Dual role of proliferating cell nuclear antigen monoubiquitination in facilitating Fanconi anemia-mediated interstrand crosslink repair.

The Fanconi anemia (FA) repair pathway governs repair of highly genotoxic DNA interstrand crosslinks (ICLs) and relies on translesion synthesis (TLS). TLS is facilitated by REV1 or site-specific monoubiquitination of proliferating cell nuclear antigen (PCNA) (PCNA-Ub) at lysine 164 (K164). A PcnaK164R/K164R but not Rev1-/- mutation renders mammals hypersensitive to ICLs. Besides the FA pathway, alternative pathways have been associated with ICL repair (1, 2), though the decision making between those remains elusive. To study the dependence and relevance of PCNA-Ub in FA repair, we intercrossed PcnaK164R/+; Fancg-/+ mice. A combined mutation (PcnaK164R/K164R; Fancg-/- ) was found embryonically lethal. RNA-seq of primary double-mutant (DM) mouse embryonic fibroblasts (MEFs) revealed elevated levels of replication stress-induced checkpoints. To exclude stress-induced confounders, we utilized a Trp53 knock-down to obtain a model to study ICL repair in depth. Regarding ICL-induced cell toxicity, cell cycle arrest, and replication fork progression, single-mutant and DM MEFs were found equally sensitive, establishing PCNA-Ub to be critical for FA-ICL repair. Immunoprecipitation and spectrometry-based analysis revealed an unknown role of PCNA-Ub in excluding mismatch recognition complex MSH2/MSH6 from being recruited to ICLs. In conclusion, our results uncovered a dual function of PCNA-Ub in ICL repair, i.e. exclude MSH2/MSH6 recruitment to channel the ICL toward canonical FA repair, in addition to its established role in coordinating TLS opposite the unhooked ICL.

Procedural Volume and Outcomes with Atrial Fibrillation Ablation: A Report from the NCDR AFib Ablation Registry.

BACKGROUND: The association between hospital and physician procedure volume outcome has not been well evaluated for atrial fibrillation (AF) ablation in contemporary practice. OBJECTIVE: To determine the association between hospital and physician AF ablation volume and procedural success (isolation of all pulmonary veins) and major adverse events (MAE). METHODS: Procedures reported to the NCDR AFib Ablation Registry between July 2019 and June 2022 were included. Hospital and physician procedural volumes were annualized and stratified into quartiles (Q) to compare outcomes. Three level hierarchical (patient, hospital and physician) models were used to assess the procedural volume outcome relationship. RESULTS: A total of 70,296 first-time AF ablations at 186 U.S. hospitals were included. Overall, procedural success and MAE rate were 98.5 % and 1.0% respectively. With hospital volume (Q4) as a reference, the likelihood of procedural success was lower for Q1 (OR 0.44, 95%CI 0.29-0.68), Q2 (OR 0.50, 95%CI 0.33-0.75) and Q3 (OR 0.60, 95%CI 0.40-0.89); the results were similarly signifant for physician volume. With MAE for hospitals, there was an inverse procedural volume relationship for Q1 (OR 1.78, 95%CI 1.26-2.51) but not for Q2 (OR 1.06, 95%CI 0.77-1.46) or Q3 (OR 1.19, 95%CI 0.89-1.58) and similarly for physicians in Q1 and Q2, not in Q3. An adjusted MAE ≤ 1% was predicted by an annual volume of approximately 190 for hospitals and 60 for physicians. CONCLUSION: In this national cohort, hospital and physician AF ablation procedural volumes were directly related to acute procedural success and inversely related to rates of MAE.

Can Next Generation Ecological Risk Assessment Decisions Be Made Today?-A Case Study of Regulatory Risk Assessment in the United States.

We examined the need for new in vivo avian toxicity testing for three common industrial chemicals (1,2 dichloropropane, 1,1,2-trichloroethane and triphenyl phosphate) based on estimated avian exposures using fugacity and multimedia fate models for current conditions of use compared to hazard information including existing in vivo test data for the chemicals and analogs, interspecies correlation estimates and results from hundreds of acute avian dietary toxicity studies. The data indicated that acute avian toxicity is not likely to be observed below 10 ppm in the diet for any chemical with the exception of those with a specific mode of toxic action. Modeling indicated low exposure potential for terrestrial birds to any of the three chemicals, with estimated dietary concentration of less than 0.001 ppm. Despite uncertainty associated with the underlying data sources, the four order of magnitude gap between potential exposure and a minimum hazard threshold suggests that additional avian in vivo testing would not generate valuable data. However, a weight of evidence approach for integrating data is necessary to engender greater confidence among government decision-makers in cases where data from a particular in vivo study is not expected to improve risk decision-making and an existing data gap can remain unfilled.

The contribution of E3D imaging integrated with robotic navigation: analysis of the first 80 consecutive posterior spinal fusion cases.

Eighty consecutive complex spinal robotic cases utilizing intraoperative 3D CT imaging (E3D, Group 2) were compared to 80 age-matched controls using the Excelsius robot alone with C-arm Fluoroscopic registration (Robot Only, Group 1). The demographics between the two groups were similar-severity of deformity, ASA Score for general anesthesia, patient age, gender, number of spinal levels instrumented, number of patients with prior spinal surgery, and amount of neurologic compression. The intraoperative CT scanning added several objective factors improving patient safety. There were significantly fewer complications in the E3D group with only 3 of 80 (4%) patients requiring a return to the operating room compared to 11 of 80 (14%) patients in the Robot Only Group requiring repeat surgery for implant related problems (Chi squared analysis = 5.00, p = 0.025). There was a significant reduction the amount of fluoroscopy time in the E3D Group (36 s, range 4-102 s) compared to Robot only group (51 s, range 15-160 s) (p = 0.0001). There was also shorter mean operative time in the E3D group (257 ± 59.5 min) compared to the robot only group (306 ± 73.8 min) due to much faster registration time (45 s). A longer registration time was required in the Robot only group to register each vertebral level with AP and Lateral fluoroscopy shots. The estimated blood loss was also significantly lower in Group 2 (mean 345 ± 225 ml) vs Group 1 (474 ± 397 ml) (p = 0.012). The mean hospital length of stay was also significantly shorter for Group 2 (3.77 ± 1.86 days) compared to Group 1 (5.16 ± 3.40) (p = 0.022). There was no significant difference in the number of interbody implants nor corrective osteotomies in both groups-Robot only 52 cases vs. 42 cases in E3D group.Level of evidence: IV, Retrospective review.

Operationalizing and digitizing person-centered daily functioning: a case for functionomics.

An ever-increasing amount of data on a person's daily functioning is being collected, which holds information to revolutionize person-centered healthcare. However, the full potential of data on daily functioning cannot yet be exploited as it is mostly stored in an unstructured and inaccessible manner. The integration of these data, and thereby expedited knowledge discovery, is possible by the introduction of functionomics as a complementary 'omics' initiative, embracing the advances in data science. Functionomics is the study of high-throughput data on a person's daily functioning, that can be operationalized with the International Classification of Functioning, Disability and Health (ICF).A prerequisite for making functionomics operational are the FAIR (Findable, Accessible, Interoperable, and Reusable) principles. This paper illustrates a step by step application of the FAIR principles for making functionomics data machine readable and accessible, under strictly certified conditions, in a practical example. Establishing more FAIR functionomics data repositories, analyzed using a federated data infrastructure, enables new knowledge generation to improve health and person-centered healthcare. Together, as one allied health and healthcare research community, we need to consider to take up the here proposed methods.

Patient Satisfaction with Nonopioid Postoperative Analgesia in Head and Neck Surgery: A Prospective Randomized Trial.

OBJECTIVE: To evaluate patients' satisfaction with opioid versus opioid-sparing postoperative analgesia in patients undergoing outpatient head and neck surgery. STUDY DESIGN: Prospective randomized trial. SETTING: Tertiary care academic hospital. METHODS: Adult patients undergoing outpatient head and neck surgery were randomly assigned to 1 of 3 analgesic regimens. First- and second-line medications were the following by group (1) Hydrocodone-acetaminophen with ibuprofen, (2) ibuprofen with hydrocodone-acetaminophen, and (3) ibuprofen with acetaminophen. Preoperative counseling was provided to patients regarding expected pain and proper medication use. Postoperative questionnaires were administered to assess satisfaction. RESULTS: One hundred three patients were enrolled in the study (mean age, 56.5 years; women, 75 [73%]). The mean satisfaction score with the pain regimen assigned was similar between the 3 groups (scale 0-10, [7.7, 8.3, 8.5, P = .46]). A similar percentage of patients in each group reported that surgery was more painful than anticipated (25%, 32%, 26%, P = .978), and a similar percentage of patients reported willingness to utilize the same analgesic regimen following future surgeries (75%, 83%, 76%, P = .682). Additional questions evaluating the side effect profile, maximum and minimum pain scores, and difficulty of recovery were not statistically different between the 3 groups. CONCLUSION: In the postoperative population for outpatient head and neck surgeries, there was no significant difference in patient satisfaction and pain control between the opioid and nonopioid arms. Providers should discuss opioid-sparing regimens preoperatively with patients and describe them as effective in providing adequate pain control without a significant impact on patient's perception of care.

Structural basis for inhibition of coagulation factor VIII reveals a shared antigenic hotspot on the C1 domain.

BACKGROUND: Hemophilia A arises from dysfunctional or deficient coagulation factor (F)VIII and leads to inefficient fibrin clot formation and uncontrolled bleeding events. The development of antibody inhibitors is a clinical complication in hemophilia A patients receiving FVIII replacement therapy. LE2E9 is an anti-C1 domain inhibitor previously isolated from a mild/moderate hemophilia A patient and disrupts FVIII interactions with von Willebrand factor and FIXa, though the intermolecular contacts that underpin LE2E9-mediated FVIII neutralization are undefined. OBJECTIVES: To determine the structure of the complex between FVIII and LE2E9 and characterize its mechanism of inhibition. METHODS: FVIII was bound to the antigen binding fragment (Fab) of NB2E9, a recombinant construct of LE2E9, and its structure was determined by cryogenic electron microscopy. RESULTS: This report communicates the 3.46 Å structure of FVIII bound to NB2E9, with its epitope comprising FVIII residues S2040 to Y2043, K2065 to W2070, and R2150 to H2155. Structural analysis reveals that the LE2E9 epitope overlaps with portions of the epitope for 2A9, a murine-derived inhibitor, suggesting that these residues represent a shared antigenic region on the C1 domain between FVIII-/- mice and hemophilia A patients. Furthermore, the FVIII:NB2E9 structure elucidates the orientation of the LE2E9 glycan, illustrating how the glycan sterically blocks interactions between the FVIII C1 domain and the von Willebrand factor D' domain. A putative model of the FVIIIa:FIXa complex suggests potential clashing between the NB2E9 glycan and FIXa light chain. CONCLUSION: These results describe an antigenic "hotspot" on the FVIII C1 domain and provide a structural basis for engineering FVIII replacement therapeutics with reduced antigenicity.

Clinical Applications of Machine Learning.

Objective: This review introduces interpretable predictive machine learning approaches, natural language processing, image recognition, and reinforcement learning methodologies to familiarize end users. Background: As machine learning, artificial intelligence, and generative artificial intelligence become increasingly utilized in clinical medicine, it is imperative that end users understand the underlying methodologies. Methods: This review describes publicly available datasets that can be used with interpretable predictive approaches, natural language processing, image recognition, and reinforcement learning models, outlines result interpretation, and provides references for in-depth information about each analytical framework. Results: This review introduces interpretable predictive machine learning models, natural language processing, image recognition, and reinforcement learning methodologies. Conclusions: Interpretable predictive machine learning models, natural language processing, image recognition, and reinforcement learning are core machine learning methodologies that underlie many of the artificial intelligence methodologies that will drive the future of clinical medicine and surgery. End users must be well versed in the strengths and weaknesses of these tools as they are applied to patient care now and in the future.

Utilization of Eggshell Waste Calcite as a Sorbent for Rare Earth Element Recovery.

The green energy transition requires rare earth elements (REE) for the permanent magnets used in electric cars and wind turbines. REE extraction and beneficiation are chemically intensive and highly damaging to the environment. We investigated the use of eggshell waste as a sustainable alternative sorbent for the capture and separation of REE from aqueous solutions. Hen eggshell calcite was placed in multi-REE (La, Nd, Dy) solutions at 25 to 205 °C for up to 3 months. A pervasive diffusion of the REE inside the eggshell calcite was observed along pathways formed by the intracrystalline organic matrix and calcite crystal boundaries. At 90 °C, kozoite (REECO3OH, orthorhombic) spherulites precipitate on the surface of the dissolving calcite. At 165 and 205 °C, an interface-coupled dissolution-precipitation mechanism is observed, resulting in the complete dissolution of the calcite shell and its pseudomorphic replacement by polycrystalline kozoite. At 205 °C, kozoite is slowly replaced by hydroxylbastnäsite (REECO3OH, hexagonal), the stable form of the rare earth hydroxycarbonate polymorphs. Our results demonstrate two potential applications of eggshell waste for the uptake of rare earth elements in solution: at low temperatures, as a mixed organic-inorganic adsorbent and absorbent, given sufficient sorption time; and at higher temperatures, as an efficient sacrificial template for the precipitation of rare earth hydroxycarbonates.

For the Love of the Game: Calculating the Premium Associated with Academic Surgical Practice.

OBJECTIVE: We sought to determine the premium associated with a career in academic surgery, as measured by compensation normalized to the work relative value unit (wRVU). BACKGROUND: An academic surgical career, embodying innovation and mentorship, offers intrinsic rewards, but is not well monetized. We know compensation for academic surgeons is less than their non-academic counterparts, but the value of clinical effort, as normalized to the wRVU, between academic and non-academic surgeons has not been well characterized. Thus, we analyzed the variations in the valuation of academic and non-academic surgical work from 2010 to 2022. METHODS: We utilized Medical Group Management Association Provider Compensation data from 2010, 2014, 2018, and 2022 to compare academic and non-academic surgeons. We analyzed raw total cash compensation (TCC), wRVU, TCC per wRVU (TCC/wRVU), and TCC to collections (TCCtColl). We calculated collections per wRVU (Coll/wRVU). We adjusted TCC and TCCtColl for inflation using the Consumer Price Index. Linear modeling for trend analysis was performed. RESULTS: Compared to non-academic, academic surgeons had lower TCC (2010: $500,415.0±23,666 vs. $631,515.5±23,948.2, -21%; 2022: $564,789.8±23,993.9 vs. $628,247.4±15,753.2, -10%), despite higher wRVUs (2022: 9,109.4±474.9 vs. 8,062.7±252.7) and higher Coll/wRVU (2022: 76.68±8.15 vs. 71.80±6.10). Trend analysis indicated TCC will converge in 2038 at an estimated $660,931. CONCLUSIONS: In 2022, academic surgeons had more clinical activity and superior organizational revenue capture, despite less total and normalized clinical compensation. Based on TCC/wRVUs, academia charges a premium of 16% over non-academic surgery. However, trend analysis suggests that TCC will converge within the next twenty years.

Dimensional Scaling of Ferroelectric Properties of Hafnia-Zirconia Thin Films: Electrode Interface Effects.

Hafnia-based ferroelectric (FE) thin films are promising candidates for semiconductor memories. However, a fundamental challenge that persists is the lack of understanding regarding dimensional scaling, including thickness scaling and area scaling, of the functional properties and their heterogeneity in these films. In this work, excellent ferroelectricity and switching endurance are demonstrated in 4 nm-thick Hf0.5Zr0.5O2 (HZO) capacitors with molybdenum electrodes in capacitors as small as 65 nm × 45 nm in size. The HZO layer in these capacitors can be crystallized into the ferroelectric orthorhombic phase at the low temperature of 400 °C, making them compatible for back-end-of-line (BEOL) FE memories. With the benefits of thickness scaling, low operation voltage (1.2 V) is achieved with high endurance (>1010 cycles); however, a significant fatigue regime is noted. We observed that the bottom electrode, rather than the top electrode, plays a dominant role in the thickness scaling of HZO ferroelectric behavior. Furthermore, ultrahigh switched polarization (remanent polarization 2Pr ∼ 108 µC cm-2) is observed in some nanoscale devices. This study advances the understanding of dimensional scaling effects in HZO capacitors for high-performance FE memories.

A stargate mechanism of Microviridae genome delivery unveiled by cryogenic electron tomography.

Single-stranded DNA bacteriophages of the Microviridae family are major components of the global virosphere. Microviruses are highly abundant in aquatic ecosystems and are prominent members of the mammalian gut microbiome, where their diversity has been linked to various chronic health disorders. Despite the clear importance of microviruses, little is known about the molecular mechanism of host infection. Here, we have characterized an exceptionally large microvirus, Ebor, and provide crucial insights into long-standing mechanistic questions. Cryogenic electron microscopy of Ebor revealed a capsid with trimeric protrusions that recognise lipopolysaccharides on the host surface. Cryogenic electron tomography of the host cell colonized with virus particles demonstrated that the virus initially attaches to the cell via five such protrusions, located at the corners of a single pentamer. This interaction triggers a stargate mechanism of capsid opening along the 5-fold symmetry axis, enabling delivery of the virus genome. Despite variations in specific virus-host interactions among different Microviridae family viruses, structural data indicate that the stargate mechanism of infection is universally employed by all members of the family. Startlingly, our data reveal a mechanistic link for the opening of relatively small capsids made out of a single jelly-roll fold with the structurally unrelated giant viruses.

Outcomes of Patients With Mild Cognitive Impairment With Lewy Bodies or Alzheimer Disease at 3 and 5 Years After Diagnosis.

BACKGROUND AND OBJECTIVES: Retrospective studies indicate that dementia with Lewy bodies (DLB) may be preceded by a mild cognitive impairment (MCI) prodrome. Research criteria for the prospective identification of MCI with Lewy bodies (MCI-LB) have been developed. We aimed to assess the prognosis of a prospectively identified MCI-LB cohort at 2 key milestones, 3- and 5 years after diagnosis, to examine classification stability over time and rates of adverse outcomes (dementia or death). METHODS: This was a retrospective examination of data from 2 longitudinal observational cohort studies where participants with MCI were prospectively recruited from North East England and differentially classified as MCI due to Alzheimer disease (MCI-AD), possible MCI-LB, or probable MCI-LB. Adverse outcomes (DLB/other dementia or death) and stability of disease-specific classifications were examined in each group. RESULTS: Of 152 participants with baseline MCI (54 MCI-AD, 29 possible MCI-LB, and 69 probable MCI-LB), 126 were followed for up to 3 years (mean age 75.3 years; 40% female). We found that prospective probable MCI-LB classifications were both sensitive (91%) and specific (94%) to classifications either remaining as probable MCI-LB or progressing to DLB (in some cases autopsy confirmed) for 3 or more years after. Classifications were at least as stable as those in MCI-AD. In this cohort with disease-specific MCI classifications, rates of progression to dementia were high: 55% of MCI-LB had developed DLB within 3 years. Dementia occurred in 47% of MCI-AD over the same duration (odds ratio 1.68, 95% CI 0.66-4.26, p = 0.278). Premature death was a common competing risk, occurring in 9% of MCI-AD and 11% of MCI-LB within 3 years. DISCUSSION: These findings support that prospectively identified probable MCI-LB is a prodromal presentation of DLB and that disease-specific classifications of MCI may reliably identify different prodromal dementias.

Does Artificial Intelligence Outperform Humans Using Fluoroscopic-Assisted Computer Navigation for Total Hip Arthroplasty?

Background: Successful total hip arthroplasty (THA) relies on the correct implant position. THA accuracy can be improved with the use of intraoperative fluoroscopic-assisted computer navigation. Artificial intelligence (AI) software may enhance fluoroscopic navigation; however, the accuracy of the AI compared to human-controlled software in assessing acetabular component position and leg length discrepancy (LLD) has not been studied. Methods: We analyzed 420 consecutive primary THAs performed by a single surgeon using fluoroscopic-assisted computer navigation software. The first cohort of 211 patients required inputs from a human technician (manual), while the second cohort of 209 patients used an automated version of the software controlled by AI. The intraoperative acetabular component placement (inclination and anteversion) and LLD were recorded and compared to the 2-week postoperative standing anterior-posterior pelvis radiograph. Results: Ninety-four percent (199/211) of cups in the manual cohort and 95% (198/209) of cups in the AI cohort were within the Lewinnek "safe-zone" (P = 1.0). In the manual cohort, 69% (146/211) of THAs had a final LLD within ±2 mm of the intraoperatively navigated LLD (ie, ΔLLD ≤2 mm). In the AI cohort, 66% (137/209) of THAs had a final LLD within ±2 mm of the intraoperatively navigated LLD (P = .47). Ninety-nine percent (209/211) of hips in the manual cohort and 98% (205/209) of hips in the AI cohort had a final LLD within ±5 mm of the intraoperatively navigated LLD (P = .45). Conclusions: Both AI and human-controlled versions of the same navigation platform were similarly accurate for navigating cup position within the Lewinnek "safe zone" and LLD accuracy.

Sex Differences in Left Bundle Branch Area Pacing Versus Biventricular Pacing for Cardiac Resynchronization Therapy.

BACKGROUND: Women respond more favorably to biventricular pacing (BIVP) than men. Sex differences in atrioventricular and interventricular conduction have been described in BIVP studies. Left bundle branch area pacing (LBBAP) offers advantages due to direct capture of the conduction system. We hypothesized that men could respond better to LBBAP than BIVP. OBJECTIVES: This study aims to describe the sex differences in response to LBBAP vs BIVP as the initial cardiac resynchronization therapy (CRT). METHODS: In this multicenter prospective registry, we included patients with left ventricular ejection fraction ≤35% and left bundle branch block or a left ventricular ejection fraction ≤40% with an expected right ventricular pacing exceeding 40% undergoing initial CRT with LBBAP or BIVP. The composite primary outcome was heart failure-related hospitalization and all-cause mortality. The primary safety outcome included all procedure-related complications. RESULTS: There was no significant difference in the primary outcome when comparing men and women receiving LBBAP (P = 0.46), whereas the primary outcome was less frequent in women in the BIVP group than men treated with BIVP (P = 0.03). The primary outcome occurred less frequently in men undergoing LBBAP (29.9%) compared to those treated with BIVP (46.5%) (P = 0.004). In women, the incidence of the primary endpoint was 24.14% in the LBBAP group and 36.2% in the BIVP group; however, this difference was not statistically significant (P = 0.23). Complication rates remained consistent across all groups. CONCLUSIONS: Men and women undergoing LBBAP for CRT had similar clinical outcomes. Men undergoing LBBAP showed a lower risk of heart failure-related hospitalizations and all-cause mortality compared to men undergoing BIVP, whereas there was no difference between LBBAP and BIVP in women.

Algorithm-Based Linearly Graded Compositions of GeSn on GaAs (001) via Molecular Beam Epitaxy.

The growth of high-composition GeSn films in the future will likely be guided by algorithms. In this study, we show how a logarithmic-based algorithm can be used to obtain high-quality GeSn compositions up to 16% on GaAs (001) substrates via molecular beam epitaxy. Herein, we use composition targeting and logarithmic Sn cell temperature control to achieve linearly graded pseudomorph Ge1-xSnx compositions up to 10% before partial relaxation of the structure and a continued gradient up to 16% GeSn. In this report, we use X-ray diffraction, simulation, secondary ion mass spectrometry, and atomic force microscopy to analyze and demonstrate some of the possible growths that can be produced with the enclosed algorithm. This methodology of growth is a major step forward in the field of GeSn development and the first ever demonstration of algorithmically driven, linearly graded GeSn films.

Lower Socioeconomic Status Predicts Greater Obstacles to Care: Using Outpatient Cholecystectomy as a Model Cohort.

BACKGROUND: Patients with low socioeconomic status (SES) are disadvantaged in terms of access to health care. A novel metric for SES is the Distressed Communities Index (DCI). This study evaluates the effect of DCI on hospital choice and distance traveled for surgery. METHODS: A Florida database was queried for patients with symptomatic cholelithiasis or chronic cholecystitis who underwent an outpatient cholecystectomy between 2016 and 2019. Patients' DCI was compared with hospital ratings, comorbidities, Charlson Comorbidity Index, and distance traveled for surgery. Stepwise logistic regression was used to determine which factors most influenced distance traveled for surgery. RESULTS: There were 54,649 cases-81 open, 52,488 laparoscopic, and 2,080 robotic. There was no difference between surgical approach and patient's DCI group (p = 0.12). Rural patients traveled the farthest for surgery (avg 21.29 miles); urban patients traveled the least (avg 5.84 miles). Patients from distressed areas more often had surgery at one- or two-star hospitals than prosperous patients (61% vs 36.3%). Regression indicated distressed or at-risk areas predicted further travel for rural/small-town patients, while higher hospital ratings predicted further travel for suburban/urban patients. DISCUSSION: Compared to prosperous areas, patients from distressed areas have surgery at lower-rated hospitals, travel further if they live in rural/small-town areas, but travel less if they live in suburban areas. We postulate that farther travel in rural areas may be explained by a lack of health care resources in poor, rural areas, while traveling less in suburban areas may be explained by personal lack of resources for patients with low SES.

Transcriptional regulators with broad expression in the zebrafish spinal cord.

BACKGROUND: The spinal cord is a crucial part of the vertebrate CNS, controlling movements and receiving and processing sensory information from the trunk and limbs. However, there is much we do not know about how this essential organ develops. Here, we describe expression of 21 transcription factors and one transcriptional regulator in zebrafish spinal cord. RESULTS: We analyzed the expression of aurkb, foxb1a, foxb1b, her8a, homeza, ivns1abpb, mybl2b, myt1a, nr2f1b, onecut1, sall1a, sall3a, sall3b, sall4, sox2, sox19b, sp8b, tsc22d1, wdhd1, zfhx3b, znf804a, and znf1032 in wild-type and MIB E3 ubiquitin protein ligase 1 zebrafish embryos. While all of these genes are broadly expressed in spinal cord, they have distinct expression patterns from one another. Some are predominantly expressed in progenitor domains, and others in subsets of post-mitotic cells. Given the conservation of spinal cord development, and the transcription factors and transcriptional regulators that orchestrate it, we expect that these genes will have similar spinal cord expression patterns in other vertebrates, including mammals and humans. CONCLUSIONS: Our data identify 22 different transcriptional regulators that are strong candidates for playing different roles in spinal cord development. For several of these genes, this is the first published description of their spinal cord expression.

Crowd-sourced benchmarking of single-sample tumor subclonal reconstruction.

Subclonal reconstruction algorithms use bulk DNA sequencing data to quantify parameters of tumor evolution, allowing an assessment of how cancers initiate, progress and respond to selective pressures. We launched the ICGC-TCGA (International Cancer Genome Consortium-The Cancer Genome Atlas) DREAM Somatic Mutation Calling Tumor Heterogeneity and Evolution Challenge to benchmark existing subclonal reconstruction algorithms. This 7-year community effort used cloud computing to benchmark 31 subclonal reconstruction algorithms on 51 simulated tumors. Algorithms were scored on seven independent tasks, leading to 12,061 total runs. Algorithm choice influenced performance substantially more than tumor features but purity-adjusted read depth, copy-number state and read mappability were associated with the performance of most algorithms on most tasks. No single algorithm was a top performer for all seven tasks and existing ensemble strategies were unable to outperform the best individual methods, highlighting a key research need. All containerized methods, evaluation code and datasets are available to support further assessment of the determinants of subclonal reconstruction accuracy and development of improved methods to understand tumor evolution.

Factors associated with skeletal-related events in patients with bone metastatic melanoma: A retrospective study of 481 patients.

OBJECTIVES: Metastatic bone disease is estimated to develop in up to 17% of patients with melanoma, compromising skeleton integrity resulting in skeletal-related events (SREs), which impair quality of life and reduce survival. The objective of the study was to investigate (1) the proportion of melanoma patients developing SREs following diagnosis of bone metastasis and (2) the predictors for SREs in this patient cohort. METHODS: Four hundred and eighty-one patients with bone metastatic melanoma from two tertiary centers in the United States from 2008 to 2018 were included. The primary outcome was 90-day and 1-year occurrence of a SRE, including pathological fractures of bones, cord compression, hypercalcemia, radiotherapy, and surgery. Fine-Gray regression analysis was performed for overall SREs and pathological fracture, with death as a competing risk. RESULTS: By 1-year, 52% (258/481) of patients experienced SREs, and 28% (137/481) had a pathological fracture. At 90-day, lytic lesions, bone pain, elevated calcium and absolute lymphocyte, and decreased albumin and hemoglobin were associated with higher SRE risk. The same factors, except for decreased hemoglobin, were shown to predict development of SREs at 1-year. CONCLUSION: The high incidence of SREs and pathological fractures warrants vigilance using the identified factors in this study and preventative measures during clinical oncological care.