Spinal RAMP1-mediated neuropathic pain sensitisation in the aged mice through the modulation of CGRP-CRLR pain signalling.

Pain sensitivity varies depending on both the state and age of an individual. For example, chronic pain is more common in older individuals, but the underlying mechanisms remain unknown. This study revealed that 18-month-old mice (aged) experienced more severe and long-lasting allodynia and hyperalgesia in the chronic constriction injury (CCI)-induced pain state compared to 2-month-old mice. Interestingly, the aged mice had a higher baseline mechanical pain threshold than the adult mice. The expression of spinal receptor-active modification protein 1 (RAMP1), as a key component and regulator of the calcitonin gene-related peptide (CGRP) receptor for nociceptive transmission from the periphery to the spinal cord, was reduced in the physiological state but significantly increased after CCI in the aged mice compared to the adult mice. Moreover, when RAMP1 was knocked down using shRNA, the pain sensitivity of adult mice decreased significantly, and CCI-induced allodynia in aged mice was reduced. These findings suggest that spinal RAMP1 is involved in regulating pain sensitivity in a state- and age-dependent manner. Additionally, interfering with RAMP1 could be a promising strategy for alleviating chronic pain in older individuals.

Eosinophil-Associated Genes are Potential Biomarkers for Hepatocellular Carcinoma Prognosis.

Background: Eosinophils, a type of white blood cell originating from the bone marrow, are widely believed to play a crucial role in inflammatory processes, including allergic reactions and parasitic infections. However, the relationship between eosinophils and liver cancer is not well understood. Methods: Tumor immune infiltration scores were calculated using single-sample Gene Set Enrichment Analysis (ssGSEA). Key modules and hub genes associated with eosinophils were screened using Weighted Gene Co-expression Network Analysis (WGCNA). Univariate and multivariate Cox analyses, along with LASSO regression, were used to identify prognostic genes and create a risk model. The Tumor Immune Dysfunction and Exclusion (TIDE) score was used to evaluate the immunotherapeutic significance of the eosinophil-associated gene risk score (ERS) model. Experiments such as flow cytometry, immunohistochemical analysis, real-time quantitative PCR (RT-qPCR), and Western blotting were used to determine gene expression levels and the status of eosinophil infiltration in tumors. Results: A risk trait model including 4 eosinophil-associated genes (RAMP3, G6PD, SSRP1, PLOD2) was developed by univariate Cox analysis and Lasso screening. Pathologic grading (p < 0.001) and model risk scores (p < 0.001) were found to be independent predictors of hepatocellular carcinoma (HCC) patient survival. Western blotting revealed higher levels of eosinophil peroxidase (EPX) in HCC tissues compared to adjacent normal tissues. Immunohistochemistry showed that eosinophils mainly infiltrated the connective tissue around HCC. The HCC samples showed low expression of RAMP3 and high expression of G6PD, SSRP1, and PLOD2, as detected by IHC and RT-qPCR analysis. The in vivo mouse experiments showed that IL-33 treatment induced the recruitment of eosinophils and reduced the number of intrahepatic tumor nodules. Conclusion: Overall, eosinophil infiltration in HCC is significantly correlated with patient survival. The risk assessment model based on eosinophil-related genes serves as a reliable clinical prognostic indicator and provides insights for precise treatment of HCC.

Effects of an untreated medial meniscal ramp lesion on histological deterioration findings of the medial meniscus: A study in a porcine anterior cruciate ligament reconstruction model.

Purpose: To evaluate the effect of untreated medial meniscal ramp lesions (MMRLs) on the tendon graft after anterior cruciate ligament (ACL) reconstruction and histological findings of medial meniscus (MM) in a porcine a model. Methods: A total of 17 pigs were divided into two groups: (1) the untreated MMRL group (UM group, n = 9) and (2) intact MM group (n = 8) and euthanized 12 weeks after surgery. The specimens were then tested cyclically and loaded to failure. Side-to-side differences (SSDs) in translation under cyclic loading and structural properties were analyzed. Histological evaluation of the MM was also performed. Results: No significant differences in the SSD in translation during the cyclic testing (UM group, 0.3 ± 0.4 mm; intact MM group, 0.1 ± 1.4 mm), upper yield load (UM group, 476.3 ± 399.9 N; intact MM group, 643.2 ± 302.9 N), maximum load (UM group, 539.5 ± 265.8 N; intact MM group, 705.8 ± 282.6 N), linear stiffness (UM group, 63.5 ± 39.0 N/mm; intact MM group, 73.7 ± 60.1 N/mm) and elongation at failure (UM group, -4.6 ± 16.3 mm; intact MM group, 2.3 ± 6.6 mm) were observed. However, the UM group had significantly worse Modified Mankin's histological grading scores (1.8 ± 0.4 [1-2] vs. 0 ± 0 [0]; p < 0.001) and Modified Copenhaver classification scores (6.6 ± 2.4 [2-9] vs. 0.7 ± 1.1 [0-3]; p < 0.001) than did the intact MM group. Conclusion: Untreated MMRLs showed postoperative histological deterioration. Level of Evidence: Level IV.

RAMP1 Signaling Mitigates Acute Lung Injury by Distinctively Regulating Alveolar and Monocyte-Derived Macrophages.

Acute respiratory distress syndrome (ARDS) is a life-threatening lung injury that induces cytokine hypersecretion. Receptor activity-modifying protein (RAMP) 1, a subunit of the calcitonin gene-related peptide (CGRP) receptor, regulates the production of cytokines. This study examined the role of RAMP1 signaling during lipopolysaccharide (LPS)-induced acute lung injury (ALI). LPS administration to wild-type (WT) mice depleted alveolar macrophages (AMs) and recruited monocyte-derived macrophages (MDMs) and neutrophils. RAMP1-deficient (RAMP1-/-) mice exhibited higher lung injury scores, cytokine levels, and cytokine-producing neutrophil infiltration. RAMP1-deficient AMs produced more cytokines in response to LPS than WT AMs. Adoptive transfer of RAMP1-deficient AMs to RAMP1-/- mice increased cytokine levels and neutrophil accumulation compared to the transfer of WT AMs. RAMP1-/- mice had reduced MDM recruitment and lower pro-inflammatory and reparative macrophage profiles. Cultured bone marrow (BM)-derived RAMP1-deficient macrophages stimulated with LPS showed decreased expression of pro-inflammatory and pro-repairing genes. CGRP administration to WT mice reduced cytokine production and neutrophil accumulation. These findings indicate that RAMP1 signaling mitigates LPS-induced ALI by inactivating AMs and promoting inflammatory and repair activities of MDMs. Targeting RAMP1 signaling presents a potential therapeutic approach for the treatment of ARDS.

Understanding speeding behavior on interstate horizontal curves and ramps using networkwide probe data.

INTRODUCTION: Lane departure collisions account for many roadway fatalities across the United States. Many of these crashes occur on horizontal curves or ramps and are due to speeding. This research investigates factors that impact the odds of speeding on Interstate horizontal curves and ramps. METHOD: We collected and combined two unique sources of data. The first database involves comprehensive curve and ramp characteristics collected by an automatic road analyzer (ARAN) vehicle; the second database includes volume, average speed, and speed distribution gathered from probe data provided by StreetLight Insight®. We evaluated the impacts of level of service (LOS), which reflects traffic density or level of congestion, time of the day (morning, evening, and off-peak hours), time of the week (weekdays and weekends), and month of the year (Jan-Dec), and various information about geometric characteristics, such as curve radius, arc angle, and superelevation, on odds of speeding. RESULTS: The results show that the odds of speeding increases at horizontal curves with improved levels of service, as well as those with larger radii and superelevation. The odds of speeding decreases on curves with larger arc angles and during the winter months of the year. The findings indicate a reduction in odds of speeding at diagonal/loop ramps with larger arc angles and narrower lane widths. CONCLUSION: The results show the importance of using speed enforcement and other countermeasures to reduce speeding on curves with low traffic volumes, high speed limits, and large radius and superelevation, especially for those in rural areas. PRACTICAL APPLICATION: The results could be used to prioritize locations for the installation of speed countermeasures or dispatch enforcement resources to high-priority locations and times.

Triple three-dimensional MS/MS spectrum facilitates quantitative ginsenosides-targeted sub-metabolome characterization in notoginseng.

Although serving as the workhorse, MS/MS cannot fully satisfy the analytical requirements of quantitative sub-metabolome characterization. Because more information intrinsically correlates to more structural and concentration clues, here, efforts were devoted to comprehensively tracing and deciphering MS/MS behaviors through constructing triple three-dimensional (3×3D)-MS/MS spectrum. Ginsenosides-targeted metabolomics of notoginseng, one of the most famous edible medicinal plants, was employed as a proof-of-concept. Serial authentic ginsenosides were deployed to build the correlations between 3×3D-MS/MS spectra and structure/concentration features. Through assaying ginsenosides with progressive concentrations using QTOF-MS to configure 1st 3D spectrum, the generations of MS1 spectral signals, particularly multi-charged multimer anions, e.g., [2M-2H]2- and [2M+2HCOO]2- ions, relied on both concentration and the amount of sugar chains. By programming progressive collision energies to the front collision cell of Qtrap-MS device to gain 2nd 3D spectrum, optimal collision energy (OCE) corresponding to the glycosidic bond fission was primarily correlated with the masses of precursor and fragment ions and partially governed by the glycosidation site. The quantitative relationships between OCEs and masses of precursor and fragment ions were utilized to build large-scale quantitative program for ginsenosides. After applying progressive exciting energies to the back collision chamber to build 3rd 3D spectrum, the fragment ion and the decomposition product anion exhibited identical dissociation trajectories when they shared the same molecular geometry. After ginsenosides-focused quantitative metabolomics, significant differences occurred for sub-metabolome amongst different parts of notoginseng. The differential ginsenosides were confirmatively identified by applying the correlations between 3×3D-MS/MS spectra and structures. Together, 3×3D-MS/MS spectrum covers all MS/MS behaviors and dramatically facilitates sub-metabolome characterization from both quantitative program development and structural identification.

Physical activity based on daily steps in patients with chronic musculoskeletal pain: evolution and associated factors.

BACKGROUND: People with chronic musculoskeletal pain (CMSP) often have low physical activity. Various factors can influence the activity level. The aim of this study was to monitor physical activity, assessed by the number of steps per day, over time in people with CMSP and identify factors that could be associated with this activity feature. METHODS: This prospective study involved people undergoing rehabilitation following an orthopedic trauma that had led to CMSP. At entry, participants completed self-reported questionnaires assessing pain, anxiety, depression, catastrophyzing, kinesiophobia, and behavioural activity patterns (avoidance, pacing and overdoing). They also underwent functional tests, assessing walking endurance and physical fitness. To determine daily step counts, participants wore an accelerometer for 1 week during rehabilitation and 3 months post-rehabilitation. The number of steps per day was compared among three time points: weekend of rehabilitation (an estimate of pre-rehabilitation activity; T1), weekdays of rehabilitation (T2), and post-rehabilitation (T3). Linear regression models were used to analyze the association between daily steps at T2 and at T3 and self-reported and performance-based parameters. RESULTS: Data from 145 participants were analyzed. The mean number of steps was significantly higher during T2 than T1 and T3 (7323 [3047] vs. 4782 [2689], p < 0.001, Cohen's d = 0.769, and 4757 [2680], p < 0.001, Cohen's d = 0.693), whereas T1 and T3 results were similar (p = 0.92, Cohen's d = 0.008). Correlations of number of steps per day among time points were low (r ≤ 0.4). Multivariable regression models revealed an association between daily steps at T2 and pain interfering with walking, anxiety and overdoing behaviour. Daily steps at T3 were associated with overdoing behaviour and physical fitness. CONCLUSIONS: Despite chronic pain, people in rehabilitation after an orthopedic trauma increased their physical activity if they were given incentives to do so. When these incentives disappeared, most people returned to their previous activity levels. A multimodal follow-up approach could include both therapeutic and environmental incentives to help maintain physical activity in this population.

Signalling of the neuropeptide calcitonin gene-related peptide (CGRP) through RAMP1 promotes liver fibrosis via TGFß1/Smad2 and YAP pathways.

The liver is innervated by primary sensory nerve fibres releasing the neuropeptide calcitonin gene-related peptide (CGRP). Elevated plasma levels of CGRP have been found in patients with liver fibrosis or cirrhosis. We hypothesised that signalling of CGRP and its receptors might regulate liver fibrosis and propose a novel potential target for the treatment. In this study, hepatic expression of CGRP and its receptor component, the receptor activity-modifying protein 1 (RAMP1), was dramatically increased in diseased livers of patients. In a murine liver fibrosis model, deficiency of RAMP1 resulted in attenuated fibrogenesis characterized by less collagen deposition and decreased activity of hepatic stellate cells (HSC). Mechanistically, activity of the TGFß1 signalling core component Smad2 was severely impaired in the absence of RAMP1, and Yes-associated protein (YAP) activity was found to be diminished in RAMP1-deficient liver parenchyma. In vitro, stimulation of the HSC line LX-2 cells with CGRP induces TGFß1 production and downstream signalling as well as HSC activation documented by increased α-SMA expression and collagen synthesis. We further demonstrate in LX-2 cells that CGRP promotes YAP activation and its nuclear translocation subsequent to TGFß1/Smad2 signals. These data support a promotive effect of CGRP signalling in liver fibrosis via stimulation of TGFß1/Smad2 and YAP activity.

Lack of RAMP1 Signaling Suppresses Liver Regeneration and Angiogenesis Following Partial Hepatectomy in Mice.

BACKGROUND/AIM: The liver effectively restores both size and function following partial hepatectomy (PHx). Angiogenesis is crucial for the repair and regeneration of liver tissue post-PHx. Calcitonin gene-related peptide (CGRP) released from sensory nerves and its receptor-receptor activity-modifying protein 1 (RAMP1) are involved in angiogenesis. This study aimed to assess the role of RAMP1 signaling in angiogenesis during liver regeneration following PHx. MATERIALS AND METHODS: RAMP1 deficient (RAMP1-/-) and wild-type (WT) mice were subjected to PHx. RESULTS: RAMP1-/- mice demonstrated delayed liver regeneration, indicated by lower liver-to-body weight ratios compared to WT mice. This was associated with lower levels of Ki67+ hepatocytes and hepatic trophic growth factors. Additionally, RAMP1-/- mice exhibited lower levels of endothelial cell markers, including CD31, compared to WT mice. This reduction was associated with reduced levels of vascular endothelial growth factor (VEGF)-C, VEGF-D, and VEGF receptor 3 (VEGFR3). In WT mice with PHx, the administration of a VEGFR3 inhibitor reduced the liver-to-body weight ratio, Ki67+ hepatocytes, and VEGF-C/VEGFR3 expression levels in the liver compared to those in the vehicle-treated group. CONCLUSION: The deletion of RAMP1 signaling suppresses liver regeneration and angiogenesis through VEGFR3. Specific activation of RAMP1 signaling may represent a potential therapeutic strategy for liver regeneration following PHx.

Magnetic field and initial stress on a rotating photothermal semiconductor medium with ramp type heating and internal heat source.

This manuscript addresses a significant research gap in the study by employing a mathematical model of photo thermoelastic wave propagation in a rotator semiconductor medium under the effect of a magnetic field and initial stress, as well as ramp-type heating. The considered model is formulated during the photothermal theory and in two-dimensional (2D) electronic-elastic deformation. The governing equations represent the interaction between the primary physical parameters throughout the process of photothermal transfer. Computational simulations are performed to determine the temperature, carrier density, displacement components, normal stress, and shear stress using the application of Lame's potential and normal mode analysis. Numerical calculations are carried out and graphically displayed for an isotropic semiconductor like silicon (Si) material. Furthermore, comparisons are made with the previous results obtained by the others, as well as in the presence and absence of magnetic field, rotation, and initial stress. The obtained results illustrate that the rotation, initial stress, magnetic field, and ramp-type heating parameter all have significant effects. This investigation provides valuable insights into the synergistic dynamics among a magnetization constituent, semiconducture structures, and wave propagation, enabling advancements in nuclear reactors' construction, operation, electrical circuits, and solar cells.

Effects of different slopes on hip and ankle biomechanics of replaced and non-replaced limbs of patients with total knee arthroplasty during incline ramp walking.

Although knee biomechanics has been examined, hip and ankle biomechanics in incline ramp walking has not been explored for patients with total knee arthroplasty (TKA). The purpose of this study was to investigate the hip and ankle joint kinematic and kinetic biomechanics of different incline slopes for replaced limbs and non-replaced limbs in individuals with TKA compared to healthy controls. Twenty-five patients with TKR and ten healthy controls performed walking trials on four slope conditions of level (0°), 5°, 10° and 15° on a customized instrumented ramp system. A 3x4 (limb x slope) repeated analysis of variance was used to evaluate selected variables. The results showed a greater peak ankle dorsiflexion angle in the replaced limbs compared to healthy limbs. No significant interactions or limb main effect for other ankle and hip variables. The peak dorsiflexion angle, eversion angle and dorsiflexion moment were progressively higher in each comparison from level to 15°. The peak plantarflexion moment was also increased with each increase of slopes. Both the replaced and non-replaced limbs of patients with TKA had lower hip flexion moments than the healthy control limbs. Hip angle at contact and hip extension range of motion increased with each increase of slopes. Peak hip loading-response internal extension moment increased with each increase in slope and peak hip push-off internal flexion moment decreased with each increase of slope. Our results showed increased dorsiflexion in replaced limbs but no other compensations of hip and ankle joints of replaced limbs compared to non-replaced limbs and their healthy controls during incline walking, providing further support of using incline walking in rehabilitation for patients with TKA.

Tolerability and Safety of Large-Volume Hyaluronidase-Facilitated Subcutaneous Immunoglobulin 10% Administered with or without Dose Ramp-Up: A Phase 1 Study in Healthy Participants.

PURPOSE: Facilitated subcutaneous immunoglobulin (fSCIG; immune globulin infusion 10% [human] with recombinant human hyaluronidase [rHuPH20]) permits high-volume subcutaneous immunoglobulin (SCIG) infusion, shorter infusion times and reduced dosing frequency relative to conventional SCIG. It is initiated by gradually increasing infusion volumes over time (dose ramp-up) to achieve target dose level (TDL). Whether ramp-up strategies have tolerability or safety advantages over direct initiation at full TDL has not been evaluated clinically. METHODS: This phase 1 open-label study assessed tolerability and safety of fSCIG 10% with accelerated or no ramp-up compared with conventional ramp-up in healthy adults (NCT04578535). Participants were assigned to one of the three ramp-up arms to achieve TDLs of 0.4 or 1.0 g/kg/infusion. The primary endpoint was the proportion of infusions completed without interruption or infusion rate reduction owing to treatment-emergent adverse events (TEAEs). Safety was assessed as a secondary endpoint. RESULTS: Of 51 participants enrolled, 50 (98.0%) tolerated all fSCIG 10% infusions initiated (n = 174). Infusion rate was reduced in one participant owing to headache in the 0.4 g/kg/infusion conventional ramp-up arm. Study discontinuations were higher in the no ramp-up arm (70%) versus the conventional (0%) and accelerated (22%) arms at the 1.0 g/kg/infusion TDL. Safety outcomes did not substantially differ between treatment arms. CONCLUSION: The favorable tolerability and safety profiles of fSCIG 10% in healthy participants support initiating treatment with fSCIG 10% with accelerated ramp-up at TDLs up to 1.0 g/kg. Data support no ramp-up at TDLs close to 0.4 g/kg but additional data are needed for higher doses.

Involvement of RAMP1/p38MAPK signaling pathway in osteoblast differentiation in response to mechanical stimulation: a preliminary study.

OBJECTIVE: The present study aimed to investigate the underlying mechanism of mechanical stimulation in regulating osteogenic differentiation. MATERIALS AND METHODS: Osteoblasts were exposed to compressive force (0-4 g/cm2) for 1-3 days or CGRP for 1 or 3 days. Expression of receptor activity modifying protein 1 (RAMP1), the transcription factor RUNX2, osteocalcin, p38 and p-p38 were analyzed by western blotting. Calcium mineralization was analyzed by alizarin red straining. RESULTS: Using compressive force treatments, low magnitudes (1 and 2 g/cm2) of compressive force for 24 h promoted osteoblast differentiation and mineral deposition whereas higher magnitudes (3 and 4 g/cm2) did not produce osteogenic effect. Through western blot assay, we observed that the receptor activity-modifying protein 1 (RAMP1) expression was upregulated, and p38 mitogen-activated protein kinase (MAPK) was phosphorylated during low magnitudes compressive force-promoted osteoblast differentiation. Further investigation of a calcitonin gene-related peptide (CGRP) peptide incubation, a ligand for RAMP1, showed that CGRP at concentration of 25 and 50 ng/ml could increase expression levels of RUNX2 and osteocalcin, and percentage of mineralization, suggesting its osteogenic potential. In addition, with the same conditions, CGRP also significantly upregulated RAMP1 and phosphorylated p38 expression levels. Also, the combination of compressive forces (1 and 2 g/cm2) with 50 ng/ml CGRP trended to increase RAMP1 expression, p38 activity, and osteogenic marker RUNX2 levels, as well as percentage of mineralization compared to compressive force alone. This suggest that RAMP1 possibly acts as an upstream regulator of p38 signaling during osteogenic differentiation. CONCLUSION: These findings suggest that CGRP-RAMP1/p38MAPK signaling implicates in osteoblast differentiation in response to optimal magnitude of compressive force. This study helps to define the underlying mechanism of compressive stimulation and may also enhance the application of compressive stimulation or CGRP peptide as an alternative approach for accelerating tooth movement in orthodontic treatment.

Investigation of the anatomic risk factors in acute anterior cruciate ligament ruptures to develop ramp lesions of the medial meniscus by quantitative MRI.

OBJECTIVE: To investigate the anatomic risk factors of knee in patients with acute non-contact anterior cruciate ligament (aACL) ruptures to develop ramp lesions. METHODS: A total of 202 subjects were retrospectively divided into three groups: (1) aACL ruptures combined with ramp lesions group (n = 76); (2) isolated ACL ruptures group (n = 56) and (3) normal controls group (n = 70). Quantitative morphological parameters on MRI were measured including: diameter of medial femoral condyle (MFC), anterior-posterior length and depth of medial tibial plateau (MTP AP length and depth), lateral posterior tibial slope (LPTS) and medial posterior tibial slope (MTPS), asymmetry of LPTS and MPTS (LMPTS), lateral meniscal slope (LMS), and medial meniscal slope (MMS). RESULTS: The MTP AP length, MTP AP length/MFC diameter ratio, MTP depth, LPTS and the asymmetry of LMPTS showed significant differences among the three groups (p < 0.001). The risk factors associated with the ramp lesions including a longer MTP AP length (OR 1.17, 95% CI 1.00-1.44, p = 0.044), increased MTP depth (OR 1.91, 95% CI 1.22-3.00, p = 0.005) and lager ratio (OR 1.11, 95% CI 1.01-1.22, p = 0.036). The highest AUC was the MTP AP length/MFC diameter ratio (0.74; 95% CI, 0.66-0.82). The combination model increased higher accuracy (0.80; 95% CI, 0.72-0.88). CONCLUSION: Several bony anatomic characteristics of the knee, especially the morphology of medial tibia plateau, are additional risk factors for aACL ruptures to develop ramp lesions. CRITICAL RELEVANCE STATEMENT: Predictive anatomic risk factors of the knee for patients with acute non-contact anterior cruciate ligament (aACL) ruptures to develop ramp lesions, especially the morphology of medial tibia plateau, are detectable by MRI. KEY POINTS: Ramp lesion development can complicate aACL ruptures and requires specific treatment. Longer AP length and increased MTP depth are risk factors for concurrent ramp lesions. Identification of ramp lesions allows for the most appropriate treatment.

How to repair medial meniscal ramp lesions: A systematic review of surgical techniques.

Purpose: to provide a comprehensive overview of all the surgical techniques published in the literature for repairing meniscal ramp lesions focusing on the technical aspects and the pros and cons of every procedure. Such lesions can be managed using various approaches, each of this with its specific advantages and disadvantages. Methods: Pubmed Central, Scopus, and EMBASE databases were systematically reviewed according to the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines for studies on surgical techniques for repairing meniscal ramp lesions through May 2023. Overall, 32 articles matched the selection criteria and were included in the study. Results: Debridement alone may be sufficient for small stable meniscal ramp lesions but, for tears in the menisco-capsular junction that affect the stability of the medial meniscus, it seems reasonable to repair it, even though the clinical results available in literature are contrasting. All-inside sutures through anterior portals seems to be an effective solution for meniscal ramp lesions with MTL tears. All-inside sutures through posteromedial portals are particularly useful for large meniscal ramp lesions, in which an inside-out suture can also be performed. Conclusion: Meniscal ramp lesions can be managed using various approaches, each of this with its specific advantages and disadvantages. Further research is required to determine the optimal technique that can be considered as the gold standard and can provide the better results. Level of Evidence: Level III, systematic review.

Identifying time-varying dynamics of heart rate and oxygen uptake from single ramp incremental running tests.

Objective.The fact that ramp incremental exercise yields quasi-linear responses for pulmonary oxygen uptake (V˙O2) and heart rate (HR) seems contradictory to the well-known non-linear behavior of underlying physiological processes. Prior research highlights this issue and demonstrates how a balancing of system gain and response time parameters causes linearV˙O2responses during ramp tests. This study builds upon this knowledge and extracts the time-varying dynamics directly from HR andV˙O2data of single ramp incremental running tests.Approach.A large-scale open access dataset of 735 ramp incremental running tests is analyzed. The dynamics are obtained by means of 1st order autoregressive and exogenous models with time-variant parameters. This allows for the estimates of time constant (τ) and steady state gain (SSG) to vary with work rate.Main results.As the work rate increases,τ-values increase on average from 38 to 132 s for HR, and from 27 to 35 s forV˙O2. Both increases are statistically significant (p< 0.01). Further, SSG-values decrease on average from 14 to 9 bpm (km·h-1)-1for HR, and from 218 to 144 ml·min-1forV˙O2(p< 0.01 for decrease parameters of HR andV˙O2). The results of this modeling approach are line with literature reporting on cardiorespiratory dynamics obtained using standard procedures.Significance.We show that time-variant modeling is able to determine the time-varying dynamics HR andV˙O2responses to ramp incremental running directly from individual tests. The proposed method allows for gaining insights into the cardiorespiratory response characteristics when no repeated measurements are available.

Heavy-intensity priming exercise extends the V̇o2max plateau and increases peak-power output during ramp-incremental exercise.

This study investigated whether a heavy-intensity priming exercise precisely prescribed within the heavy-intensity domain would lead to a greater peak-power output (POpeak) and a longer maximal oxygen uptake (V̇o2max) plateau. Twelve recreationally active adults participated in this study. Two visits were required: 1) a step-ramp-step test [ramp-incremental (RI) control], and 2) an RI test preceded by a priming exercise within the heavy-intensity domain (RI primed). A piecewise equation was used to quantify the V̇o2 plateau duration (V̇o2plateau-time). The mean response time (MRT) was computed during the RI control condition. The delta (Δ) V̇o2 slope (S; mL·min-1·W-1) and V̇o2-Y intercept (Y; mL·min-1) within the moderate-intensity domain between conditions (RI primed minus RI control) were also assessed using a novel graphical analysis. V̇o2plateau-time (P = 0.001; d = 1.27) and POpeak (P = 0.003; d = 1.08) were all greater in the RI primed. MRT (P < 0.001; d = 2.45) was shorter in the RI primed compared with the RI control. A larger ΔV̇o2plateau-time was correlated with a larger ΔMRT between conditions (r = -0.79; P = 0.002). This study demonstrated that heavy-intensity priming exercise lengthened the V̇o2plateau-time and increased POpeak. The overall faster RI-V̇o2 responses seem to be responsible for the longer V̇o2plateau-time. Specifically, a shorter MRT, but not changes in RI-V̇o2-slopes, was associated with a longer V̇o2plateau-time following priming exercise.NEW & NOTEWORTHY It remains unclear whether priming exercise extends the maximal oxygen uptake (V̇o2max) plateau and increases peak-power output (POpeak) during ramp-incremental (RI) tests. This study demonstrates that a priming exercise, precisely prescribed within the heavy-intensity domain, extends the plateau at V̇o2max and leads to a greater POpeak. Specifically, the extended V̇o2max plateau was associated with accelerated RI-V̇o2 responses.

Identifying unstable ramp lesions using ultrasonography.

BACKGROUND: Patients with suspected ramp lesions on magnetic resonance imaging (MRI) or ultrasonography (US) healed and showed no instability based on intraoperative arthroscopic findings. The purpose of this study was to assess the use of US in evaluating ramp lesions preoperatively and intraoperatively. METHODS: Eighty-two knees that underwent anterior cruciate ligament (ACL) reconstruction between January 2022 and June 2023 were included to assess the ramp lesion complication rate and instability using arthroscopic findings. The detection rate of ramp lesions using US at the initial visit and preoperatively was also investigated. The test-retest reliability was assessed using the intraclass correlation coefficient and analyzed using two-way random effects and absolute agreement. The patients were divided into two groups based on the presence or absence of ramp lesions, and these data were compared using Student's t-test. Statistical significance was set at p < 0.05. RESULTS: On ultrasound examination, 90.0% of the cases had a ramp lesion at the initial examination, of which 22.2% were poorly delineated on the day of surgery. In the cases where the ramp lesion was unstable at the time of surgery, it could be delineated using US. In the cases where the ramp lesion was stable, it was difficult to delineate the lesion using US. CONCLUSIONS: Unstable ramp lesions complicating ACL injuries could be detected using US.

Management of Meniscus Pathology with Concomitant Anterior Cruciate Ligament Injury.

PURPOSE OF REVIEW: The purpose of this review is to summarize current clinical knowledge on the prevalence and types of meniscus pathology seen with concomitant anterior cruciate ligament (ACL) injury, as well as surgical techniques, clinical outcomes, and rehabilitation following operative management of these pathologies. RECENT FINDINGS: Meniscus pathology with concomitant ACL injury is relatively common, with reports of meniscus pathology identified in 21-64% of operative ACL injuries. These concomitant injuries have been associated with increased age and body mass index. Lateral meniscus pathology is more common in acute ACL injury, while medial meniscus pathology is more typical in chronic ACL deficiency. Meniscus tear patterns associated with concomitant ACL injury include meniscus root tears, lateral meniscus oblique radial tears of the posterior horn (14%), and ramp lesions of the medial meniscus (8-24%). These meniscal pathologies with concomitant ACL injury are associated with increased rotational laxity and meniscal extrusion. There is a paucity of comparative studies to determine the optimal meniscus repair technique, as well as rehabilitation protocol, depending on specific tear pattern, location, and ACL reconstruction technique. There has been a substantial increase in recent publications demonstrating the importance of meniscus repair at the time of ACL repair or reconstruction to restore knee biomechanics and reduce the risk of progressive osteoarthritic degeneration. Through these studies, there has been a growing understanding of the meniscus tear patterns commonly identified or nearly missed during ACL reconstruction. Surgical management of meniscal pathology with concomitant ACL injury implements the same principles as utilized in the setting of isolated meniscus repair alone: anatomic reduction, biologic preparation and augmentation, and circumferential compression. Advances in repair techniques have demonstrated promising clinical outcomes, and the ability to restore and preserve the meniscus in pathologies previously deemed irreparable. Further research to determine the optimal surgical technique for specific tear patterns, as well as rehabilitation protocols for meniscus pathology with concomitant ACL injury, is warranted.

Secondary Meniscectomy Rates and Risk Factors for Failed Repair of Ramp Lesions Performed at the Time of Primary ACL Reconstruction: An Analysis of 1037 Patients From the SANTI Study Group.

BACKGROUND: Studies evaluating secondary meniscectomy rates and risk factors for failure of ramp repair are sparse and limited by small numbers and heterogeneity. PURPOSES/HYPOTHESIS: The purposes were to determine the secondary meniscectomy rate for failure of ramp repair performed using a posteromedial portal suture hook at the time of anterior cruciate ligament reconstruction (ACLR) and to identify risk factors for secondary meniscectomy. It was hypothesized that patients who underwent ACLR combined with a lateral extra-articular procedure (LEAP) would experience significantly lower rates of secondary meniscectomy compared with those undergoing isolated ACLR. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: Patients undergoing primary ACLR and ramp repair between 2013 and 2020 were included in the study. Final follow-up for each patient was defined by his or her last appointment recorded in a prospective database (with a study end date of March 2023). The database and medical records were used to determine whether patients had undergone secondary meniscectomy for failure of ramp repair. Survivorship of ramp repair (using secondary meniscectomy as an endpoint) was determined using the Kaplan-Meier method. Multivariate analysis was used to investigate possible risk factors. RESULTS: A total of 1037 patients were included in the study. The secondary meniscectomy rate after ramp repair was 7.7% at a mean final follow-up of 72.4 months. Patients without combined ACLR + LEAP were >2-fold more likely to undergo a secondary medial meniscectomy compared with those with combined ACLR + LEAP (hazard ratio, 2.455; 95% CI, 1.457-4.135; P = .0007). Age, sex, preoperative Tegner score, and time between injury and surgery were not significant risk factors for failure. CONCLUSION: The rate of secondary meniscectomy after ramp repair performed through a posteromedial portal at the time of primary ACLR was low. Patients who underwent isolated ACLR (rather than ACLR + LEAP) were >2-fold more likely to undergo a secondary medial meniscectomy for failure of ramp repair. Additional risk factors for failure of ramp repair were not identified.