs, and there are minimal organoid models to discover new therapeutic targets against these aggressive tumors. Here, using a combination of patient tumor proteomics, RNA sequencing, spatial-omics, and a synthetic hydrogel-based organoid, putative extracellular matrix (ECM) cues that regulate the phenotypic, transcriptomic, and epigenetic underpinnings of CRPC-NEPCs are defined. Short-term culture in tumor-expressed ECM differentially regulated DNA methylation and mobilized genes in CRPC-NEPCs. The ECM type distinctly regulates the response to small-molecule inhibitors of epigenetic targets and Dopamine Receptor D2 (DRD2), the latter being an understudied target in neuroendocrine tumors. In vivo patient-derived xenograft in immunocompromised mice showed strong anti-tumor response when treated with a DRD2 inhibitor. Finally, we demonstrate that therapeutic response in CRPC-NEPCs under drug-resistant ECM conditions can be overcome by first cellular reprogramming with epigenetic inhibitors, followed by DRD2 treatment. The synthetic organoids suggest the regulatory role of ECM in therapeutic response to targeted therapies in CRPC-NEPCs and enable the discovery of therapies to overcome resistance.

STAT5 is activated in macrophages by breast cancer cell-derived factors and regulates macrophage function in the tumor microenvironment.

BACKGROUND: In breast cancer, complex interactions between tumor cells and cells within the surrounding stroma, such as macrophages, are critical for tumor growth, progression, and therapeutic response. Recent studies have highlighted the complex nature and heterogeneous populations of macrophages associated with both tumor-promoting and tumor-inhibiting phenotypes. Defining the pathways that drive macrophage function is important for understanding their complex phenotypes within the tumor microenvironment. Signal transducer and activator of transcription (STAT) transcription factors, such as STAT5, are key regulators of immune cell function. The studies described here investigate the functional contributions of STAT5 to tumor-associated macrophage function in breast cancer. METHODS: Initial studies were performed using a panel of human breast cancer and mouse mammary tumor cell lines to determine the ability of tumor cell-derived factors to induce STAT5 activation in macrophages. Further studies used these models to identify soluble factors that activate STAT5 in macrophages. To delineate STAT5-specific contributions to macrophage function, a conditional model of myeloid STAT5 deletion was used for in vitro, RNA-sequencing, and in vivo studies. The effects of STAT5 deletion in macrophages on tumor cell migration and metastasis were evaluated using in vitro co-culture migration assays and an in vivo tumor cell-macrophage co-injection model. RESULTS: We demonstrate here that STAT5 is robustly activated in macrophages by tumor cell-derived factors and that GM-CSF is a key cytokine stimulating this pathway. The analysis of RNA-seq studies reveals that STAT5 promotes expression of immune stimulatory genes in macrophages and that loss of STAT5 in macrophages results in increased expression of tissue remodeling factors. Finally, we demonstrate that loss of STAT5 in macrophages promotes tumor cell migration in vitro and mammary tumor metastasis in vivo. CONCLUSIONS: Breast cancer cells produce soluble factors, such as GM-CSF, that activate the STAT5 pathway in macrophages and drive expression of inflammatory factors. STAT5 deletion in myeloid cells enhances metastasis, suggesting that STAT5 activation in tumor-associated macrophages protects against tumor progression. Understanding mechanisms that drive macrophage function in the tumor microenvironment will ultimately lead to new approaches that suppress tumor-promoting functions while enhancing their anti-tumor functions.

Bilateral Osteonecrosis of the Capitate: A Case Report.

CASE: We report a case of bilateral capitate osteonecrosis in a patient who has a history of acute lymphocytic leukemia treated with systemic steroids and other chemotherapeutic agents. After exhausting conservative treatment, the patient underwent surgical management with a right-sided 4-corner arthrodesis and left-sided vascular pedicle graft, providing pain relief and improved function. CONCLUSION: In patients with a history of hematologic malignancy, clinicians should consider osteonecrosis of the capitate as a cause of wrist pain. Salvage procedures and vascularized grafts can provide pain relief in the presence of both early and late capitate osteonecrosis or collapse.

RNA Splicing Factors SRRM3 and SRRM4 Distinguish Molecular Phenotypes of Castration-Resistant Neuroendocrine Prostate Cancer.

Neuroendocrine (NE) differentiation in metastatic castration-resistant prostate cancer (mCRPC) is an increasingly common clinical feature arising from cellular plasticity. We recently characterized two mCRPC phenotypes with NE features: androgen receptor (AR)-positive NE-positive amphicrine prostate cancer (AMPC) and AR-negative small cell or neuroendocrine prostate cancer (SCNPC). Here, we interrogated the regulation of RE1-silencing transcription factor (REST), a transcriptional repressor of neuronal genes, and elucidated molecular programs driving AMPC and SCNPC biology. Analysis of prostate cancer cell lines, mCRPC specimens, and LuCaP patient-derived xenograft models detected alternative splicing of REST to REST4 and attenuated REST repressor activity in AMPC and SCNPC. The REST locus was also hypermethylated and REST expression was reduced in SCNPC. While serine/arginine repetitive matrix protein 4 (SRRM4) was previously implicated in alternative splicing of REST in mCRPC, we detected SRRM3 expression in REST4-positive, SRRM4-negative AMPC, and SCNPC. In CRPC cell lines, SRRM3 induced alternative splicing of REST to REST4 and exacerbated the expression of REST-repressed genes. Furthermore, SRRM3 and SRRM4 expression defined molecular subsets of AMPC and SCNPC across species and tumor types. Two AMPC phenotypes and three SCNPC phenotypes were characterized, denoted either by REST attenuation and ASCL1 activity or by progressive activation of neuronal transcription factor programs, respectively. These results nominate SRRM3 as the principal REST splicing factor expressed in early NE differentiation and provide a framework to molecularly classify diverse NE phenotypes in mCRPC. SIGNIFICANCE: This study identifies SRRM3 as a key inducer of cellular plasticity in prostate cancer with neuroendocrine features and delineates distinct neuroendocrine phenotypes to inform therapeutic development and precision medicine applications.

Temporal evolution of cellular heterogeneity during the progression to advanced AR-negative prostate cancer.

Despite advances in the development of highly effective androgen receptor (AR)-directed therapies for the treatment of men with advanced prostate cancer, acquired resistance to such therapies frequently ensues. A significant subset of patients with resistant disease develop AR-negative tumors that lose their luminal identity and display neuroendocrine features (neuroendocrine prostate cancer (NEPC)). The cellular heterogeneity and the molecular evolution during the progression from AR-positive adenocarcinoma to AR-negative NEPC has yet to be characterized. Utilizing a new genetically engineered mouse model, we have characterized the synergy between Rb1 loss and MYCN (encodes N-Myc) overexpression which results in the formation of AR-negative, poorly differentiated tumors with high metastatic potential. Single-cell-based approaches revealed striking temporal changes to the transcriptome and chromatin accessibility which have identified the emergence of distinct cell populations, marked by differential expression of Ascl1 and Pou2f3, during the transition to NEPC. Moreover, global DNA methylation and the N-Myc cistrome are redirected following Rb1 loss. Altogether, our data provide insight into the progression of prostate adenocarcinoma to NEPC.

Erratum: Witschen, P.M., et al. Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer. Cancers 2020, 12, 1325.

The authors wish to make the following corrections to this paper [...].

Tumor Cell Associated Hyaluronan-CD44 Signaling Promotes Pro-Tumor Inflammation in Breast Cancer.

Cancer has been conceptualized as a chronic wound with a predominance of tumor promoting inflammation. Given the accumulating evidence that the microenvironment supports tumor growth, we investigated hyaluronan (HA)-CD44 interactions within breast cancer cells, to determine whether this axis directly impacts the formation of an inflammatory microenvironment. Our results demonstrate that breast cancer cells synthesize and fragment HA and express CD44 on the cell surface. Using RNA sequencing approaches, we found that loss of CD44 in breast cancer cells altered the expression of cytokine-related genes. Specifically, we found that production of the chemokine CCL2 by breast cancer cells was significantly decreased after depletion of either CD44 or HA. In vivo, we found that CD44 deletion in breast cancer cells resulted in a delay in tumor formation and localized progression. This finding was accompanied by a decrease in infiltrating CD206+ macrophages, which are typically associated with tumor promoting functions. Importantly, our laboratory results were supported by human breast cancer patient data, where increased HAS2 expression was significantly associated with a tumor promoting inflammatory gene signature. Because high levels of HA deposition within many tumor types yields a poorer prognosis, our results emphasize that HA-CD44 interactions potentially have broad implications across multiple cancers.