Modeling the extracellular matrix in cell migration and morphogenesis: a guide for the curious biologist.

The extracellular matrix (ECM) is a highly complex structure through which biochemical and mechanical signals are transmitted. In processes of cell migration, the ECM also acts as a scaffold, providing structural support to cells as well as points of potential attachment. Although the ECM is a well-studied structure, its role in many biological processes remains difficult to investigate comprehensively due to its complexity and structural variation within an organism. In tandem with experiments, mathematical models are helpful in refining and testing hypotheses, generating predictions, and exploring conditions outside the scope of experiments. Such models can be combined and calibrated with in vivo and in vitro data to identify critical cell-ECM interactions that drive developmental and homeostatic processes, or the progression of diseases. In this review, we focus on mathematical and computational models of the ECM in processes such as cell migration including cancer metastasis, and in tissue structure and morphogenesis. By highlighting the predictive power of these models, we aim to help bridge the gap between experimental and computational approaches to studying the ECM and to provide guidance on selecting an appropriate model framework to complement corresponding experimental studies.

Surgical Margins in Musculoskeletal Sarcoma.

¼ Negative margin resection of musculoskeletal sarcomas is associated with reduced risk of local recurrence.¼ There is limited evidence to support an absolute margin width of soft tissue or bone that correlates with reduced risk of local recurrence.¼ Factors intrinsic to the tumor, including histologic subtype, grade, growth pattern and neurovascular involvement impact margin status and local recurrence, and should be considered when evaluating a patient's individual risk after positive margins.¼ Appropriate use of adjuvant therapy, critical analysis of preoperative advanced cross-sectional imaging, and the involvement of a multidisciplinary team are essential to obtain negative margins when resecting sarcomas.

Rapid antigen testing for SARS-CoV-2 by lateral flow assay: A field evaluation of self- and professional testing at UK community testing sites.

BACKGROUND: The advent of lateral flow devices (LFDs) for SARS-CoV-2 detection enabled widespread use of rapid self-tests during the pandemic. While self-testing using LFDs is now common, whether self-testing provides comparable performance to professional testing was a key question that remained important for pandemic planning. METHODS: Three prospective multi-centre studies were conducted to compare the performance of self- and professional testing using LFDs. Participants tested themselves or were tested by trained (professional) testers at community testing sites in the UK. Corresponding qRT-PCR test results served as reference standard. The performance of Innova, Orient Gene and SureScreen LFDs by users (self) and professional testers was assessed in terms of sensitivity, specificity, and kit failure (void) rates. Impact of age, sex and symptom status was analysed using logistic regression modelling. RESULTS: 16,617 participants provided paired tests, of which 15,418 were included in the analysis. Self-testing with Innova, Orient Gene or SureScreen LFDs achieved sensitivities of 50 %, 53 % or 72 %, respectively, compared to qRT-PCR. Self and professional LFD testing showed no statistically different sensitivity with respect to corresponding qRT-PCR testing. Specificity was consistently equal to or higher than 99 %. Sex and age had no or only marginal impact on LFD performance while sensitivity was significantly higher for symptomatic individuals. Sensitivity of LFDs increased strongly to up to 90 % with higher levels of viral RNA measured by qRT-PCR. CONCLUSIONS: Our results support SARS-CoV-2 self-testing with LFDs, especially for the detection of individuals whose qRT-PCR tests showed high viral concentrations.

Dual role for microbial short-chain fatty acids in modifying SIV disease trajectory following anti-α4ß7 antibody administration.

BACKGROUND: Human Immunodeficiency Virus (HIV)/Simian Immunodeficiency Virus (SIV) infection is associated with significant gut damage, similar to that observed in patients with inflammatory bowel disease (IBD). This pathology includes loss of epithelial integrity, microbial translocation, dysbiosis, and resultant chronic immune activation. Additionally, the levels of all-trans-retinoic acid (atRA) are dramatically attenuated. Data on the therapeutic use of anti-α4ß7 antibodies has shown promise in patients with ulcerative colitis and Crohn's disease. Recent evidence has suggested that the microbiome and short-chain fatty acid (SCFA) metabolites it generates may be critical for anti-α4ß7 efficacy and maintaining intestinal homeostasis. MATERIALS AND METHODS: To determine whether the microbiome contributes to gut homeostasis after anti-α4ß7 antibody administered to SIV-infected rhesus macaques, faecal SCFA concentrations were determined, 16S rRNA sequencing was performed, plasma viral loads were determined, plasma retinoids were measured longitudinally, and gut retinoid synthesis/response gene expression was quantified. RESULTS: Our results suggest that anti-α4ß7 antibody facilitates the return of retinoid metabolism to baseline levels after SIV infection. Furthermore, faecal SCFAs were shown to be associated with retinoid synthesis gene expression and rebound viral loads after therapy interruption. CONCLUSIONS: Taken together, these data demonstrate the therapeutic advantages of anti-α4ß7 antibody administration during HIV/SIV infection and that the efficacy of anti-α4ß7 antibody may depend on microbiome composition and SCFA generation.

CRP Predicts the Need to Escalate Care After Initial Debridement for Musculoskeletal Infection.

BACKGROUND: Musculoskeletal infections (MSKIs) are a major cause of morbidity in the pediatric population and account for nearly 1 in every 10 consultations with a pediatric orthopaedic provider at a tertiary care center. To prevent or deescalate the risk of adverse medical and musculoskeletal outcomes, timely medical intervention in the form of antibiotics and potential surgical debridement is required. While there have been numerous studies indicating the value of laboratory testing during the initial workup of a child with MSKI, few studies to date have examined the utility of longitudinal assessment of laboratory measures in the acute setting to monitor the efficacy of antibiotic therapy and/or surgical intervention. The purpose of this investigation was to retrospectively determine whether measuring changes in the inflammatory response could indicate the need for escalated care. Specifically, this study examined the hypothesis that serial measurements of C-reactive protein (CRP), immediately preoperatively and 2 days after surgical debridement, could predict the need for medical (change in antibiotics) or surgical (additional debridement) escalation. METHODS: Retrospective review of pediatric patients undergoing operative debridement for the treatment of MSKI between September 2009 and December 2015 from whom laboratory data (CRP) was obtained preoperatively and at postoperative day (POD) 2. Patient demographics, the need for escalated care, and patient outcomes were evaluated. RESULTS: Across 135 pediatric patients, preoperative CRP values >90 mg/L and a positive change in CRP at POD2 effectively predicted the need for escalation of care after initial surgical debridement (Area under the Receiver Operator Curve: 0.883). For each 10-unit increase in preoperative CRP or postoperative change in CRP, there was a 21% or 22% increased risk of needing escalated care, respectively. Stratification by preoperative CRP >90 mg/L and change in CRP postoperatively likewise correlated with increased rates of disseminated disease, percent tissue culture positivity, length of stay, and rate of adverse outcomes. CONCLUSIONS: This study demonstrates the utility of serial CRP to assess the need for escalated care in patients being treated for MSKI. As serial CRP measurements become standard of practice in the acute setting, future prospective studies are needed to optimize the timing of CRP reassessment during inpatient hospitalization to prognosticate patient outcomes, weighing both improvements of patient care and clinical burden. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Deceleration Profiles Between the Penultimate and Final Steps of Planned and Reactive Side-Step Cutting.

CONTEXT: Noncontact anterior cruciate ligament injury often occurs during rapid deceleration and change-of-direction maneuvers. These activities require an athlete to generate braking forces to slow down the center of mass and change direction in a dynamic environment. During preplanned cutting, athletes can use the penultimate step for braking before changing direction, resulting in less braking demand during the final step. During reactive cutting, athletes use different preparatory movement strategies during the penultimate step when planning time is limited. However, possible differences in the deceleration profile between the penultimate and final steps of preplanned and reactive side-step cuts remain unknown. OBJECTIVE: To comprehensively evaluate deceleration during the penultimate and final steps of preplanned and reactive cutting. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: Thirty-six women (age = 20.9 ± 1.7 years, height = 1.66 ± 0.07 m, mass = 62.4 ± 8.7 kg). INTERVENTION: Participants completed 90° side-step cutting maneuvers under preplanned and reactive conditions. MAIN OUTCOME MEASURE(S): Approach velocity, velocity at initial contact, and cutting angle were compared between conditions. Stance time, deceleration time, and biomechanical indicators of deceleration were assessed during the penultimate and final steps of preplanned and reactive 90° cuts. Separate repeated-measures analysis-of-variance models were used to assess the influence of step, condition, and their interaction on the biomechanical indicators of deceleration. RESULTS: Approach velocity (P = .69) and velocity at initial contact of the penultimate step (P = .33) did not differ between conditions. During reactive cutting, participants achieved a smaller cutting angle (P < .001). We identified a significant step-by-condition interaction for all biomechanical indicators of deceleration (P values < .05). CONCLUSIONS: A lack of planning time resulted in less penultimate step braking and greater final step braking during reactive cutting. As a result, participants exhibited a decreased cutting angle and longer stance time during the final step of reactive cutting. Improving an athlete's ability to respond to an external stimulus may facilitate a more effective penultimate step braking strategy that decreases the braking demand during the final step of reactive cutting.

BG4 antibody can recognize telomeric G-quadruplexes harboring destabilizing base modifications and lesions.

BG4 is a single-chain variable fragment antibody shown to bind various G-quadruplex (GQ) topologies with high affinity and specificity, and to detect GQ in cells, including GQ structures formed within telomeric TTAGGG repeats. Here, we used ELISA and single-molecule pull-down (SiMPull) detection to test how various lengths and GQ destabilizing base modifications in telomeric DNA constructs alter BG4 binding. We observed high-affinity BG4 binding to telomeric GQ independent of telomere length, although three telomeric repeat constructs that cannot form stable intramolecular GQ showed reduced affinity. A single guanine substitution with 8-aza-7-deaza-G, T, A, or C reduced affinity to varying degrees depending on the location and base type, whereas two G substitutions in the telomeric construct dramatically reduced or abolished binding. Substitution with damaged bases 8-oxoguanine and O6-methylguanine failed to prevent BG4 binding although affinity was reduced depending on lesion location. SiMPull combined with FRET revealed that BG4 binding promotes folding of telomeric GQ harboring a G to T substitution or 8-oxoguanine. Atomic force microscopy revealed that BG4 binds telomeric GQ with a 1:1 stoichiometry. Collectively, our data suggest that BG4 can recognize partially folded telomeric GQ structures and promote telomeric GQ stability.

Theoretical and DFT Study of Atypical Pentanuclear [(iPr3P)Ni]5Hn (n = 4, 6, 8) Clusters: What are the Rules?

The structure, bonding, and properties of a series of atypical pentanuclear nickel hydride clusters supported by electron-rich iPr3P of the type [(iPr3P)Ni]5Hn (n = 4, 6, 8; H4, H6, H8) and their anionic models where iPr3P are substituted by H- (H4', H6', H8') were investigated by density functional theory (DFT) calculations. All clusters were calculated to adopt a similar square pyramidal core geometry. Calculations indicate singlet ground states with small singlet-triplet gaps for H4 and H6, similar to previously reported experimental values. Molecular orbital theory description clusters were investigated using the simplified model complexes [HNi]5Hn5- (n = 4, 6, 8; H4', H6', H8'). The results show that there are three skeletal electron pairs (SEPs) in H4'. The addition of two molecules of H2 to form H6' and H8' results in the partial or full occupation of two degenerate MOs (e* set) that give two SEPs and one SEP, respectively. Indeed, the occupation of these low-lying weakly antibonding orbitals governs the multielectron chemistry available for these clusters and plays a role in their unique reactivity.

Rituximab reference vs biosimilar utilization for oncology vs nononcology indications.

OBJECTIVES: Limited data exist on the adoption of rituximab biosimilars vs the reference product by indication. Available data from real-world studies comparing rituximab biosimilar and reference use have focused predominantly on oncology indications. This is the first study to assess the utilization of the 3 US rituximab biosimilars vs the reference product. STUDY DESIGN: Comparative analysis. METHODS: Deidentified real-world data of rituximab, rituximab-abbs, rituximab-pvvr, and rituximab-arrx dispensations between December 31, 2018, and February 1, 2022, were extracted using Trisus Medication Compare (The Craneware Group). The primary outcome was rituximab reference vs biosimilar utilization for oncology vs nononcology indications. Results were stratified by on-label and off-label use and treatment settings. RESULTS: A total of 28,025 encounters were captured for rituximab and its biosimilars across 193 facilities (rituximab: n = 23,395; biosimilars, n = 4631 [rituximab-abbs: n = 2550; rituximab-pvvr, n = 2081; rituximab-arrx: n = 0]). Rituximab reference had higher dispensations for oncology (78.4%) and nononcology (88.3%) indications than its biosimilars (21.6% and 11.7%, respectively; P < .01). The 3-year annual trends from 2019 to 2021 revealed decreased rituximab reference utilization (99.99% to 40.1%) and increased biosimilar use (0.01% to 59.9%). Most oncology dispensations were on label (94.5%), whereas most nononcology dispensations were off label (73.6%; P < .01). A higher proportion of biosimilar use was attributed to on-label indications (67.7%; off-label, 32.2%) compared with rituximab reference (58.0% vs42.0%, respectively; P < .01). Nonacademic settings showed higher biosimilar adoption than academic settings (22.2% vs 10.3%, respectively; P < .01). CONCLUSIONS: Real-world evidence shows an increase in rituximab biosimilar adoption over time, with higher adoption for oncology vs nononcology indications and in nonacademic settings.

Nudges, regulations, and behavioral public choice.

Chater & Loewenstein have done a service to the field by raising the fundamental issue of how the political process distorts well-intentioned efforts at behavioral public policy. We connect this argument to broader research on government failure, particularly public choice theory in economics. We further suggest ways that behavioral research can help identify and mitigate such failures.

Influence and influenceability: global directionality in directed complex networks.

Knowing which nodes are influential in a complex network and whether the network can be influenced by a small subset of nodes is a key part of network analysis. However, many traditional measures of importance focus on node level information without considering the global network architecture. We use the method of trophic analysis to study directed networks and show that both 'influence' and 'influenceability' in directed networks depend on the hierarchical structure and the global directionality, as measured by the trophic levels and trophic coherence, respectively. We show that in directed networks trophic hierarchy can explain: the nodes that can reach the most others; where the eigenvector centrality localizes; which nodes shape the behaviour in opinion or oscillator dynamics; and which strategies will be successful in generalized rock-paper-scissors games. We show, moreover, that these phenomena are mediated by the global directionality. We also highlight other structural properties of real networks related to influenceability, such as the pseudospectra, which depend on trophic coherence. These results apply to any directed network and the principles highlighted-that node hierarchy is essential for understanding network influence, mediated by global directionality-are applicable to many real-world dynamics.

Head and Neck Necrotizing Fasciitis: Abbreviated SOFA Score Associated With Death and Infection Spread.

Objective: Describe features unique to head and neck (H&N) necrotizing fasciitis (NF) compared to other anatomic regions and specify a prognostic score associated with death and descending necrotizing mediastinitis (DNM). Study Design: Retrospective cohort. Setting: Tertiary care, level 1 trauma center. Methods: A single-institution database identified 399 confirmed cases of NF between 2006 and 2021, 33 of which involved the H&N. Patients with confirmed H&N NF were sorted into cohorts based on clinical outcomes, with the "poor" outcomes group defined by death and/or DNM. Results: Thirty-three patients with H&N NF were included. Compared to NF of other regions, patients with H&N NF had a significantly lower mortality rate (6.06% vs 20.8%, p = .041) and significantly lower rates of obesity (27.3% vs 63.7%, p < .001) and hypertension (42.4% vs 60.9%, p = .038). Within the H&N group, there were 2 deaths (6.06%) and 8 cases of DNM (24.2%). Diabetes was associated with poor outcomes (p = .047), as was an abbreviated sequential organ failure assessment score for necrotizing fasciitis (nfSOFA) of 2 or greater (p = .015). Conclusion: H&N NF is unique among other forms of NF, with a lower mortality rate and lower rates of obesity and hypertension in affected patients. Within the H&N cohort, worse outcomes were associated with diabetes as well as a nfSOFA score of 2 or greater. Timely surgical debridement alongside broad-spectrum antibiotics remains the mainstay of treatment for NF; however, this simple prognostic score may play a role during the early stages of care for patients with H&N NF.

Single-Legged Triple-Hop Propulsion Strategies in Females With and Those Without a History of Anterior Cruciate Ligament Reconstruction.

CONTEXT: The single-legged triple hop is a commonly used functional task after anterior cruciate ligament reconstruction (ACLR). Recently, researchers have suggested that individuals may use a compensatory propulsion strategy to mask underlying quadriceps dysfunction and achieve symmetric hop performance. OBJECTIVE: To evaluate the performance and propulsion strategies used by females with and those without ACLR during a single-legged triple hop. DESIGN: Cross-sectional study. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 38 females, 19 with ACLR (age = 19.21 ± 1.81 years, height = 1.64 ± 0.70 m, mass = 63.79 ± 7.59 kg) and 19 without ACLR (control group; age = 21.11 ± 3.28 years, height = 1.67 ± 0.73 m, mass = 67.28 ± 9.25 kg). MAIN OUTCOME MEASURE(S): Hop distance and limb symmetry index (LSI) were assessed during a single-legged triple hop for distance. Propulsion strategies were evaluated during the first and second hops of the single-legged triple hop. Separate 2-way analysis-of-variance models were used to examine the influence of ACLR, joint, and their interaction on mechanical joint work, moment impulse, and the relative joint contributions to total work and moment impulse in females with and those without a history of ACLR. RESULTS: Despite achieving a mean LSI of approximately 96%, the ACLR group produced less total work in the reconstructed than the uninvolved limb during single-legged triple-hop propulsion (first hop: t18 = -3.73, P = .002; second hop: t18 = -2.55, P = .02). During the first and second hops, the reconstructed knee generated 19.3% (t18 = -2.33, P = .03) and 27.3% (t18 = -4.47, P < .001) less work than the uninvolved knee. No differences were identified between the involved and uninvolved limbs of the ACLR group in moment impulse (first hop: t18 = -0.44, P = .67; second hop: t18 = -0.32; P = .76). Irrespective of limb or group, the ankle was the largest contributor to both work and moment during both the first and second hops (P < .001). CONCLUSIONS: Clinicians should exercise caution when using a single-legged triple hop as a surrogate for restored lower extremity function in females post-ACLR. This recommendation is driven by the compelling findings that knee-joint deficits persisted in the reconstructed limb despite an LSI of approximately 96% and, regardless of previous injury status, single-legged triple-hop propulsion was predominantly driven by the ankle.

When do consumers favor overly precise information about investment returns?

Consumers are often shown investment returns with high levels of precision, which could lead them to misunderstand the inherent uncertainty. We test whether consumers are drawn to precision-that is offset the uncertainty in investment decisions by over-relying on precise numerical information. Five incentivized experiments compared decisions when expected growth is presented in precise forecasts as opposed to ranges. Consumers are more likely to prefer and invest more in precise forecasts when they are evaluated jointly with ranges and when the range features a potential loss. Under these circumstances, precise forecasts give consumers more confidence to invest. This effect holds when consumers are told investment returns are uncertain. On the other hand, experiencing discrepancies between expected and actual growth dissipates the preference for precise forecasts. We identify conditions under which consumers are more likely to favor precise forecasts and how this could be avoided if necessary. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Surgical Fixation Method in Lower Extremity Intercalary Allograft Reconstruction After Oncologic Resection: A Comparison of Plates and Nails.

INTRODUCTION: Fixation in intercalary allograft reconstruction includes plates and intramedullary nails. The purpose of this study was to examine rates of nonunion, fracture, the overall need for revision surgery, and allograft survival based on the surgical fixation method in lower extremity intercalary allografts. METHODS: A retrospective chart review was performed on 51 patients with intercalary allograft reconstruction in the lower extremity. Fixation methods compared were intramedullary fixation with nails (IMN) and extramedullary fixation with plates (EMP). Complications compared were nonunion, fracture, and wound complications. The alpha was set at 0.05 for statistical analysis. RESULTS: Nonunion incidence at all allograft-to-native bone junction sites was 21% (IMN) and 25% (EMP) ( P = 0.8). Fracture incidence was 24% (IMN) and 32% (EMP) ( P = 0.75). Median fracture-free allograft survival was 7.9 years (IMN) and 3.2 years (EMP) ( P = 0.04). Infection was seen in 18% (IMN) and 12% (EMP) ( P = 0.7). The overall need for revision surgery was 59% (IMN) and 71% (EMP) ( P = 0.53). Allograft survival at the final follow-up was 82% (IMN) and 65% (EMP) ( P = 0.33). When the EMP group was subdivided into single plate (SP) and multiple plate (MP) groups and compared with the IMN groups, fracture rates were 24% (IMN), 8% (SP), and 48% (MP) ( P = 0.04). Rates of revision surgery were 59% (IMN), 46% (SP), and 86% (MP) ( P = 0.04). Allograft survival at the final follow-up was 88% (IMN), 92% (SP), and 52% (MP) ( P = 0.05). DISCUSSION: Median fracture-free allograft survival was notably longer for the IMN group than the EMP group; otherwise, there were no notable differences between the intramedullary and extramedullary groups. When the EMP group was subdivided into the SP and MP groups, patients with MPs had higher rates of fracture, higher rates of revision surgery, and lower overall allograft survival. LEVEL OF EVIDENCE: III, Therapeutic Study, Retrospective Comparative Study.