In vivo CRISPR screens identify a dual function of MEN1 in regulating tumor-microenvironment interactions.

Functional genomic screens in two-dimensional cell culture models are limited in identifying therapeutic targets that influence the tumor microenvironment. By comparing targeted CRISPR-Cas9 screens in a two-dimensional culture with xenografts derived from the same cell line, we identified MEN1 as the top hit that confers differential dropout effects in vitro and in vivo. MEN1 knockout in multiple solid cancer types does not impact cell proliferation in vitro but significantly promotes or inhibits tumor growth in immunodeficient or immunocompetent mice, respectively. Mechanistically, MEN1 knockout redistributes MLL1 chromatin occupancy, increasing H3K4me3 at repetitive genomic regions, activating double-stranded RNA expression and increasing neutrophil and CD8+ T cell infiltration in immunodeficient and immunocompetent mice, respectively. Pharmacological inhibition of the menin-MLL interaction reduces tumor growth in a CD8+ T cell-dependent manner. These findings reveal tumor microenvironment-dependent oncogenic and tumor-suppressive functions of MEN1 and provide a rationale for targeting MEN1 in solid cancers.

Vibrational properties of heme-nitrosoalkane complexes in comparison with those of their HNO analogs, and reactivity studies towards nitric oxide and Lewis acids.

C-Nitroso compounds (RNO, R = alkyl and aryl) are byproducts of drug metabolism and bind to heme proteins, and their heme-RNO adducts are isoelectronic to ferrous nitroxyl (NO-/HNO) complexes. Importantly, heme-HNO compounds are key intermediates in the reduction of NO to N2O and nitrite to ammonium in the nitrogen cycle. Ferrous heme-RNO complexes act as stable analogs of these species, potentially allowing for the investigation of the vibrational and electronic properties of unstable heme-HNO intermediates. In this paper, a series of six-coordinate ferrous heme-RNO complexes (where R = iPr and Ph) were prepared using the TPP2- and 3,5-Me-BAFP2- co-ligands, and tetrahydrofuran, pyridine, and 1-methylimidazole as the axial ligands (bound trans to RNO). These complexes were characterized using different spectroscopic methods and X-ray crystallography. The complex [Fe(TPP)(THF)(iPrNO)] was further utilized for nuclear resonance vibrational spectroscopy (NRVS), allowing for the detailed assignment of the Fe-N(R)O vibrations of a heme-RNO complex for the first time. The vibrational properties of these species were then correlated with those of their HNO analogs, using DFT calculations. Our studies support previous findings that RNO ligands in ferrous heme complexes do not elicit a significant trans effect. In addition, the complexes are air-stable, and do not show any reactivity of their RNO ligands towards NO. So although ferrous heme-RNO complexes are suitable structural and electronic models for their HNO analogs, they are unsuitable to model the reactivity of heme-HNO complexes. We further investigated the reaction of our heme-RNO complexes with different Lewis acids. Here, [Fe(TPP)(THF)(iPrNO)] was found to be unreactive towards Lewis acids. In contrast, [Fe(3,5-Me-BAFP)(iPrNO)2] is reactive towards all of the Lewis acids investigated here, but in most cases the iron center is simply oxidized, resulting in the loss of the iPrNO ligand. In the case of the Lewis acid B2(pin)2, the reduced product [Fe(3,5-Me-BAFP)(iPrNH2)(iPrNO)] was identified by X-ray crystallography.

Parsing digital or analog TCR performance through piconewton forces.

αß T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP366-374/Db and PA224-233/Db, respectively) following in vivo influenza A virus infection were studied with optical tweezers. While certain NP repertoire CD8 T lymphocytes require many ligands for activation, others are digital, needing just few. Conversely, all PA TCRs perform digitally, exhibiting pronounced bond lifetime increases through sustained, energizing volleys of structural transitioning. Optimal digital performance is superior in vivo, correlating with ERK phosphorylation, CD3 loss, and activation marker up-regulation in vitro. Given neoantigen array paucity, digital TCRs are likely critical for immunotherapies.

Role of thymectomy in surgical treatment of renal hyperparathyroidism.

INTRODUCTION: The role for routine thymectomy in patients with secondary or tertiary hyperparathyroidism (SHPT, THPT) is unclear. We aim to compare rates of recurrence and complications in patients who underwent subtotal parathyroidectomy with and without thymectomy. METHODS: Patients who underwent surgery for renal HPT at a tertiary endocrine surgery center between 2010 and 2022 were reviewed. Presence of parathyroid tissue in resected tissue was identified through pathology reports. A multivariate logistic regression was used to compare baseline characteristics, recurrence rates and complications between those who did and did not undergo thymectomy. RESULTS: Of 107 patients who underwent subtotal parathyroidectomy, 29 (27.1 â€‹%) underwent concomitant thymectomy. Recurrence occurred in 15 patients (14 â€‹%). Thymectomy did not affect recurrence (OR: 0.33, 95%CI: 0.06-1.28, p â€‹= â€‹0.14), but was associated with permanent hypoparathyroidism (OR: 4.62, 95%CI: 1.67-13.18, p â€‹= â€‹0.003). Fewer parathyroid specimens increased the odds of thymectomy (p â€‹= â€‹0.04). Parathyroid glands were found in 6 thymectomy samples (20.7 â€‹%). CONCLUSION: Thymectomy at the time of subtotal parathyroidectomy for renal HPT was not associated with disease recurrence, but increased likelihood of permanent hypoparathyroidism.

Identification of genetic subtypes in follicular lymphoma.

Follicular lymphoma (FL) exhibits considerable variability in biological features and clinical trajectories across patients. To dissect the diversity of FL, we utilized a Bernoulli mixture model to identify genetic subtypes in 713 pre-treatment tumor tissue samples. Our analysis revealed the existence of five subtypes with unique genetic profiles that correlated with clinicopathological characteristics. The clusters were enriched in specific mutations as follows: CS (CREBBP and STAT6), TT (TNFAIP3 and TP53), GM (GNA13 and MEF2B), Q (quiescent, for low mutation burden), and AR (mutations of mTOR pathway-related genes). The subtype Q was enriched for patients with stage I disease and associated with a lower proliferative history than the other subtypes. The AR subtype was unique in its enrichment for IgM-expressing FL cases and was associated with advanced-stage and more than 4 nodal sites. The existence of subtypes was validated in an independent cohort of 418 samples from the GALLIUM trial. Notably, patients assigned to the TT subtype consistently experienced inferior progression-free survival when treated with immunochemotherapy. Our findings offer insight into core pathways distinctly linked with each FL cluster and are expected to be informative in the era of targeted therapies.

GNAS knockout potentiates HDAC3 inhibition through viral mimicry-related interferon responses in lymphoma.

Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.

Assessment of left ventricular wall thickness and dimension: accuracy of a deep learning model with prediction uncertainty.

Left ventricular (LV) geometric patterns aid clinicians in the diagnosis and prognostication of various cardiomyopathies. The aim of this study is to assess the accuracy and reproducibility of LV dimensions and wall thickness using deep learning (DL) models. A total of 30,080 unique studies were included; 24,013 studies were used to train a convolutional neural network model to automatically assess, at end-diastole, LV internal diameter (LVID), interventricular septal wall thickness (IVS), posterior wall thickness (PWT), and LV mass. The model was trained to select end-diastolic frames with the largest LVID and to identify four landmarks, marking the dimensions of LVID, IVS, and PWT using manually labeled landmarks as reference. The model was validated with 3,014 echocardiographic cines and the accuracy of the model was evaluated with a test set of 3,053 echocardiographic cines. The model accurately measured LVID, IVS, PWT, and LV mass compared to study report values with a mean relative error of 5.40%, 11.73%, 12.76%, and 13.93%, respectively. The 𝑅2 of the model for the LVID, IVS, PWT, and the LV mass was 0.88, 0.63, 0.50, and 0.87, respectively. The novel DL model developed in this study was accurate for LV dimension assessment without the need to select end-diastolic frames manually. DL automated measurements of IVS and PWT were less accurate with greater wall thickness. Validation studies in larger and more diverse populations are ongoing.

Comparison of CT-Guided needle biopsy versus percutaneous endoscopic debridement and drainage in pathogen identification and pain outcomes for spondylodiscitis patients: A systematic review and literature review.

Introduction: Spondylodiscitis (SD) is an infection of the intervertebral disc with involvement of the adjacent vertebral bodies. Diagnostic tests with CT-guided biopsy only provide a positive yield in 14%-48% of cases. Percutaneous endoscopic debridement and drainage (PEDD) has recently shown promise in the treatment of spondylodiscitis. Research question: The purpose of this study is to determine differences in pathogen identification and clinical outcomes for PEDD versus CT-guided needle biopsy in SD patients. Materials and methods: We conducted a systematic review of the literature using PRISMA guidelines to determine differences in positive microbiology results, perioperative complications, pain control, and long-term clinical outcomes for PEDD vs. CT-guided needle biopsy in SD patients. Results: 1078 studies were evaluated, 87 of which underwent full review. 15 studies met the inclusion and exclusion criteria, including 7 PEDD, 7 CT-guided biopsy, and 1 CT-guided biopsy vs. PEDD article, for a total of 192 PEDD patients and 604 CT-guided biopsy patients. We found 36.59% of CT-guided biopsy patients had positive microbiology results, compared to 84.38% of PEDD patients. No major perioperative complications occurred as a result of the PEDD procedure. Of the five PEDD studies that reported pain outcomes, greater than 80% of patients experienced relief after intervention. Discussion and conclusion: These results suggest that PEDD may improve pathogen identification while simultaneously reducing pain compared to CT-guided needle biopsy in SD. Although current treatment guidelines recommend CT-guided biopsy, in patients with severe back pain and suspected SD, PEDD can be considered an alternative intervention.

Lattice dynamics of119Sn impurity in a bcc-Cr crystal.

The chromium crystal doped with119Sn isotope was studied using the nuclear resonance inelastic x-ray scattering and first principles calculations. The Sn partial phonon density of states (PDOS) was obtained for three temperatures that correspond to different magnetic states of Cr. At all temperatures, the energy spectrum consists of a broad band around 18 meV and a narrow peak at 43 meV. The additional peak around 39 meV is observed only in the magnetically ordered phases, indicating the influence of magnetic order in chromium on lattice dynamics. The partial PDOS calculated with the antiferromagnetic order on Cr atoms show a very good agreement with the experimental data. It is revealed that the high-energy peak is lying above the phonon spectra of the pure bcc-Cr crystal. These are the local modes with the increased energies due to a strongly reduced distance between Sn and the nearest-neighbor Cr atoms.

Predictors of patient satisfaction in the surgical treatment of cervical spondylotic myelopathy.

OBJECTIVE: Patients with cervical spondylotic myelopathy (CSM) experience progressive neurological impairment. Surgical intervention is often pursued to halt neurological symptom progression and allow for recovery of function. In this paper, the authors explore predictors of patient satisfaction following surgical intervention for CSM. METHODS: This is a retrospective review of prospectively collected data from the multicenter Quality Outcomes Database. Patients who underwent surgical intervention for CSM with a minimum follow-up of 2 years were included. Patient-reported satisfaction was defined as a North American Spine Society (NASS) satisfaction score of 1 or 2. Patient demographics, surgical parameters, and outcomes were assessed as related to patient satisfaction. Patient quality of life scores were measured at baseline and 24-month time points. Univariate regression analyses were performed using the chi-square test or Student t-test to assess patient satisfaction measures. Multivariate logistic regression analysis was conducted to assess for factors predictive of postoperative satisfaction at 24 months. RESULTS: A total of 1140 patients at 14 institutions with CSM who underwent surgical intervention were included, and 944 completed a patient satisfaction survey at 24 months postoperatively. The baseline modified Japanese Orthopaedic Association (mJOA) score was 12.0 ± 2.8. A total of 793 (84.0%) patients reported satisfaction (NASS score 1 or 2) after 2 years. Male and female patients reported similar satisfaction rates (female sex: 47.0% not satisfied vs 48.5% satisfied, p = 0.73). Black race was associated with less satisfaction (26.5% not satisfied vs 13.2% satisfied, p < 0.01). Baseline psychiatric comorbidities, obesity, and length of stay did not correlate with 24-month satisfaction. Crossing the cervicothoracic junction did not affect satisfactory scores (p = 0.19), and minimally invasive approaches were not associated with increased patient satisfaction (p = 0.14). Lower baseline numeric rating scale neck pain scores (5.03 vs 5.61, p = 0.04) and higher baseline mJOA scores (12.28 vs 11.66, p = 0.01) were associated with higher satisfaction rates. CONCLUSIONS: Surgical treatment of CSM results in a high rate of patient satisfaction (84.0%) at the 2-year follow-up. Patients with milder myelopathy report higher satisfaction rates, suggesting that intervention earlier in the disease process may result in greater long-term satisfaction.

Cost-effectiveness of posterior lumbar interbody fusion and/or transforaminal lumbar interbody fusion for grade 1 lumbar spondylolisthesis: a 5-year Quality Outcomes Database study.

OBJECTIVE: Posterior lumbar interbody fusion (PLIF) and/or transforaminal lumbar interbody fusion (TLIF), referred to as "PLIF/TLIF," is a commonly performed operation for lumbar spondylolisthesis. Its long-term cost-effectiveness has not been well described. The aim of this study was to determine the 5-year cost-effectiveness of PLIF/TLIF for grade 1 degenerative lumbar spondylolisthesis using prospective data collected from the multicenter Quality Outcomes Database (QOD). METHODS: Patients enrolled in the prospective, multicenter QOD grade 1 lumbar spondylolisthesis module were included if they underwent single-stage PLIF/TLIF. EQ-5D scores at baseline, 3 months, 12 months, 24 months, 36 months, and 60 months were used to calculate gains in quality-adjusted life years (QALYs) associated with surgery relative to preoperative baseline. Healthcare-related costs associated with the index surgery and related reoperations were calculated using Medicare reimbursement-based cost estimates and validated using price transparency diagnosis-related group (DRG) charges and Medicare charge-to-cost ratios (CCRs). Cost per QALY gained over 60 months postoperatively was assessed. RESULTS: Across 12 surgical centers, 385 patients were identified. The mean patient age was 60.2 (95% CI 59.1-61.3) years, and 38% of patients were male. The reoperation rate was 5.7%. DRG 460 cost estimates were stable between our Medicare reimbursement-based models and the CCR-based model, validating the focus on Medicare reimbursement. Across the entire cohort, the mean QALY gain at 60 months postoperatively was 1.07 (95% CI 0.97-1.18), and the mean cost of PLIF/TLIF was $31,634. PLIF/TLIF was associated with a mean 60-month cost per QALY gained of $29,511. Among patients who did not undergo reoperation (n = 363), the mean 60-month QALY gain was 1.10 (95% CI 0.99-1.20), and cost per QALY gained was $27,591. Among those who underwent reoperation (n = 22), the mean 60-month QALY gain was 0.68 (95% CI 0.21-1.15), and the cost per QALY gained was $80,580. CONCLUSIONS: PLIF/TLIF for degenerative grade 1 lumbar spondylolisthesis was associated with a mean 60-month cost per QALY gained of $29,511 with Medicare fees. This is far below the well-established societal willingness-to-pay threshold of $100,000, suggesting long-term cost-effectiveness. PLIF/TLIF remains cost-effective for patients who undergo reoperation.

Predictors of Delayed Clinical Benefit Following Surgical Treatment for Low Grade Spondylolisthesis.

STUDY DESIGN: Retrospective review of prospectively collected data. OBJECTIVE: To investigate what factors predict delayed improvement after surgical treatment of low grade spondylolisthesis. SUMMARY OF BACKGROUND DATA: Lumbar surgery leads to clinical improvement in the majority of patients with low grade spondylolisthesis. Most patients improve rapidly after surgery, but some patients demonstrate a delayed clinical course. METHODS: The Quality and Outcomes Database (QOD) was queried for grade 1 spondylolisthesis patients who underwent surgery who had patient reported outcome measures (PROMs) collected at baseline, 3-, 6- and 12-months, including back and leg pain numeric rating scale (NRS), Oswestry Disability Index (ODI), and EuroQol-5D (EQ-5D). Patients were stratified as "Early responders" reaching MCID at 3 months and maintaining improvement through 12 months and "Delayed responders" not reaching MCID at 3 months but ultimately reaching MCID at 12 months. These two groups were compared with respect to factors which predicted delayed improvement. RESULTS: Of 608 patients enrolled, 436 (72%) met inclusion criteria for this study. Overall, 317 patients (72.7%) reached MCID for ODI at 12 months following surgery. Of these patients, 249 (78.5%) exhibited a rapid clinical improvement trajectory and had achieved ODI MCID threshold by the 3-month postop follow-up. 68 patients (21.4%) showed a delayed trajectory, and had not achieved ODI MCID threshold at 3 months, but did ultimately reach MCID at 12-month follow-up. Factors associated with delayed improvement included impaired preoperative ambulatory status, better baseline back and leg pain scores, and worse 3-month leg pain scores (P<0.01). CONCLUSIONS: The majority of patients undergoing surgery for low grade spondylolisthesis reach ODI MCID threshold rapidly, within the first three months after surgery. Factors associated with a delayed clinical course include impaired preoperative ambulation status, relatively better preoperative back and leg pain, and persistent leg pain at 3 months.

Pedicle screw placement in the cervical vertebrae using augmented reality-head mounted displays: a cadaveric proof-of-concept study.

BACKGROUND: The accurate and safe positioning of cervical pedicle screws is crucial. While augmented reality (AR) use in spine surgery has previously demonstrated clinical utility in the thoracolumbar spine, its technical feasibility in the cervical spine remains less explored. PURPOSE: The objective of this study was to assess the precision and safety of AR-assisted pedicle screw placement in the cervical spine. STUDY DESIGN: In this experimental study, five cadaveric cervical spine models were instrumented from C3 to C7 by five different spine surgeons. The navigation accuracy and clinical screw accuracy were evaluated. METHODS: Post-procedural CT scans were evaluated for clinical accuracy by two independent neuroradiologists using the Gertzbein-Robbins scale. Technical precision was assessed by calculating the angular trajectory (°) and linear screw tip (mm) deviations in the axial and sagittal planes from the virtual pedicle screw position as recorded by the AR-guided platform during the procedure compared to the actual pedicle screw position derived from post-procedural imaging. RESULTS: A total of forty-one pedicle screws were placed in five cervical cadavers, with each of the five surgeons navigating at least seven screws. Gertzbein-Robbins grade of A or B was achieved in 100% of cases. The mean values for tip and trajectory errors in the axial and sagittal planes between the virtual versus actual position of the screws was less than 3 mm and 30°, respectively (p<0.05). None of the cervical screws violated the cortex by more than 2 mm or displaced neurovascular structures. CONCLUSIONS: AR-assisted cervical pedicle screw placement in cadavers demonstrated clinical accuracy comparable to existing literature values for image-guided navigation methods for the cervical spine. CLINICAL SIGNIFICANCE: This study provides technical and clinical accuracy data that supports clinical trialing of AR-assisted subaxial cervical pedicle screw placement.

Blunting specific T-dependent antibody responses with engineered 'decoy' B cells.

Antibody inhibitors pose an ongoing challenge to the treatment of subjects with inherited protein deficiency disorders, limiting the efficacy of both protein replacement therapy and corrective gene therapy. Beyond their central role as producers of serum antibody, B cells also exhibit many unique properties that could be exploited in cell therapy applications, notably including antigen-specific recognition and the linked capacity for antigen presentation. Here we employed CRISPR/Cas9 to demonstrate that ex vivo antigen-primed Blimp1-knockout "decoy" B cells, incapable of differentiation into plasma cells, participated in and downregulated host antigen-specific humoral responses after adoptive transfer. Following ex vivo antigen pulse, adoptively transferred high affinity antigen-specific decoy B cells were diverted into germinal centers en masse, thereby reducing participation by endogenous antigen-specific B cells in T-dependent humoral responses and suppressing both cognate and linked antigen-specific IgG following immunization with conjugated antigen. This effect was dose-dependent and, importantly, did not impact concurrent unrelated antibody responses. We demonstrated the therapeutic potential of this approach by treating factor VIII (FVIII)-knockout mice with antigen-pulsed decoy B cells prior to immunization with a FVIII conjugate protein, thereby blunting the production of serum FVIII-specific IgG by an order of magnitude as well as reducing the proportion of animals exhibiting functional FVIII inhibition by 6-fold.

Addition of pyloroplasty may improve glycemic control and refractory early satiety in gastroparesis at rates similar to gastric neurostimulation alone: a retrospective analysis.

OBJECTIVES: Gastroparesis that is refractory to standard dietary and medical management may benefit from surgical treatment with gastric electrical neurostimulation, which has shown promise in reducing symptoms of the disease. Pyloroplasty may serve an adjunctive role to a gastric stimulator, but the precise benefit remains unclear. The present study compares reported rates of symptom improvement following gastric neurostimulator implantation with and without pyloroplasty. MATERIALS AND METHODS: A single center retrospective analysis of consecutive patients who received operative management for symptom refractory gastroparesis from 1 January 2020 to 31 December 2021 was performed. Subjects were assigned to cohorts based on treatment with gastric electrical stimulation alone (GES-only) or combined with pyloroplasty (GES + PP). A survey-based assessment was administered post-operatively that evaluated cardinal symptoms of gastroparesis (nausea, vomiting, early satiety) before and after treatment. RESULTS: In total, 42 patients (15 GES-only, 27 GES + PP) were included in the study. Both groups reported a high degree of improvement in global symptom control following surgery (93% vs 81%) with no differences between treatment cohorts (p = 0.09). Early satiety demonstrated better improvement in patients who received gastric stimulation alone (p = 0.012). Subgroup analysis of diabetic gastroparesis patients showed a 2.2% decrease in hemoglobin A1c levels in the GES + PP group (p-0.034). CONCLUSIONS: Symptom reduction in refractory gastroparesis appears to improve after placement of a gastric neurostimulator with or without the addition of a pyloroplasty procedure.

Episodic Transport of Protein Aggregates Achieves a Positive Size Selectivity in Aggresome Formation.

Eukaryotic cells direct toxic misfolded proteins to various protein quality control pathways based on their chemical features and aggregation status. Aggregated proteins are targeted to selective autophagy or specifically sequestered into the "aggresome," a perinuclear inclusion at the microtubule-organizing center (MTOC). However, the mechanism for selectively sequestering protein aggregates into the aggresome remains unclear. To investigate aggresome formation, we reconstituted MTOC-directed aggregate transport in Xenopus laevis egg extract using AgDD, a chemically inducible aggregation system. High-resolution single-particle tracking revealed that dynein-mediated transport of aggregates was highly episodic, with average velocity positively correlated with aggregate size. Our mechanistic model suggests that the recurrent formation of the dynein transport complex biases larger aggregates towards the active transport state, compensating for the slowdown due to viscosity. Both episodic transport and positive size selectivity are specifically associated with aggresome-dynein adaptors. Coupling conventional dynein-activating adaptors to the aggregates perturbs aggresome formation and reverses size selectivity.

Lineage-specific canonical and non-canonical activity of EZH2 in advanced prostate cancer subtypes.

Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and emerging therapeutic target that is overexpressed in most castration-resistant prostate cancers and implicated as a driver of disease progression and resistance to hormonal therapies. Here we define the lineage-specific action and differential activity of EZH2 in both prostate adenocarcinoma and neuroendocrine prostate cancer (NEPC) subtypes of advanced prostate cancer to better understand the role of EZH2 in modulating differentiation, lineage plasticity, and to identify mediators of response and resistance to EZH2 inhibitor therapy. Mechanistically, EZH2 modulates bivalent genes that results in upregulation of NEPC-associated transcriptional drivers (e.g., ASCL1) and neuronal gene programs in NEPC, and leads to forward differentiation after targeting EZH2 in NEPC. Subtype-specific downstream effects of EZH2 inhibition on cell cycle genes support the potential rationale for co-targeting cyclin/CDK to overcome resistance to EZH2 inhibition.

Estimating causes of maternal death in data-sparse contexts.

Understanding the underlying causes of maternal death across all regions of the world is essential to inform policies and resource allocation to reduce the mortality burden. However, in many countries there exists very little data on the causes of maternal death, and data that do exist do not capture the entire population at risk. In this article, we present a Bayesian hierarchical multinomial model to estimate maternal cause of death distributions globally, regionally, and for all countries worldwide. The framework combines data from various sources to inform estimates, including data from civil registration and vital systems, smaller-scale surveys and studies, and high-quality data from confidential enquiries and surveillance systems. The framework accounts for varying data quality and coverage, and allows for situations where one or more causes of death are missing. We illustrate the results of the model on three case-study countries that have different data availability situations.

Predictors of patient satisfaction after surgery for grade 1 degenerative spondylolisthesis: a 5-year analysis of the Quality Outcomes Database.

OBJECTIVE: Lumbar decompression and/or fusion surgery is a common operation for symptomatic lumbar spondylolisthesis refractory to conservative management. Multiyear follow-up of patient outcomes can be difficult to obtain but allows for identification of preoperative patient characteristics associated with durable pain relief, improved functional outcome, and higher patient satisfaction. METHODS: A query of the Quality Outcomes Database (QOD) low-grade spondylolisthesis module for patients who underwent surgery for grade 1 lumbar spondylolisthesis (from July 2014 to June 2016 at the 12 highest-enrolling sites) was used to identify patient satisfaction, as measured with the North American Spine Society (NASS) questionnaire, which uses a scale of 1-4. Patients were considered satisfied if they had a score ≤ 2. Multivariable logistic regression was performed to identify baseline demographic and clinical predictors of long-term satisfaction 5 years after surgery. RESULTS: Of 573 eligible patients from a cohort of 608, patient satisfaction data were available for 81.2%. Satisfaction (NASS score of 1 or 2) was reported by 389 patients (83.7%) at 5-year follow-up. Satisfied patients were predominantly White and ambulation independent and had lower baseline BMI, lower back pain levels, lower Oswestry Disability Index (ODI) scores, and greater EQ-5D index scores at baseline when compared to the unsatisfied group. No significant differences in reoperation rates between groups were reported at 5 years. On multivariate analysis, patients who were independently ambulating at baseline had greater odds of long-term satisfaction (OR 1.12, p = 0.04). Patients who had higher 5-year ODI scores (OR 0.99, p < 0.01) and were uninsured (OR 0.43, p = 0.01) were less likely to report long-term satisfaction. CONCLUSIONS: Lumbar surgery for the treatment of grade 1 spondylolisthesis can provide lasting pain relief with high patient satisfaction. Baseline independent ambulation is associated with a higher long-term satisfaction rate after surgery. Higher ODI scores at 5-year follow-up and uninsured status are associated with lower postoperative long-term satisfaction.