The interaction between RIPK1 and FADD controls perinatal lethality and inflammation.

Perturbation of the apoptosis and necroptosis pathways critically influences embryogenesis. Receptor-associated protein kinase-1 (RIPK1) interacts with Fas-associated via death domain (FADD)-caspase-8-cellular Flice-like inhibitory protein long (cFLIPL) to regulate both extrinsic apoptosis and necroptosis. Here, we describe Ripk1-mutant animals (Ripk1R588E [RE]) in which the interaction between FADD and RIPK1 is disrupted, leading to embryonic lethality. This lethality is not prevented by further removal of the kinase activity of Ripk1 (Ripk1R588E K45A [REKA]). Both Ripk1RE and Ripk1REKA animals survive to adulthood upon ablation of Ripk3. While embryonic lethality of Ripk1RE mice is prevented by ablation of the necroptosis effector mixed lineage kinase-like (MLKL), animals succumb to inflammation after birth. In contrast, Mlkl ablation does not prevent the death of Ripk1REKA embryos, but animals reach adulthood when both MLKL and caspase-8 are removed. Ablation of the nucleic acid sensor Zbp1 largely prevents lethality in both Ripk1RE and Ripk1REKA embryos. Thus, the RIPK1-FADD interaction prevents Z-DNA binding protein-1 (ZBP1)-induced, RIPK3-caspase-8-mediated embryonic lethality, affected by the kinase activity of RIPK1.

Comparative three-dimensional jaw muscle anatomy of marsupial carnivores (Dasyurus spp.) and the termite-eating numbat (Myrmecobius fasciatus).

Among marsupials, the endangered numbat (Myrmecobius fasciatus) is the only obligate myrmecophage with a diet comprised strictly of termites. Like many other specialised myrmecophagous mammals, numbats have a gracile and highly specialised skull morphology with an elongated rostrum and small braincase. Myrmecobiidae is one of four taxonomic families within the Australasian marsupial order Dasyuromorphia, and to date, the muscular anatomy of any member of this group is relatively poorly known. We utilised microdissection and contrast-enhanced microcomputed tomography scanning to provide the first comprehensive qualitative and quantitative descriptions of jaw muscle anatomy in numbats and quolls (Dasuyrus species). The arrangement of the jaw muscles across these species was conservative, both in gross anatomy and muscle proportions, corresponding to a 'generalised' mammalian pattern. In contrast to Dasyurus, the jaw muscles of the numbat were greatly reduced. Many aspects of the muscle anatomy of the numbat were similar to patterns reported in other myrmecophagous species, particularly a greatly reduced temporalis muscle. Unusually, the digastric muscle in the numbat was comprised of a single, large anterior belly while the posterior belly was absent. We propose that the enlarged anterior belly of the digastric may be linked to jaw stabilisation and coordination of tongue movements during feeding. The lateral insertion and fascial connection of the digastric to the tongue in numbats may also aid in distributing stress evenly across the jaw and minimise muscle fatigue. The muscle descriptions and three-dimensional models provided in this study will facilitate further analysis of musculoskeletal adaptation and evolution within the Dasyuromorphia.

Composite material in the sea urchin Cidaris rugosa: ordered and disordered micrometre-scale bicontinuous geometries.

The sponge-like biomineralized calcite materials found in echinoderm skeletons are of interest in terms of both structure formation and biological function. Despite their crystalline atomic structure, they exhibit curved interfaces that have been related to known triply periodic minimal surfaces. Here, we investigate the endoskeleton of the sea urchin Cidaris rugosa that has long been known to form a microstructure related to the Primitive surface. Using X-ray tomography, we find that the endoskeleton is organized as a composite material consisting of domains of bicontinuous microstructures with different structural properties. We describe, for the first time, the co-occurrence of ordered single Primitive and single Diamond structures and of a disordered structure within a single skeletal plate. We show that these structures can be distinguished by structural properties including solid volume fraction, trabeculae width and, to a lesser extent, interface area and mean curvature. In doing so, we present a robust method that extracts interface areas and curvature integrals from voxelized datasets using the Steiner polynomial for parallel body volumes. We discuss these very large-scale bicontinuous structures in the context of their function, formation and evolution.

Modified Clavien-Dindo-Sink Classification System for operative complications in adult spine surgery.

OBJECTIVE: Currently there is no standardized mechanism to describe or compare complications in adult spine surgery. Thus, the purpose of the present study was to modify and validate the Clavien-Dindo-Sink complication classification system for applications in spine surgery. METHODS: The Clavien-Dindo-Sink complication classification system was evaluated and modified for spine surgery by four fellowship-trained spine surgeons using a consensus process. A distinct group of three fellowship-trained spine surgeons completed a randomized electronic survey grading 71 real-life clinical case scenarios. The survey was repeated 2 weeks after its initial completion. Fleiss' and Cohen's kappa (κ) statistics were used to evaluate interrater and intrarater reliabilities, respectively. RESULTS: Overall, interobserver reliability during the first and second rounds of grading was excellent with a κ of 0.847 (95% CI 0.785-0.908) and 0.852 (95% CI 0.791-0.913), respectively. In the first round, interrater reliability ranged from good to excellent with a κ of 0.778 for grade I (95% CI 0.644-0.912), 0.698 for grade II (95% CI 0.564-0.832), 0.861 for grade III (95% CI 0.727-0.996), 0.845 for grade IV-A (95% CI 0.711-0.979), 0.962 for grade IV-B (95% CI 0.828-1.097), and 0.960 for grade V (95% CI 0.826-1.094). Intraobserver reliability testing for all three independent observers was excellent with a κ of 0.971 (95% CI 0.944-0.999) for rater 1, 0.963 (95% CI 0.926-1.001) for rater 2, and 0.926 (95% CI 0.869-0.982) for rater 3. CONCLUSIONS: The Modified Clavien-Dindo-Sink Classification System demonstrates excellent interrater and intrarater reliability in adult spine surgery cases. This system provides a useful framework to better communicate the severity of spine-related complications.

Characterizing Negative Online Reviews of Spine Surgeons.

DESIGN: Retrospective review. OBJECTIVE: Characterize negative reviews of spine surgeons in the United States. SUMMARY: Physician rating websites significantly influence the selection of doctors by other patients. Negative experiences are impacted by various factors, both clinical and nonclinical, geography, and practice structure. The purpose of this study was to evaluate and categorize negative reviews of spine surgeons in the United States, with a focus on surgical versus nonsurgical reviewers. METHODS: Spine surgeons were selected from available online professional society membership directories. A search for reviews was performed on Healthgrades.com, Vitals.com, and RateMDs.com for the past 10 years. Free response reviews were coded by complaint, and qualitative analysis was performed. χ 2 and Fisher exact tests were used to compare categorical variables, and multiple comparisons were adjusted with Benjamini-Hochberg correction. A binary logistic regression model was performed for the top three most mentioned nonclinical and clinical complaint labels. A P -value <0.05 was considered statistically significant. RESULTS: A total of 16,695 online reviews were evaluated, including 1690 one-star reviews (10.1%). Among one-star reviews, 64.7% were written by nonsurgical patients and 35.3% by surgical patients. Nonclinical and clinical comments constituted 54.9% and 45.1% of reviews, respectively. Surgeons in the South had more "bedside manner" comments (43.3%, P <0.0001), while Northeast surgeons had more "poor surgical outcome" remarks compared with all other geographic regions (14.4%, P <0.001). Practicing in the South and Northeast were independent predictors of having complaints about "bedside manner" and "poor surgical outcome," respectively. CONCLUSION: Most one-star reviews of spine surgeons were attributed to nonsurgical patients, who tended to be unsatisfied with nonclinical factors, especially "bedside manner." However, there was substantial geographic variation. These results suggest that spine surgeons could benefit from focusing on nonclinical factors (bedside manner), especially among nonoperative patients, and that regional nuances should be considered in delivering spine care. LEVEL OF EVIDENCE: Level- 5.

Formal Radiologist Interpretations of Intraoperative Spine Radiographs Have Low Clinical Value.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To evaluate the clinical relevance, usefulness, and financial implications of intraoperative radiograph interpretation by radiologists in spine surgery. SUMMARY OF BACKGROUND DATA: Due to rising health care costs, spine surgery is under scrutiny to maximize value-based care. Formal radiographic analysis remains a potential source of unnecessary health care costs, especially for intraoperative radiographs. MATERIALS AND METHODS: A retrospective cohort analysis was performed on all adult elective spine surgeries at a single institution between July 2020 and July 2021. Demographic and radiographic data were collected, including intraoperative localization and post-instrumentation radiographs. Financial data were obtained through the institution's price estimator. Radiographic characteristics included time from radiographic imaging to completion of radiologist interpretation report, completion of radiologist interpretation report before the conclusion of surgical procedure, clinical relevance, and clinical usefulness. Reports were considered clinically relevant if the spinal level of the procedure was described and clinically useful if completed before the conclusion of the procedure and deemed clinically relevant. RESULTS: Four hundred eighty-one intraoperative localization and post-instrumentation radiographs from 360 patients revealed a median delay of 128 minutes between imaging and completion of the interpretive report. Only 38.9% of reports were completed before the conclusion of surgery. There were 79.4% deemed clinically relevant and only 33.5% were clinically useful. Localization reports were completed more frequently before the conclusion of surgery (67.2% vs. 34.4%) but with lower clinical relevance (90.1% vs. 98.5%) and clinical usefulness (60.3% vs. 33.6%) than post-instrumentation reports. Each patient was charged $32 to $34 for the interpretation fee, cumulating a minimum total cost of $15,392. CONCLUSIONS: Formal radiographic interpretation of intraoperative spine radiographs was of low clinical utility for spine surgeons. Institutions should consider optimizing radiology workflows to improve timeliness and clinical relevance or evaluate the necessity of reflexive consultation to radiology for intraoperative imaging interpretation to ensure that value-based care is maximized during spine surgeries. LEVEL OF EVIDENCE: 3.

Diagnostic utility of different types of somatosensory evoked potential changes in pediatric idiopathic scoliosis correction surgery.

PURPOSE: To evaluate the diagnostic accuracy of intraoperative somatosensory evoked potential (SSEP) monitoring and types of SSEP changes in predicting the risk of postoperative neurological outcomes during correction surgery for idiopathic scoliosis (IS) in the pediatric age group (≤ 21 years). METHODS: Database review was performed to identify literature on pediatric patients with IS who underwent correction with intraoperative neuromonitoring. The sensitivity, specificity, and diagnostic odds ratio (DOR) of transient and persistent SSEP changes and complete SSEP loss in predicting postoperative neurological deficits were calculated. RESULTS: Final analysis included 3778 patients. SSEP changes had a sensitivity of 72.9%, specificity of 96.8%, and DOR of 102.3, while SSEP loss had a sensitivity of 41.8%, specificity of 99.3%, and DOR of 133.2 for predicting new neurologic deficits. Transient and persistent SSEP changes had specificities of 96.8% and 99.1%, and DORs of 16.6 and 59, respectively. CONCLUSION: Intraoperative SSEP monitoring can predict perioperative neurological injury and improve surgical outcomes in pediatric scoliosis fusion surgery. LEVEL OF EVIDENCE: Level 2. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Topical tranexamic acid (TXA) is non-inferior to intravenous TXA in adult spine surgery: a meta-analysis.

Tranexamic acid (TXA) has long been utilized in spine surgery and can be administered through intravenous (IV) and topical routes. Although, topical and IV administration of TXA are both effective in decreasing blood loss during spine surgery, complications like deep vein thrombosis (DVT) and pulmonary embolism have been reported with the use of intravenous TXA (ivTXA). These potential complications may be mitigated through the use of topical TXA (tTXA). To assess optimal dosing protocols and efficacy of topical TXA in spine surgery, Embase, Ovid-MEDLINE, Scopus, Cochrane, and clinicaltrials.gov were queried for original research on the use of tTXA in adult patients undergoing spine surgery. Data parameters analyzed included blood loss, transfusion rate, thromboembolic, and other complications. Data was synthesized and confidence evaluated according to the Grades of Recommendation, Assessment, Development, and Evaluation approach. Nineteen studies were included in the final analysis with 2197 patients. Of the 18 published studies, 9 (50%) displayed high levels of evidence. Topical TXA showed a trend towards a lower risk of transfusion and complications. Protocols that used 1g tTXA showed a significantly reduced risk for transfusion when compared to controls (risk ratio -1.05, 95% CI (-1.62, -0.48); P = 0.94, I2 = 0%). Complications associated with tTXA included DVTs and wound infections. Topical TXA was non-inferior to intravenous TXA with similar efficacy and complication profiles for bleeding control in spine surgery; however, more studies are needed to discern benefits and risks.

Contrasting morphology and growth habits of Frutexites in Late Devonian reef complexes of the Canning Basin, northwestern Australia.

Frutexites-like microstructures are described from the exhumed Late Devonian reef complexes of the northern Canning Basin, Western Australia. Several high-resolution imaging techniques, including X-ray microcomputerised tomography, scanning electron microscopy and X-ray fluorescence microscopy, were used to investigate morphology and composition in two samples. Three types of Frutexites-like microstructures (Types I-III) have been identified. Type I, found lining an early marine cement-filled cavity in fore-reef grainstone facies, consists of dendritic structures formed primarily of coccoid bacteria with filamentous bacteria embedded in sheets of amorphous extracellular polymeric substances (EPS). These ferromanganiferous dendrites have laminated to spheroidal textures. Types II and III are from a toe-of-slope hardground. Type II grew in a crypt between two corals, is also dendritic and composed of bacilliform and filamentous bacteria embedded in an amorphous EPS sheet. The opaqueness of these ferriferous dendrites precludes more detailed description of textures. Type III grew as branching columnar microstromatolites and is composed of entwined filaments of Girvanella, Rothpletzella and Wetheredella with Fe-enriched outer walls that generate Frutexites-like microstructures. Types I and II resemble Frutexites sensu stricto as defined by Maslov (Stromatolites, Trudy Instituta geologicheskikh nauk Akademiya nauk SSR, 1960) and are the result of the consecutive growth and permineralisation of biofilms composed of mixed bacterial communities growing in cryptic habitats. Type III superficially resembles Frutexites sensu stricto based on macroscopic field observations, however, detailed microscopic analysis reveals that it is composed of Fe-enriched tubular walls surrounded by Mn-enriched calcite.

Transcranial Motor Evoked Potentials as a Predictive Modality for Postoperative Deficit in Cervical Spine Decompression Surgery - A Systematic Review and Meta-Analysis.

STUDY DESIGN: Systematic Review and Meta-analysis. OBJECTIVE: The purpose of this study was to evaluate whether transcranial motor evoked potential (TcMEP) alarms can predict postoperative neurologic complications in patients undergoing cervical spine decompression surgery. METHODS: A meta-analysis of the literature was performed using PubMed, Web of Science, and Embase to retrieve published reports on intraoperative TcMEP monitoring for patients undergoing cervical spine decompression surgery. The sensitivity, specificity, and diagnostic odds ratio (DOR), of overall, reversible, and irreversible TcMEP changes for predicting postoperative neurological deficit were calculated. A subgroup analysis was performed to compare anterior vs posterior approaches. RESULTS: Nineteen studies consisting of 4608 patients were analyzed. The overall incidence of postoperative neurological deficits was 2.58% (119/4608). Overall TcMEP changes had a sensitivity of 56%, specificity of 94%, and DOR of 19.26 for predicting deficit. Reversible and irreversible changes had sensitivities of 16% and 49%, specificities of 95% and 98%, and DORs of 3.54 and 71.74, respectively. In anterior procedures, TcMEP changes had a DOR of 17.57, sensitivity of 49%, and specificity of 94%. In posterior procedures, TcMEP changes had a DOR of 21.01, sensitivity of 55%, and specificity of 94%. CONCLUSION: TcMEP monitoring has high specificity but low sensitivity for predicting postoperative neurological deficit in cervical spine decompression surgery. Patients with new postoperative neurological deficits were 19 times more likely to have experienced intraoperative TcMEP changes than those without new deficits, with irreversible TcMEP changes indicating a much higher risk of deficit than reversible TcMEP changes.

Development and validation of a large animal ovine model for implant-associated spine infection using biofilm based inocula.

Postoperative implant-associated spine infection remains poorly understood. Currently there is no large animal model using biofilm as initial inocula to study this challenging clinical entity. The purpose of the present study was to develop a sheep model for implant-associated spine infection using clinically relevant biofilm inocula and to assess the in vivo utility of methylene blue (MB) for visualizing infected tissues and guiding debridement. This 28-day study used five adult female Rambouillet sheep, each with two non-contiguous surgical sites- in the lumbar and thoracic regions- comprising randomized positive and negative infection control sites. A standard mini-open approach to the spine was performed to place sterile pedicle screws and Staphylococcus aureus biofilm-covered (positive control), or sterile (negative control) spinal fusion rods. Surgical site bioburden was quantified at the terminal procedure. Negative and positive control sites were stained with MB and staining intensity quantified from photographs. Specimens were analyzed with x-ray, micro-CT and histologically. Inoculation rods contained ∼10.44 log10 colony forming units per rod (CFU/rod). Biofilm inocula persisted on positive-control rod explants with ∼6.16 log10 CFU/rod. There was ∼6.35 log10 CFU/g of tissue in the positive controls versus no identifiable bioburden in the negative controls. Positive controls displayed hallmarks of deep spine infection and osteomyelitis, with robust local tissue response, bone resorption, and demineralization. MB staining was more intense in infected, positive control sites. This work presents an animal-efficient sheep model displaying clinically relevant implant-associated deep spine infection.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell-death-promoting signaling lipid that plays a central role in therapy-induced cell death. We previously determined that acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug LCL-805 across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 µM was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 µM was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

Examining the safety profile of a standard dose tranexamic acid regimen in spine surgery.

OBJECTIVE: Perioperative blood loss during spinal surgery is associated with complications and in-hospital mortality. Weight-based administration of tranexamic acid (TXA) has the potential to reduce blood loss and related complications in spinal surgery; however, evidence for standardized dosing is lacking. The purpose of this study was to evaluate the impact of a standardized preoperative 2 g bolus TXA dosing regimen on perioperative transfusion, blood loss, thromboembolic events, and postoperative outcomes in spine surgery patients. METHODS: An institutional review board approved this retrospective review of prospectively enrolled adult spine patients (> 18 years of age). Patients were included who underwent elective and emergency spine surgery between September 2018 and July 2021. Patients who received a standardized 2 g dose of TXA were compared to patients who did not receive TXA. The primary outcome measure was perioperative transfusion. Secondary outcomes included estimated blood loss and thromboembolic or other perioperative complications. Descriptive statistics were calculated, and continuous variables were analyzed with the two-tailed independent t-test, while categorical variables were analyzed with the Fisher's exact test or chi-square test. Stepwise multivariate regression analysis was performed to examine independent risk factors for perioperative outcomes. RESULTS: TXA was administered to 353 of 453 (78%) patients, and there were no demographic differences between groups. Although the TXA group had more operative levels and a longer operative time, the transfusion rate was not different between the TXA and no-TXA groups (7.4% vs 8%, p = 0.83). Stepwise multivariate regression found that the number of operative levels was an independent predictor of perioperative transfusion and that both operative levels and operative time were correlated with estimated blood loss. TXA was not identified as an independent predictor of any postoperative complication. CONCLUSIONS: A standardized preoperative 2 g bolus TXA dosing regimen was associated with an excellent safety profile, and despite increased case complexity in terms of number of operative levels and operative time, patients treated with TXA did not require more blood transfusions than patients not treated with TXA.

Utility of transcranial motor-evoked potential changes in predicting postoperative deficit in lumbar decompression and fusion surgery: a systematic review and meta-analysis.

PURPOSE: The primary aim of this study was to evaluate whether TcMEP alarms can predict the occurrence of postoperative neurological deficit in patients undergoing lumbar spine surgery. The secondary aim was to determine whether the various types of TcMEP alarms including transient and persistent changes portend varying degrees of injury risk. METHODS: This was a systematic review and meta-analysis of the literature from PubMed, Web of Science, and Embase regarding outcomes of transcranial motor-evoked potential (TcMEP) monitoring during lumbar decompression and fusion surgery. The sensitivity, specificity, and diagnostic odds ratio (DOR) of TcMEP alarms for predicting postoperative deficit were calculated and presented with forest plots and a summary receiver operating characteristic curve. RESULTS: Eight studies were included, consisting of 4923 patients. The incidence of postoperative neurological deficit was 0.73% (36/4923). The incidence of deficits in patients with significant TcMEP changes was 11.79% (27/229), while the incidence in those without changes was 0.19% (9/4694). All TcMEP alarms had a pooled sensitivity and specificity of 63 and 95% with a DOR of 34.92 (95% CI 7.95-153.42). Transient and persistent changes had sensitivities of 29% and 47%, specificities of 96% and 98%, and DORs of 8.04 and 66.06, respectively. CONCLUSION: TcMEP monitoring has high specificity but low sensitivity for predicting postoperative neurological deficit in lumbar decompression and fusion surgery. Patients who awoke with new postoperative deficits were 35 times more likely to have experienced TcMEP changes intraoperatively, with persistent changes indicating higher risk of deficit than transient changes. LEVEL OF EVIDENCE II: Diagnostic Systematic Review.

The Effects of Cervical Orthoses on Head and Intervertebral Range of Motion.

STUDY DESIGN: Prospective Cohort. OBJECTIVE: Quantify and compare the effectiveness of cervical orthoses in restricting intervertebral kinematics during multiplanar motions. SUMMARY OF BACKGROUND DATA: Previous studies evaluating the efficacy of cervical orthoses measured global head motion and did not evaluate individual cervical motion segment mobility. Prior studies focused only on the flexion/extension motion. METHODS: Twenty adults without neck pain participated. Vertebral motion from the occiput through T1 was imaged using dynamic biplane radiography. Intervertebral motion was measured using an automated registration process with validated accuracy better than 1 degree. Participants performed independent trials of maximal flexion/extension, axial rotation, and lateral bending in a randomized order of unbraced, soft collar (foam), hard collar (Aspen), and cervical thoracic orthosis (CTO) (Aspen) conditions. Repeated-measures ANOVA was used to identify differences in the range of motion (ROM) among brace conditions for each motion. RESULTS: Compared with no collar, the soft collar reduced flexion/extension ROM from occiput/C1 through C4/C5, and reduced axial rotation ROM at C1/C2 and from C3/C4 through C5/C6. The soft collar did not reduce motion at any motion segment during lateral bending. Compared with the soft collar, the hard collar reduced intervertebral motion at every motion segment during all motions, except for occiput/C1 during axial rotation and C1/C2 during lateral bending. The CTO reduced motion compared with the hard collar only at C6/C7 during flexion/extension and lateral bending. CONCLUSIONS: The soft collar was ineffective as a restraint to intervertebral motion during lateral bending, but it did reduce intervertebral motion during flexion/extension and axial rotation. The hard collar reduced intervertebral motion compared with the soft collar across all motion directions. The CTO provided a minimal reduction in intervertebral motion compared with the hard collar. The utility in using a CTO rather than a hard collar is questionable, given the cost and little or no additional motion restriction.

Non-lethal outcomes of engaging regulated cell death pathways in cancer.

Regulated cell death (RCD) is essential for successful systemic cancer therapy. Yet, the engagement of RCD pathways does not inevitably result in cell death. Instead, RCD pathways can take part in diverse biological processes if the cells survive. Consequently, these surviving cells, for which we propose the term 'flatliners', harbor important functions. These evolutionarily conserved responses can be exploited by cancer cells to promote their own survival and growth, with challenges and opportunities for cancer therapy.

Acute myeloid leukemia stratifies as two clinically relevant sphingolipidomic subtypes.

Acute myeloid leukemia (AML) is an aggressive disease with complex and heterogeneous biology. Although several genomic classifications have been proposed, there is a growing interest in going beyond genomics to stratify AML. In this study, we profile the sphingolipid family of bioactive molecules in 213 primary AML samples and 30 common human AML cell lines. Using an integrative approach, we identify two distinct sphingolipid subtypes in AML characterized by a reciprocal abundance of hexosylceramide (Hex) and sphingomyelin (SM) species. The two Hex-SM clusters organize diverse samples more robustly than known AML driver mutations and are coupled to latent transcriptional states. Using transcriptomic data, we develop a machine-learning classifier to infer the Hex-SM status of AML cases in TCGA and BeatAML clinical repositories. The analyses show that the sphingolipid subtype with deficient Hex and abundant SM is enriched for leukemic stemness transcriptional programs and comprises an unappreciated high-risk subgroup with poor clinical outcomes. Our sphingolipid-focused examination of AML identifies patients least likely to benefit from standard of care and raises the possibility that sphingolipidomic interventions could switch the subtype of AML patients who otherwise lack targetable alternatives.