α-Synuclein modulates fibronectin expression in the trabecular meshwork independent of TGFß2.

α-Synuclein (α-Syn) is implicated in Parkinson's disease (PD), a neuromotor disorder with prominent visual symptoms. The underlying cause of motor dysfunction has been studied extensively, and is attributed to the death of dopaminergic neurons mediated in part by intracellular aggregation of α-Syn. The cause of visual symptoms, however, is less clear. Neuroretinal degeneration due to the presence of aggregated α-Syn has been reported, but the evidence is controversial. Other symptoms including those arising from primary open angle glaucoma (POAG) are believed to be the side-effects of medications prescribed for PD. Here, we explored the alternative hypothesis that dysfunction of α-Syn in the anterior eye alters the interaction between the actin cytoskeleton of trabecular meshwork (TM) cells with the extracellular matrix (ECM), impairing their ability to respond to physiological changes in intraocular pressure (IOP). A similar dysfunction in neurons is responsible for impaired neuritogenesis, a characteristic feature of PD. Using cadaveric human and bovine TM tissue and primary human TM cells as models, we report two main observations: 1) α-Syn is expressed in human and bovine TM cells, and significant amounts of monomeric and oligomeric α-Syn are present in the AH, and 2) primary human TM cells and human and bovine TM tissue endocytose extracellular recombinant monomeric and oligomeric α-Syn via the prion protein (PrPC), and upregulate fibronectin (FN) and α-smooth muscle actin (α-SMA), fibrogenic proteins implicated in POAG. Transforming growth factor ß2 (TGFß2), a fibrogenic cytokine implicated in ∼50% cases of POAG, is also increased, and so is RhoA-associated coiled-coil-containing protein kinase 1 (ROCK-1). However, silencing of α-Syn in primary human TM cells reduces FN, α-SMA, and ROCK-1 in the absence or presence of over-expressed active TGFß2, suggesting modulation of FN and ROCK-1 independent of, or upstream of TGFß2. These observations suggest that extracellular α-Syn modulates ECM proteins in the TM independently or via PrPC by activating the RhoA-ROCK pathway. These observations reveal a novel function of α-Syn in the anterior eye, and offer new therapeutic options.

Editorial Commentary: Social Determinants of Health Influence the Success of Shoulder Rotator Cuff Repair Outcomes: When You Do Everything Right, Yet Things Still Go Wrong.

Our ability to perform a technically sound surgery is not sufficient to ensure patients have an excellent clinical outcome. Social determinants of health disparities (SDHDs) profoundly impact health equality. Health disparities that exist in the United States are risk factors for inferior patient-reported outcomes and result in greater complication rates following rotator cuff repair surgery. The presence of SDHDs was associated with an increased risk of revision, stiffness, emergency department visits, medical complications, and costs. Economic and educational SDHDs were associated with the greatest risk of 1-year revision surgery. Improved understanding of these social variables can help with risk identification preoperatively. Surgeons may employ additional, holistic, bio-psycho-social, perioperative resources to provide high-quality, value-based care to at-risk patients who might be marginalized by our health care system.

Influence of Extracellular Vesicles on Lung Stromal Cells during Breast Cancer Metastasis.

Breast cancer is a prominent cause of cancer diagnosis and death in women globally, with over 90% of deaths being attributed to complications that arise from metastasis. One of the common locations for breast cancer metastasis is the lung, which is associated with significant morbidity and mortality. Curative treatments for metastatic breast cancer patients are not available and the molecular mechanisms that underlie lung metastasis are not fully understood. In order to better treat these patients, identifying events that occur both prior to and during metastatic spread to the lung is essential. Several studies have demonstrated that breast cancer-derived extracellular vesicles secreted from the primary breast tumor play a key role in establishing the lung pre-metastatic niche to support colonization of metastatic tumor cells. In this review, we summarize recent work supporting the influence of extracellular vesicles on stromal components of the lung to construct the pre-metastatic niche and support metastasis. Furthermore, we discuss the potential clinical applications of utilizing extracellular vesicles for diagnosis and treatment. Together, this review highlights the dynamic nature of extracellular vesicles, their roles in breast cancer metastasis to the lung, and their value as potential biomarkers and therapeutics for cancer prevention.

Segmental and Circumferential Acetabular Labral Reconstruction Have Comparable Outcomes in the Treatment of Irreparable or Unsalvageable Labral Pathology: A Systematic Review.

PURPOSE: To perform a systematic review comparing outcomes of segmental versus circumferential arthroscopic labral reconstruction as a treatment for symptomatic irreparable or unsalvageable acetabular labral pathology. METHODS: A systematic review was conducted according to PRISMA guidelines using defined inclusion and exclusion criteria. The study groups were divided into segmental and circumferential labral reconstructions. Studies with <2 years follow up, overlapping patient populations, or indications for labral reconstruction other than irreparable or unsalvageable pathology were excluded. RESULTS: The literature search resulted in nine included publications. Five studies presented data on segmental labral reconstruction (166 hips in 164 patients), and seven studies presented data on circumferential labral reconstruction (261 hips in 253 patients). All circumferential reconstruction studies used allograft only, while segmental studies used a combination of autograft and allograft. The range of conversion to total hip arthroplasty was 9.1% to 26.8% in the segmental studies and 3.1% to 9.9% in the circumferential studies. The modified Harris Hip Score (mHHS) was the only patient-reported outcome measure reported in three or more studies in both groups. The mean change from preoperative to postoperative mHHS ranged from 17.8 to 29 in the segmental group and from 20.4 to 31.7 in the circumferential group. Weighted estimates were not calculated due to significant heterogeneity for both the segmental and circumferential groups (I2 = 63.9% and 72.9%, respectively). CONCLUSIONS: Segmental and circumferential reconstructions are both reasonable options for arthroscopic treatment of irreparable or unsalvageable labral pathology. Articles in both groups demonstrated improvement in patient-reported outcomes (mHHS). Because of study heterogeneity, low level of evidence, and high risk of bias, the scores were unable to be directly compared. Although there are theoretical biomechanical and technical advantages of one technique over another, this systematic review did not demonstrate clinical superiority of either technique. LEVEL OF EVIDENCE: Level IV, systematic review of level III and IV studies.

Early COVID-19 First-Dose Vaccination Coverage Among Residents and Staff Members of Skilled Nursing Facilities Participating in the Pharmacy Partnership for Long-Term Care Program - United States, December 2020-January 2021.

Residents and staff members of long-term care facilities (LTCFs), because they live and work in congregate settings, are at increased risk for infection with SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19) (1,2). In particular, skilled nursing facilities (SNFs), LTCFs that provide skilled nursing care and rehabilitation services for persons with complex medical needs, have been documented settings of COVID-19 outbreaks (3). In addition, residents of LTCFs might be at increased risk for severe outcomes because of their advanced age or the presence of underlying chronic medical conditions (4). As a result, the Advisory Committee on Immunization Practices has recommended that residents and staff members of LTCFs be offered vaccination in the initial COVID-19 vaccine allocation phase (Phase 1a) in the United States (5). In December 2020, CDC launched the Pharmacy Partnership for Long-Term Care Program* to facilitate on-site vaccination of residents and staff members at enrolled LTCFs. To evaluate early receipt of vaccine during the first month of the program, the number of eligible residents and staff members in enrolled SNFs was estimated using resident census data from the National Healthcare Safety Network (NHSN†) and staffing data from the Centers for Medicare & Medicaid Services (CMS) Payroll-Based Journal.§ Among 11,460 SNFs with at least one vaccination clinic during the first month of the program (December 18, 2020-January 17, 2021), an estimated median of 77.8% of residents (interquartile range [IQR] = 61.3%- 93.1%) and a median of 37.5% (IQR = 23.2%- 56.8%) of staff members per facility received ≥1 dose of COVID-19 vaccine through the Pharmacy Partnership for Long-Term Care Program. The program achieved moderately high coverage among residents; however, continued development and implementation of focused communication and outreach strategies are needed to improve vaccination coverage among staff members in SNFs and other long-term care settings.

Distal Femoral Replacement and Periprosthetic Joint Infection After Non-Oncological Reconstruction: A Retrospective Analysis.

BACKGROUND: Distal femoral replacement (DFR) is commonly used to manage massive bone loss around the knee arising from aseptic loosening, periprosthetic joint infection (PJI), and distal femoral fractures. A number of studies report the outcome of DFR with considerable variation in long-term survivorship. This study investigated the outcome of DFR for patients with aseptic failures, fractures, and PJI. METHODS: A retrospective review of 182 patients who underwent DFR for non-oncological indications between 2002 and 2018 was conducted. Data collected included the following: indication, postoperative complications, reoperation, revision, and follow-up. Implant survivorship with Kaplan-Meier curves along with a log-rank test for different preoperative indications was performed. A Cox regression model was used to evaluate the risk of revision. RESULTS: The overall postoperative complication rate was very high at 36%. The most common complication was PJI (17%). The rate of reoperation for any cause was 29.7%, and the revision rate was 13.7%. The most common cause of re-revision was PJI (7.1%). Revision-free survivorship of the DFR implant was 91.6% at 1 year, 87.9% at 2 years, 82.5% at 5 years, and 73.4% at 10 years. Patients who had a prior-PJI had the lowest survivorship compared to patients undergoing DFR for management of periprosthetic fracture and mechanical loosening. Additionally, the prior-PJI group was at a fourfold increased risk of postoperative PJI compared to the aseptic group. CONCLUSION: DFR is a valuable reconstructive option for patients with massive bone loss around the knee. However, patients undergoing DFR are at high risk of complications, reoperations, and failure.

Variation in the accuracy of ultrasound for the detection of intubation by endotracheal tube size.

INTRODUCTION: Rapid and accurate confirmation of endotracheal tube (ETT) placement is a fundamental step in definitive airway management. Multiple techniques with different limitations have been reported. Recent studies have evaluated the accuracy, time to performance, and physician confidence for ultrasound in both cadaveric models and live patients. However, no study to date has measured the effect of ETT size. Our study is the first to measure the accuracy of ultrasound for ETT confirmation based on ETT size. METHODS: This study was performed in a cadaver lab using three different cadavers chosen to represent varying neck circumferences. Cadavers were intubated in a random sequence with respect to both the location of intubation (i.e., tracheal vs esophageal) and sizes of ETT. Three ETT sizes were utilized: 6.0-, 7.0-, and 8.0-mm. Blinded sonographers assessed the location of the ETT using the static technique. Accuracy of sonographer identification, time to identification, and operator confidence were assessed. RESULTS: 453 assessments were performed. Overall, ultrasound was 99.1% (95% CI 97.8% to 99.7%) accurate in identification of correct location of intubation. The mean time to placement was 6.45 s (95% CI 5.62 to 7.28). The mean operator confidence level was 4.72/5.0 (95% CI 4.65 to 4.78). There was no significant difference between ETT sizes with respect to any of the outcomes. CONCLUSION: The diagnostic accuracy of ultrasound for ETT confirmation did not vary with the use of different ETT sizes. Further studies are needed to determine if the accuracy would change with more novice providers or in specific patient populations.

Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise.

Serotonergic neurons of the raphe nucleus regulate sleep, mood, endocrine function, and other processes that mature during adolescence. Alcohol abuse and binge drinking are common during human adolescence. We tested the novel hypothesis that adolescent intermittent ethanol exposure would alter the serotonergic system that would persist into adulthood. Using a Wistar rat model of adolescent intermittent ethanol (AIE; 5.0g/kg, i.g., 2-day on/2-day off from postnatal day [P]25 to P55), we found a loss of dorsal raphe nucleus (DRN) serotonin (5-HT)-immunoreactive (+IR) neurons that persisted from late adolescence (P56) into adulthood (P220). Hypothalamic and amygdalar DRN serotonergic projections were reduced following AIE. Tryptophan hydroxylase 2, the rate-limiting 5-HT synthesizing enzyme, and vesicular monoamine transporter 2, which packages 5-HT into synaptic vesicles, were also reduced in the young adult midbrain following AIE treatment. Adolescent intermittent ethanol treatment increased expression of phosphorylated (activated) NF-κB p65 as well as markers of microglial activation (i.e., Iba-1 and CD11b) in the adult DRN. Administration of lipopolysaccharide to mimic AIE-induced innate immune activation reduced 5-HT+IR and increased phosphorylated NF-κB p65+IR similar to AIE treatment. Voluntary exercise during adolescence through young adulthood blunted microglial marker and phosphorylated NF-κB p65+IR, and prevented the AIE-induced loss of 5-HT+IR neurons in the DRN. Together, these novel data reveal that AIE reduces 5-HT+IR neurons in the adult DRN, possibly through an innate immune mechanism, which might impact adult cognition, arousal, or reward sensitivity. Further, exercise prevents the deleterious effects of AIE on the serotonergic system.

Adjunctive dorsal spanning plate fixation for challenging distal radius injuries.

Background: Distal radius fractures with severely osteoporotic bone or articular comminution can provide challenges to fixation with traditional volar locked plating alone. The purpose of this study was to evaluate the clinical, radiographic, and patient reported outcomes of patients undergoing distal radius fixation with volar locked plating and adjunctive dorsal bridge plating. Methods: We retrospectively identified 16 patients with distal radius fractures who underwent our preferred surgical technique for fixation. Patients underwent volar locked plate fixation as well as dorsal bridge fixation at time of surgery. Seven patients were indicated for severe articular comminution with volar rim fragmentation (44%), three patients were revised for nonunion after previous volar locked late fixation (19%), and six patients had severely osteoporotic bone with articular comminution (38%). Two patients (13%) sustained AO/OTA 23-A3 distal radius fracture, two patients (13%) had a 23-B3 fracture, two patients (13%) had a 23-C2 fracture and ten patients (63%) had a 23-C3 fracture. Results: The average patient age was 51.8 years ± 20.6. Patients were followed for an average of 12.2±6.3 months. The dorsal bridge plate was removed at an average of 11.1±2.4 weeks. The average post-operative radial inclination was 18.9±2.4°, radial height 12.4 mm ± 2.6 mm, and volar tilt 7.1±1.9°. There were no cases of deep or superficial infection. After dorsal bridge plate removal, patients demonstrated an average wrist extension of 55.3±9.5°, flexion 54.4±12.8°, radial deviation 15.7±3.2°, 25.2±3.9 degrees of ulnar deviation. Conclusion: Distal radius fractures in the setting of severely osteoporotic bone, salvage procedures, articular comminution, volar rim fractures, and revision surgery present uniquely difficult surgical challenges. Volar locked plating with adjunctive dorsal bridge plating can be used with good short- and long-term results.

Lung-derived soluble factors support stemness/plasticity and metastatic behaviour of breast cancer cells via the FGF2-DACH1 axis.

Patients with triple-negative breast cancer (TNBC) have an increased propensity to develop lung metastasis. Our previous studies demonstrated that stem-like ALDHhiCD44+ breast cancer cells interact with lung-derived soluble factors, resulting in enhanced migration and lung metastasis particularly in TNBC models. We have also observed that the presence of a primary TNBC tumor can 'prime' the lung microenvironment in preparation for metastasis. In this study, we hypothesized that soluble lung-derived factors secreted in the presence of a primary TNBC tumor can influence stemness/plasticity of breast cancer cells. Using an ex vivo pulmonary metastasis assay (PuMA), we observed that the lung microenvironment supports colonization and growth of ALDHhiCD44+ TNBC cells, potentially via interactions with lung-derived FGF2. Exposure of TNBC cells to lung-conditioned media (LCM) generated from mice bearing TNBC primary tumors (tbLCM) significantly enhanced the proportion of ALDHhiCD44+ cells compared to control or LCM from tumor-naïve mice (tnLCM). Further analysis using a human cancer stem cell qPCR array revealed that, relative to tnLCM or control, exposure of TNBC cells to tbLCM leads to downregulation of the transcription factor and putative tumor suppressor Dachshund homolog 1 (DACH1), a downstream regulator of FGF2. In addition, inhibition of DACH1 using siRNA or treatment with recombinant FGF2 enhanced the ALDHhiCD44+ phenotype. Taken together, our findings suggest that the FGF2-DACH1 signaling axis supports stemness/plasticity of TNBC cells in the lung microenvironment and lays the foundation for future evaluation of FGF2 as a potential novel therapeutic target for treatment or prevention of breast cancer metastasis to the lung.

No Differences in Clinical, Functional, or Patient-Reported Outcomes Following Trial of Nonoperative Management Before Open Reduction and Internal Fixation of Humeral Shaft Fractures.

OBJECTIVES: To test the hypothesis that primary osteosynthesis of humeral shaft fractures may lead to more favorable clinical, functional, and patient-reported outcomes than fixation following a trial of nonoperative management. DESIGN: Retrospective cohort review. SETTING: Academic level I trauma center. PATIENT SELECTION CRITERIA: Adult patients who presented with humeral shaft fractures and ultimately underwent open reduction and internal fixation (ORIF) from May 2011 to May 2021. Patients who underwent ORIF within 2 weeks of injury were grouped into the primary osteosynthesis cohort, and patients who underwent ORIF >4 weeks from the date of injury were grouped into the trial of nonoperative cohort. OUTCOME MEASURES AND COMPARISONS: Postoperative complications, elbow arc of motion, time to radiographic union, and patient-reported outcomes were investigated and compared between the primary osteosynthesis and trial of nonoperative management cohorts. RESULTS: One hundred twenty-seven patients fit the study criteria, 84 underwent primary osteosynthesis and 43 trialed initial nonoperative treatment. No differences were found in patient demographics between the primary osteosynthesis and trial of nonoperative management cohorts, including age (53 ± 19 vs. 57 ± 18; P = 0.25), sex (39% vs. 44% male, 61% vs. 56% female; P = 0.70), and Body Mass Index (BMI) (30 ± 6 vs. 32 ± 9; P = 0.38). The average time to operative intervention in the primary osteosynthesis group was 4 days (0-14 days) and 105 days (28-332 days) in the trial of nonoperative treatment group ( P < 0.01). No differences were found with regard to intraoperative blood loss, total operative time, time to radiographic union (determined using the Radiographic Union Scores for Humeral scoring system), or overall complication rates, including primary and secondary radial nerve injuries ( P = 0.23 and 0.86, respectively). Patients reported similar patient-reported outcomes measurement information system pain interference ( P = 0.73), depression (D) ( P = 0.99), and physical function ( P = 0.66) scores at their 6-month postsurgical follow-up visits. CONCLUSIONS: Patients who attempted a trial of nonoperative management for humeral shaft fractures before ORIF had similar clinical, functional, and patient-reported outcomes as those who underwent primary osteosynthesis. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

PROTAC-mediated NR4A1 degradation as a novel strategy for cancer immunotherapy.

An effective cancer therapy requires killing cancer cells and targeting the tumor microenvironment (TME). Searching for molecules critical for multiple cell types in the TME, we identified NR4A1 as one such molecule that can maintain the immune suppressive TME. Here, we establish NR4A1 as a valid target for cancer immunotherapy and describe a first-of-its-kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 degrades NR4A1 within hours in vitro and exhibits long-lasting NR4A1 degradation in tumors with an excellent safety profile. NR-V04 inhibits and frequently eradicates established tumors. At the mechanistic level, NR-V04 induces the tumor-infiltrating (TI) B cells and effector memory CD8+ T (Tem) cells and reduces monocytic myeloid-derived suppressor cells (m-MDSC), all of which are known to be clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anticancer immune responses and offers a new avenue for treating various types of cancers such as melanoma.

Comparable Injury to the Indirect Head of the Rectus Femoris During Interportal and Periportal Capsulotomy: A Cadaveric Study.

Background: There is concern for maintaining the integrity of the reflected head of the rectus femoris during arthroscopic hip joint access. Because of the proximity to the indirect head of the rectus femoris (IHRF), capsulotomy technique and capsular closure during routine hip arthroscopy may play a role in postoperative tendinitis. Purpose: To quantify the extent of injury sustained to the IHRF during interportal versus periportal capsulotomy for routine arthroscopic hip joint access. Study Design: Controlled laboratory study. Methods: A cadaveric study was conducted using 20 fresh-frozen cadaveric hips, in which hip joint access through a periportal capsulotomy (n = 10) or interportal capsulotomy (n = 10) was performed. Capsular closure followed by a layered dissection to the capsuloligamentous complex of the hip joint was then performed to localize the IHRF. Suture proximity to the tendon, tendon disruption, and the IHRF footprint was documented to the nearest 0.01 mm using digital calipers. Statistical analysis was performed using unpaired Student t tests. Results: The mean capsulotomy length for the interportal specimens was 19.27 ± 3.25 mm, and the mean medial and lateral capsulotomy length for the periportal specimens was 4.47 ± 1.60 and 4.26 ± 0.89 mm, respectively. There was violation of the tendon in 3 of 10 interportal specimens and 4 of 10 periportal specimens. There was no significant difference in the closest suture measured to the IHRF for specimens with versus without tendon violation, for either interportal or periportal capsulotomy. Conclusion: We found comparable outcomes with regard to violation of the IHRF between interportal and periportal capsulotomy, with no significant difference in suture proximity to the IHRF in specimens with or without tendon violation. There remains no consensus on the ideal method by which to avoid iatrogenic damage to the IHRF. Clinical Relevance: Our findings provide insight that may lead to future advances in surgical care, such that protection of the tendon during routine hip arthroscopy may allow for improved postoperative rehabilitation and strength.

MycoPins: a metabarcoding-based method to monitor fungal colonization of fine woody debris.

The MycoPins method described here is a rapid and affordable protocol to monitor early colonization events in communities of wood-inhabiting fungi in fine woody debris. It includes easy to implement field sampling techniques and sample processing, followed by data processing, and analysis of the development of early dead wood fungal communities. The method is based on fieldwork from a time series experiment on standard sterilized colonization targets followed by the metabarcoding analysis and automated molecular identification of species. This new monitoring method through its simplicity, moderate costs, and scalability paves a way for a broader and scalable project pipeline. MycoPins establishes a standard routine for research stations or regularly visited field sites for monitoring of fungal colonization of woody substrates. The routine uses widely available consumables and therefore presents a unifying method for monitoring of fungi of this type.

Altered binding affinity of SIX1-Q177R correlates with enhanced WNT5A and WNT pathway effector expression in Wilms tumor.

Wilms tumors present as an amalgam of varying proportions of tissues located within the developing kidney, one being the nephrogenic blastema comprising multipotent nephron progenitor cells (NPCs). The recurring missense mutation Q177R in NPC transcription factors SIX1 and SIX2 is most correlated with tumors of blastemal histology and is significantly associated with relapse. Yet, the transcriptional regulatory consequences of SIX1/2-Q177R that might promote tumor progression and recurrence have not been investigated extensively. Utilizing multiple Wilms tumor transcriptomic datasets, we identified upregulation of the gene encoding non-canonical WNT ligand WNT5A in addition to other WNT pathway effectors in SIX1/2-Q177R mutant tumors. SIX1 ChIP-seq datasets from Wilms tumors revealed shared binding sites for SIX1/SIX1-Q177R within a promoter of WNT5A and at putative distal cis-regulatory elements (CREs). We demonstrate colocalization of SIX1 and WNT5A in Wilms tumor tissue and utilize in vitro assays that support SIX1 and SIX1-Q177R activation of expression from the WNT5A CREs, as well as enhanced binding affinity within the WNT5A promoter that may promote the differential expression of WNT5A and other WNT pathway effectors associated with SIX1-Q177R tumors.

Increased Neighborhood Deprivation Is Associated with Prolonged Hospital Stays After Surgical Fixation of Traumatic Pelvic Ring Injuries.

BACKGROUND: The purpose of this study was to understand the role of social determinants of health assessed by the Area Deprivation Index (ADI) on hospital length of stay and discharge destination following surgical fixation of pelvic ring fractures. METHODS: A retrospective chart analysis was performed for all patients who presented to our level-I trauma center with pelvic ring injuries that were treated with surgical fixation. Social determinants of health were determined via use of the ADI, a comprehensive metric of socioeconomic status, education, income, employment, and housing quality. ADI values range from 0 to 100 and are normalized to a U.S. mean of 50, with higher scores representing greater social deprivation. We stratified our cohort into 4 ADI quartiles. Statistical analysis was performed on the bottom (25th percentile and below, least deprived) and top (75th percentile and above, most deprived) ADI quartiles. Significance was set at p < 0.05. RESULTS: There were 134 patients who met the inclusion criteria. Patients in the most deprived group were significantly more likely to have a history of smoking, to self-identify as Black, and to have a lower mean household income (p = 0.001). The most deprived ADI quartile had a significantly longer mean length of stay (and standard deviation) (19.2 ± 19 days) compared with the least deprived ADI quartile (14.7 ± 11 days) (p = 0.04). The least deprived quartile had a significantly higher percentage of patients who were discharged to a resource-intensive skilled nursing facility or inpatient rehabilitation facility compared with those in the most deprived quartile (p = 0.04). Race, insurance, and income were not significant predictors of discharge destination or hospital length of stay. CONCLUSIONS: Patients facing greater social determinants of health had longer hospital stays and were less likely to be discharged to resource-intensive facilities when compared with patients of lesser social deprivation. This may be due to socioeconomic barriers that limit access to such facilities. LEVEL OF EVIDENCE: Prognostic Level III . See Instructions for Authors for a complete description of levels of evidence.

Unleashing the Power of NR4A1 Degradation as a Novel Strategy for Cancer Immunotherapy.

An effective cancer therapy requires both killing cancer cells and targeting tumor-promoting pathways or cell populations within the tumor microenvironment (TME). We purposely search for molecules that are critical for multiple tumor-promoting cell types and identified nuclear receptor subfamily 4 group A member 1 (NR4A1) as one such molecule. NR4A1 has been shown to promote the aggressiveness of cancer cells and maintain the immune suppressive TME. Using genetic and pharmacological approaches, we establish NR4A1 as a valid therapeutic target for cancer therapy. Importantly, we have developed the first-of-its kind proteolysis-targeting chimera (PROTAC, named NR-V04) against NR4A1. NR-V04 effectively degrades NR4A1 within hours of treatment in vitro and sustains for at least 4 days in vivo, exhibiting long-lasting NR4A1-degradation in tumors and an excellent safety profile. NR-V04 leads to robust tumor inhibition and sometimes eradication of established melanoma tumors. At the mechanistic level, we have identified an unexpected novel mechanism via significant induction of tumor-infiltrating (TI) B cells as well as an inhibition of monocytic myeloid derived suppressor cells (m-MDSC), two clinically relevant immune cell populations in human melanomas. Overall, NR-V04-mediated NR4A1 degradation holds promise for enhancing anti-cancer immune responses and offers a new avenue for treating various types of cancer.

A Systematic Review of Periprocedural Risk Prediction Scores in Chronic Total Occlusion Percutaneous Coronary Intervention.

Chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is associated with high incidence of complications. We queried PubMed and the Cochrane Library (last search: October 26, 2022) for CTO PCI-specific periprocedural complication risk scores. We identified 8 CTO PCI-specific risk scores: (1) Angiographic coronary artery perforation (OPEN-CLEAN [Outcomes, Patient Health Status, and Efficiency iN (OPEN) Chronic Total Occlusion (CTO) Hybrid Procedures - CABG, Length (occlusion), EF <50%, Age, CalcificatioN] perforation, c-statistic 0.75): previous coronary artery bypass graft surgery, occlusion length 20 to 60 mm or ≥60 mm, left ventricular ejection fraction (LVEF) <50%, age 50 to 70 years or ≥70 years, heavy calcification. (2) Major adverse cardiovascular events (MACE) (PROGRESS-CTO complication, c-statistic 0.76): age >65 years, lesion length ≥23 mm, retrograde strategy, and (3) MACE (PROGRESS-CTO MACE, c-statistic 0.74): age ≥65 years, female gender, moderate/severe calcification, blunt/no stump, anterograde dissection and re-entry (ADR) or retrograde strategy. (4) All-cause mortality (PROGRESS-CTO mortality, c-statistic 0.80): age ≥65, moderate/severe calcification, LVEF ≤45%, ADR or retrograde strategy. (5) Perforation requiring pericardiocentesis (PROGRESS-CTO pericardiocentesis, c-statistic 0.78): age ≥65 years, moderate/severe calcification, female gender, ADR or retrograde strategy. (6) Acute myocardial infarction (PROGRESS-CTO acute myocardial infarction, c-statistic 0.72): previous coronary artery bypass graft surgery, atrial fibrillation, blunt/no stump. (7) Perforation requiring any treatment (PROGRESS-CTO perforation, c-statistic 0.74): age ≥65 years, moderate/severe calcification, blunt/no stump, ADR, or retrograde strategy. (8) Contrast-induced acute kidney injury (c-statistic 0.84): age ≥75, LVEF <40%, serum creatinine >1.5 mg/100 ml, serum albumin ≤30, 3040 g/L. There are 8 CTO PCI periprocedural risk scores that may facilitate risk assessment and procedural planning in patients who underwent CTO PCI.

Assessment of Fungal Succession in Decomposing Swine Carcasses (Sus scrofa L.) Using DNA Metabarcoding.

The decomposition of animal bodies is a process defined by specific stages, described by the state of the body and participation of certain guilds of invertebrates and microorganisms. While the participation of invertebrates in decomposing is well-studied and actively used in crime scene investigations, information on bacteria and fungi from the scene is rarely collected or used in the identification of important factors such as estimated time of death. Modern molecular techniques such as DNA metabarcoding allow the identification and quantification of the composition of microbial communities. In this study, we used DNA metabarcoding to monitor fungal succession during the decomposition of juvenile pigs in grasslands of New Jersey, USA. Our findings show that decomposition stages differ in a diversity of fungal communities. In particular, we noted increased fungal species richness in the more advanced stages of decomposition (e.g., bloat and decay stages), with unique fungal taxa becoming active with the progression of decay. Overall, our findings improve knowledge of how fungi contribute to forensically relevant decomposition and could help with the assessment of crime scenes.

The Use of DMAIC to Improve Quality Vaccination Recommendations in Chain Community Pharmacies.

Community pharmacies provide the convenience and ease of administrating vaccinations outside traditional settings. Vaccinations are health initiatives that protect communities and improve health outcomes in all populations. Despite their accessibility and supporting clinical data, various influential factors contribute to the current suboptimal rates of vaccine administration. Given the common barriers to vaccine administration, this research narrows down to address a specific barrier and attempts to implement a method that focuses on improving vaccine rates in community pharmacies. This research is a case study that utilizes the Define, Measure, Analyze, Improve, Control (DMAIC) model of Lean Six Sigma and aims to use this quality improvement process to identify, measure, analyze, and implement a training program to facilitate pharmacists in high-quality vaccine recommendations to promote higher rates of pneumococcal vaccinations in community settings.