Towards high performance and durable soft tactile actuators.

Soft actuators are gaining significant attention due to their ability to provide realistic tactile sensations in various applications. However, their soft nature makes them vulnerable to damage from external factors, limiting actuation stability and device lifespan. The susceptibility to damage becomes higher with these actuators often in direct contact with their surroundings to generate tactile feedback. Upon onset of damage, the stability or repeatability of the device will be undermined. Eventually, when complete failure occurs, these actuators are disposed of, accumulating waste and driving the consumption of natural resources. This emphasizes the need to enhance the durability of soft tactile actuators for continued operation. This review presents the principles of tactile feedback of actuators, followed by a discussion of the mechanisms, advancements, and challenges faced by soft tactile actuators to realize high actuation performance, categorized by their driving stimuli. Diverse approaches to achieve durability are evaluated, including self-healing, damage resistance, self-cleaning, and temperature stability for soft actuators. In these sections, current challenges and potential material designs are identified, paving the way for developing durable soft tactile actuators.

GLP-1 Receptor Agonists Promote Weight Loss Among People with HIV.

BACKGROUND: Weight gain and associated metabolic complications are increasingly prevalent among people with HIV (PWH). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin-based therapies for diabetes and weight management that have been shown to result in substantial weight loss; however, studies of their effects in PWH are limited. METHODS: A retrospective single-center cohort study was conducted among PWH who were taking GLP-1RAs at UC San Diego Owen Clinic between 2/1/2021 to 2/1/2023. Baseline clinical data were collected and changes in weight, body mass index (BMI), and hemoglobin A1C (A1C) before starting GLP-1RAs compared to the most recent clinic visit were calculated (with a minimum of 3 months follow-up time required). Logistic regression was performed to identify variables associated with >5% of total body weight loss. RESULTS: A total of 225 patients received on average 13 months of GLP-1RA therapy, with 85 (37.8%) achieving the maximum GLP-1RA dose. GLP-1RA therapy resulted, on average, in a loss of 5.4 kg, decrease in BMI by 1.8 kg/m2, and decrease in A1C by 0.6%. In the multivariable analysis, higher baseline BMI [OR 1.10 (1.03-1.16)], treatment duration of GLP-1RA therapy greater than 6 months [OR 3.12 (1.49-6.49], and use of tirzepatide [OR 5.46 (1.44-20.76)] were significantly more likely to be associated with >5% weight loss. CONCLUSIONS: Use of GLP-1RAs led to declines in weight, BMI, and hemoglobin A1C among PWH and offers an additional strategy to address weight gain and diabetes.

Multi-disciplinary diabetic limb salvage programme in octogenarians with diabetic foot ulcers is not futile: An observational study with historical controls.

This study evaluated the effectiveness of a multi-disciplinary diabetic limb salvage programme in improving clinical outcomes and optimising healthcare utilisation in 406 patients aged ≥80 years with diabetic foot ulcers (DFUs), compared to 2392 younger patients enrolled from June 2020 to June 2021 and against 1716 historical controls using one-to-one propensity score matching. Results showed that elderly programme patients had lower odds of amputation-free survival (odds ratio: 0.64, 95% CI: 0.47, 0.88) and shorter cumulative length of stay (LOS) compared to younger programme patients (incidence rate ratio: 0.45, 95% CI: 0.29, 0.69). Compared to the matched controls, participating in the programme was associated with 5% higher probability of minor lower extremity amputation, reduced inpatient admissions and emergency visits, shorter LOS but increased specialist and primary care visits (all p-values <0.05). The findings suggest that the programme yielded favourable impacts on the clinical outcomes of patients aged≥80 years with DFUs. Further research is needed to develop specific interventions tailoring to the needs of the elderly population and to determine their effectiveness on patient outcomes while accounting for potential confounding factors.

Rapid 3D Bioprinting of Glioblastoma Model Mimicking Native Biophysical Heterogeneity.

Glioblastoma multiforme (GBM) is the most lethal primary brain tumor characterized by high cellular and molecular heterogeneity, hypervascularization, and innate drug resistance. Cellular components and extracellular matrix (ECM) are the two primary sources of heterogeneity in GBM. Here, biomimetic tri-regional GBM models with tumor regions, acellular ECM regions, and an endothelial region with regional stiffnesses patterned corresponding to the GBM stroma, pathological or normal brain parenchyma, and brain capillaries, are developed. Patient-derived GBM cells, human endothelial cells, and hyaluronic acid derivatives are used to generate a species-matched and biochemically relevant microenvironment. This in vitro study demonstrates that biophysical cues are involved in various tumor cell behaviors and angiogenic potentials and promote different molecular subtypes of GBM. The stiff models are enriched in the mesenchymal subtype, exhibit diffuse invasion of tumor cells, and induce protruding angiogenesis and higher drug resistance to temozolomide. Meanwhile, the soft models demonstrate enrichment in the classical subtype and support expansive cell growth. The three-dimensional bioprinting technology utilized in this study enables rapid, flexible, and reproducible patient-specific GBM modeling with biophysical heterogeneity that can be employed by future studies as a tunable system to interrogate GBM disease mechanisms and screen drug compounds.

A Systematic Review of the Impact of Foot Care Education on Self Efficacy and Self Care in Patients With Diabetes.

OBJECTIVE: This review aims to assess the evidence supporting the impact of patient foot care education on self efficacy, self care behaviour, and self care knowledge in individuals with diabetes. METHODS: This systematic review was registered prospectively on the PROSPERO database (CRD42019106171). Ovid EMBASE and MEDLINE databases were searched from 1946 to the end of March 2019, using search terms related to the domains diabetic foot, patient education, self efficacy, self care behaviour, and self care knowledge. All included studies were prospective, randomised controlled trials that assessed foot care education interventions in individuals with diabetes and recorded an outcome related to self efficacy, self care behaviour, and/or self care knowledge. RESULTS: Thirteen randomised controlled trials were included, reporting on a total of 3948 individuals. The risk of bias was high or unclear in 11 of the 13 included studies, and low in two studies. Both the education interventions delivered, and the outcome assessment tools used were heterogenous across included studies: meta-analysis was therefore not performed. Eight of 11 studies identified significantly better foot self care behaviour scores in individuals randomised to education compared with controls. Self efficacy scores were significantly better in education groups in four of five studies reporting this primary outcome. Foot care knowledge was significantly better in intervention vs. control in three of seven studies. In general, studies assessing secondary endpoints including quality of life and ulcer/amputation incidence tended not to identify significant clinical improvements. CONCLUSION: The available evidence is of inadequate quality to reliably conclude that foot care education has a positive impact on foot self care behaviour and self efficacy in individuals with diabetes. Quality data supporting accompanying benefits on quality of life or ulcer/amputation incidence are also lacking and should be considered as an important outcome measure in future studies.

A Methodological Assessment of Diabetic Foot Syndrome Clinical Practice Guidelines.

OBJECTIVE: Diabetic foot syndrome (DFS) contributes to significant morbidity in diabetic patients. Diagnostic and therapeutic approaches to DFS may be summarised in clinical practice guidelines (CPGs) to aid clinical practice but may only benefit patients if the CPG is of high quality. This study determines the methodological quality of DFS CPGs using a validated assessment tool to identify CPGs adequate for use in clinical practice. METHODS: Medline, EMBASE, and CPG databases were searched to 31 May 2019. Reference lists were also searched. Full text English evidence based DFS CPGs were included. CPGs based on expert consensus, guideline summaries, or those only available if purchased were excluded. Four reviewers independently assessed methodological quality using the Appraisal of Guidelines for Research and Evaluation II instrument. An overall guideline assessment scaled score of ≥80% was considered to be of adequate quality to recommend use. RESULTS: Sixteen CPGs were identified. Good inter-reviewer reliability (ICC 0.985, 95% CI 0.980-0.989) was achieved. Poor scores were noted in domains 2 (stakeholder involvement), 5 (applicability), and 6 (editorial independence). Significant methodological heterogeneity was observed in all domains with the most noted in domain 6 (mean scaled score 43.2 ± 32.1%). Four CPGs achieved overall assessment scores of ≥80%. CONCLUSION: Four CPGs were considered to be adequate for clinical practice based on methodological quality. However, elements of methodological quality were still lacking, and all CPGs had areas for improvement, potentially through increased multidisciplinary team involvement and trial application of recommendations. Methodological rigour may be improved using structured approaches with validated CPG creation tools in the future. Future work should also assess recommendation accuracy using available validated assessment tools.

Metabolic Phenotyping in Venous Disease: The Need for Standardization.

Venous thromboembolism (VTE), chronic venous disease (CVD), and venous leg ulceration (VLU) are clinical manifestations of a poorly functioning venous system. Though common, much is unknown of the pathophysiology and progression of these conditions. Metabolic phenotyping has been employed to explore mechanistic pathways involved in venous disease. A systematic literature review was performed: full text, primary research articles on the applications of nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry (MS) in human participants and animals were included for qualitative synthesis. Seventeen studies applying metabolic phenotyping to venous disease were identified: six on CVD, two on VLU, and nine on VTE; both animal (n = 6) and human (n = 10) experimental designs were reported, with one study including both. NMR, MS, and MS imaging were employed to characterize serum, plasma, urine, wound fluid, and tissue. Metabolites found to be upregulated in CVD included lipids, branched chain amino acids (BCAA), glutamate, taurine, lactate, and myo-inositol identified in vein tissue. Upregulated metabolites in VLU included lactate, BCAA, lysine, 3-hydroxybutyrate, and glutamate identified in wound fluid and ulcer biopsies. VTE cases were associated with reduced carnitine levels, upregulated aromatic amino acids, 3-hydroxybutyrate, BCAA, and lipids in plasma, serum, thrombus, and vein wall; kynurenine and tricarboxylic acid pathway dysfunction were reported. Future research should focus on targeted studies with internal and external validation.

The Relationship Between Vein Diameters, Clinical Severity, and Quality of Life: A Systematic Review.

OBJECTIVE/BACKGROUND: The aim was to summarise the evidence for the relationship between vein diameters and clinical severity, and elucidate the relationship between diameters and health related quality of life (HRQoL) METHODS: A systematic review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) guidelines. The MEDLINE and Embase databases were searched from 1946 to 31 August 2018. Reference lists of included studies were searched for further relevant papers. Full text studies in English reporting the relationship between great and small saphenous vein diameters and clinical severity and/or HRQoL scores measured using validated instruments were included. All study designs were included. Studies that did not include relationships between these parameters, non-English studies, and studies focusing on non-truncal veins were excluded. Two reviewers independently performed the study selection, data extraction, and risk of bias assessment. RESULTS: Eleven eligible studies were identified, reporting on 2,732 limbs (range 22-681). Four studies correlated truncal vein diameter with both clinical severity and HRQoL, while seven reported only on clinical severity measures. Multiple instruments were used to quantify HRQoL and clinical severity. Seven studies assessed the relationship with CEAP class, with the majority observing a positive correlation between vein diameter and disease severity. Four studies found weak correlations with VCSS, with one showing correlations with VCSS components. No significant relationship between diameters and HRQoL scores was reported. One study also revealed no correlation with Aberdeen Varicose Vein Questionnaire improvements post-treatment. The majority of studies failed to include C0 and C1 participants. CONCLUSIONS: While further studies are required to improve the level of evidence, the existing literature suggests that truncal vein diameters correlate with clinical severity. Diameters are a poor predictor of HRQoL, with no relationship to patients' perceived impact of chronic venous disease. As such, vein diameter should not be used as a measure to decide who needs venous intervention.

Venous Leg Ulcer Clinical Practice Guidelines: What is AGREEd?

OBJECTIVE: The aim was to evaluate the quality of current venous leg ulcer (VLU) clinical practice guidelines (CPGs) to assist healthcare professionals in choosing an accessible high quality CPG to advise their practice, and to identify areas for improvement in future versions of current CPGs. METHODS: A systematic review of PubMed, Embase, online CPG databases, and reference lists of included CPGs was carried out. Full text CPGs published no earlier than 1998 reporting evidence based recommendations on VLU diagnosis and management in English were included. CPGs that were only available if purchased were excluded. Two reviewers identified eligible CPGs, extracted data, and assessed the quality independently using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. Significant scoring discrepancies were discussed with a third reviewer. RESULTS: Fourteen eligible CPGs were identified (1999-2016). The majority of CPGs originated from Europe or North America. Overall, there was good inter-reviewer reliability of scores with an intraclass correlation coefficient of 0.986 (95% confidence interval 0.979-0.991). No single CPG achieved the highest score in all six domains. Significant methodological heterogeneity was observed across VLU CPGs; however, consistently, poor performance was noted in domain 5, concerning CPG applicability. CONCLUSION: Four CPGs were considered of adequate quality for clinical use. Consolidation of efforts to drive high quality, comprehensive VLU CPGs is necessary to reduce the number of and heterogeneity seen in currently published guidelines. Elements of methodological quality are lacking and a structured approach with use of checklists and CPG creation tools, such as AGREE II or others, may bolster rigour in future VLU CPGs.

Thrombophilia in non-thrombotic chronic venous disease of the lower limb - a systematic review.

Chronic venous disease (CVD) represents a significant healthcare burden. Thrombophilia is proposed as a risk factor, particularly for post-thrombotic CVD. A systematic review was performed to determine the relationship between thrombophilia and non-thrombotic CVD. MEDLINE® and Embase® databases were searched from 1946 up to March 2018. Case-control studies, cohort studies or randomised clinical trials reporting on thrombophilias in non-thrombotic lower limb CVD in adult patients were included. Non-English and post-thrombotic syndrome studies were excluded. Study selection and data extraction were performed by two reviewers. Fifteen studies were included, reporting on 916 cases and 1261 controls. Studies largely focused on venous ulceration and investigated multiple haemostatic factors. An association between thrombophilia and non-thrombotic CVD was identified, with greater prevalence and factor concentration alteration reported in patients compared to controls. Concomitant thrombophilia presence was associated with earlier CVD onset. Relationship strength varied, with commoner aetiologies showing clearer correlation than rarer ones. Thrombophilia is associated with non-thrombotic CVD but the mechanism is unclear and causation cannot be determined. Future research should focus on prospective studies with larger populations and identify adjunct therapies targeting thrombophilia.

Elastic deformation of soft coatings due to lubrication forces.

Elastic deformation of rigid materials with soft coatings (stratified materials) due to lubrication forces can alter the interpretation of dynamic surface forces measurements and prevent contact formation between approaching surfaces. Understanding the role of elastic deformation on the process of fluid drainage is necessary, in particular for the case where one (or both) of the interacting materials consists of a rigid substrate with a soft coating. We combine lubrication theory and solid linear elasticity to describe the dynamic of fluid drainage past a compliant stratified boundary. The analysis presented covers the full range of coating thicknesses, from an elastic foundation to a half-space for an incompressible coating. We decouple the individual contributions of the coating thickness and material properties on the elastic deformation, hydrodynamic forces, and fluid film thickness. We obtain a simple expression for the shift in contact position during force measurements that is valid for many experimental conditions. We compare directly the effect of stratification on the out-of-contact deformation to the well-known effect of stratification on indentation. We show that corrections developed for stratification in contact mechanics are not applicable to elastohydrodynamic deformation. Finally, we provide generalized contour maps that can be employed directly to estimate the elastic deformation present in most dynamic surface force measurements.

AXIAL BMD IN DIABETIC AND NONDIABETIC SOUTHEAST ASIANS WITH HIP FRACTURES: DO RACE AND BODY MASS INDEX MATTER?

OBJECTIVE: Obesity is less prevalent in Asian subjects with type 2 diabetes mellitus (T2DM) in contrast to Caucasians. Whether higher axial bone mineral density (BMD) often reported in T2DM is independent of body mass index (BMI) has not been clearly shown. BMD characterization in T2DM patients with hip fractures has also not been performed. We compared the BMD of Asian diabetic and nondiabetic patients with new hip fractures and explored how BMD was influenced by BMI. METHODS: We included 255 diabetic and 148 nondiabetic patients. BMD adjusted for age; BMI; race; sex; renal function; and use of statins, proton pump inhibitors, steroids, anticonvulsants, and calcium and/or vitamin D supplements were compared between the groups. We were particularly interested in the BMD comparison between underweight diabetics and nondiabetics with hip fractures. RESULTS: The presence of T2DM was associated with higher BMD (g/cm(2)) at the femoral neck (0.527 ± 0.103 vs. 0.491 ± 0.102, P<.01) and lumbar spine [LS] (0.798 ± 0.147 vs. 0.723 ± 0.156, P<.01). This association persisted after adjustment for multiple confounding variables including BMI. The age-, BMI-, and sex-adjusted LS BMD was higher in underweight (BMI <18.5 kg/m(2)) diabetics compared to similar weight nondiabetics (0.733 ± 0.126 vs. 0.649 ± 0.131 g/cm(2), P = .014). CONCLUSION: T2DM is independently associated with higher axial BMD in patients with new hip fractures. The finding of higher BMD even in underweight diabetics with hip fractures compared to their nondiabetic counterparts suggests that higher BMD in subjects with T2DM is not due to higher BMI. ABBREVIATIONS: BMD = bone mineral density BMI = body mass index CV = coefficient of variation DXA = dual-energy X-ray absorptiometry HbA1c = glycated hemoglobin IGF-1 = insulin growth factor-1 LS = lumbar spine 25(OH)D = 25-hydroxyvitamin D T2DM = type 2 diabetes mellitus.

Dropping the Ball and Falling Off the Care Wagon. Factors Correlating With Nonadherence to Secondary Fracture Prevention Programs.

Health care systems and hospitals in several countries have implemented Fracture Liaison Services (FLSs). Success rates of FLSs with regard to osteoporosis assessment and treatment, fracture reduction, and adherence to osteoporosis medications have been reported by several groups including ours. A significant drop-out rate among patients in these programs may occur. This has not been evaluated before. We explored the factors correlating with nonadherence among a multiethnic population of patients in the FLS at our institution, the largest tertiary teaching hospital in South East Asia. Our secondary objective was to explore whether patients who defaulted follow-up visits continued to be compliant with medications. A retrospective analysis of our FLS's computerized database was performed. Of 938 patients followed up more than 2 years, 237 defaulted at various time points. A significant percentage of patients who dropped out of the program opined that it was because the follow-up visits were too time consuming. Non-Chinese patients were more likely than Chinese (adjusted hazard ratio [aHR] = 1.98, 1.33-2.94), patients with primary school education and below were more likely than those with secondary school and above education (aHR = 1.65, 1.11-2.45) and those with nonvertebral and/or multiple fractures were more likely than those with spine fractures (aHR = 1.38, 1.06-1.81) to be nonadherent. A fraction of patients who defaulted continued to fill osteoporosis medication prescriptions. Median medication possession ratio among the patients who defaulted was 12.3% (interquartile range: 4.1%-36.7%) at 2 years. Persistence ranged from 15.1% to 20.8% and from 1.9% to 7.5% at 1 and 2 years, respectively after defaulting from the program. Our study, which to the best of our knowledge is the first of its kind, provides insight into the factors correlating with nonadherence to FLSs. Knowledge of the challenges faced by patients may be of help to health care providers interested in developing FLSs.

Novel inhibitors of nuclear transport cause cell cycle arrest and decrease cyst growth in ADPKD associated with decreased CDK4 levels.

Autosomal-dominant polycystic kidney disease (ADPKD) is a progressive, proliferative renal disease. Kidneys from ADPKD patients are characterized by the presence of cysts that are marked by enhanced proliferation and apoptosis of renal tubular epithelial cells. Current treatment of this disease is supportive, as there are few if any clinically validated targeted therapeutics. Given the parallels between cystic disease and cancer, and in light of our findings of the efficacy of the nuclear transport inhibitors in kidney cancer, which has similarities to ADPKD, we asked whether such inhibitors show utility in ADPKD. In this study, we tested selective inhibitors of nuclear export (SINE) in two human ADPKD cell lines and in an in vivo mouse model of ADPKD. After effective downregulation of a nuclear exporter, exportin 1 (XPO1), with KPT-330, both cell lines showed dose-dependent inhibition of cell proliferation through G0/G1 arrest associated with downregulation of CDK4, with minimal apoptosis. To analyze mechanisms of CDK4 decrease by XPO1 inhibition, localization of various XPO1 target proteins was examined, and C/EBPß was found to be localized in the nucleus by XPO1 inhibition, resulting in an increase of C/EBPα, which activates degradation of CDK4. Furthermore, inhibition of XPO1 with the parallel inhibitor KPT-335 attenuated cyst growth in vivo in the PKD1 mutant mouse model Pkd1(v/v). Thus, inhibition of nuclear export by KPT-330, which has shown no adverse effects in renal serum chemistries and urinalyses in animal models, and which is already in phase 1 trials for cancers, will be rapidly translatable to human ADPKD.

Toughening Self-Healing Elastomers with Chain Mobility.

Enhancing fracture toughness and self-healing within soft elastomers is crucial to prolonging the operational lifetimes of soft devices. Herein, it is revealed that tuning the polymer chain mobilities of carboxylated-functionalized polyurethane through incorporating plasticizers or thermal treatment can enhance these properties. Self-healing is promoted as polymer chains gain greater mobility toward the broken interface to reassociate their bonds. Raising the temperature from 80 to 120 °C, the recovered work of fracture is increased from 2.86 to 123.7 MJ m-3. Improved fracture toughness is realized through two effects. First, strong carboxyl hydrogen bonds dissipate large energies when broken. Second, chain mobilities enable the redistribution of localized stress concentrations to allow crack blunting, enlarging the size of dissipation zones. At optimal conditions of plasticizers (3 wt.%) or temperature (40 °C) to promote chain mobilities, fracture toughness improves from 16.3 to 19.9 and 25.6 kJ m-2, respectively. Insights of fracture properties at healed soft interfaces are revealed through double cantilever beam tests. These measurements indicate that fracture mechanics play a critical role in delaying complete failure at partial self-healing. By imparting optimal polymer chain mobilities within tough and self-healing elastomers, effective prevention against damage and better recovery are realized.

Identification of outcomes in clinical studies for pelvic venous disorders.

OBJECTIVE: There is increasing recognition that health systems need to measure and improve the value of patient care by measuring outcomes. Chronic pelvic pain secondary to pelvic venous insufficiency can have a significant impact on the quality of life (QOL) of women affected. Despite growing recognition, pelvic venous disorders (PeVDs), an important cause of chronic pelvic pain, remain underdiagnosed. Developing a core outcome set (COS) for benchmarking care delivery enhances the standardization of care. However, there is no consensus regarding a standardized minimum set of outcomes for PeVD. We aimed to generate a list of outcomes reported in previous PeVD treatment studies to lay the foundation for developing a COS for PeVD. METHODS: This scoping review was undertaken according to the PRISMA-ScR guidelines. Initially, screening, full-text review and extraction was conducted on studies published between 2018 and 2023. Subsequently, the search was expanded using 1-year intervals, until, over a 1-year interval, no new outcomes were recorded. Closely related outcomes were classified into domains, and domains into three core areas: disease-specific, treatment-related, and QOL-related outcomes. RESULTS: Of the 1579 records identified, 51 publications were included. From these studies, 108 different outcomes were identified. The median number of outcomes per study was 8 (interquartile range, 6-13). Closely related outcomes were organized into 42 outcome domains, which were then categorized into 3 core outcome areas; 47.6% (20/42) were disease specific, 35.7% (15/42) treatment related, and 16.7% (7/42) were QOL related. Of the 51 included studies, disease-specific outcomes were identified in 96.1% of the studies (49/51), treatment-related outcomes in 94.1% (48/51), and QOL outcomes in only 13.7% (7/51). CONCLUSIONS: There was significant heterogeneity in outcomes reported in PeVD studies. Most PeVD treatment studies evaluated disease-specific and treatment-related outcomes of PeVD, but few reported outcomes that measured the impact on QOL. These findings will inform the next steps in developing a COS for PeVD.

A scoping review of scores or grading systems for pelvic venous disorders.

BACKGROUND: Pelvic venous disorders (PeVD) encompass a variety of conditions linked to chronic pelvic pain in women. However, PeVD remain underdiagnosed due to the absence of universally accepted diagnostic criteria. The complexity of PeVD classifications across specialties leads to delays in treatment. This scoping review aims to fill a gap in PeVD diagnosis and management by identifying all existing scoring or grading systems to lay the foundation for standardized clinical scoring tools for PeVD. METHODS: This scoping review was undertaken according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping reviews. Online databases were searched up to April 2023. Studies implementing a scoring or grading system for patients with confirmed or suspected PeVD were included. Scores or grading systems were classified into four main categories based on their use in the study: screening, diagnosis, measure of disease severity, and measure of response to treatment. RESULTS: Of the 2976 unique records identified, 82 were reviewed in full, and 20 were included in this study. The publication dates ranged from 1984 to 2023 (median, 2018; interquartile range, 2003-2022). A total of 21 scores and/or grading systems were identified. Of these 21 scores, 10 (47.6%) were clinical scores, and 10 (47.6%) were scores based on radiological findings; one study included a score that used both clinical and radiological findings. The identified scores were used in various settings. Of the 21 scores, 2 (9.52%) were used for screening in a tertiary care setting; 3 (14.3%) were used to establish the PeVD diagnosis; 8 (38.1%) were used to assess disease severity; and 8 (38.1%) were used as measures of response to treatment. Of the eight scores assessing disease severity, four (50.0%) assessed the degree of dilatation of pelvic veins and four (50%) assessed the severity of reflux. Only three of the scores were validated. CONCLUSIONS: This scoping review identified a range of scoring and grading systems for PeVD. We note a lack of a validated scoring system, both clinical and radiological, for screening and assessment of disease severity. This is an important first step in developing validated disease-specific scoring systems for patient screening, appropriate referral, assessment of symptom severity, and assessment of the response to treatment.

Convergent Approaches to Delineate the Metabolic Regulation of Tumor Invasion by Hyaluronic Acid Biosynthesis.

Metastasis is the leading cause of breast cancer-related deaths and is often driven by invasion and cancer-stem like cells (CSCs). Both the CSC phenotype and invasion are associated with increased hyaluronic acid (HA) production. How these independent observations are connected, and which role metabolism plays in this process, remains unclear due to the lack of convergent approaches integrating engineered model systems, computational tools, and cancer biology. Using microfluidic invasion models, metabolomics, computational flux balance analysis, and bioinformatic analysis of patient data, the functional links between the stem-like, invasive, and metabolic phenotype of breast cancer cells as a function of HA biosynthesis are investigated. These results suggest that CSCs are more invasive than non-CSCs and that broad metabolic changes caused by overproduction of HA play a role in this process. Accordingly, overexpression of hyaluronic acid synthases (HAS) 2 or 3 induces a metabolic phenotype that promotes cancer cell stemness and invasion in vitro and upregulates a transcriptomic signature predictive of increased invasion and worse patient survival. This study suggests that HA overproduction leads to metabolic adaptations to satisfy the energy demands for 3D invasion of breast CSCs highlighting the importance of engineered model systems and multidisciplinary approaches in cancer research.

Endothelial cells metabolically regulate breast cancer invasion toward a microvessel.

Breast cancer metastasis is initiated by invasion of tumor cells into the collagen type I-rich stroma to reach adjacent blood vessels. Prior work has identified that metabolic plasticity is a key requirement of tumor cell invasion into collagen. However, it remains largely unclear how blood vessels affect this relationship. Here, we developed a microfluidic platform to analyze how tumor cells invade collagen in the presence and absence of a microvascular channel. We demonstrate that endothelial cells secrete pro-migratory factors that direct tumor cell invasion toward the microvessel. Analysis of tumor cell metabolism using metabolic imaging, metabolomics, and computational flux balance analysis revealed that these changes are accompanied by increased rates of glycolysis and oxygen consumption caused by broad alterations of glucose metabolism. Indeed, restricting glucose availability decreased endothelial cell-induced tumor cell invasion. Our results suggest that endothelial cells promote tumor invasion into the stroma due, in part, to reprogramming tumor cell metabolism.