Initiation of vedolizumab did not provoke new-onset spondylarthritis in patients with inflammatory bowel disease: A prospective 24-week study with imaging assessments.

BACKGROUND: A temporal relationship between vedolizumab and new-onset spondyloarthritis (SpA) has been suggested. AIMS: We evaluated the relationship between vedolizumab initiation and development of new-onset SpA in patients with inflammatory bowel disease (IBD) through serial clinical evaluation and magnetic resonance imaging (MRI). METHODS: A single-centre prospective observational study of 24 patients with IBD. Patients were eligible if they had active ulcerative colitis or Crohn's disease (CD), were initiating vedolizumab, had no prior history of arthritis or SpA and were suitable for serial MRI. A rheumatologist performed clinical evaluation prior to the first dose and 8 and 24 weeks. Axial MRI was evaluated by a blinded central reader and performed at baseline 8 and 24 weeks. RESULTS: Nine tumor necrosis factor (TNF) inhibitor-naïve patients (4 male; mean age 53.2 years; 6 UC; 3 CD) and eight TNF inhibitor-experienced patients (7 male; mean age 48 years; 3 UC; 5 CD) completed all assessments. No patients developed new features of axial arthritis or features of peripheral SpA (inflammatory oligoarthritis, enthesitis, dactylitis, or psoriasis (nail, body, or scalp)). Both groups demonstrated a good intestinal response. CONCLUSION: Vedolizumab initiation did not induce new features of axial or peripheral SpA after 24 weeks of treatment in TNF inhibitor-experienced or TNF inhibitor-naive patients with IBD.

Interplay between Topological States and Rashba States as Manifested on Surface Steps at Room Temperature.

The unique spin texture of quantum states in topological materials underpins many proposed spintronic applications. However, realizations of such great potential are stymied by perturbations, such as temperature and local fields imposed by impurities and defects, that can render a promising quantum state uncontrollable. Here, we report room-temperature scanning tunneling microscopy/spectroscopy observation of interaction between Rashba states and topological surface states, which manifests local electronic structure along step edges controllable by the layer thickness of thin films. The first-principles theoretical calculation elucidates the robust Rashba states coexisting with topological surface states along the surface steps with characteristic spin textures in momentum space. Furthermore, the Rashba edge states can be switched off by reducing the thickness of a topological insulator Bi2Se3 to bolster their interaction with the hybridized topological surface states. The study unveils a manipulating mechanism of the spin textures at room temperature, reinforcing the necessity of thin film technology in controlling the quantum states.

Physical fitness profile of a large urban fire department: Exploring age and rank dynamics.

BACKGROUND: Firefighter physical fitness (PF) plays a crucial role in mitigating health issues and supporting occupational performance. The influence of rank on firefighter PF remains understudied and previous research is often limited by small sample sizes of firefighters volunteering for research studies, potentially biasing results towards fitter firefighters not representative of entire departments. OBJECTIVE: To examine the PF profile of firefighters in a large urban fire department and the influence of age and rank on PF. METHODS: Data, including muscular fitness, estimated aerobic capacity (VO2max), and body fat percentage (BF%) measures from 1361 firefighters (90% male; age: 37.4±10.1yrs; 60 recruits, 973 firefighters, 290 lieutenants/captains, 38 chiefs) were analyzed. Correlation and ANCOVAs were conducted to examine the impact of rank on PF while controlling for age. Score distributions were scrutinized to profile the PF of the department. RESULTS: Age was negatively associated with pull-ups (r = - 0.39), sit-ups (r = - 0.39), and push-ups (r = - 0.32), but positively associated with relative VO2max (r = 0.17) and BF% (r = 0.39). Rank had a statistically significant, but trivial effect size, on pull-ups (p = 0.028, η2 = 0.007) and sit-ups (p = 0.034, η2 = 0.005). Firefighters with lower PF levels were older, had higher BF%, lower fat-free mass, and were a greater proportion of females. CONCLUSIONS: Firefighters exhibited diverse levels of PF. Age, not rank, appeared to influence firefighters' PF. The findings that firefighters who were older, female, with poorer body composition are more likely to have lower PF levels highlights the need for individualized PF training to enhance occupational performance and health across the fire department.

Robustness of Turing models and gene regulatory networks with a sweet spot.

Traditional linear stability analysis based on matrix diagonalization is a computationally intensive process for high-dimensional systems of differential equations, posing substantial limitations for the exploration of Turing systems of pattern formation where an additional wave-number parameter needs to be investigated. In this paper, we introduce an efficient and intuitive technique that leverages Gershgorin's theorem to determine upper limits on regions of parameter space and the wave number beyond which Turing instabilities cannot occur. This method offers a streamlined avenue for exploring the phase diagrams of other complex multi-parametric models, such as those found in gene regulatory networks in systems biology. Due to its suitability for the asymptotic limit of infinitely large systems, it predicts the existence of a sweet spot in network size for maximal Jacobian stability.

An IDR-dependent mechanism for nuclear receptor control of Mediator interaction with RNA polymerase II.

The essential Mediator (MED) coactivator complex plays a well-understood role in regulation of basal transcription in all eukaryotes, but the mechanism underlying its role in activator-dependent transcription remains unknown. We investigated modulation of metazoan MED interaction with RNA polymerase II (RNA Pol II) by antagonistic effects of the MED26 subunit and the CDK8 kinase module (CKM). Biochemical analysis of CKM-MED showed that the CKM blocks binding of the RNA Pol II carboxy-terminal domain (CTD), preventing RNA Pol II interaction. This restriction is eliminated by nuclear receptor (NR) binding to CKM-MED, which enables CTD binding in a MED26-dependent manner. Cryoelectron microscopy (cryo-EM) and crosslinking-mass spectrometry (XL-MS) revealed that the structural basis for modulation of CTD interaction with MED relates to a large intrinsically disordered region (IDR) in CKM subunit MED13 that blocks MED26 and CTD interaction with MED but is repositioned upon NR binding. Hence, NRs can control transcription initiation by priming CKM-MED for MED26-dependent RNA Pol II interaction.

The Surgical Infection Society Guidelines on the Management of Intra-Abdominal Infection: 2024 Update.

Background: The Surgical Infection Society (SIS) published evidence-based guidelines for the management of intra-abdominal infection (IAI) in 1992, 2002, 2010, and 2017. Here, we present the most recent guideline update based on a systematic review of current literature. Methods: The writing group, including current and former members of the SIS Therapeutics and Guidelines Committee and other individuals with content or guideline expertise within the SIS, working with a professional librarian, performed a systematic review using PubMed/Medline, the Cochrane Library, Embase, and Web of Science from 2016 until February 2024. Keyword descriptors combined "surgical site infections" or "intra-abdominal infections" in adults limited to randomized controlled trials, systematic reviews, and meta-analyses. Additional relevant publications not in the initial search but identified during literature review were included. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system was utilized to evaluate the evidence. The strength of each recommendation was rated strong (1) or weak (2). The quality of the evidence was rated high (A), moderate (B), or weak (C). The guideline contains new recommendations and updates to recommendations from previous IAI guideline versions. Final recommendations were developed by an iterative process. All writing group members voted to accept or reject each recommendation. Results: This updated evidence-based guideline contains recommendations from the SIS for the treatment of adult patients with IAI. Evidence-based recommendations were developed for antimicrobial agent selection, timing, route of administration, duration, and de-escalation; timing of source control; treatment of specific pathogens; treatment of specific intra-abdominal disease processes; and implementation of hospital-based antimicrobial agent stewardship programs. Summary: This document contains the most up-to-date recommendations from the SIS on the prevention and management of IAI in adult patients.

The Predictors of Surgery for Symptomatic, Atraumatic Full-Thickness Rotator Cuff Tears Change Over Time: Ten-Year Outcomes of the MOON Shoulder Prospective Cohort.

BACKGROUND: A prospective cohort study was conducted to assess the predictors of failure of nonoperative treatment, defined as the patient undergoing surgery for symptomatic, atraumatic full-thickness rotator cuff tears. We present the 10-year follow-up data of this population to determine if predictors for surgery change over time, and secondarily we report the outcomes of the cohort. METHODS: At the time of enrollment, demographic, symptom, rotator cuff anatomy, and patient-reported outcome data were collected in patients with symptomatic, atraumatic full-thickness rotator cuff tears. Patients underwent a standard physical therapy protocol for 6 to 12 weeks. Patient data were then collected at 1, 2, 5, 7, and 10 years. Failure of nonoperative treatment was defined as the patient electing to undergo surgery. RESULTS: Of the 452 patients in the original cohort, 20 patients (5%) withdrew from the study, 37 (9%) died before 10 years, and 40 (9%) were otherwise lost to follow-up. A total of 115 patients (27.0%) underwent a surgical procedure at some point during the 10-year follow-up period. Of these patients, 56.5% underwent surgery within 6 months of enrollment and 43.5%, between 6 months and 10 years. Low patient expectations regarding the efficacy of physical therapy were found to be a predictor of early surgery. Workers' Compensation status and activity level were more important predictors of later surgery. Patient-reported outcome measures all improved following physical therapy. For patients who did not undergo a surgical procedure, patient-reported outcome measures did not decline over the 10-year follow-up period. CONCLUSIONS: Low patient expectations regarding the efficacy of physical therapy were found to be a predictor of early surgery, whereas Workers' Compensation status and activity level were predictors of later surgery. Physical therapy was successful in >70% of patients with symptomatic, atraumatic full-thickness rotator cuff tears at 10 years. Outcome measures improved with physical therapy and did not decline over the 10-year follow-up period. LEVEL OF EVIDENCE: Prognostic Level I. See Instructions for Authors for a complete description of levels of evidence.

Scalar and Tensor Charmonium Resonances in Coupled-Channel Scattering from Lattice QCD.

We determine J^{PC}=0^{++} and 2^{++} hadron-hadron scattering amplitudes in the charmonium energy region up to 4100 MeV using lattice QCD, a first-principles approach to QCD. Working at m_{π}≈391 MeV, more than 200 finite-volume energy levels are computed and these are used in extensions of the Lüscher formalism to determine infinite-volume coupled-channel scattering amplitudes. We find that this energy region contains a single χ_{c0} and a single χ_{c2} resonance. Both are found as pole singularities on the closest unphysical Riemann sheet, just below 4000 MeV with widths around 70 MeV. The largest couplings are to kinematically closed D^{*}D[over ¯]^{*} channels in S-wave, and couplings to several decay channels consisting of pairs of open-charm mesons are found to be large and significant in both cases. Above the ground state χ_{c0}, no other scalar bound states or near-DD[over ¯] threshold resonances are found, in contrast to several theoretical and experimental studies.

HIF-1 inactivation empowers HIF-2 to drive hypoxia adaptation in aggressive forms of medulloblastoma.

Medulloblastoma (MB) is the most prevalent brain cancer in children. Four subgroups of MB have been identified; of these, Group 3 is the most metastatic. Its genetics and biology remain less clear than the other groups, and it has a poor prognosis and few effective treatments available. Tumor hypoxia and the resulting metabolism are known to be important in the growth and survival of tumors but, to date, have been only minimally explored in MB. Here we show that Group 3 MB tumors do not depend on the canonical transcription factor hypoxia-inducible factor-1α (HIF-1α) to mount an adaptive response to hypoxia. We discovered that HIF-1α is rendered inactive either through post-translational methylation, preventing its nuclear localization specifically in Group 3 MB, or by a low expression that prevents modulation of HIF-target genes. Strikingly, we found that HIF-2 takes over the role of HIF-1 in the nucleus and promotes the activation of hypoxia-dependent anabolic pathways. The exclusion of HIF-1 from the nucleus in Group 3 MB cells enhances the reliance on HIF-2's transcriptional role, making it a viable target for potential anticancer strategies. By combining pharmacological inhibition of HIF-2α with the use of metformin, a mitochondrial complex I inhibitor to block respiration, we effectively induced Group 3 MB cell death, surpassing the effectiveness observed in Non-Group 3 MB cells. Overall, the unique dependence of MB cells, but not normal cells, on HIF-2-mediated anabolic metabolism presents an appealing therapeutic opportunity for treating Group 3 MB patients with minimal toxicity.

The Use of Musculoskeletal Fitness Measures as Indicators of Performance in Police Occupational Tasks.

Fitness testing is employed by some law enforcement agencies to assure performance in occupational tasks. The aim of this study was to investigate associations between musculoskeletal fitness assessment scores and performance in police occupational tasks. Retrospective data from 106 law enforcement officers who completed five musculoskeletal fitness assessments (vertical jump (VJ), hand grip strength, leg back dynamometer, 1-minute push-ups and sit-ups) and three routine occupational tasks (1.22m fence jump (FJ), 8.5m victim drag (VD) with 101kg and a get-up (GU)) were collected. A standard multiple regression was performed to determine if the results in fitness assessments were predictive of performance in the occupational tasks. Models combining all fitness assessments significantly predicted performance in FJ (F(5,88)=12.228, p<0.001; adjusted R2=0.38), VD (F(5,88)=9.407, p<0.001; adjusted R2=0.31) and GU (F(5,87)=14.319, p<0.001; adjusted R2=0.42). Further analysis of individual predictors highlighted that performance in the VJ test was a significant contributor for all models, uniquely predicting 15% of FJ (p<0.001), 4% of VD (p=0.03) and 8% of GU (p=0.001) performance. Grip strength uniquely contributed 3% to performance in the VD (p=0.05) and performance in the sit-up test contributed 8% to GU performance (p=0.001). Performance in police-specific occupational tasks requires a combination of muscular strength, power, and endurance. These musculoskeletal fitness components should be ideally assessed in recruitment and return-to work practices to ensure officers can safely and optimally perform their occupational requirements.

Covalency-Driven Differences in the Hydrogenation Chemistry of Lanthanide- and Actinide-Based Frustrated Lewis Pairs.

The electronic organization of Frustrated Lewis Pairs (FLPs) allows them to activate strong bonds in mechanisms that are usually free of redox events at the Lewis acidic site. The unique 6d/5f manifold of uranium could serve as an interesting FLP acceptor site, but to date FLP-like catalysis with actinide ions is unknown. In this paper, the catalytic, FLP-like hydrogenation reactivity of trivalent uranium complexes is explored in the presence of base-stabilized silylenes. Comparison to isoelectronic, isostructural lanthanide and thorium complexes lends insight into the electronic factors governing dihydrogen activation. Mechanistic studies of the uranium- and lanthanide-catalyzed hydrogenations are presented, including discussion of likely intermediates. Computational modeling of the f-element complexes, combined with experimental comparison to p-block Lewis acids, elucidates the relevance of steric hindrance to productive reactivity with dihydrogen. Consideration of the complete experimental and theoretical evidence provides a clear picture of the electronic and steric factors governing dihydrogen activation by these FLPs.

Navigating Neurologic Illness: Skills in Neuropalliative Care for Persons Hospitalized with Neurologic Disease.

Persons hospitalized for neurologic illness face multidimensional care needs. They can benefit from a palliative care approach that focuses on quality of life for persons with serious illness. We describe neurology provider "skills" to help meet these palliative needs: assessing the patient as a whole; facilitating conversations with patients to connect prognosis to care preferences; navigating neurologic illness to prepare patients and care partners for the future; providing high-quality end-of-life care to promote peace in death; and addressing disparities in care delivery.

Transient formation of collaterals contributes to the restoration of the arterial tree during cardiac regeneration in neonatal mice.

Revascularization of ischemic myocardium following cardiac damage is an important step in cardiac regeneration. However, the mechanism of arteriogenesis has not been well described during cardiac regeneration. Here we investigated coronary artery remodeling and collateral growth during cardiac regeneration. Neonatal MI was induced by ligature of the left descending artery (LAD) in postnatal day (P) 1 or P7 pups from the Cx40-GFP mouse line and the arterial tree was reconstructed in 3D from images of cleared hearts collected at 1, 2, 4, 7 and 14 days after infarction. We show a rapid remodeling of the left coronary arterial tree induced by neonatal MI and the formation of numerous collateral arteries, which are transient in regenerating hearts after MI at P1 and persistent in non-regenerating hearts after MI at P7. This difference is accompanied by restoration of a perfused or a non-perfused LAD following MI at P1 or P7 respectively. Interestingly, collaterals ameliorate cardiac perfusion and drive LAD repair, and lineage tracing analysis demonstrates that the restoration of the LAD occurs by remodeling of pre-existing arterial cells independently of whether they originate in large arteries or arterioles. These results demonstrate that the restoration of the LAD artery during cardiac regeneration occurs by pruning as the rapidly forming collaterals that support perfusion of the disconnected lower LAD subsequently disappear on restoration of a unique LAD. These results highlight a rapid phase of arterial remodeling that plays an important role in vascular repair during cardiac regeneration.

Classification Criteria for Axial Disease in Youth with Juvenile Spondyloarthritis.

OBJECTIVES: To develop and validate classification criteria for axial disease in youth with juvenile spondyloarthritis (SpA; AxJSpA). METHODS: This international initiative consisted of four phases: 1) Item generation; 2) Item reduction; 3) Criteria development; and 4) Validation of the AxJSpA criteria by an independent team of experts in an internationally representative Validation cohort. RESULTS: These criteria are intended to be used on youth with a physician diagnosis of juvenile SpA and for whom axial disease is suspected. Item generation consisted of a systematic literature review and a free-listing exercise using input from international physicians and collectively resulted in 108 items. After the item reduction exercise and expert panel input, 37 items remained for further consideration. The final AxJSpA criteria domains included: imaging: active inflammation, imaging: structural lesions, pain chronicity, pain pattern, pain location, stiffness, and genetics. The most heavily weighted domains were active inflammation and structural lesions on imaging. Imaging typical of sacroiliitis was deemed necessary, but not sufficient, to classify a youth with AxJSpA. The threshold for classification of AxJSpA was a score of ≥55 (out of 100). When tested in the validation data set, the final criteria had a specificity of 97.5% (95% CI: 91.4-99.7), sensitivity of 64.3% (95% CI: 54.9-73.1) and Area Under the Receiver Operating Characteristic (AUROC) curve of 0.81 (95% CI: 0.76-0.86). CONCLUSIONS: The new AxJSpA classification criteria require an entry criterion, physician diagnosis of juvenile SpA, and include seven weighted domains. The AxJSpA classification criteria are validated and designed to identify participants for research studies.

Recovery of arterial blood pressure after chest compression pauses in patients with out-of-hospital cardiac arrest.

BACKGROUND AND AIMS: Chest compressions generating good perfusion during cardiopulmonary resuscitation (CPR) in cardiac arrest patients are critical for positive patient outcomes. Conventional wisdom advises minimizing compression pauses because several compressions are required to recover arterial blood pressure (ABP) back to pre-pause values. Our study examines how compression pauses influence ABP recovery post-pause in out-of-hospital cardiac arrest. METHODS: We analyzed data from a subset of a prospective, randomized LUCAS 2 Active Decompression trial. Patients were treated by an anesthesiologist-staffed rapid response car program in Oslo, Norway (2015-2017) with mechanical chest compressions using the LUCAS device at 102 compressions/min. Patients with an ABP signal during CPR and at least one compression pause >2 sec were included. Arterial cannulation, compression pauses, and ECG during the pause were verified by physician review of patient records and physiological signals. Pauses were excluded if return of spontaneous circulation occurred during the pause (pressure pulses associated with ECG complexes). Compression, mean, and decompression ABP for 10 compressions before/after each pause and the mean ABP during the pause were measured with custom MATLAB code. The relationship between pause duration and ABP recovery was investigated using linear regression. RESULTS: We included 56 patients with a total of 271 pauses (pause duration: median = 11 sec, Q1 = 7 sec, Q3 = 18 sec). Mean ABP dropped from 53 ± 10 mmHg for the last pre-pause compression to 33 ± 7 mmHg during the pause. Compression and mean ABP recovered to >90% of pre-pause pressure within 2 compressions, or 1.7 sec. Pause duration did not affect the recovery of ABP post-pause (R2: 0.05, 0.03, 0.01 for compression, mean, and decompression ABP, respectively). CONCLUSIONS: ABP generated by mechanical CPR recovered quickly after pauses. Recovery of ABP after a pause was independent of pause duration.

Characterizing replisome disassembly in human cells.

To ensure timely duplication of the entire eukaryotic genome, thousands of replication machineries (replisomes) act on genomic DNA at any time during S phase. In the final stages of this process, replisomes are unloaded from chromatin. Unloading is driven by polyubiquitylation of MCM7, a subunit of the terminated replicative helicase, and processed by p97/VCP segregase. Most of our knowledge of replication termination comes from model organisms, and little is known about how this process is executed and regulated in human somatic cells. Here we show that replisome disassembly in this system requires CUL2LRR1-driven MCM7 ubiquitylation, p97, and UBXN7 for unloading and provide evidence for "backup" mitotic replisome disassembly, demonstrating conservation of such mechanisms. Finally, we find that small-molecule inhibitors against Cullin ubiquitin ligases (CULi) and p97 (p97i) affect replisome unloading but also lead to induction of replication stress in cells, which limits their usefulness to specifically target replisome disassembly processes.

Obesity is associated with muscle atrophy in rotator cuff tear.

Objective: The primary goal of this study is to evaluate the relationship between Body Mass Index (BMI) and muscle atrophy in individuals with rotator cuff tears. Methods: This study consists of patients with rotator cuff tears identified by MRI from two independent cohorts, the Rotator Cuff Outcomes Workgroup (ROW) and the Multicenter Orthopaedic Outcomes Network (MOON). Presence of atrophy (yes/no) and severity of atrophy (as an ordinal variable) were assessed on MRI by expert physicians. We used multivariable regression models to evaluate the relationship between BMI and muscle atrophy while adjusting for age and sex in each study, conducted sensitivity analyses for full-thickness tear and combined results using inverse variance-weighted meta-analysis. Results: A total of 539 patients (MOON=395, ROW=144) from the combined cohorts had MRI data available on muscle atrophy. Among these patients, 246 (46%) had atrophy of at least one of the muscles of the rotator cuff and 282 (52%) had full-thickness tears. In meta-analysis across both cohorts, each 5 kg/m2 increase in BMI was associated with a 21% (aOR=1.21, 95% CI=1.02, 1.43) increased odds of having muscle atrophy among individuals with any tear size, and 36% (aOR=1.36, 95% CI=1.01-1.81) increased odds among individuals with full-thickness tear. Conclusions: Higher BMI was associated with significantly higher odds of muscle atrophy in patiens with rotator cuff tears. More study is needed to unders1tand why and how this relationship exists, as well as whether interventions to reduce BMI may help improve outcomes for these patients. Level of Evidence: III.

Design, Fabrication, and Validation of a Portable Perturbation Treadmill for Balance Recovery Research.

Trips and falls are a major concern for older adults. The resulting injury and loss of mobility can have a significant impact on quality of life. An emerging field of study, known as Perturbation Training, has been shown to reduce injury rates associated with trips and falls in older adults. Treadmills traditionally used for Perturbation Training are large, expensive, and immobile, forcing users to travel long distances to receive care. A portable treadmill would serve a larger portion of the at-risk population than current methods. We developed a portable, low-cost, twin-belt perturbation treadmill capable of high-intensity Perturbation Training. Belt speeds are controlled by a custom mechanical and software interface, allowing operators with no programming experience to control the device. The treadmill can accommodate users up to 118 kg and provides a maximum acceleration and speed of 12 m/s2 and 3.3 m/s, respectively, under full load. The total weight is 180 kg, and the treadmill can be moved like a wheelbarrow, with handles in the back and wheels in the front. The prototype was validated with mechanical and human participant testing, showing it as a viable device for Perturbation Training. In this paper, we will go over the design, fabrication, and validation processes used to create the Portable Perturbation Treadmill.