Local photo-crosslinking of native tissue matrix regulates cell function.

Within most tissues, the extracellular microenvironment provides mechanical cues that guide cell fate and function. Changes in the extracellular matrix such as aberrant deposition, densification and increased crosslinking are hallmarks of late-stage fibrotic diseases that often lead to organ dysfunction. Biomaterials have been widely used to mimic the mechanical properties of the fibrotic matrix and study cell function. However, the initiation of fibrosis has largely been overlooked, due to the challenges in recapitulating early fibrotic lesions within the native extracellular microenvironment. Using visible light mediated photochemistry, we induced local crosslinking and stiffening of extracellular matrix proteins within ex vivo murine and human tissue. In ex vivo lung tissue of epithelial cell lineage-traced mice, local matrix crosslinking mimicked early fibrotic lesions that increased alveolar epithelial cell spreading, differentiation and extracellular matrix remodeling. However, inhibition of cytoskeletal tension or integrin engagement reduced epithelial cell spreading and differentiation, resulting in alveolar epithelial cell dedifferentiation and reduced extracellular matrix deposition. Our findings emphasize the role of local extracellular matrix crosslinking and remodeling in early-stage tissue fibrosis and have implications for ex vivo disease modeling and applications to other tissues.

A systematic review of anatomical reflux patterns in primary chronic venous disease.

OBJECTIVE: Patients with chronic venous disease (CVD) can present with different underlying hemodynamic abnormalities affecting the deep, superficial, and perforator veins. This review explores the relationship between reflux patterns, extent of venous reflux, and clinical manifestations of CVD. METHODS: The Medline and EMBASE databases were searched systematically from 1946 to April 1, 2024. References of shortlisted papers were searched for relevant articles. Studies were included if they were in English language, included participants ≥16 years of age, documented reflux patterns in two or more of the following: deep, superficial, and/or perforator systems, and related patterns to presentation or severity. Exclusion criteria included patients with isolated deep venous thrombosis, post-thrombotic syndrome or stenotic or obstructive disease. RESULTS: We identified 18 studies (11,177 participants; range, 55-3016). Meta-analysis showed significant odds ratios (OR) for C4-6 disease being associated with deep reflux (OR, 2.41; 95% confidence interval [CI], 1.53-3.78) and perforator reflux (OR, 3.37; 95% CI, 2.16-5.27), but not superficial reflux (OR, 2.11; 95% CI, 0.87-5.14), vs C0-3 disease. Severe CVD (C4-6) was significantly associated with isolated deep, combined deep and superficial, and combined superficial and perforator reflux. The greatest risk of CVD progression (defined as de novo development of varicose veins and progression to greater CVD severity) was shown by two studies to be related to combined deep and superficial reflux. CONCLUSIONS: Although limited by the heterogenous nature of the studies, this review confirms that reflux pattern is a significant predictor of clinical class, and higher clinical, etiological, anatomical, and pathophysiological stages are associated with a higher prevalence of superficial, deep, and perforator reflux. Isolated deep and combined reflux also seem to be to predict the onset of leg ulceration. Future studies should relate reflux patterns to treatment outcomes, including recurrence risk. This work could help to inform health policies and management guidelines so that reflux patterns, in conjunction with other demographic and hemodynamic parameters, could be used to risk stratify patients and identify individuals who may benefit from earlier treatment.

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.

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.

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.

Glucagon-like Peptide 1 Receptor Agonists Promote Weight Loss Among People With HIV.

BACKGROUND: Weight gain and associated metabolic complications are increasingly prevalent among people with human immunodeficiency virus (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 the University of California, San Diego Owen Clinic between 1 February 2021 and 1 February 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 weight 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 (odds ratio [OR], 1.10 [95% confidence interval {CI}, 1.03-1.16]), treatment duration of GLP-1RA therapy >6 months (OR, 3.12 [95% CI, 1.49-6.49]), and use of tirzepatide (OR, 5.46 [95% CI, 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 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.

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.

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.