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Study Design: Cross-sectional Cohort Study., Objective: To determine the cervicothoracic inflection point in an asymptomatic, adult population., Introduction: The cervicothoracic inflection point (CTIP) is an important sagittal marker to understand for patients with cervical deformities. We aimed to identify the CTIP and understand the relationship to other sagittal alignment markers., Methods: 468 adult asymptomatic volunteers (18-80 years) from 5 countries (United States, France, Japan, Singapore, Tunisia). All volunteers underwent standing full body, low dose stereo radiographs. The CTIP was identified by measuring the cervical sagittal angle (CSA) and thoracic kyphosis maximum angle (TK Max ), using the end vertebra concept. The CTIP was defined as the vertebra or disc between the lower end vertebra of the CSA and upper end vertebra of TK Max . A correlation matrix was utilized to identify the relationship between the CTIP and spinopelvic sagittal parameters of interest., Results: The most common CTIP value was the T1 vertebra. CTIPs ranged from C5 to T4, respectively. CTIP showed a weak positive correlation to age (r = 0.10, P = 0.03) and negative correlation to BMI (r = -0.11, P = 0.04). Additionally, CTIP had a minor positive correlation with OC2-CL, C7 slope, T1 slope, T1PA, T1-T12 TK, and T4-T12 TK, all statistically significant. Linear regression demonstrated increased cervical lordosis and increased TK was associated with more caudal CTIP segments., Conclusion: CTIP segments ranged from C5 to T4, with the most common segment being T1. Understanding the relationship of the CTIP to other sagittal variables is critical to patients with CD., 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.

Purpose: To evaluate previously popular technologies in the field of spine surgery, and to better understand their advantages and limitations to the current standards of care. Spine surgery is an ever-evolving field that serves to resolve various spinal pathologies in patients of all ages. While there are established treatments for various conditions, such as lumbar spinal stenosis, idiopathic scoliosis, and degenerative lumbar disease, there is always further research and development in these areas to produce innovative technologies that can lead to better outcomes. As this process progresses, we must remind ourselves of previously tried and tested inventions and their outcomes that have fallen short of becoming a standard to ensure we are able to learn lessons from the past., Methods: A thorough literature review was conducted with the aim of compiling literature of previously utilized technologies in spine surgery. Biomedical databases were utilized to gather relevant articles including PubMed, MEDLINE, and EMBASE. Emphasis was placed on gathering articles with technologies or therapeutics aimed at treating common spinal pathologies including lumbar spinal stenosis (LSS), adolescent idiopathic scoliosis (AIS), and other degenerative lumbar spine diseases. The keywords used were: "failed technologies", "historical technologies", "spine surgery", "spinal stenosis", "adolescent idiopathic scoliosis", and "degenerative lumbar spine disease". A total of 47 articles were gathered after initial review., Results: Different technologies pertaining to spine surgery were identified and critically evaluated. Some of these technologies included X-STOP, Vertiflex, Vertebral Body Stapling, and Dynesys. These technologies were evaluated for their strengths and limitations across their spinal pathology applications. While each type of technology had their benefits, the data tended to be mixed with various limitations across studies., Conclusion: These technologies have been trialed in the field of spine surgery across various spinal pathologies, but still prove of limited efficacy and shortcomings to the current standards of care., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Patients with COVID-19 are at an increased risk for venous thromboembolism (VTE). With the advent of vaccinations and novel treatments from 2020 through 2022, the landscape of COVID-19 has evolved. Notably, the effects of such interventions on the outcomes of COVID-19-associated VTE have not been thoroughly examined. Data from the RIETE registry were analyzed to evaluate 90-day VTE-related outcomes (all-cause mortality, major bleeding, and VTE recurrences) in patients with COVID-19-associated VTE. We compared the periods before and after the widespread introduction of COVID-19 vaccines: March to December 2020 (pre-vaccine period) and March 2021 to December 2022 (post-vaccine period). Statistical analysis included mixed-effects parametric survival-time models. Among 1,620 patients with COVID-19-associated VTE, most (74.1%) were identified during 2020 period. The analysis revealed a more than two-fold increase in the risk of death within 90 days (adjusted hazard ratio [HR]: 2.27; 95% confidence interval, CI: 1.18-4.38) and major bleeding (adjusted HR: 2.91; 95%CI: 1.08-7.84) for patients from the 2020 period compared to those from the 2021-2022 period. Inpatient subgroup analysis confirmed the observed mortality differences. The frequency of recurrent VTE was low (1.1 vs. 0.7%, respectively), and did not show significant variation between the two periods. Our research provides a comparative perspective on the clinical outcomes of COVID-19-associated VTE before and after the introduction of vaccines. Our findings reveal a significant decrease in the incidence of 90-day mortality and major bleeding in patients with COVID-19-associated VTE in the 2021-2022 period., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The NLRP3 receptor can assemble inflammasome platforms to trigger inflammatory responses; however, accumulating evidence suggests that it can also display anti-inflammatory properties. Here, we explored the role of nucleotide-binding oligomerization domain pyrin-containing protein 3 (NLRP3) in Taenia crassiceps experimental infection, which requires immune polarization into a Th2-type profile and peritoneal influx of suppressive macrophages for successful colonization. NLRP3 deficient mice (NLRP3 -/- ) were highly resistant against T. crassiceps, relative to wild-type (WT) mice. Resistance in NLRP3 -/- mice was associated with a diminished IL-4 output, high levels of IL-15, growth factor for both innate and adaptive lymphocytes, and a dramatic decrease in peritoneum-infiltrating suppressive macrophages. Also, a transcriptional analysis on bone marrow-derived macrophages exposed to Taenia-secreted antigens and IL-4 revealed that NLRP3 -/- macrophages express reduced transcripts of relm-α and PD-1 ligands, markers of alternative activation and suppressive ability, respectively. Finally, we found that the resistance displayed by NLRP3 -/- mice is transferred through intestinal microbiota exchange, since WT mice co-housed with NLRP3 -/- mice were significantly more resistant than WT animals preserving their native microbiota. Altogether, these data demonstrate that NLRP3 is a component of innate immunity required for T. crassiceps to establish, most likely contributing to macrophage recruitment, and controlling lymphocyte-stimulating cytokines such as IL-15., Competing Interests: Declarations Conflicts of interest The authors declare no competing interests. Institutional review board statement The study was approved by the FES-Iztacala Bioethics Committee (CE/FESI/042022/1513) and met the recommended guidelines issued by government for experimental animal care (NOM-062-ZOO-1999). Informed consent Not applicable., (© 2024. The Author(s).)

Purpose: To explore the role of the proinflammatory cytokine, macrophage migration inhibitory factor (MIF), in a murine model of dry eye disease (DED)., Methods: The role of MIF on DED was determined using genetically MIF deficient mice and pharmacological inhibition of MIF. DED was induced with 0.5 mg of scopolamine via subcutaneous injection in wild type (WT) and mice lacking MIF (Mif -/- ), three times a day for 21 days. DED signs, tear volume, ferning pattern and cytology impression were evaluated. Also, eye tissues were collected to determine transcripts of key inflammatory mediators and histopathological damage. In a second set of experiments, we neutralized MIF with ISO-1, an isozaxiline-derivative MIF tautomerase activity-inhibiting small molecule in WT mice, following an acute DED model for 10 days. ISO-1 was given starting on day 3 after DED induction and signs were evaluated, including a recovery phase in both experimental approaches., Results: When compared to WT, Mif -/- mice showed attenuated signs of DED like preserved mucin pattern and increased tear volume. Also, Mif -/- mice maintained conjunctival epithelial cells and less corneal damage, associated with lower levels of TNFα and IL-1β. At recovery phase, Mif -/- mice presented improved signs. Interestingly, in cornea and conjunctiva the absence of MIF selectively downregulated the transcription of inflammatory enzymes like inos and nox4 whereas displayed enhanced transcripts of il-4, il-13, tgfβ and cox2. Finally, pharmacological inhibition of MIF using ISO-1, replicated the above findings in the mouse model., Conclusion: MIF is a central positive mediator of the inflammatory process in experimental DED, thus, targeting MIF could be used as a novel therapy in ocular surface inflammatory pathologies.

Study Design: Systematic Review., Objective: The primary purpose of this article was to survey the present literature and report on return to play outcomes in elite athletes after undergoing motion preservation spinal surgery., Summary of Background Data: For elite performance, athletes require adequate mobility and throughout the trunk, torso, and spine to achieve maximal force production. Therefore, elite athletes that have failed conservative treatment may seek to undergo motion preserving surgical options such as total disc arthroplasty and lumbar microdiscectomy. Individual studies have reported on return to play (RTP) outcomes following individual motion preservation surgical procedures, no systematic reviews have formally to reported on RTP outcomes, post-operative performance, and reoperation rates on these procedures in elite athletes., Methods: A systematic review was conducted from inception until February 2024 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. One reviewer queried PubMed for relevant studies that reported on RTP outcomes in elite athletes following motion preservation spinal surgery (MPSS) based on title and abstract (n=1,404). After the original search query, an additional reviewer screened full length articles. A total of 11 studies met the inclusion criteria. Special consideration was given to RTP rates, post-operative performance, and reoperation rates., Results: A total of 612 elite athletes from the National Basketball Association, Major League Baseball, National Football League, National Hockey League, and other professional sporting organizations underwent cervical and lumbar MPSS to treat various spinal pathologies. Various motion sparing techniques were used to treat various pathologies. After undergoing MPSS, RTP rates ranged from 75-100% for lumbar cases and 83.3-100% for cervical cases. Most athletes successfully returned to sport between. Post-operative performance varied with some athletes performing at the same level prior to surgery and some performing at a decreased level., Conclusions: Motion preservation spinal surgery is a feasible option when properly indicated. Future studies are needed to compare return to sport rates, post-operative performance, and re-operation rates between motion preservation spinal surgery to spinal arthrodesis., Competing Interests: Disclosures/Conflicts: There are no conflicts of interest that are pertinent to this manuscript., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Postoperative physical therapy (PT) is a cornerstone of orthopedic and musculoskeletal rehabilitation, proven to provide various positive clinical benefits. However, there is a paucity of literature evaluating the utility of preoperative rehabilitation specific to spine surgery. Thus, this review article aims to provide an overview of previously published studies discussing the efficacy of preoperative rehabilitation programs and its role in spinal surgery. Special emphasis was given to preoperative frailty assessments, physical performance tests, interventional strategies, feasibility, and future directions., Methods: We performed a literature review using PubMed, Google Scholar, EMBASE, and PubMed Central (PMC) using directed search terms. Articles that examined preoperative rehabilitation in adult spine surgery were compiled for this review. Prehabilitation programs focused on exercise, flexibility, and behavioral modifications have been shown to significantly improve pain levels and functional strength assessments in patients undergoing elective spine surgery. In addition, studies suggest that these programs may also decrease hospital stays, return to work time, and overall direct health care expenditure costs. Screening tools such as the FRAIL scale can be used to assess frailty while physical function tests like the timed-up-and go (TUGT), 5 repetition sit-to-stand test (5R-STST), and hand grip strength (HGS) can help identify patients who would most benefit from prehabilitation., Conclusions: This review illustrates that prehabilitation programs have the potential to increase quality of life, improve physical function and activity levels, and decrease pain, hospital stays, return to work time, and overall direct costs. However, there is a paucity of literature in this field that requires further study and investigation., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Prognostication in acute pulmonary embolism (PE) requires reliable markers. While cellular indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index (SII) appear promising, their utility in PE prognostication needs further exploration. We utilized data from the RIETE registry and the Loyola University Medical Center (LUMC) to assess the prognostic value of NLR, PLR, and SII in acute PE, using logistic regression models. The primary outcome was 30-day all-cause mortality. We compared their prognostic value versus the simplified Pulmonary Embolism Severity Index (sPESI) alone. We included 10 085 patients from RIETE and 700 from the LUMC. Thirty-day mortality rates were 4.6% and 8.3%, respectively. On multivariable analysis, an elevated NLR (>7.0) was associated with increased mortality (adjusted odds ratio [aOR]: 3.46; 95% CI: 2.60-4.60), outperforming the PLR > 220 (aOR: 2.36; 95% CI: 1.77-3.13), and SII > 1600 (aOR: 2.52; 95% CI: 1.90-3.33). The c-statistic for NLR in patients with low-risk PE was 0.78 (95% CI: 0.69-0.86). Respective numbers were 0.66 (95% CI: 0.63-0.69) and 0.68 (95% CI: 0.59-0.76) for intermediate-risk and high-risk patients. These findings were mirrored in the LUMC cohort. Among 9810 normotensive patients in RIETE, those scoring 0 points in sPESI and with an NLR ≤ 7.0 (35% of the population) displayed superior sensitivity (97.1%; 95% CI: 95.5-98.7) and negative predictive value (99.7%; 95% CI: 99.5-99.8) than sPESI alone (87.1%; 95% CI: 83.9-90.3, and 98.7%; 95% CI: 98.4-99.1, respectively) for 30-day mortality. The NLR is a significant prognostic marker for 30-day mortality in PE patients, especially useful to identify patients with very low-risk PE., (© 2024 Wiley Periodicals LLC.)

Spinal deformity surgery often requires complex surgical interventions that can have a drastic effect on both patient quality of life and functional capacity. Modern-day corrective solutions for these deformities include spinal osteotomies, pedicle screw instrumentation, and dual/multirod constructs. These solutions are efficacious and are currently considered standard practice for spinal surgeons, but they lack individualization. Patient-specific rods (PSRs) are a novel technology that attempts to offer a personalized approach to spinal deformity correction based on preoperative computerized tomography scans. Moreover, PSRs may offer several advantages to conventional rods, which include achievement of desired rod contour angles according to surgical planning alignment goals, reduced operative time, and reduced blood loss. In adolescent idiopathic scoliosis, those instrumented with PSR have observed coronal Cobb reductions up to 74%. In adult spinal deformity, PSRs have offered superior correction in radiographic parameters such as sagittal vertical axis and pelvic incidence minus lumbar lordosis. However, there still remains a paucity of research in this area, mainly in health care expenditure, cost-effectiveness, and longitudinal clinical outcomes. The purpose of this article is to survey the current body of knowledge of PSR instrumentation in both adolescent and adult spinal deformity populations. The current strength, limitations, and future directions of PSRs are highlighted throughout this article., Competing Interests: Declaration of Conflicting Interests : A.G.B., J.L.R., N.J.L., and M.W.F. report no relevant conflicts. Z.M.S. has received consulting fees from Medtronic. L.G.L. has received royalties from Medtronic and consulting fees from Medtronic, Acuity Surgical, and Abyrx. J.M.L. has received consulting fees from Medtronic and Stryker. R.A.L. has received royalties from Medtronic and Stryker and consulting fees from Medtronic and Pacira., (This manuscript is generously published free of charge by ISASS, the International Society for the Advancement of Spine Surgery. Copyright © 2024 ISASS. To see more or order reprints or permissions, see http://ijssurgery.com.)

Purpose: To assess and compare coronal alignment correction at 2 year follow-up in adult spinal deformity (ASD) patients treated with and without the kickstand rod (KSR) construct., Methods: ASD patients who underwent posterior spinal fusion at a single-center with a preoperative coronal vertical axis (CVA) ≥ 3 cm and a minimum of 2 year clinical and radiographic follow-up were identified. Patients were divided into two groups: those treated with a KSR and those who were not. Patients were propensity score-matched (PSM) controlling for preoperative CVA and instrumented levels to limit potential biases that my influence the magnitude of coronal correction., Results: One hundred sixteen patients were identified (KSR = 42, Control = 74). There were no statistically significant differences in patient characteristics (p > 0.05). At baseline, the control group presented with a greater LS curve (29.0 ± 19.6 vs. 21.5 ± 10.8, p = 0.0191) while the KSR group presented with a greater CVA (6.3 ± 3.6 vs. 4.5 ± 1.8, p = 0.0036). After 40 PSM pairs were generated, there were no statistically significant differences in baseline patient and radiographic characteristics. Within the matched cohorts, the KSR group demonstrated greater CVA correction at 1 year (4.7 ± 2.4 cm vs. 2.9 ± 2.2 cm, p = 0.0012) and 2 year follow-up (4.7 ± 2.6 cm vs. 3.1 ± 2.6 cm, p = 0.0020) resulting in less coronal malalignment one (1.5 ± 1.3 cm vs. 2.4 ± 1.6 cm, p = 0.0056) and 2 year follow-up (1.6 ± 1.0 vs. 2.5 ± 1.5 cm, p = 0.0110). No statistically significant differences in PROMs, asymptomatic mechanical complications, reoperations for non-mechanical complications were observed at 2 year follow-up. However, the KSR group experienced a lesser rate of mechanical complications requiring reoperations (7.1% vs. 24.3%. OR = 0.15 [0.03-0.72], p = 0.0174)., Conclusions: Patients treated with a KSR had a greater amount of coronal realignment at the 2 year follow-up time period and reported less mechanical complications requiring reoperation. However, 2 year patient-reported outcomes were similar between the two groups., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Purpose: To determine if an improvement in cord-level intraoperative neuromonitoring (IONM) data following data loss results in a reduced risk for new postoperative motor deficit in pediatric and adult spinal deformity surgery., Methods: A consecutive series of 1106 patients underwent spine surgery from 2015 to 2023 by a single surgeon. Cord alerts were defined by Somatosensory-Evoked Potentials (SSEP; warning criteria: 10% increase in latency or > 50% loss in amplitude) and Motor-Evoked Potentials (MEP; warning criteria: 75% loss in amplitude without return to acceptable limits after stimulation up 100 V above baseline level). Timing of IONM loss and recovery, interventions, and baseline/postoperative day 1 (POD1) lower extremity motor scores were analyzed., Results: IONM Cord loss was noted in 4.8% (53/11,06) of patients and 34% (18/53) with cord alerts had a POD1 deficit compared to preoperative motor exam. MEP and SSEP loss attributed to 98.1% (52/53) and 39.6% (21/53) of cord alerts, respectively. Abnormal descending neurogenic-evoked potential (DNEP) was seen in 85.7% (12/14) and detected 91.7% (11/12) with POD1 deficit. Abnormal wake-up test (WUT) was seen in 38.5% (5/13) and detected 100% (5/5) with POD1 deficit. Most cord alerts occurred during a three-column osteotomy (N = 23/53, 43%); decompression (N = 12), compression (N = 7), exposure (N = 4), and rod placement (N = 14). Interventions were performed in all 53 patients with cord loss and included removing rods/less correction (N = 11), increasing mean arterial pressure alone (N = 10), and further decompression with three-column osteotomy (N = 9). After intervention, IONM data improved in 45(84.9%) patients (Full improvement: N = 28; Partial improvement: 17). For those with full and partial IONM improvement, the POD1 deficit was 10.7% (3/28) and 41.2% (7/17), respectively. For those without any IONM improvement (15.1%, 8/53), 100% (8/8) had a POD1 deficit, P < 0.001., Conclusion: A full or partial improvement in IONM data loss after intraoperative intervention was significantly associated with a lower risk for POD1 deficit with an absolute risk reduction of 89.3% and 58.8%, respectively. All patients without IONM improvement had a POD1 neurologic deficit., (© 2024. The Author(s), under exclusive licence to Scoliosis Research Society.)

Study Design: Asymptomatic Multi-Ethnic Alignment Normative Study (MEANS) cohort: cross-sectional, multicenter. Symptomatic cohort: retrospective, multisurgeon, single-center., Objective: To assess the association of odontoid-coronal vertical axis (OD-CVA) and orbital-coronal vertical axis (ORB-CVA) with radiographic parameters, patient-reported outcomes, and clinical outcomes., Summary of Background Data: Previous literature studied the OD-CVA in an asymptomatic cohort and ORB-CVA in a symptomatic cohort, demonstrating their correlations with radiographic parameters and ORB-CVA with outcomes., Materials and Methods: A total of 468 asymptomatic adult participants were prospectively enrolled in the MEANS cohort. 174 symptomatic patients with adult spinal deformity with ≥6 fused levels and 2-year follow-ups were retrospectively enrolled in the symptomatic cohort. The association between OD-CVA and ORB-CVA, and radiographic parameters, perioperative variables, PROs, and outcomes were analyzed. Pearson correlation was used to assess correlation and logistic regression odds of outcomes., Results: In the MEANS cohort, the ORB-CVA correlated with C7-CVA ( r = 0.58) and OD-CVA ( r = 0.74). In the symptomatic cohort, preoperative ORB-CVA correlated better with leg length discrepancy; r = 0.17, P = 0.029), whereas preoperative OD-CVA correlated better with C7-CVA ( r = 0.90, P < 0.001). Postoperative ORB-CVA correlated with postoperative C7-CVA ( r = 0.66, P < 0.001), and postoperative OD-CVA correlated strongly with postoperative C7-CVA ( r = 0.81, P < 0.001). Both preoperative OD-CVA ( r = 0.199) and ORB-CVA ( r = 0.208) correlated with the preoperative Oswestry Disability Index. ORB-CVA correlated better than OD-CVA in the preoperative Scoliosis Research Society-22r pain category but worse in total and other subcategories. Preoperative ORB-CVA was associated with increased odds of intraoperative complication (odds ratio = 1.28, 1.01-1.22), like OD-CVA (odds ratio = 1.30, 1.12-1.53). Neither preoperative ORB-CVA nor OD-CVA was associated with reoperations and readmissions after multivariate analysis. Preoperative OD-ORB mismatch >1.5 cm was not associated with increased odds of intraoperative and postoperative complications, reoperations, or readmissions., Conclusion: ORB-CVA and OD-CVA correlated with radiographic parameters, patient-reported outcomes, and intraoperative complications. ORB-CVA and OD-CVA can be used interchangeably as cranial coronal parameters in adult spinal deformity surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To examine the association of left atrial (LA) function with incident chronic kidney disease (CKD) and assess the clinical utility of adding LA function to a CKD risk prediction equation., Patients and Methods: We included 4002 Atherosclerosis Risk in Communities study participants without prevalent CKD (mean ± SD age, 75±5 years; 58% female, 18% Black). Left atrial function (reservoir, conduit, and contractile strain) was evaluated by 2D-echocardiograms on 2011 to 2013. Chronic kidney disease was defined as greater than 25% decline in estimated glomerular filtration rate of less than 60 mL/min/1.73 m 2 , end-stage kidney disease, or hospital records. Cox proportional hazards models were used. Risk prediction and decision curve analyses evaluated 5-year CKD risk by diabetes status., Results: Median follow-up was 7.2 years, and 598 participants developed incident CKD. Incidence rate for CKD was 2.29 per 100 person-years. After multivariable adjustments, the lowest quintile of LA reservoir, conduit, and contractile strain (vs highest quintile) had a higher risk of CKD (hazard ratios [95% CIs]: 1.94 [1.42-2.64], 1.62 [1.19-2.20], and 1.49 [1.12-1.99]). Adding LA reservoir strain to the CKD risk prediction equation variables increased the C-index by 0.026 (95% CI: 0.005-0.051) and 0.031 (95% CI: 0.006-0.058) in participants without and with diabetes, respectively. Decision curve analysis found the model with LA reservoir strain had a higher net benefit than the model with CKD risk prediction equation variables alone., Conclusion: Lower LA function is independently associated with incident CKD. Adding LA function to the CKD risk prediction enhances prediction and yields a higher clinical net benefit. These findings suggest that impaired LA function may be a novel risk factor for CKD., Competing Interests: Dr Eaton reported grant support from the National Institutes of Health to the institution. Dr Herzog reported grant support from the National Heart, Lung, and Blood Institute, National Institutes of Health to the institution, consulting fees from Astra-Zeneca, personal fees from Merck (DSMB) for participation on a Data Safety Monitoring, and stock ownership in Merck, Pfizer and Boston Scientific. Dr Matsushita reported grant supports from the National Institutes of Health and Resolve to Save Lives, consulting fees from Fukuda Denshi and RhythmX AI. Dr Coresh reported grant supports from the National Institutes of Health and National Kidney Foundation, consulting fees from Healthy.IO, and stock ownership in Healthy.IO. Dr Shah reported funding from Novartis and Philips Ultrasound, and consulting fees from Philips Ultrasound and Janssen outside the submitted work. Dr Solomon reported funding from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, NIH/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI grant to institution, outside the submitted work and personal fees from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi- Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, SanofiPasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, PureHealth consulting outside the submitted work. The other authors declare no competing interests., (© 2024 The Authors.)

Colorectal cancer (CRC) is one of the most prevalent fatal neoplasias worldwide. Despite efforts to improve the early diagnosis of CRC, the mortality rate of patients is still nearly 50%. The primary treatment strategy for CRC is surgery, which may be accompanied by chemotherapy and radiotherapy. The conventional and first-line chemotherapeutic agent utilized is 5-fluorouracil (5FU). However, it has low efficiency. Combination treatment with leucovorin and oxaliplatin or irinotecan improves the effectiveness of 5FU therapy. Unfortunately, most patients develop drug resistance, leading to disease progression. Here, we evaluated the effect of a potential alternative adjuvant treatment for 5FU, helminth-derived Taenia crassiceps (TcES) molecules, on treating advanced colitis-associated colon cancer. The use of TcES enhanced the effects of 5FU on established colonic tumors by downregulating the expression of the immunoregulatory cytokines, Il-10 and Tgf-β, and proinflammatory cytokines, Tnf-α and Il-17a, and reducing the levels of molecular markers associated with malignancy, cyclin D1, and Ki67, both involved in apoptosis inhibition and the signaling pathway of β-catenin. TcES+5FU therapy promoted NK cell recruitment and the release of Granzyme B1 at the tumor site, consequently inducing tumor cell death. Additionally, it restored P53 activity which relates to decreased Mdm2 expression. In vitro assays with human colon cancer cell lines showed that therapy with TcES+5FU significantly reduced cell proliferation and migration by modulating the P53 and P21 signaling pathways. Our findings demonstrate, for the first time in vivo, that helminth-derived excreted/secreted products may potentiate the effect of 5FU on established colon tumors., Competing Interests: Declaration of Competing Interest All the authors declare no conflict of interest for the current study., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: The Spinal Cord Shape Classification System (SCSCS) class has been associated with spinal cord monitoring data loss during spinal deformity surgery. The objective of the current study was to prospectively validate the SCSCS as a predictor of spinal cord monitoring data loss during spinal deformity surgery., Methods: A prospective cohort study of consecutive patients who were undergoing primary deformity surgery at a single institution from 2018 to 2023 and whose major curve was in the spinal cord region was undertaken. Spinal cord morphology at the apex of the major curve on preoperative axial T2-weighted magnetic resonance imaging was used to categorize patients into 3 spinal cord shape types based on the SCSCS. The primary outcome was intraoperative neuromonitoring (IONM) data loss related to spinal cord dysfunction. Demographics and surgical and radiographic variables were compared between patients with IONM data loss and those without loss. Predictors of IONM loss were determined using bivariate and multivariable logistic regression analyses., Results: A total of 256 patients (168 adult, 88 pediatric) were included and were separated into 3 SCSCS types: 110 (43.0%) with Type I, 105 (41.0%) with Type II, and 41 (16.0%) with Type III. IONM loss was observed in 30 (11.7%) of the 256 patients, including 7 (6.4%) of 110 with SCSCS Type I, 7 (6.7%) of 105 with Type II, and 16 (39.0%) of 41 with Type III. IONM loss was associated with SCSCS Type III, the preoperative deformity angular ratio, performance of 3-column osteotomies, greater operative time, greater transfusion volume, and greater postoperative sagittal corrections. SCSCS type was the strongest independent predictor of IONM data loss. SCSCS Type III had the greatest odds of IONM loss (odds ratio [OR] = 6.68, 95% confidence interval [CI] = 2.45 to 18.23 compared with Types I and II combined). The overall predictive performance with respect to IONM loss (area under the receiver operating characteristic curve = 0.827) was considered excellent., Conclusions: This prospective cohort study of patients undergoing spinal deformity correction confirmed that patients with a Type-III spinal cord shape had greater odds of IONM loss. Inclusion of the SCSCS in preoperative risk stratification and intraoperative management of spinal deformity corrective surgery is recommended., Level of Evidence: Prognostic Level II . See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: No external funding was received for this work. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article ( http://links.lww.com/JBJS/H906 )., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

The current state of global biodiversity is confronted with escalating threats arising from human-induced environmental changes and a growing array of unpredictable challenges. However, effective conservation efforts are often hindered by limited knowledge, especially in developing economies such as the Philippines. The limitations imposed by these shortfalls in biodiversity knowledge hamper the capacity to protect biodiversity in light of the continuing extinction crisis. Our study revealed that areas with higher conflict levels exhibited lower species richness, fewer occurrence records, and reduced forest cover. This finding provides initial evidence for the relationship between sociopolitical conflict and biodiversity in the Philippines. We posit that the security risks caused by sociopolitical conflicts could have a negative impact on conservation efforts, particularly in terms of monitoring and implementing measures to protect natural resources. The links that bind armed conflict and biodiversity conservation are multifaceted and complex issues that warrant greater scientific and political attention. Finally, we identified 10 meaningful approaches to address shortfalls in biodiversity knowledge in conflicted areas, particularly incorporating conflict-sensitive approaches, considering the geopolitical context and conflict dynamics to adapt and align their strategies with local realities for more effective conservation efforts., (© 2024. The Author(s).)

Study Design: Cross-sectional cohort study., Objective: To classify spinal morphology using the "current" and "theoretical" Roussouly systems and assess sagittal alignment in an asymptomatic cohort., Methods: 467 asymptomatic volunteers were recruited from 5 countries. Radiographic parameters were measured via the EOS imaging system. "Current" and "theoretical" Roussouly classification was assigned with sagittal whole spine imaging using sacral slope (SS), pelvic incidence (PI), and the lumbar apex. One-way analysis of variance (ANOVA) was performed to compare subject characteristics across Roussouly types, followed by post hoc Bonferroni correction., Results: Volunteers were categorized into 4 groups (Types 1-4) and 1 subgroup (Type 3 AP) using the "current" and "theoretical" Roussouly systems. The mean PI in "current" Roussouly groups was 40.8° (Type 1), 43.6° (Type 2), 52.4° (Type 3), 62.4° (Type 4), and 43.7° (Type 3AP). The mean PI in "theoretical" Roussouly groups was 36.5° (Type 1), 39.1°(Type 2), 52.5° (Type 3), 67.3° (Type 4), and 51.0° (Type 3AP). The difference in PI between "current" and "theoretical" Roussouly types was significant for Type 1 ( P = .02), Type 2 ( P < .001), Type 4 ( P < .001), and Type 3AP ( P < .001). 34.7% of subjects had a "current" Roussouly type different from the "theoretical" type. Type 3 theoretical shape had the most frequent mismatch, constituting 61.1% of the mismatched subjects. 51.5% of mismatched Type 3 become "current" Type 4., Conclusion: The distribution of Roussouly types differs depending on whether the "current" or "theoretical" classification are employed. A sizeable proportion of volunteers exhibited current and theoretical type mismatch, highlighting the need to interpret sagittal alignment cautiously when utilizing the Roussouly system., 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.

Late Embryogenesis Abundant (LEA) proteins are a group of intrinsically disordered proteins implicated in plant responses to water deficit. In vitro studies revealed that LEA proteins protect reporter enzymes from inactivation during low water availability. Group 4 LEA proteins constitute a conserved protein family, displaying in vitro protective capabilities. Under water deficiency or macromolecular crowding, the N-terminal of these proteins adopts an alpha-helix conformation. This region has been identified as responsible for the protein in vitro protective activity. This study investigates whether the attainment of alpha-helix conformation and/or particular amino acid residues are required for the in vitro protective activity. The LEA4-5 protein from Arabidopsis thaliana was used to generate mutant proteins. The mutations altered conserved residues, deleted specific conserved regions, or introduced prolines to hinder alpha-helix formation. The results indicate that conserved residues are not essential for LEA4-5 protective function. Interestingly, the C-terminal region was found to contribute to this function. Moreover, alpha-helix conformation is necessary for the protective activity only when the C-terminal region is deleted. Overall, LEA4-5 shows the ability to adopt alternative functional conformations under the tested conditions. These findings shed light on the in vitro mechanisms by which LEA proteins protect against water deficit stress., (© 2024. The Author(s).)

Objetivo: Determinar la carga económica anual del asma, desde una perspectiva institucional y con base en la clasificación recomendada por GINA, en una cohorte retrospectiva de adultos atendidos en el Instituto Nacional de Enfermedades Respiratorias (INER) de México., Métodos: Estudio observacional, longitudinal y retrospectivo, llevado a cabo a partir de la información recabada de 247 pacientes femeninas con asma. Se estimaron los costos directos anuales: visitas, pruebas de laboratorio, tratamiento farmacológico y de las crisis o exacerbaciones, para determinar la carga anual de la enfermedad desde una perspectiva institucional, y según la clasificación de la Iniciativa Global para el Asma., Resultados: El costo promedio anual fue de $43,813,92, que aumentó en relación con la necesidad de aumento de dosis de corticoides inhalados y beta-agonistas de acción prolongada. El costo promedio de la consulta médica fue de $2004.57, $982.82 por gestión de crisis y $2645.95 por pruebas de laboratorio. El tratamiento farmacológico representó la principal carga económica, con un costo promedio anual de $38,180.58., Conclusiones: Los resultados resaltan una carga económica del asma estimada en un costo anual por paciente de $43,813.92 MXN (DE=93,348.85), en el contexto del tercer nivel de atención en el sistema de salud público mexicano. La gravedad del asma, los tratamientos y los biológicos fueron los principales factores que aumentaron los costos directos de la atención.

Objective: Health care workers are at risk for work-related asthma, which may be affected by changes in cleaning practices. We examined associations of cleaning tasks and products with work-related asthma in health care workers in 2016, comparing them with prior results from 2003., Methods: We estimated asthma prevalence by professional group and explored associations of self-reported asthma with job-exposure matrix-based cleaning tasks/products in a representative Texas sample of 9914 physicians, nurses, respiratory/occupational therapists, and nurse aides., Results: Response rate was 34.8% (n = 2421). The weighted prevalence rates of physician-diagnosed (15.3%), work-exacerbated (4.1%), and new-onset asthma (6.7%) and bronchial hyperresponsiveness symptoms (31.1%) were similar to 2003. New-onset asthma was associated with building surface cleaning (odds ratio [OR], 1.91; 95% confidence interval [CI], 1.10-3.33), use of ortho-phthalaldehyde (OR, 1.77; 95% CI, 1.15-2.72), bleach/quaternary compounds (OR, 1.91; 95% CI, 1.10-3.33), and sprays (OR, 1.97; 95% CI, 1.12-3.47)., Conclusion: Prevalence of asthma/bronchial hyperresponsiveness seems unchanged, whereas associations of new-onset asthma with exposures to surface cleaning remained, and decreased for instrument cleaning., Competing Interests: Conflicts of interest: None declared., (Copyright © 2023 American College of Occupational and Environmental Medicine.)

Introduction: The abrupt transition of the mode of learning due to the COVID-19 pandemic resulted in an increase in complaints of musculoskeletal (MSK) discomfort among students in Higher Education Institutions (HEI). Inadequate physical space and equipment are one major cause of these complaints. Among HEIs, physical therapy (PT) students have sufficient background in managing MSK discomforts. However, this does not prevent them from experiencing pain and discomfort during online classes. This analytical cross-sectional study aims to determine the correlation between ergonomic knowledge and MSK discomfort among first-year to fourth-year PT students., Methods and Analysis: The study will use two questionnaires, the Ergonomic Knowledge Questionnaire, and the Cornell Musculoskeletal Discomfort Questionnaire, that determine the level of ergonomic knowledge and MSK discomfort, respectively. This will be disseminated to 144 students through google forms. Results will then be analysed using Pearson Correlation Test. The study anticipates a correlation between the level of ergonomic knowledge and MSK discomfort among the participants., Ethics and Dissemination: The study has been approved by the University of Santo Tomas-College of Rehabilitation Sciences Ethics Review Committee. The participants will receive the results prior to publication in a peer-reviewed scientific journal., Trial Registration Number: Philippine Health Research Registry with registry ID PHRR230216-005443., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Inflammatory ocular diseases are characterized by the presence of a persistent inflammatory response which cause tissue injury, decrease visual acuity and in severe cases, blindness. Several cytokines represent a therapeutic opportunity since they are key amplifiers of these pathologies, and thus neutralizing agents against them have been developed. Amongst others, macrophage migration inhibitory factor (MIF), an early produced inflammatory cytokine, has consistently been found elevated in patients with distinct ocular diseases (inflammatory and autoimmune). Here, we present and discuss evidence showing that preclinical trials using diverse strategies to neutralize MIF resulted in significant attenuation of disease signs and therefore MIF blockage might be a promising therapy for ocular diseases., (© 2023. Springer-Verlag GmbH Germany, part of Springer Nature.)

Study Design: Prospective cohort study., Objectives: To show population variance in the Inflection Point (IP) and its role in defining maximum Thoracic Kyphosis (TK) and Lumbar Lordosis (LL)., Methods: 468 asymptomatic adult volunteers were included in the Multi-Ethnic Normative Alignment Study (MEANS). To find parameters correlating with IP, the vertebrae and discs were numbered such that C7 was 0, T1 was 1, with T1-T2 disc being 1.5, etc. Statistical analysis was performed by a correlation matrix for IP and the 9 other selected parameters along with linear regressions., Results: The overall mean IP was 12.44 approximately corresponding to T12-L1 disc with the median being 12.50, range was T8-L4. The cohort was then stratified by sex and ethnicity, but there was no significant difference in IP between groups. IP in younger subjects was 13 (L1), compared to 12.5 (T12-L1 disc) in older subjects ( P < .05). IP was moderately correlated with the TK apex (r = .66). No strong correlation was found between IP and LL magnitude or apex, TK magnitude, sacral slope, or Pelvic Incidence (PI). In terms of other sagittal parameters, PI and LL demonstrated a significant positive correlation. PI and TK did not have a strong association., Conclusions: The mean IP was at the T12-L1 disc, however IP ranged from T8 to L4. Older subjects tended to have a relatively more cephalad IP. No radiographic variable was found to be a strong predictor of the IP. TK apex was found to have a moderate correlation., 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.

Background: Recent evidence indicates that abnormal P-wave parameters (PWPs)-ECG markers of atrial myopathy-are associated with incident dementia, independent of atrial fibrillation (AF) and clinical ischemic stroke. However, the mechanisms remain unclear and may include subclinical vascular brain injury. Hence, we evaluated the association of abnormal PWPs with brain MRI correlates of vascular brain injury in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS)., Methods: ARIC-NCS participants who underwent 3T brain MRI scans in 2011-2013 were included. PWPs were measured from standard 12-lead ECGs. Brain MRI outcomes included cortical infarcts, lacunar infarcts, cerebral microhemorrhages, brain volumes, and white matter disease (WMD) volume. We used weighted multivariable logistic and linear regression to evaluate the associations of abnormal PWPs with brain MRI outcomes., Results: Among 1715 participants (mean age, 76.1 years; 61% women; 29% Black), 797 (46%) had ≥1 abnormal PWP. After multivariable adjustment, including adjusting for prevalent AF, abnormal P-wave terminal force in lead V1 (aPTFV1) and prolonged P-wave duration (PPWD) were associated with increased odds of both cortical (OR 1.41; 95% CI, 1.14 to 1.74 and OR 1.30; 95% CI, 1.04 to 1.63, respectively) and lacunar infarcts (OR 1.36; 95% CI, 1.15 to 1.63 and OR 1.37; 95% CI, 1.15 to 1.65, respectively). Advanced interatrial block (aIAB) was associated with higher odds of subcortical microhemorrhage (OR 2.04; 95% CI, 1.36 to 3.06). Other than a significant association between aPTFV1 with lower parietal lobe volume, there were no other significant associations with brain or WMD volume., Conclusion: In this exploratory analysis of a US community-based cohort, ECG surrogates of atrial myopathy are associated with a higher prevalence of brain infarcts and microhemorrhage, suggesting subclinical vascular brain injury as a possible mechanism underlying the association of atrial myopathy with dementia., (© 2023 The Authors. Pacing and Clinical Electrophysiology published by Wiley Periodicals LLC.)

Plants colonized the land approximately 470 million years ago, coinciding with the development of apical cells that divide in three planes. The molecular mechanisms that underly the development of the 3D growth pattern are poorly understood, mainly because 3D growth in seed plants starts during embryo development. In contrast, the transition from 2D to 3D growth in the moss Physcomitrium patens has been widely studied, and it involves a large turnover of the transcriptome to allow the establishment of stage-specific transcripts that facilitate this developmental transition. N 6 -Methyladenosine (m 6 A) is the most abundant, dynamic and conserved internal nucleotide modification present on eukaryotic mRNA and serves as a layer of post-transcriptional regulation directly affecting several cellular processes and developmental pathways in many organisms. In Arabidopsis, m 6 A has been reported to be essential for organ growth and determination, embryo development and responses to environmental signals. In this study, we identified the main genes of the m 6 A methyltransferase complex (MTC), MTA, MTB and FIP37, in P. patens and demonstrate that their inactivation leads to the loss of m 6 A in mRNA, a delay in the formation of gametophore buds and defects in spore development. Genome-wide analysis revealed several transcripts affected in the Ppmta background. We demonstrate that the PpAPB1-PpAPB4 transcripts, encoding central factors orchestrating the transition from 2D to 3D growth in P. patens, are modified by m 6 A, whereas in the Ppmta mutant the lack of the m 6 A marker is associated with a corresponding decrease in transcript accumulation. Overall, we suggest that m 6 A is essential to enable the proper accumulation of these and other bud-specific transcripts directing the turnover of stage-specific transcriptomes, and thus promoting the transition from protonema to gametophore buds in P. patens., (© 2023 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

Background: Lung cancer (LC) continues to be the leading cause of cancer deaths in the United States. Surgical treatment has proven to offer a favorable prognosis and a better 5-year relative survival for patients with early or localized tumors. This novel study investigates the factors associated with the odds of receiving surgical treatment for localized malignant LC in Tennessee., Methods: Population-based data of 9679 localized malignant LC patients from the Tennessee Cancer Registry (2005-2015) were utilized to examine the factors associated with receiving surgical treatment for localized malignant LC. Bivariate and multivariate logistic regression analyses, cross-tabulation, and Chi-Square ( χ 2 ) tests were conducted to assess these factors., Results: Patients with localized malignant LC who initiated treatment after 2.7 weeks were 46% less likely to receive surgery (adjusted odds ratio [AOR] = 0.54; 95% confidence interval [CI] = 0.50-0.59; p < 0.0001). Females had a greater likelihood (AOR = 1.14; CI = 1.03-1.24) of receiving surgical treatment compared to men. Blacks had lower odds (AOR = 0.76; CI = 0.65-0.98) of receiving surgical treatment compared to Whites. All marital groups had higher odds of receiving surgical treatment compared to those who were single/never married. Patients living in Appalachian county had lower odds of receiving surgical treatment (AOR = 0.65; CI = 0.59-0.71) compared with those in the non-Appalachian county. Patients with private (AOR = 2.09; CI = 1.55-2.820) or public (AOR = 1.42; CI = 1.06-1.91) insurance coverage were more likely to receive surgical treatment compared to self-pay/uninsured patients. Overall, the likelihood of patients receiving surgical treatment for localized malignant LC decreases with age., Conclusion: Disparities exist in the receipt of surgical treatment among patients with localized malignant LC in Tennessee. Health policies should target reducing these disparities to improve the survival of these patients., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

The clinical characteristics and outcomes of patients with coronavirus disease 2019 (COVID-19) who develop pulmonary embolism (PE) in the full spectrum of patient care settings need to be elucidated. The aim of this study was to compare the clinical characteristics, treatment, and 90-day outcomes in patients diagnosed with PE while recovering from COVID-19 in the outpatient setting versus those who were diagnosed with PE while being hospitalized with COVID-19. Data from the international Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry were used. The major study outcomes were all-cause death, major bleeding, and venous thromboembolism (VTE) recurrences during the first 90 days after PE. From March 2020 to March 2021, 737 patients with COVID-19 experienced acute PE. Of these, 340 (46%) were recovering from COVID-19 as outpatients (267 patients who had been treated at home for COVID-19 and 73 discharged after being hospitalized with COVID-19). Compared with inpatients with COVID-19, those recovering in the outpatient setting upon PE were less likely to be men (odds ratio [OR]: 0.54; 95% confidence interval [CI]: 0.40-0.72) and less likely to have hypertension (OR: 0.55; 95% CI: 0.41-0.74) or diabetes (OR: 0.51; 95% CI: 0.33-0.76). At 90-day follow-up, eight patients (none recovering from COVID-19 as outpatient vs. 2.4% of inpatients with COVID-19) developed recurrent VTE, 34 (1.9 vs. 7.9%) had major bleeding, and 128 (10 vs. 24%) died. On multivariable analysis, inpatients with COVID-19 were at a higher risk of major bleeding (adjusted hazard ratio [HR]: 6.80; 95% CI: 1.52-30.4) or death (adjusted HR: 2.24; 95% CI: 1.40-3.58). In conclusion, using a large multinational registry of patients with COVID-19 who experienced PE, thromboembolic episodes occurring in those recovering from COVID-19 as outpatients were associated with less ominous outcomes than inpatients with COVID-19., Competing Interests: B.B. reported being a consulting expert, on behalf of the plaintiff, for litigation related to two specific brand models of inferior vena cava filters. M.M. reported honoraria for lectures from Sanofi, Pfizer, Rovi, and Alfa sigma, support for meetings from Sanofi, and he participated in advisory meetings with Sanofi and Leo Pharma. The other coauthors have nothing to disclose., (Thieme. All rights reserved.)

In 2013, recognizing that Colorectal Cancer (CRC) is the second leading cause of death by cancer worldwide and that it was a neglected disease increasing rapidly in Mexico, the community of researchers at the Biomedicine Research Unit of the Facultad de Estudios Superiores Iztacala from the Universidad Nacional Autónoma de México (UNAM) established an intramural consortium that involves a multidisciplinary group of researchers, technicians, and postgraduate students to contribute to the understanding of this pathology in Mexico. This article is about the work developed by the Mexican Colorectal Cancer Research Consortium (MEX-CCRC): how the Consortium was created, its members, and its short- and long-term goals. Moreover, it is a narrative of the accomplishments of this project. Finally, we reflect on possible strategies against CRC in Mexico and contrast all the data presented with another international strategy to prevent and treat CRC. We believe that the Consortium's characteristics must be maintained to initiate a national strategy, and the reported data could be useful to establish future collaborations with other countries in Latin America and the world.

In recent years, miR528, a monocot-specific miRNA, has been assigned multifaceted roles during development and stress response in several plant species. However, the transcription regulation and the molecular mechanisms controlling MIR528 expression in maize are still poorly explored. Here we analyzed the zma- MIR528a promoter region and found conserved transcription factor binding sites related to diverse signaling pathways, including the nitrate (TGA1/4) and auxin (AuxRE) response networks. Accumulation of both pre-miR528a and mature miR528 was up-regulated by exogenous nitrate and auxin treatments during imbibition, germination, and maize seedling establishment. Functional promoter analyses demonstrated that TGA1/4 and AuxRE sites are required for transcriptional induction by both stimuli. Overall, our findings of the nitrogen- and auxin-induced zma- MIR528a expression through cis -regulatory elements in its promoter contribute to the knowledge of miR528 regulome.

The Growth Arrest-Specific protein 1 (Gas1) has been recently described in kidney as an endogenous inhibitor of cell proliferation in mesangial cells and with an important role in the maintenance of nephron progenitor cells. Furthermore, the expression of Gas1 was demonstrated in NCAM + progenitor parietal cells of Bowman's capsule. Thus, the aim of this study was to analyze the expression of Gas1 in the collecting ducts (CD) of healthy rats and to examine whether high glucose levels modify its expression during the early stages of diabetes in STZ-treated rats. Immunofluorescence reveals that principal cells AQP2 + express Gas1 in both healthy and diabetic conditions. Western blot from enriched fractions of medullary CD suggests that diabetes promotes the increase of Gas1. AQP2 + cells are also positive for the expression of CD24 and CD1133 in diabetic rats. In addition, diabetes modifies the cell morphology in the CD and favors the increase of principal cells (AQP2+/Gas1+), induces a significant decrease of intercalated cells (V-ATPase+/Gas1-) and the presence of intermediate cells (Gas1+/V-ATPase+) which express both principal and intercalated cell markers. The expression of Gas1 in the distal tubules was also determined by immunofluorescence, western blot and ELISA in diabetic rats. The results identify Gas1 as a specific marker of principal cells in healthy and diabetic rats and suggest that diabetes promotes the expression of Gas1. Gas1 may have an important role in the maintenance and differentiation to principal cells in the CD during early stages of diabetes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Both plant- and rhizobia-derived small RNAs play an essential role in regulating the root nodule symbiosis in legumes. Small RNAs, in association with Argonaute proteins, tune the expression of genes participating in nodule development and rhizobial infection. However, the role of Argonaute proteins in this symbiosis has been overlooked. In this study, we provide transcriptional evidence showing that Argonaute5 (AGO5) is a determinant genetic component in the root nodule symbiosis in Phaseolus vulgaris . A spatio-temporal transcriptional analysis revealed that the promoter of PvAGO5 is active in lateral root primordia, root hairs from rhizobia-inoculated roots, nodule primordia, and mature nodules. Transcriptional analysis by RNA sequencing revealed that gene silencing of PvAGO5 affected the expression of genes involved in the biosynthesis of the cell wall and phytohormones participating in the rhizobial infection process and nodule development. PvAGO5 immunoprecipitation coupled to small RNA sequencing revealed the small RNAs bound to PvAGO5 during the root nodule symbiosis. Identification of small RNAs associated to PvAGO5 revealed miRNAs previously known to participate in this symbiotic process, further supporting a role for AGO5 in this process. Overall, the data presented shed light on the roles that PvAGO5 plays during the root nodule symbiosis in P. vulgaris ., Competing Interests: The 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 © 2022 Sánchez-Correa, Isidra-Arellano, Pozas-Rodríguez, Reyero-Saavedra, Morales-Salazar, del Castillo, Sanchez-Flores, Jiménez-Jacinto, Reyes, Formey and Valdés-López.)

Background & Objectives: Comparison of clinical outcomes across anticoagulation regimens using different apixaban dosing or warfarin is not well-defined in patients with nonvalvular atrial fibrillation (AF) who are receiving dialysis. This study compared these outcomes in a US national cohort of patients with kidney failure receiving maintenance dialysis., Study Design: Retrospective cohort study., Setting & Participants: Patients receiving dialysis represented in the US Renal Data System database 2013-2018 who had AF and were treated with apixaban or warfarin., Exposure: First prescribed treatment with apixaban dosed according to the label, apixaban dosed below the label, or warfarin., Outcome: Ischemic stroke/systemic embolism, major bleeding, and all-cause mortality., Analytical Approach: Cox proportional hazards models with inverse probability of treatment weighting. Analyses simulating an intention-to-treat (ITT) approach as well as those incorporating censoring at drug switch or discontinuation (CAS) were also implemented. Inverse probability of censoring weighting was used to account for possible informative censoring., Results: Among 17,156 individuals, there was no difference in risk of stroke/systemic embolism among the label-concordant apixaban, below-label apixaban, and warfarin treatment groups. Both label-concordant (HR, 0.67 [95% CI, 0.55-0.81]) and below-label (HR, 0.68 [95% CI, 0.55-0.84]) apixaban dosing were associated with a lower risk of major bleeding compared with warfarin in ITT analyses. Compared with label-concordant apixaban, below-label apixaban was not associated with a lower bleeding risk (HR, 1.02 [95% CI, 0.78-1.34]). In the ITT analysis of mortality, label-concordant apixaban dosing was associated with a lower risk versus warfarin (HR, 0.85 [95% CI, 0.78-0.92]) while there was no significant difference in mortality between below-label dosing of apixaban and warfarin (HR, 0.97 [95% CI, 0.89-1.05]). Overall, results were similar for the CAS analyses., Limitations: Study limited to US Medicare beneficiaries; reliance on administrative claims to ascertain outcomes of AF, stroke, and bleeding; likely residual confounding., Conclusions: Among patients with nonvalvular AF undergoing dialysis, warfarin is associated with an increased risk of bleeding compared with apixaban. The risk of bleeding with below-label apixaban was not detectably less than with label-concordant dosing. Label-concordant apixaban dosing is associated with a mortality benefit compared to warfarin. Label-concordant dosing, rather than reduced-label dosing, may offer the most favorable benefit-risk trade-off for dialysis patients with nonvalvular AF., (Copyright © 2022 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: The association of apixaban compared with warfarin for the treatment of venous thromboembolism in patients receiving maintenance dialysis is not well studied., Design, Setting, Participants, & Measurements: We conducted a retrospective cohort study of Medicare fee-for-service beneficiaries receiving dialysis using United States Renal Data System data from 2013 to 2018. The study included patients who received a new prescription for apixaban or warfarin following a venous thromboembolism diagnosis. The outcomes were recurrent venous thromboembolism, major bleeding, and death. Outcomes were analyzed using Cox proportional hazards regression for intention-to-treat and censored-at-drug-switch-or-discontinuation analyses. Models incorporated inverse probability of treatment and censoring weights to minimize confounding and informative censoring., Results: In 12,206 individuals, apixaban, compared with warfarin, was associated with lower risks of both recurrent venous thromboembolism (hazard ratio [HR], 0.58; 95% confidence interval [95% CI], 0.43 to 0.77) and major bleeding (HR, 0.78; 95% CI, 0.62 to 0.98) in the intention-to-treat analysis over 6 months of follow-up. However, there was no difference between apixaban and warfarin in terms of risk of all-cause death (HR, 1.04; 95% CI, 0.94 to 1.16). Corresponding hazard ratios for the 6-month censored-at-drug-switch-or-discontinuation analysis and for corresponding analyses limited to a shorter (3-month) follow-up were all highly similar to the primary analysis., Conclusions: In a large group of US patients on dialysis with recent venous thromboembolism, we observed that apixaban was associated with lower risk of recurrent venous thromboembolism and of major bleeding than warfarin. There was no observed difference in mortality., (Copyright © 2022 by the American Society of Nephrology.)

Cell cycle progression requires control of the abundance of several proteins and RNAs over space and time to properly transit from one phase to the next and to ensure faithful genomic inheritance in daughter cells. The proteasome, the main protein degradation system of the cell, facilitates the establishment of a proteome specific to each phase of the cell cycle. Its activity also strongly influences transcription. Here, we detected the upregulation of repetitive RNAs upon proteasome inhibition in human cancer cells using RNA-seq. The effect of proteasome inhibition on centromeres was remarkable, especially on α-Satellite RNAs. We showed that α-Satellite RNAs fluctuate along the cell cycle and interact with members of the cohesin ring, suggesting that these transcripts may take part in the regulation of mitotic progression. Next, we forced exogenous overexpression and used gapmer oligonucleotide targeting to demonstrate that α-Sat RNAs have regulatory roles in mitosis. Finally, we explored the transcriptional regulation of α-Satellite DNA. Through in silico analyses, we detected the presence of CCAAT transcription factor-binding motifs within α-Satellite centromeric arrays. Using high-resolution three-dimensional immuno-FISH and ChIP-qPCR, we showed an association between the α-Satellite upregulation and the recruitment of the transcription factor NFY-A to the centromere upon MG132-induced proteasome inhibition. Together, our results show that the proteasome controls α-Satellite RNAs associated with the regulation of mitosis., (© 2021 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

The long noncoding RNA (lncRNA) telomeric repeat-containing RNA (TERRA) has been associated with telomeric homeostasis, telomerase recruitment, and the process of chromosome healing; nevertheless, the impact of this association has not been investigated during the carcinogenic process. Determining whether changes in TERRA expression are a cause or a consequence of cell transformation is a complex task because studies are usually carried out using either cancerous cells or tumor samples. To determine the role of this lncRNA in cellular aging and chromosome healing, we evaluated telomeric integrity and TERRA expression during the establishment of a clone of untransformed myeloid cells. We found that reduced expression of TERRA disturbed the telomeric homeostasis of certain loci, but the expression of the lncRNA was affected only when the methylation of subtelomeric bivalent chromatin domains was compromised. We conclude that the disruption in TERRA homeostasis is a consequence of cellular transformation and that changes in its expression profile can lead to telomeric and genomic instability.

Cholestasis, which is impaired bile flow from the liver into the intestine, can be caused by cholangitis and/or bile duct obstruction. Cholangitis can arise from bacterial infections and cholelithiasis, however, immune-mediated cholangitis in primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC) is characterized by a strong immune response targeting the biliary epithelial cells (BECs). Persistent biliary inflammation further represents a risk for biliary neoplasia, cholangiocarcinoma (CCA) by driving chronic cellular stress in the BECs. Currently, immune-mediated cholangitis is considered a Th1-Th17-dominant disease, however, the presence of Th2-related mast cells (MCs) in tissue samples from PBC, PSC and CCA patients has been described, showing that these MCs are active players in these diseases. Here, we reviewed and discussed experimental and clinical data supporting a pro-fibrotic role for MCs in immune-mediated cholangitis as well as their participation in supporting tumor growth acting as angiogenesis promoters. Thus, although MCs have classically been identified as downstream effectors of Th2 responses in allergies and parasitic infections, evidence suggests that these MCs are relevant players in biliary inflammation and neoplasia. The availability of strategies to prevent MCs' activation represents a therapeutic opportunity in biliary diseases.

Background: The association of patient and prescriber characteristics with use of warfarin versus direct-acting oral anticoagulants (DOACs) in patients with atrial fibrillation (AF) and chronic kidney disease (CKD) is not well studied., Methods: The 20% Centers for Medicare & Medicaid Services Parts A, B, and D claims data from 2010 to 2017 were used to identify patients with stage 3, 4, or 5 CKD and AF who received a DOAC (apixaban, dabigatran, rivaroxaban) or warfarin. Prescribers were categorized as cardiologists, primary care providers (PCPs), and others. Using logistic regression, we estimated odds ratios (ORs) for the association of baseline characteristics and prescriber specialty with first use of a DOAC, relative to warfarin., Results: We identified 22,739 individuals with CKD who were newly initiated on oral anticoagulation for AF. New DOAC prescriptions increased from 490 in 2011 to 3261 in 2017, and displaced warfarin over time (1849, 2011; 945, 2017). By Q4 of 2014, cardiologists prescribed DOACs as initial treatment more frequently than warfarin, but non-cardiologists did not do so until 2015. As of 2017, apixaban was the most widely prescribed anticoagulant, comprising 56% and 50% of prescriptions by cardiologists and non-cardiologists, respectively. PCPs (OR 0.54, 0.51-0.58) and other providers (OR 0.55, 0.51-0.59) were less likely than cardiologists to prescribe DOACs., Conclusions: DOAC prescriptions, particularly apixaban, increased over time and gradually displaced warfarin. The total number of patients with AF and CKD receiving anticoagulation increased over time. Cardiologists increased DOAC prescriptions more rapidly than non-cardiologists.

Background Black Americans have more atrial fibrillation risk factors but lower atrial fibrillation risk than White Americans. Left atrial (LA) enlargement and/or dysfunction, frequent atrial tachycardia (AT), and premature atrial contractions (PAC) are associated with increased atrial fibrillation risk. Racial differences in these factors may exist that could explain the difference in atrial fibrillation risk. Methods and Results We included 2133 ARIC (Atherosclerosis Risk in Communities) study participants (aged 74±4.5 years[mean±SD], 59% women, 27% Black participants) who had echocardiograms in 2011 to 2013 and wore the Zio XT Patch (a 2-week continuous heart monitor) in 2016 to 2017. Linear regression was used to analyze (1) differences in AT/day or PAC/hour between Black and White participants, (2) differences in LA measures between Black and White participants, and (3) racial differences in the association of LA measures with AT or PAC frequency. Compared with White participants, Black participants had a higher prevalence of cardiovascular risk factors and disease, lower AT frequency, greater LA size, and lower LA function. After multivariable adjustments, Black participants had 37% (95% CI, 24%-47%) fewer AT runs/day than White participants. No difference in PAC between races was noted. Greater LA size and reduced LA function are associated with more AT and PAC runs; however, no race interaction was present. Conclusions Differences in LA measures are unlikely to explain the difference in atrial fibrillation risk between Black and White individuals. Despite more cardiovascular risk factors and greater atrial remodeling, Black participants have lower AT frequency than White participants. Future research is needed to elucidate the protective mechanisms that confer resilience to atrial arrhythmias in Black individuals.