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Background & Aims: Isthmic progenitors, tissue-specific stem cells in the stomach corpus, maintain mucosal homeostasis by balancing between proliferation and differentiation to gastric epithelial lineages. The progenitor cells rapidly adopt an active state in response to mucosal injury. However, it remains unclear how the isthmic progenitor cell niche is controlled during the regeneration of damaged epithelium., Methods: We recapitulated tissue recovery process after acute mucosal injury in the mouse stomach. Bromodeoxyuridine incorporation was used to trace newly generated cells during the injury and recovery phases. To define the epithelial lineage commitment process during recovery, we performed single-cell RNA-sequencing on epithelial cells from the mouse stomachs. We validated the effects of amphiregulin (AREG) on mucosal recovery, using recombinant AREG treatment or AREG-deficient mice., Results: We determined that an epidermal growth factor receptor ligand, AREG, can control progenitor cell lineage commitment. Based on the identification of lineage-committed subpopulations in the corpus epithelium through single-cell RNA-sequencing and bromodeoxyuridine incorporation, we showed that isthmic progenitors mainly transition into short-lived surface cell lineages but are less frequently committed to long-lived parietal cell lineages in homeostasis. However, mucosal regeneration after damage directs the lineage commitment of isthmic progenitors towards parietal cell lineages. During recovery, AREG treatment promoted repopulation with parietal cells, while suppressing surface cell commitment of progenitors. In contrast, transforming growth factor-α did not alter parietal cell regeneration, but did induce expansion of surface cell populations. AREG deficiency impairs parietal cell regeneration but increases surface cell commitment., Conclusions: These data demonstrate that different epidermal growth factor receptor ligands can distinctly regulate isthmic progenitor-driven mucosal regeneration and lineage commitment., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: The primary goal of this study was to establish the current microbial trends in vertebral osteomyelitis/discitis (VOD) amid the opioid epidemic and to determine if intravenous drug use (IVDU) predisposes one to a unique microbial profile of infection., Methods: The authors performed a retrospective cohort study consisting of 1175 adult patients diagnosed with VOD between 2011 and 2022 at a single quaternary center. Data were acquired through retrospective chart review, with pertinent demographic and clinical information collected., Results: Staphylococcus aureus was the most cultured organism in both the IVDU and non-IVDU groups at 56.1% and 40.7%, respectively. In the IVDU cohort, Serratia marcescens was the next most prevalently cultured organism at 13.9%., Conclusions: The present study demonstrates that in the IVDU population S. marcescens is an organism of high concern. The potential for Serratia spp. infection should be accounted for when selecting empirical antimicrobial therapy in VOD patients.

Introduction: Hundreds of children suffer burn injuries each day, yet care guidelines regarding the need for acute inpatient treatment vs outpatient follow-up vs no required follow-up remain nebulous. This gap in the literature is particularly salient for the emergency clinician, who must be able to rapidly determine appropriate disposition., Methods: This was a retrospective review of patients presenting to a Level II pediatric trauma center, January 1, 2017-December 31, 2019, and discharged with an International Classification of Diseases, Rev 10, burn diagnosis. We obtained and analyzed demographics, burn characteristics, and follow-up data using univariate and bivariate analysis as well as logistic regression modeling. Patients were stratified into three outcome groups: group 1-patients who underwent emergent evaluation at a burn center or were admitted at their first follow-up appointment; group 2-patients who followed up at a burn center (as an outpatient) or at the emergency department (and were discharged home); and group 3-patients with no known follow-up., Results: A total of 572 patients were included in this study; 58.9% of patients were 1-5 years of age. Sixty-five patients met group 1 criteria, 189 patients met group 2 criteria, and 318 patients met group 3 criteria. Sixty-five percent of patients met at least one American Burn Association criteria, and 79% of all burns were second-degree burns. Flame and scald burns were associated with increased odds (odds ratio [OR] 1.21, OR 1.12) of group 1 vs group 2 + group 3 ( P  = 0.02, P  < 0.001). Second/third-degree burns and concern for non-accidental trauma were also associated with increased odds of group 1 vs 2 or 3 (OR = 1.11, 1.35, P  ≤ 0.001, 0.001, respectively). Scald burns were associated with increased odds of group 2 compared to group 3 (OR 1.11, P  = 0.04). Second/third degree burns were also associated with increased odds of group 2 vs 3 (OR 1.19, P  ≤ 0.001)., Conclusion: There were few statistically significant variables strongly associated with group 1 (emergent treatment/admission) vs group 2 (follow-up/outpatient treatment) vs group 3 (no follow- up). However, one notable finding in this study was the association of scald burns with treatment (admission or follow-up) suggesting that the presence of a scald burn in a child may signify to clinicians that a burn center consult is warranted., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.

The Data Coordinating Center (DCC) of the Human Tumor Atlas Network (HTAN) has played a crucial role in enabling the broad sharing and effective utilization of HTAN data within the scientific community. Data from the first phase of HTAN are now available publicly. We describe the diverse datasets and modalities shared, multiple access routes to HTAN assay data and metadata, data standards, technical infrastructure and governance approaches, as well as our approach to sustained community engagement. HTAN data can be accessed via the HTAN Portal, explored in visualization tools-including CellxGene, Minerva, and cBioPortal-and analyzed in the cloud through the NCI Cancer Research Data Commons nodes. We have developed a streamlined infrastructure to ingest and disseminate data by leveraging the Synapse platform. Taken together, the HTAN DCC's approach demonstrates a successful model for coordinating, standardizing, and disseminating complex cancer research data via multiple resources in the cancer data ecosystem, offering valuable insights for similar consortia, and researchers looking to leverage HTAN data.

Objective  To investigate whether patients undergoing anatomic total shoulder arthroplasty (ATSA) between January and March 2020 experienced different postoperative outcomes than patients in 2019. We hypothesized that patients in 2020 would have less access to physical therapy (PT) and experience different postoperative outcomes. Methods  Records from patients who received ATSA between January 1st, 2019, and March 17th, 2019, and January 1st, 2020, to March 17th, 2020, were analyzed. Patient data, including demographic information, range of motion (ROM), strength, and PT was collected and compared between the two groups. The 2020 patients were contacted by phone during October 2022 and patient-reported metrics were gathered. Results  The present study identified 24 patients in 2019 and 27 patients in 2020 who underwent ATSA during the specified time frame and had a minimum 1-year follow-up. Patients in 2019 experienced improvements in forward elevation (FE) ROM (125.4° to 146.7°; p  = 0.008), external rotation (ER; 33.0° to 47.7°; p  < 0.001), and internal rotation (IR; S1 to L4; p  = 0.019). Patients in 2020 also experienced significant improvements in FE (120.2° to 141.1°; p  = 0.009), ER (32.9° to 42.0°; p  = 0.037), and IR (S1 to L3; p  = 0.002). Patients in 2020 terminated PT earlier (2019: 125.8 days; 2020: 91.1 days; p  = 0.046) and completed fewer sessions (2019: 21.4 sessions; 2020: 13.1 sessions; p  = 0.003). At the final follow-up, patients in 2020 reported an average Visual Analogue Scale (VAS) pain score of 1.67 ± 1.1. Conclusion  Despite decreased PT, patients who underwent ATSA in 2020 had significant improvements in ROM and strength and were comparable to patients in 2019., Competing Interests: Conflito de Interesses Os autores não têm conflito de interesses a declarar., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution 4.0 International License, permitting copying and reproduction so long as the original work is given appropriate credit ( https://creativecommons.org/licenses/by/4.0/ ).)

The treatment of metastatic melanoma has been revolutionised by immunotherapy, yet a significant number of patients do not respond, and many experience autoimmune adverse events. Associations have been reported between patient outcome and monocyte subsets, whereas vitamin C (ascorbate) has been shown to mediate changes in cancer-stimulated monocytes in vitro. We therefore investigated the relationship of ascorbate with monocyte subsets and epigenetic modifications in patients with metastatic melanoma receiving immunotherapy. Patients receiving immunotherapy were compared to other cancer cohorts and age-matched healthy controls. Ascorbate levels in plasma and peripheral blood-derived mononuclear cells (PBMCs), monocyte subtype and epigenetic markers were measured, and adverse events, tumour response and survival were recorded. A quarter of the immunotherapy cohort had hypovitaminosis C, with plasma and PBMC ascorbate levels significantly lower than those from other cancer patients or healthy controls. PBMCs from the immunotherapy cohort contained similar frequencies of non-classical and classical monocytes. DNA methylation markers and intracellular ascorbate concentration were correlated with monocyte subset frequency in healthy controls, but correlation was lost in immunotherapy patients. No associations between ascorbate status and immune-related adverse events or tumour response or overall survival were apparent.

Study Design: Retrospective chart review of patients receiving long-segment fusion during a five-year period., Objective: To determine whether obese patients receive comparable benefits when receiving long-segment fusion compared to non-obese patients and to identify factors that may predict hardware failure and post-surgical complications among obese patients., Methods: Demographic, spinopelvic radiographic, patient-reported outcome measures (PROMs), and complications data was retrospectively collected from 120 patients who underwent long-segment fusion during a five-year period at one tertiary care medical center. Radiographic measurements were pelvic incidence, pelvic tilt (PT), lumbar lordosis, L4-S1 lordosis, thoracic kyphosis, sagittal vertical axis, PI-LL mismatch, and proximal junction cobb angle at upper instrumented vertebrae + 2 (UIV+2). PROMs were Oswestry disability index, numeric rating scale (NRS) Back Pain, NRS Leg Pain, RAND SF-36 pain, and RAND SF-36 physical functioning. Included patients were adults and had at least 2-years of postoperative follow-up. Descriptive and multivariate statistical analysis was performed with α = 0.05., Results: Patients with a BMI ≥ 30 (n=63) and patients with a BMI < 30 (n=57) demonstrated comparable improvements (P>0.05) for all spinopelvic radiographic measurements and PROMs. Each cohort demonstrated significant improvements from pre-assessment to post-assessment on nearly all spinopelvic radiographic measurements and PROMs (P<0.05), except PT and L4-S1 lordosis where neither group improved (p=0.95 and 0.58 for PT and P=0.23 and 0.11 for L4-S1 lordosis fornon-obese and obese cohorts respectively) and SF-36 physical functioning where the non-obese cohort not statistically improve (P=0.08). Patients with a BMI ≥ 30 demonstrated an increased incidence of cardiovascular complications (P=0.0293), acute kidney injury (P=0.0241), rod fractures (P=0.0293), and reoperations (P=0.0241) when compared to patients with a BMI < 30., Conclusion: This study adds to a growing body of evidence linking demographic factors with risks of hardware failure. Further, this data challenges the assumption that obese patients may not receive sufficient benefit to be long-segment surgical candidates. However, given their elevated risk for post-operative and delayed hardware complications, obese patients should be appropriately counseling before undergoing surgery., Competing Interests: Declaration of competing interest Andrew Grossbach MD: Consultaton fees from Depuy, Medtronic and 3M/KCI. All other authors have no conflicts of interest to report related to the creation of this manuscript, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objective: Osteodiscitis has been demonstrated to show significant morbidity and mortality. Cultures and CT guided biopsy (CTB) are commonly used diagnosis of osteodiscitis. This study's purpose is to evaluate the cost burden of CTB and to evaluate how IVDU affects patient management in the setting of osteodiscitis., Methods: Patients admitted for osteodiscitis from 2011-2021 were retrospectively reviewed and stratified into cohorts by CTB status. Additional cohorts were stratified by Intravenous Drug Use (IVDU). Patient demographics, total cost of hospitalization, length of hospitalization, time to biopsy, IVDU status, and other factors were recorded. T-Test, Chi-squared analysis, and ANOVA were used for statistical analysis., Results: Total cost of hospitalization was recorded for 140 patients without CTB and 346 patients with CTB. Average cost of hospitalization for non-CTB was $227,317.86 compared to CTB at $119,799.20 (p < 0.001). Length of stay (LOS) was found to be 18.01 days for non-CTB and 14.07 days for CTB patients (0.00282). When stratified by days until biopsy, patients who had CTB sooner, had significantly reduced cost of hospitalization (p = 0.0003). Patients with IVDU history were significantly younger (p < 0.001) with lower BMI (p < 0.001) and a significantly different clinical profile. There was a significant difference in positive open biopsy when separated by IVDU status (p = 0.025)., Conclusion: CTB was associated with significantly reduced cost of hospitalization and LOS compared to non-CTB. IVDU patients with osteodiscitis have significantly different clinical profiles than non-IVDU that may impact diagnosis and treatment. Further work is indicated to elucidate causes of these differences to provide high value care to patients with osteodiscitis., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The usefulness of closed suction drains (CSD) after open reduction and internal fixation (ORIF) of tibial plateau fractures is a contested topic. The purpose of this study was to examine the impact of CSD in postoperative outcomes after tibial plateau fracture., Methods: Data were retrospectively collected from patients who underwent primary repair of closed tibial plateau fractures via an anterolateral approach between June 2021 to May 2022 at a single academic center. Fifty-six patients were included and 28 received CSDs at time of surgery. P values less than 0.05 were considered significant., Results: Fifty-six patients were included. There was no significant difference in demographics, pre- and post-op hemoglobin, estimated blood loss during surgery, length of stay, postoperative MMEs and pain at 3 month follow-up, deep vein thrombosis (DVT), compartment syndrome, flexion contracture, use of incisional vac, infection rate, wound drainage, hematoma, neurologic pain, dehiscence, additional surgery, or range of motion at 3 months follow-up. We noted a significant difference in Defense and Veterans Pain Rating Scale (DVPRS) on POD1, demonstrating greater pain in those in the CSD group., Conclusion: Our findings suggest that the use of CSD in ORIF of tibial plateau fractures may not be of significant prophylactic benefit. CSDs in ORIF patients were associated with increased early postoperative pain and had no identifiable benefits., Level of Evidence: III., (© 2023. The Author(s), under exclusive licence to Springer-Verlag France SAS, part of Springer Nature.)

Background: Many educational disciplines, especially in health professions, are required by accrediting bodies to introduce or include health informatics (HI); however, faculty (academics) teaching this content may not be well prepared. Objective: The aim of this project was to explore how a doctoral physical therapy (DPT) program could more accurately represent compliance with HI accreditation requirements by identifying hidden instances of relevant content within the curriculum. Method: This exploratory, mixed methods, action research study utilised document review, questionnaires and interviews in the collection of quantitative and qualitative data to enable assessment of knowledge about HI, to determine if HI content was already incorporated in current courses, and, whether the content was accurately reflected in course student learning objectives (SLOs). Change in faculty understanding of HI as a result of this study was also assessed. Results: Of 16 DPT faculty, 13 participated in the pre-interview questionnaire; 8 (50%) representing 22/39 courses participated in the full study. Most were unfamiliar with HI and had unrecognised HI already incorporated in their courses leading to several SLO revisions and additions. Interview and post-interview questionnaire results documented significant increases in HI understanding among faculty. Conclusion: Physical therapy and HIM collaboration was successful in identifying HI content hiding in plain sight. Results revealed multiple instances of unrecognised HI content across the DPT curriculum. Revised and newly added SLOs, with others likely to follow due to this study, will assist faculty with future reaccreditation and in preparing graduates to more fully utilise HI in today's digital healthcare environments., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The remarkable advances of artificial intelligence (AI) technology are revolutionizing established approaches to the acquisition, interpretation, and analysis of biomedical imaging data. Development, validation, and continuous refinement of AI tools requires easy access to large high-quality annotated datasets, which are both representative and diverse. The National Cancer Institute (NCI) Imaging Data Commons (IDC) hosts large and diverse publicly available cancer image data collections. By harmonizing all data based on industry standards and colocalizing it with analysis and exploration resources, the IDC aims to facilitate the development, validation, and clinical translation of AI tools and address the well-documented challenges of establishing reproducible and transparent AI processing pipelines. Balanced use of established commercial products with open-source solutions, interconnected by standard interfaces, provides value and performance, while preserving sufficient agility to address the evolving needs of the research community. Emphasis on the development of tools, use cases to demonstrate the utility of uniform data representation, and cloud-based analysis aim to ease adoption and help define best practices. Integration with other data in the broader NCI Cancer Research Data Commons infrastructure opens opportunities for multiomics studies incorporating imaging data to further empower the research community to accelerate breakthroughs in cancer detection, diagnosis, and treatment. Published under a CC BY 4.0 license.

Background: Recent advances have begun to identify the nonphysical factors facilitating successful return to sport (RTS) after shoulder instability surgery, yet little is currently known regarding psychological factors and RTS., Purpose/hypothesis: The purposes of this study were to (1) identify psychological factors associated with RTS, (2) evaluate the prognostic utility of various psychological factors, and (3) evaluate the available metrics used to assess psychological RTS readiness. It was hypothesized that psychological factors would be identified as critical elements influencing a patient's RTS., Study Design: Systematic review; Level of evidence, 4., Methods: Clinical studies reporting on the psychological determinants of RTS for patients who had surgery for shoulder instability between 1996 and 2022 were identified from MEDLINE, Embase, and Cochrane databases. Demographic, clinical, and psychometric properties were extracted for pooled weighted analysis., Results: Of the 969 studies screened, 24 (2.5%) met inclusion criteria. Overall, 2135 patients were included (mean age, 26.0 years; range, 17.4-35.5 years; 84.7% male). The mean time to RTS was 6.8 months (range, 3.7-11.9 months). There was a 76.3% rate of any RTS; of the 1212 patients who reported level of play at return, 305 (25.2%) were unable to perform at their prior level. Psychological reasons were cited by 85% (n = 360) of patients who did not RTS. Fear of reinjury was the most common reason (n = 154; 42.8%); other psychological factors included lack of confidence (n = 46; 12.8%), anxiety (n = 45; 12.5%), depression (n = 44; 12.2%), psychosocial factors (n = 48; 13.3%), and lack of motivation (n = 23; 6.4%). The Shoulder Instability Return to Sport after Injury, Western Ontario Shoulder Instability Index, Quick Inventory of Depressive Symptoms Self Report, Degree of Shoulder Involvement in Sports, Tampa Scale of Kinesiophobia-11, and Veterans Rand 12-Item Health Survey were reported measures for assessing psychology and RTS., Conclusion: Fear of reinjury was found to be the most commonly reported impediment to RTS. The psychological characteristics identified through this review may be incorporated into future RTS protocols seeking to address resilience and nonphysical factors associated with RTS., Competing Interests: One or more of the authors has declared the following potential conflict of interest or source of funding: C.H. has received honoraria from Musculoskeletal Transplant Foundation. G.J. has received honoraria from MTF Biologics. J.B. has received consulting fees from Stryker and Linvatec, nonconsulting fees from Smith & Nephew, and hospitality payments from Stryker. G.C. has received education payments from Arthrex and Smith & Nephew. R.R. has received education payments from Smith & Nephew and hospitality payments from Smith & Nephew. AOSSM checks author disclosures against the Open Payments Database (OPD). AOSSM has not conducted an independent investigation on the OPD and disclaims any liability or responsibility relating thereto., (© The Author(s) 2023.)

Background: The application of different approaches calculating the anthropogenic carbon net flux from land, leads to estimates that vary considerably. One reason for these variations is the extent to which approaches consider forest land to be "managed" by humans, and thus contributing to the net anthropogenic flux. Global Earth Observation (EO) datasets characterising spatio-temporal changes in land cover and carbon stocks provide an independent and consistent approach to estimate forest carbon fluxes. These can be compared against results reported in National Greenhouse Gas Inventories (NGHGIs) to support accurate and timely measuring, reporting and verification (MRV). Using Brazil as a primary case study, with additional analysis in Indonesia and Malaysia, we compare a Global EO-based dataset of forest carbon fluxes to results reported in NGHGIs., Results: Between 2001 and 2020, the EO-derived estimates of all forest-related emissions and removals indicate that Brazil was a net sink of carbon (- 0.2 GtCO 2 yr -1 ), while Brazil's NGHGI reported a net carbon source (+ 0.8 GtCO 2 yr -1 ). After adjusting the EO estimate to use the Brazilian NGHGI definition of managed forest and other assumptions used in the inventory's methodology, the EO net flux became a source of + 0.6 GtCO 2 yr -1 , comparable to the NGHGI. Remaining discrepancies are due largely to differing carbon removal factors and forest types applied in the two datasets. In Indonesia, the EO and NGHGI net flux estimates were similar (+ 0.6 GtCO 2 yr -1 ), but in Malaysia, they differed in both magnitude and sign (NGHGI: -0.2 GtCO 2 yr -1 ; Global EO: + 0.2 GtCO 2 yr -1 ). Spatially explicit datasets on forest types were not publicly available for analysis from either NGHGI, limiting the possibility of detailed adjustments., Conclusions: By adjusting the EO dataset to improve comparability with carbon fluxes estimated for managed forests in the Brazilian NGHGI, initially diverging estimates were largely reconciled and remaining differences can be explained. Despite limited spatial data available for Indonesia and Malaysia, our comparison indicated specific aspects where differing approaches may explain divergence, including uncertainties and inaccuracies. Our study highlights the importance of enhanced transparency, as set out by the Paris Agreement, to enable alignment between different approaches for independent measuring and verification., (© 2023. The Author(s).)

Objective: Sagittal alignment is an important predictor of functional outcomes after surgery for adult spinal deformity (ASD). A rigid spinal column may create a large lever arm that may impact the rate of proximal junctional kyphosis (PJK) after ASD surgery. In this study, the authors sought to determine whether relatively low preoperative global spinal flexibility (i.e., rigid spine) predicts increased incidence of PJK at 1 year after ASD surgery., Methods: The authors retrospectively reviewed long-segment thoracolumbar fusions with pelvic fixation performed at a single tertiary care center between October 2015 and September 2020 in patients with a minimum of 1-year radiographic and clinical follow-up. Two cohorts were established on the basis of the optimal value for spinal flexibility, as defined by the absolute difference between the preoperative standing and supine C7 sagittal vertical axes, which the authors termed global sagittal flexibility (GSF). Demographic information, radiographs, various associated complications, and patient-reported outcome measures (PROMs) were analyzed., Results: Eighty-five patients met the inclusion criteria. Receiver operating characteristic (ROC) analysis using GSF to predict an increase in the proximal junctional sagittal Cobb angle (PJCA) greater than or equal to 10° at 1-year follow-up provided an area under the curve of 0.64 and identified an optimal GSF threshold value of 3.7 cm. Patients with GSF > 3.7 cm were considered globally flexible (48 patients), and those with GSF ≤ 3.7 cm were classified as rigid (37 patients). Rigid patients were noted to have a significantly higher risk of ΔPJCA ≥ 10° at 1-year follow-up (51.4% vs 29.3%, p = 0.049). No changes in the reoperation rates or PROMs based on GSF were observed in the 1- or 2-year postoperative window., Conclusions: Based on these retrospective data, preoperative global spinal rigidity portends an independently elevated risk for the development of PJK after ASD surgery. No differences in other complication rates or PROMs data were observed between groups. Data collection was limited to a 2-year postoperative window; therefore, longer follow-up is required to further elucidate the relationship between rigidity and reoperation rates. Based on these retrospective data, flexibility may influence the outcomes of patients with ASD.

Summary: Gene set scoring (or enrichment) is a common dimension reduction task in bioinformatics that can be focused on the differences between groups or at the single sample level. Gene sets can represent biological functions, molecular pathways, cell identities, and more. Gene set scores are context dependent values that are useful for interpreting biological changes following experiments or perturbations. Single sample scoring produces a set of scores, one for each member of a group, which can be analyzed with statistical models that can include additional clinically important factors such as gender or age. However, the sparsity and technical noise of single-cell expression measures create difficulties for these methods, which were originally designed for bulk expression profiling (microarrays, RNAseq). This can be greatly remedied by first applying a smoothing transformation that shares gene measure information within transcriptomic neighborhoods. In this work, we use the nearest neighbor graph of cells for matrix smoothing to produce high quality gene set scores on a per-cell, per-group, level which is useful for visualization and statistical analysis., Availability and Implementation: The gssnng software is available using the python package index (PyPI) and works with Scanpy AnnData objects. It can be installed using "pip install gssnng." More information and demo notebooks: see https://github.com/IlyaLab/gssnng., Competing Interests: None declared., (© The Author(s) 2023. Published by Oxford University Press.)

The efficacy of PD-1 monoclonals such as pembrolizumab can be modulated by the signals delivered via their Fc region. Tumour/inflammation associated proteases can generate F(ab')2 fragments of therapeutic monoclonals, and subsequent recognition of F(ab')2 epitopes by circulating anti-hinge antibodies (AHA) can then, potentially, link F(ab')2 binding to the target antigen with novel Fc signalling. Although elevated in inflammatory diseases, AHA levels in cancer patients have not been investigated and functional studies utilising the full repertoire of AHA present in sera have been limited. AHA levels in pembrolizumab treated melanoma patients (n = 23) were therefore compared to those of normal donors and adalimumab treated patients. A subset of melanoma patients and the majority of adalimumab patients had elevated levels of AHA reactive with F(ab')2 fragments of IgG4 anti-PD-1 monoclonals (nivolumab, pembrolizumab) and IgG1 therapeutic monoclonals (rituximab, adalimumab). Survival analysis was restricted by the small patient numbers but those melanoma patients with the highest levels (>75% percentile, n = 5) of pembrolizumab-F(ab')2 reactive AHA had significantly better overall survival post pembrolizumab treatment (p = 0.039). In vitro functional studies demonstrated that the presence of AHA+ sera restored the neutrophil activating capacity of pembrolizumab to its F(ab')2 fragment. Neither pembrolizumab nor its F(ab')2 fragments can induce NK cell or complement dependent cytotoxicity (CDC). However, AHA+ sera in combination with pembrolizumab-F(ab')2 provided Fc regions that could activate NK cells. The ability of AHA+ sera to restore CDC activity was more restricted and observed using only one pembrolizumab and one adalimumab patient serum in combination with rituximab- F(ab')2. This study reports the presence of elevated AHA levels in pembrolizumab treated melanoma patients and highlight the potential for AHA to provide additional Fc signaling. The issue of whether tumour associated proteolysis of PD-1 mAbs and subsequent AHA recognition impacts on treatment efficacy requires further study., Competing Interests: The authors have declared that no competing interests exist, (Copyright: © 2023 Hock et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: It is unclear whether genetic variants affecting vitamin D metabolism are associated with melanoma prognosis. Two functional missense variants in the vitamin D-binding protein gene (GC), rs7041 and rs4588, determine 3 common haplotypes, Gc1s, Gc1f, and Gc2, of which Gc1f may be associated with decreased all-cause death among melanoma patients based on results of a prior study, but the association of Gc1f with melanoma-specific death is unclear., Methods: We investigated the association of the Gc1s, Gc1f, and Gc2 haplotypes with melanoma-specific and all-cause death among 4490 individuals with incident, invasive primary melanoma in 2 population-based studies using multivariable Cox-proportional hazards regression., Results: In the pooled analysis of both datasets, the patients with the Gc1f haplotype had a 37% lower risk of melanoma-specific death than the patients without Gc1f (hazard ratio [HR] = 0.63, 95% confidence interval [CI] = 0.47 to 0.83, P = .001), with adjustments for age, sex, study center, first- or higher-order primary melanoma, tumor site, pigmentary phenotypes, and Breslow thickness. Associations were similar in both studies. In pooled analyses stratified by Breslow thickness, the corresponding melanoma-specific death HRs for those patients with the Gc1f haplotype compared with those without Gc1f were 0.89 (95% CI = 0.63 to 1.27) among participants with tumor Breslow thickness equal to or less than 2.0 mm and 0.40 (95% CI = 0.25 to 0.63) among participants with tumor Breslow thickness greater than 2.0 mm (Pinteraction = .003)., Conclusions: Our findings suggest that individuals with the GC haplotype Gc1f may have a lower risk of dying from melanoma-specifically from thicker, higher-risk melanoma-than individuals without this Gc1f haplotype., (© The Author(s) 2023. Published by Oxford University Press.)

Neuroblastoma is a lethal childhood solid tumor of developing peripheral nerves. Two percent of children with neuroblastoma develop opsoclonus myoclonus ataxia syndrome (OMAS), a paraneoplastic disease characterized by cerebellar and brainstem-directed autoimmunity but typically with outstanding cancer-related outcomes. We compared tumor transcriptomes and tumor-infiltrating T and B cell repertoires from 38 OMAS subjects with neuroblastoma to 26 non-OMAS-associated neuroblastomas. We found greater B and T cell infiltration in OMAS-associated tumors compared to controls and showed that both were polyclonal expansions. Tertiary lymphoid structures (TLSs) were enriched in OMAS-associated tumors. We identified significant enrichment of the major histocompatibility complex (MHC) class II allele HLA-DOB ∗ 01:01 in OMAS patients. OMAS severity scores were associated with the expression of several candidate autoimmune genes. We propose a model in which polyclonal auto-reactive B lymphocytes act as antigen-presenting cells and drive TLS formation, thereby supporting both sustained polyclonal T cell-mediated anti-tumor immunity and paraneoplastic OMAS neuropathology., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

» Accounting for up to 24% of all meniscus tears, horizontal cleavage tears (HCTs) are a common pathology orthopaedic practitioners should be comfortable managing.» Historically, HCTs were treated with partial meniscectomy; however, recent studies have demonstrated that these procedures have an adverse biomechanical effect, while HCT repairs restore the knee's natural biomechanics.» Indications for the surgical repair of HCTs remain disputed, but surgery is generally considered for young, active patients and older patients without significant concomitant osteoarthritis.» Early clinical findings surrounding HCT repair are promising. They suggest that this treatment adequately restores meniscus mechanics, leads to good knee functional outcomes, and results in a high likelihood of return to preinjury activity levels., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/A999)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Objective: There is ongoing debate on the relative benefits and drawbacks of polyetheretherketone (PEEK) versus titanium (Ti) in generating a bone-to-implant surface microenvironment conducive to osseointegration. Micro- and nanoscale internal and topographic cage modifications have recently been posited to facilitate osseointegration and fusion, but human in vivo confirmation remains lacking. The authors of this study sought to directly compare early radiological outcomes in adults undergoing 1- and 2-level transforaminal lumbar interbody fusion (TLIF) procedures using either PEEK or nano-etched Ti interbody cages with an incorporated microlattice structure., Methods: Patients were enrolled in a single academic center using a single-blind randomized controlled superiority design. Screening was undertaken from a pool of consecutive patients eligible for TLIF to undergo placement in a 1:1 ratio of either lordotic PEEK or activated Ti cages at each level of 1- or 2-level procedures. An a priori power analysis was performed and a preplanned interim analysis was undertaken once 50 of 70 patients were enrolled. Patient study data were collected perioperatively and uploaded to a Research Electronic Data Capture (REDCap) registry. Interbody fusion was assessed based on 6-month postoperative lumbar dual-energy CT (DECT) studies using the method of Brantigan and Steffee, as modified to describe the Fraser definition of locked pseudarthrosis (Brantigan-Steffee-Fraser [BSF] scale)., Results: In the final cohort of 50 patients, 40 interbody levels implanted with PEEK cages were compared with 34 interbody levels with activated Ti cages. The trial was stopped early given the results of an interim analysis with respect to the primary outcome. Surgical parameters including number of levels treated, average cage height, and position were not different between groups. For the PEEK and activated Ti groups, 20.6% versus 84.0% demonstrated BSF grade 3 fusion on 6-month postoperative DECT imaging (p < 0.001). Subsidence at 6 months on DECT was identified in 12 (41.4%) of PEEK levels versus 5 (20.8%) of activated Ti levels (p < 0.001). BSF-3 grading was predictive of segmental stability and numeric rating scale (NRS) leg pain improvement at 1 year postoperatively. Oswestry Disability Index and NRS back and leg pain scores all improved similarly in both cohorts at 1 year postoperatively., Conclusions: Activated Ti interbody cages mediate early fusion at significantly higher rates with lower rates of subsidence as compared with PEEK cages. These findings support the idea that interbody cage microscale properties, including surface topography, may play a primary role in facilitating osseointegration and fusion.

Background: Many clinicians associate nicotine as the causative agent in the negative and deleterious effects of smoking on bone growth and spine fusion. Although nicotine is the primary driver of physiological addiction in smoking, isolated and controlled use of nicotine is one of the most effective adjuncts to quitting smoking., Objective: To explore the relationship between nicotine and noncombustion cigarette products on bone growth., Methods: One thousand five studies were identified, of which 501 studies were excluded, leaving 504 studies available for review. Of note, 52 studies were deemed to be irrelevant. Four hundred fifty-two studies remained for eligibility assessment. Of the remaining 452, 218 failed to assess study outcomes, 169 failed to assess bone biology, 13 assessed 5 patients or fewer, and 12 were deemed to be ineligible of the study criteria. Forty studies remained for inclusion within this systematic review., Results: Of the 40 studies identified for inclusion within the study, 30 studies were classified as "Animal Basic Science," whereas the remaining 10 were categorized as "Human Basic Science." Of the 40 studies, 11 noted decreased cell proliferation and boney growth, whereas 8 showed an increase. Four studies noted an increase in gene expression products, whereas 11 noted a significant decrease., Conclusion: The results of this study demonstrate that nicotine has a variety of complex interactions on osteoblast and osteoclastic activities. Nicotine demonstrates dose-dependent effects on osteoblast proliferation, boney growth, and gene expression. Further study is warranted to extrapolate the effects of solitary nicotine on clinical outcomes., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Objective: Immune checkpoint inhibitor (ICI) efficacy in the treatment of metastatic renal cell carcinoma (RCC) without brain metastases (BMs) is well established in several clinical trials; however, patients with BMs were typically excluded from these trials. Therefore, the efficacy of ICI in the treatment or prevention of BM remains unclear. The primary aim of the study was to address the efficacy of ICI in treatment of patients with RCC BMs compared with patients receiving targeted therapies. A secondary aim was to evaluate the risk of RCC BM development among patients who received ICI versus targeted therapies early in their treatment course., Methods: A retrospective single-center review between 2011 and 2018 identified 425 patients treated for metastatic RCC. The study group included patients who received ICI and/or targeted therapies during their disease. Data analyzed included demographic information, systemic treatments, overall survival from RCC diagnosis (OSRCC) and from BM diagnosis (OSBM), and BM development. Fisher's exact test was used to evaluate the frequency of BM occurrence. Survival was assessed using Kaplan-Meier curves and log-rank tests., Results: Of the 425 patients, 125 received ICI and 300 were treated with molecular targeted agents only during their clinical course. BMs occurred in 113 (9.5%) of the 425 patients. Among patients with BMs, OSRCC was improved with the use of ICI (77.2 vs 25.2 months, p < 0.001), with 1-, 2-, and 5-year survival rates of 93.9%, 81.8%, and 62.6%, respectively. The use of ICI was associated with increased OSBM (21.7 vs 8.9 months, p = 0.001). The rate of BM development was lower when patients were treated with ICI (8/100 [8.0%]) compared with targeted therapy (47/267 [17.6%]) (OR 0.41, 95% CI 0.18-0.89; p = 0.021)., Conclusions: ICI was associated with improved OSRCC and OSBM in patients with BMs and decreased the probability of BM development in patients with metastatic RCC. Prospective trials are needed to further evaluate optimal use of ICI in treatment of RCC BMs.

Background: Spine metastases often cause significant pain, instability, and/or neurological morbidity. Local control (LC) of spine metastases has been augmented with advances in systemic therapies, radiation, and surgical technique. Prior reports suggest an association between preoperative arterial embolization and improved LC and palliative pain control., Objective: To further elucidate the role of neoadjuvant embolization on LC of spine metastases and the potential for improved pain control in patients receiving surgery and stereotactic body radiotherapy (SBRT)., Method: A retrospective single-center review between 2012 and 2020 identified 117 patients with spinal metastases from various solid tumor malignancies managed with surgery and adjuvant SBRT with or without preoperative spinal arterial embolization. Demographic information, radiographic studies, treatment characteristics, Karnofsky Performance Score, Defensive Veterans Pain Rating Scale, and mean daily doses of analgesic medications were reviewed. LC was assessed using magnetic resonance imaging obtained at a median 3-month interval and defined as progression at the surgically treated vertebral level., Results: Of 117 patients, 47 (40.2%) underwent preoperative embolization, followed by surgery and SBRT and 70 (59.8%) underwent surgery and SBRT alone. Within the embolization cohort, the median LC was 14.2 months compared with 6.3 months among the nonembolization cohort ( P = .0434). Receiver operating characteristic analysis suggests ≥82.5% embolization predicted significantly improved LC (area under the curve = 0.808; P < .0001). Defensive Veterans Pain Rating Scale mean and maximum scores significantly decreased immediately after embolization ( P < .001)., Conclusion: Preoperative embolization was associated with improved LC and pain control suggesting a novel role for its use. Additional prospective study is warranted., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Background & Aims: Elements of field cancerization, including atrophic gastritis, metaplasia, and dysplasia, promote gastric cancer development in association with chronic inflammation. However, it remains unclear how stroma changes during carcinogenesis and how the stroma contributes to progression of gastric preneoplasia. Here we investigated heterogeneity of fibroblasts, one of the most important elements in the stroma, and their roles in neoplastic transformation of metaplasia., Methods: We used single-cell transcriptomics to evaluate the cellular heterogeneity of mucosal cells from patients with gastric cancer. Tissue sections from the same cohort and tissue microarrays were used to identify the geographical distribution of distinct fibroblast subsets. We further evaluated the role of fibroblasts from pathologic mucosa in dysplastic progression of metaplastic cells using patient-derived metaplastic gastroids and fibroblasts., Results: We identified 4 subsets of fibroblasts within stromal cells defined by the differential expression of PDGFRA, FBLN2, ACTA2, or PDGFRB. Each subset was distributed distinctively throughout stomach tissues with different proportions at each pathologic stage. The PDGFRα + subset expanded in metaplasia and cancer compared with normal, maintaining a close proximity with the epithelial compartment. Co-culture of metaplasia- or cancer-derived fibroblasts with gastroids showing the characteristics of spasmolytic polypeptide-expressing metaplasia-induced disordered growth, loss of metaplastic markers, and increases in markers of dysplasia. Culture of metaplastic gastroids with conditioned media from metaplasia- or cancer-derived fibroblasts also promoted dysplastic transition., Conclusions: These findings indicate that fibroblast associations with metaplastic epithelial cells can facilitate direct transition of metaplastic spasmolytic polypeptide-expressing metaplasia cell lineages into dysplastic lineages., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

» There is increased integration of machine learning (ML) to aid clinical decision-making in orthopaedic surgery.» ML has the ability to predict both clinical outcomes such as range of motion and complications in total shoulder arthroplasty patients.» An increased area of focus is the ability for ML to identify implants to aid in revision surgery planning.» In this article, we review the current applications of ML in shoulder arthroplasty and discuss future areas where it may enhance orthopaedic practice., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSREV/A985)., (Copyright © 2023 by The Journal of Bone and Joint Surgery, Incorporated.)

Purpose: Electric bicycles (e-bikes) achieve higher speeds than pedal bicycles, but few studies have investigated the impact on injury rates specific to the pediatric population. Utilizing the National Electronic Injury Surveillance System (NEISS), we compared rates of pediatric injury for e-bikes, bicycles, and gas-engine bicycles (mopeds) from 2011 to 2020., Methods: Descriptive and bivariate inferential analyses were performed upon NEISS estimates of e-bike, bicycle, and moped injuries in children aged 2-18 years. Analyses were stratified by patient age and helmet usage. The Mann-Kendall test of trends was used., Results: We identified 3945 e-bike, 23,389 moped, and 2.05 million bicycle injuries. Over time, the incidence of injury increased for e-bikes (Kendall's τ =0.73, p = 0.004), decreased for pedal bicycles (Kendall's τ = - 0.91, p = 0.0003), and did not change for mopeds (Kendall's τ  = 0.06, p = 0.85). Males accounted for 82.5 % of e-bike injuries. The age group most commonly affected by e-bike injury (44.3 %) was 10-13 years old. The proportion of injuries requiring hospitalization was significantly higher for e-bikes (11.5 %), compared to moped and bicycle (7.0 and 4.8 %, respectively, p < 0.0001). In cases where helmet use or absence was reported, 97.3 % of e-bike riders were without a helmet at the time of injury, compared to 82.1 % of pedal bicycle riders and 87.2 % of moped riders., Conclusions: The rate of pediatric e-bike injuries increased over the study period. Compared to riders on pedal bicycles or mopeds, children on e-bikes had infrequent helmet use and increased rate of hospitalization. These findings suggest that attention to e-bike safety and increasing helmet usage are important to public health among the pediatric population., Level of Evidence: IV., Competing Interests: The authors have no competing interests to declare., (© 2023 The Authors.)

Importance: Variants in the vitamin D-binding protein (DBP) gene (GC) encode DBP isoforms that may affect vitamin D metabolism. However, whether these isoforms modify the effects of vitamin D3 and/or calcium supplementation on colorectal adenoma recurrence is unclear. We hypothesized that supplementation effects may be stronger among those with the DBP2 isoform (encoded by the rs4588*A allele), which is associated with vitamin D deficiency and modified the associations of circulating vitamin D with risk for colorectal neoplasms in observational studies., Objective: To estimate supplemental vitamin D3 and/or calcium effects on colorectal adenoma recurrence according to 3 common DBP isoforms (DBP1s, DBP1f, DBP2) encoded by 2 missense variants: rs7041 (NG&#95;012837.3:g.57904T>G NP&#95;001191235.1:p.Asp432Glu) and rs4588 (NG&#95;012837.3:g.57915C>A NP&#95;001191235.1:p.Thr436Lys)., Design, Setting, and Participants: Secondary analysis of a randomized, double-blind, placebo-controlled clinical trial of 2259 participants with a recently diagnosed adenoma and no remaining polyps after complete colonoscopy in the US from July 1, 2004, to August 31, 2013. The current analyses were performed from August 12, 2019, to July 16, 2022., Interventions: Daily vitamin D3 (1000 IU), calcium (1200 mg), both, or placebo., Main Outcomes and Measures: One or more adenomas diagnosed during 3 to 5 years of follow-up. Treatment effects were estimated according to DBP isoform as risk ratios (RRs) and 95% CIs using Poisson regression analysis., Results: Of the 2259 participants randomized (mean [SD] age, 58 [6.8] years; 1033 [64%] men), 1604 non-Hispanic White participants (chosen to avoid population stratification bias) were included in the analysis. Among those with the DBP2 isoform (rs4588*AC or AA), the RRs (95% CI) for adenoma recurrence were 0.84 (0.72-1.00) with vitamin D3 relative to no vitamin D3, 0.83 (95% CI, 0.70-0.99) with calcium relative to no calcium, and 0.76 (95% CI, 0.59-0.98) with both agents relative to neither agent. Conversely, among those without DBP2 (rs4588*CC), the corresponding values were 1.08 (95% CI, 0.93-1.26; P = .03 for interaction) with vitamin D3 relative to no vitamin D3, 0.98 (95% CI, 0.84-1.14; P = .37 for interaction) with calcium relative to no calcium, and 1.09 (0.88-1.36; P = .03 for interaction) with both agents relative to neither agent. Among DBP2 homozygotes (rs4588*AA), the RR for adenoma recurrence was 0.57 (95% CI, 0.31-1.08) with both agents relative to neither agent., Conclusions and Relevance: The findings of this secondary analysis of a randomized clinical trial suggest that individuals with the DBP2 isoform-encoding rs4588*A allele may particularly benefit from vitamin D3 and/or calcium supplementation for colorectal adenoma prevention., Trial Registration: ClinicalTrials.gov Identifier: NCT00153816.

Objective: Patient-reported outcome measures (PROMs) are key tools used to inform clinical research and patient-centered care. Application of data collected from PROMs, however, may be limited by incomplete responses, and little is known regarding the efficacy of varied PROM delivery methods. The objective of this study was to compare PROMs compliance when delivered via paper and electronic formats., Methods: Elective adult spinal deformity patients were screened for inclusion. Data collected included demographics, type of surgery, PROMs compliance, and discharge care. Descriptive statistics and multivariate analysis (MVA) were performed to compare pre- and postoperative compliance rates., Results: Of the 474 included patients, 177 were administered paper PROMs, while 297 were electronic. Preoperatively, 101 patients (57.1%) had any portion of their paper PROMs available; 179 (60.3%) had any of their electronic PROMs available (p = 0.492). Among all patients, 76 (42.9%) and 170 (57.2%) had all of their completed preop PROMs available (p = 0.003). Among patients with any of their preop PROMs completed, 75.2% with paper and 95.0% with electronic were completed in their entirety (p < 0.001). Similar trends were observed among postoperative PROMs. MVA demonstrated electronic delivery as the only significant correlate with pre- and post-operative PROMs compliance (p < 0.001 and p = 0.003, respectively)., Conclusions: No differences were observed across modalities when considering any available PROMs, yet electronic PROM delivery was associated with higher completion of PROMs. In order to improve the quality of patient-reported data, electronic delivery with alternative methods of quality improvement may be considered to increase PROMs retention rates., Competing Interests: Conflicts of Interest There are no relevant conflicts of interest related to this submission. Below are all potential conflicts of interest: Andrew Grossbach: Research funding from DePuy, Medtronic, 3 M/KCI; Consultation fees from 3 M/KCI. Stephanus Viljoen: Research funding from Medtronic. David Xu: Consultation fees from NuVasive., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background Context: Adult spinal deformity (ASD) is a prevalent condition often requiring surgical intervention. Improved outcomes among ASD patients have been shown to correlate with postoperative spinopelvic parameters, yet little is currently known about the role of postural stability and balance assessment for ASD patients., Purpose: Explore early changes in postural stability following ASD correction., Study Design: Prospective cohort study., Patient Sample: Sixteen adult patients who underwent four-level or greater posterolateral fusion to address global spinal malalignment and 14 healthy controls with no known spinal deformity nor surgery., Outcome Measures: Postural stability parameters, spinopelvic parameters preoperatively and postoperatively., Methods: Force plate balance assessment was completed where participants and healthy controls were instructed to stand with their hands at their sides, standing still, with eyes open. Center of pressure (COP), center of gravity (COG), and cone of economy (COE) parameters were analyzed with paired and unpaired t tests with an alpha of 0.05., Results: Preoperatively, ASD patients demonstrated more COG (P=0.0244) and sagittal and coronal head (P<0.05) sway than healthy controls. Postoperatively, ASD patients exhibited less COP (P=0.0308), COG (P=0.0276) and head (P=0.0345) sway. Compared to healthy controls, ASD patients postoperatively exhibited similar postural stability, aside from COP and COG sway amplitudes (P<0.05), and coronal head sway (P=0.0309). Pelvic incidence-lumbar lordosis and sagittal vertical axis improved from 16.2° to 4.8° (P<0.01) and 82.2 to 22.5 mm (P<0.01), respectively., Conclusion: We report a novel early improvement in postural stability, comparable to healthy controls, following ASD correction that may be related to improved spinopelvic alignment. Force plate evaluation may be a useful tool for ASD patients postoperatively. Future clinical trials assessing the impact of postural stability on clinical and radiographic outcomes are warranted., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Study Design: Retrospective Cohort Study., Objective: To determine whether 3D-printed porous titanium (3DPT) interbody cages offer any clinical or radiographic advantage over standard solid titanium (ST) interbody cages in transforaminal lumbar interbody fusions (TLIF)., Methods: A consecutive series of adult patients undergoing one- or two-level TLIF with either 3DPT or ST "banana" cages were analyzed for patient reported outcome measures (PROMs), radiographic complications, and clinical complications. Exclusion criteria included clinical or radiographic follow-up less than 1 year., Results: The final cohort included 90 ST interbody levels from 74 patients, and 73 3DPT interbody levels from 50 patients for a total of 124 patients. Baseline demographic variables and comorbidity rates were similar between groups ( P > .05). Subsidence of any grade occurred more frequently in the ST group compared with the 3DPT group (24.4% vs 5.5%, respectively, P = .001). Further, the ST group was more likely to have higher grades of subsidence than the 3DPT group ( P = .009). All PROMs improved similarly after surgery and revision rates did not differ between groups (both P > .05). On multivariate analysis, significant positive correlators with increasing subsidence grade included greater age ( P = .015), greater body mass index ( P = .043), osteoporosis/osteopenia ( P < .027), and ST cage type ( P = .019)., Conclusions: When considering interbody material for TLIF, both ST and 3DPT cages performed well; however, 3DPT cages were associated with lower rates of subsidence. The clinical relevance of these findings deserves further randomized, prospective investigation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Andrew Grossbach, MD: Research funding from DePuy Synthes, Medtronic, 3M/KCI; consultation fees from 3M/KCI. Stephanus Viljoen, MD: Research funding from Medtronic. David Xu, MD: NuVasive consultation fees

Back pain is a common condition affecting millions of individuals each year. A biopsychosocial approach to back pain provides the best clinical framework. A detailed history and physical examination with a thorough workup are required to exclude emergent or nonoperative etiologies of back pain. The treatment of back pain first uses conventional therapies including lifestyle modifications, nonsteroidal anti-inflammatory drugs, physical therapy, and cognitive behavioral therapy. If these options have been exhausted and pain persists for greater than 6 weeks, imaging and a specialist referral may be indicated., Competing Interests: Disclosure The authors have nothing to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Competing Interests: Conflicts of interest None disclosed.

Development of a growth factor delivery vehicle providing appropriate temporal-spatial release together with an appropriate preclinical large animal model to evaluate bone formation is critical in the development of delivery strategies for bone tissue regeneration. Smectite nanoclays such as LAPONITE™ possess unique thixotropic and protein retention properties offering promise for use in growth factor delivery in bone repair and regeneration. This study has examined bone formation mediated by a clinically approved growth factor delivery system (InductOs®) in combination with Laponite gel in an aged female ovine femoral condyle defect preclinical model (10 weeks). Two different designs, one containing a low volume of Laponite gel (LLG) in combination with the InductOs® absorbable collagen sponge (ACS), the other in which Laponite gel formed the implant (HLG), were compared against InductOs® alone and an autograft positive control. Thus, five groups: (i) empty defect, (ii) autograft, (iii) BMP2 + ACS, (iv) BMP2 + ACS + LLG and (v) BMP2 + HLG + ACS were examined in 9 mm × 12 mm defects performed bilaterally in the medial femoral condyles of 24 aged (>5 years) sheep. Bone formation within the defect was assessed using micro-computed tomography (micro-CT), digital volume correlation (DVC) for biomechanical characterisation as well as histology. The autograft and InductOs® mediated enhanced bone formation ( p < 0001) compared to blank controls, while no significant differences were observed between the Laponite/Collagen/BMP delivery vehicles. However, the current study illustrated the excellent biocompatibility of Laponite and its ability to deliver localised active BMP-2, with the opportunity for improved efficacy with further optimisation. Interestingly, DVC-computed strain distributions indicated that the regenerated bone structure is mechanically adapted to bear external loads from the early remodelling stages of the bone reparation cascade. The current studies of selected nanoclay delivery platforms for BMP, assessed in a clinically relevant large animal model auger well for the development of bone fracture therapeutics for an ageing population., Competing Interests: Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JD, RO and DG are shareholders of Renovos., (© The Author(s) 2022.)

Objective: Degenerative cervical myelopathy (DCM) is routinely treated with surgical decompression, but disparate postoperative outcomes are frequently observed, ranging from complete neurological recovery to persistent decline. Although numerous clinical and radiological factors have been independently associated with failure to improve, the relative impact of these proposed risk factors remains obscure. In this study, the authors assess the combined role of clinical and radiographic parameters in contributing to failure to attain neurological improvement after surgery., Methods: A consecutive series of patients who underwent surgery for DCM between July 2013 and August 2018 at a single institution was identified from a prospectively maintained database. Retrospective chart review was undertaken to record perioperative clinical and radiographic parameters. Failure to improve on the last follow-up evaluation after surgery, defined as a change in modified Japanese Orthopaedic Association (mJOA) score less than 2, was the primary outcome in univariate and multivariate analyses., Results: The authors included 183 patients in the final cohort. In total, 109 (59.6%) patients improved (i.e., responders with ΔmJOA score ≥ 2) after surgery and 74 (40.4%) were nonresponders with ΔmJOA score < 2. Baseline demographic variables and comorbidity rates were similar, whereas baseline Nurick score was the only clinical variable that differed between responders and nonresponders (2.7 vs 3.0, p = 0.02). In contrast, several preoperative radiographic variables differed between the groups, including presence and degree of cervical kyphosis, number of levels with bidirectional cord compression, presence and number of levels with T2-weighted signal change, intramedullary lesion (IML) length, Torg ratio, and both narrowest spinal canal and cord diameter. On multivariate analysis, preoperative degree of kyphosis at C2-7 (OR 1.19, p = 0.004), number of levels with bidirectional compression (OR 1.83, p = 0.003), and IML length (OR 1.14, p < 0.001) demonstrated the highest predictive power for nonresponse (area under the receiver operating characteristic curve 0.818). A risk factor point system that predicted failure of improvement was derived by incorporating these 3 variables., Conclusions: When a large spectrum of both clinical and radiographic variables is considered, the degree of cervical kyphosis, number of levels with bidirectional compression, and IML length are the most predictive of nonresponse after surgery for DCM. Assessment of these radiographic factors can help guide surgical decision-making and more appropriately stratify patients in clinical trials.

Background: Although vitiligo is often treated medically, there is increasing evidence for surgical therapies. Overlap with in-office surgical therapies that are already employed for other dermatologic conditions suggest that there is a significant opportunity to expand dermatologists' therapeutic repertoire for vitiligo., Objective: To systematically review the efficacy of nonphototherapy surgical treatments for vitiligo in comparative or placebo-controlled trials., Methods: A systematic review for surgical treatments for vitiligo was conducted. Primary outcomes were treatment success (>75% repigmentation) and failure (<25% repigmentation) for which meta-analyses were performed. Adverse effects were noted. The Cochrane risk of bias tool was used to assess study quality., Results: Surgical treatments reviewed included platelet-rich plasma, microneedling, ablative therapies, and surgical modalities. Seventy-three studies with 2,911 patients were included. The repigmentation benefits and adverse events are summarized. Meta-analyses suggest benefits for ablative laser therapies or microneedling in combination with narrowband ultraviolet B (NB-UVB) and for suction blister epidermal grafting over punch grafting., Conclusion: The addition of microneedling or ablative laser therapy to NB-UVB phototherapy may improve repigmentation with minimal adverse effects. Surgical therapies, such as suction blister grafting and punch grafting, may offer the highest likelihood of repigmentation but have a risk of adverse effects including scarring and hyperpigmentation., (Copyright © 2022 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.)

In 1995, journalist Gary Taubes published an article in Science titled "Epidemiology faces its limits," which questioned the utility of nonrandomized epidemiologic research and has since been cited more than 1000 times. He highlighted numerous examples of research topics he viewed as having questionable merit. Studies have since accumulated for these associations. We systematically evaluated current evidence of 53 example associations discussed in the article. Approximately one-quarter of those presented as doubtful are now widely viewed as causal based on current evaluations of the public health consensus. They include associations between alcohol consumption and breast cancer, residential radon exposure and lung cancer, and the use of tanning devices and melanoma. This history should inform current debates about the reproducibility of epidemiologic research results.

Background: Ankylosing spondylitis (AS) is a complex, debilitating disease with few available medical therapies in its later stages., Methods: We reviewed current clinical approaches for caring for AS patients with an emphasis on the risks and outcomes associated with surgical intervention., Results: It is critical to understand the natural history and surgical outcomes of patient with AS. Surgery is not without risks, as a vertebral body osteotomy is often required to re-establish spinopelvic equilibrium. However, surgery can lead to clinical improvements in pain, disability, cardiac function, respiration, digestion, and sexual activity., Conclusion: Deformity correction for AS should be carefully considered in symptomatic patients., Competing Interests: There are no conflicts of interest or disclosures relevant to any aspect of this submission and manuscript. Listed below are all disclosures: Andrew Grossbach, MD: Research funding from DePuy, Medtronic, 3M/KCI; consultation fees from 3M/KCI Stephanus Viljoen, MD: Research funding from Medtronic David Xu, MD: NuVasive consultation fees., (Copyright: © 2022 Surgical Neurology International.)

Background: Blunt cerebrovascular injury (BCVI) is a rare finding in trauma patients. The previously validated BCVI (Denver and Memphis) prediction model in adult patients was shown to be inadequate as a screening option in injured children. We sought to improve the detection of BCVI by developing a prediction model specific to the pediatric population., Methods: The National Trauma Databank (NTDB) was queried from 2007 to 2015. Test and training datasets of the total number of patients (885,100) with complete ICD data were used to build a random forest model predicting BCVI. All ICD features not used to define BCVI (2268) were included within the random forest model, a machine learning method. A random forest model of 1000 decision trees trying 7 variables at each node was applied to training data (50% of the dataset, 442,600 patients) and validated with test data in the remaining 50% of the dataset. In addition, Denver and Memphis model variables were re-validated and compared to our new model., Results: A total of 885,100 pediatric patients were identified in the NTDB to have experienced blunt pediatric trauma, with 1,998 (0.2%) having a diagnosis of BCVI. Skull fractures (OR 1.004, 95% CI 1.003-1.004), extremity fractures (OR 1.001, 95% 1.0006-1.002), and vertebral injuries (OR 1.004, 95% CI 1.003-1.004) were associated with increased risk for BCVI. The BCVI prediction model identified 94.4% of BCVI patients and 76.1% of non-BCVI patients within the NTDB. This study identified ICD9/ICD10 codes with strong association to BCVI. The Denver and Memphis criteria were re-applied to NTDB data to compare validity and only correctly identified 13.4% of total BCVI patients and 99.1% of non BCVI patients., Conclusion: The prediction model developed in this study is able to better identify pediatric patients who should be screened with further imaging to identify BCVI., Level of Evidence: Retrospective diagnostic study-level III evidence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: Steerable "banana" cages have been posited to increase segmental lordosis in short-segment transforaminal lumbar interbody fusions (TLIF). The same is not necessarily true for straight "bullet" cages. Although increased lordosis is generally thought to be advantageous, a potential complication is decreased foraminal height. Here we evaluate for any association between cage type and change in foraminal height and clinical outcomes following short-segment TLIFs., Methods: We retrospectively reviewed consecutive 1- and 2-level TLIFs with bilateral facetectomies with minimum 1-year clinical and radiographic follow-up. Two cohorts were based on cage morphology: steerable "banana" cage or straight "bullet" cage. Patient reported outcome measures (PROMs), radiographic measurements, and revision rates were compared., Results: A total of 46 patients with 53 straight and 95 patients with 131 steerable cage levels were included. Steerable cages showed increased segmental lordosis (9.1° vs. 13.5°, P < 0.001) and decreased foraminal height (20.3 vs. 18.5 mm, P < 0.001) after surgery. Straight cages demonstrated similar segmental lordosis (8.7° vs 8.1°, P = 0.30) and foraminal height (19.4 vs 20.0 mm, P < 0.065). Both cohorts showed improved PROMs at last follow-up (P ≤ 0.005). Subanalysis comparing patients who had increased or decreased foraminal height revealed similarly improved PROMs between cohorts. Revision rates at 1 year were similar between cohorts (4.3% for straight and 3.2% for steerable group, P = 0.72)., Conclusions: Although the increased segmental lordosis afforded by placement of steerable cages may decrease foraminal height after short segment TLIF, clinical outcomes are not negatively affected by this association., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Conflict-of-Interest Disclosures: Dr. Michener discloses serving as Principal Investigator for the Practical Playbook™ and as consultant for HHS, OAHS, NIH, CDC, HRSA, UC Davis, and Rockefeller University.

Cells are complex systems in which many functions are performed by different genetically defined and encoded functional modules. To systematically understand how these modules respond to drug or genetic perturbations, we develop a functional module states framework. Using this framework, we (1) define the drug-induced transcriptional state space for breast cancer cell lines using large public gene expression datasets and reveal that the transcriptional states are associated with drug concentration and drug targets, (2) identify potential targetable vulnerabilities through integrative analysis of transcriptional states after drug treatment and gene knockdown-associated cancer dependency, and (3) use functional module states to predict transcriptional state-dependent drug sensitivity and build prediction models for drug response. This approach demonstrates a similar prediction performance as approaches using high-dimensional gene expression values, with the added advantage of more clearly revealing biologically relevant transcriptional states and key regulators., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Genome-wide association studies (GWAS) and candidate pathway studies have identified low-penetrant genetic variants associated with cutaneous melanoma. We investigated the association of melanoma-risk variants with primary melanoma tumor prognostic characteristics and melanoma-specific survival. The Genes, Environment, and Melanoma Study enrolled 3285 European origin participants with incident invasive primary melanoma. For each of 47 melanoma-risk single nucleotide polymorphisms (SNPs), we used linear and logistic regression modeling to estimate, respectively, the per allele mean changes in log of Breslow thickness and odds ratios for presence of ulceration, mitoses, and tumor-infiltrating lymphocytes (TILs). We also used Cox proportional hazards regression modeling to estimate the per allele hazard ratios for melanoma-specific survival. Passing the false discovery threshold ( p = 0.0026) were associations of IRF4 rs12203592 and CCND1 rs1485993 with log of Breslow thickness, and association of TERT rs2242652 with presence of mitoses. IRF4 rs12203592 also had nominal associations ( p < 0.05) with presence of mitoses and melanoma-specific survival, as well as a borderline association ( p = 0.07) with ulceration. CCND1 rs1485993 also had a borderline association with presence of mitoses ( p = 0.06). MX2 rs45430 had nominal associations with log of Breslow thickness, presence of mitoses, and melanoma-specific survival. Our study indicates that further research investigating the associations of these genetic variants with underlying biologic pathways related to tumor progression is warranted.

Objective: There are few objective measures for evaluating individual performance throughout surgical residency. Two commonly used objective measures are the case log numbers and written board examination scores. The objective of this study was to investigate possible correlations between these measures., Methods: We conducted a retrospective review of the American Board of Neurological Surgery (ABNS) written board scores and the Accreditation Council for Graduate Medical Education case logs of 27 recent alumni from neurologic surgery residency training programs at The Ohio State Wexner Medical Center and the University of Nebraska Medical Center., Results: The number of spine cases logged was significantly correlated with the ABNS written examination performance in univariate linear regression (r 2  = 0.182, P = 0.0265). However, case numbers from all other neurosurgical subspecialties did not significantly correlate with ABNS written board performance (P > 0.1)., Conclusions: Identifying which objective measures correlate most closely with resident education could help optimize the structure of residency training programs. We believe that early exposure to focused aspects of neurosurgery helps the young resident learn quickly and efficiently and ultimately score highly on standardized examinations. Therefore program directors may want to ensure focused exposure during the early years of residency, with particular attention to worthwhile rotations in spine neurosurgery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Unintentional falls are a leading cause of pediatric traumatic injury. This study evaluates clinical outcomes of fall-related injuries in children under the age of 10., Methods: The National Trauma Database was queried for children who experienced an unintentional fall. Patients were stratified by age in two groups: 1-5 and 6-10 years old. The primary outcome was post discharge extension of care, defined as transfer to skilled nursing facility or rehabilitation center after discharge from the hospital. Descriptive statistics and a multivariable logistic regression analysis were used to compare the two groups., Results: From 2009 to 2016, a total of 8,277 pediatric patients experienced an unintentional fall, with 93.6% of patients being discharged home. Falls were more common in younger children, with greater odds of post discharge extension of care. Predictors of increased associated risk of extended medical care included intracranial hemorrhage (OR 1.05, 95% CI 1.03-1.06) and thoracic injuries (OR 1.03, 95% CI 1.00-1.1.05) (P< 0.05). Mortality in pediatric patients suffering unintentional falls was a rare event occurring in 0.7% of cases in children 1-5 years old and 0.4% of children 6-10 years old., Conclusion: The majority of children experiencing an unintentional fall are discharged home, with mortality being very rare. However, younger age is prone to more severe and serious injury patterns. Intracranial hemorrhage and thoracic injury were a predictor of need for extended medical care., (Copyright © 2021. Published by Elsevier Inc.)

The maintenance and function of tissues in health and disease depends on cell-cell communication. This work shows how high-level features, representing cell-cell communication, can be defined and used to associate certain signaling "axes" with clinical outcomes. We generated a scaffold of cell-cell interactions and defined a probabilistic method for creating per-patient weighted graphs based on gene expression and cell deconvolution results. With this method, we generated over 9,000 graphs for The Cancer Genome Atlas (TCGA) patient samples, each representing likely channels of intercellular communication in the tumor microenvironment (TME). It was shown that cell-cell edges were strongly associated with disease severity and progression, in terms of survival time and tumor stage. Within individual tumor types, there are predominant cell types, and the collection of associated edges were found to be predictive of clinical phenotypes. Additionally, genes associated with differentially weighted edges were enriched in Gene Ontology terms associated with tissue structure and immune response. Code, data, and notebooks are provided to enable the application of this method to any expression dataset (https://github.com/IlyaLab/Pan-Cancer-Cell-Cell-Comm-Net)., Competing Interests: AR is a employee of Bristol Myers Squibb. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gibbs, Aguilar, Thorsson, Ratushny and Shmulevich.)