Systematic Review Examining the Association Between Angiotensin Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Prescription and Abdominal Aortic Aneurysm Growth and Events.

OBJECTIVE: Whether angiotensin II blockade is an effective medical treatment for abdominal aortic aneurysms (AAAs) has not been established. This systematic review and meta-analysis aimed to determine the association between angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) prescription and AAA growth and events. DATA SOURCES: MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Library databases were searched from their inception to 4 January 2024, with no language restrictions. REVIEW METHODS: The five databases were searched for randomised controlled trials (RCTs) and observational studies reporting the association between ACEi or ARB prescription and AAA growth, repair, or rupture. The primary outcome was AAA growth, with secondary outcomes of AAA rupture, AAA repair, and AAA related events (rupture and repair combined). Risk of bias was assessed using the Risk of Bias 2 tool for RCTs and with a modified Newcastle-Ottawa scale for observational studies. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). Random effects models were used for meta-analyses. RESULTS: Eleven studies (two RCTs, eight observational studies, and one meta-analysis of individual patient data from seven populations) involving 58 022 patients were included. ACEi prescription was not associated with a statistically significant reduction in AAA growth (standard mean difference 0.01 mm/year, 95% confidence interval [CI] -0.26 - 0.28; p = .93; I2 = 98%) or AAA repair (odds ratio [OR] 0.73, 95% CI 0.50 - 1.09; p = .65; I2 = 61%), but was associated with a statistically significantly lower risk of AAA rupture (OR 0.87, 95% CI 0.81 - 0.93; p < .001; I2 = 26%) and AAA related events (OR 0.82, 95% CI 0.72 - 0.95; p = .006; I2 = 80%). ARB prescription was not associated with significantly reduced AAA growth or a lower risk of AAA related events. The two RCTs had a low risk of bias, with one observational study having low, seven moderate, and one high risk of bias. All of the findings had a very low certainty of evidence based on the GRADE analysis. CONCLUSION: There was no association between ACEi or ARB prescription and AAA growth, but ACEi prescription was associated with a reduced risk of AAA rupture and AAA related events with very low certainty of evidence.

Network Meta-analysis of Randomised Controlled Trials Comparing the Outcomes of Different Endovascular Revascularisation Treatments for Infra-inguinal Peripheral Arterial Disease Causing Chronic Limb Threatening Ischaemia.

OBJECTIVE: The aim of this study was to compare the efficacy of different endovascular revascularisation procedures for treating chronic limb threatening ischaemia (CLTI) using network meta-analysis (NMA). DATA SOURCES: The databases PubMed and Cochrane Central Register for Controlled Trials were searched on 14 March 2023. REVIEW METHODS: A NMA of randomised controlled trials (RCTs) reporting the efficacy of different endovascular revascularisation techniques for treating CLTI was performed according to PRISMA guidelines. The primary and secondary outcomes were major amputation and death, respectively. Random effects models were developed and the results were presented using surface under the cumulative ranking curve plots and forest plots. A p value of ≤ .050 was considered statistically significant. The Cochrane collaborative tool was used to assess risk of bias. RESULTS: A total of 2 655 participants of whom 94.8% had CLTI were included. Eleven trials compared plain balloon angioplasty (PBA) vs. drug coated balloon (DCB) angioplasty (n = 1 771), five trials compared bare metal stent (BMS) vs. drug coated stent (DCS) (n = 466), three trials compared atherectomy vs. DCB (n = 194), two trials compared PBA vs. BMS (n = 70), one trial compared PBA vs. atherectomy (n = 50), and one trial compared BMS vs. DCB (n = 104). None of the revascularisation strategies significantly reduced the risk of major amputation or death compared with PBA. Using the network estimates, GRADE certainty of evidence for improvement in major amputation outcomes for DCB was moderate, for atherectomy and BMS was low, and for DCS was very low compared with PBA. Risk of bias was low in 16 trials, of some concerns in six trials, and high in one trial, respectively. CONCLUSION: There is no current evidence from RCTs to reliably conclude that BMS, DCB, DCS, or atherectomy are superior to PBA in preventing major amputation and death in patients with CLTI. Larger comparative RCTs are needed to identify the best endovascular revascularisation strategy.

A novel k-mer set memory (KSM) motif representation improves regulatory variant prediction.

The representation and discovery of transcription factor (TF) sequence binding specificities is critical for understanding gene regulatory networks and interpreting the impact of disease-associated noncoding genetic variants. We present a novel TF binding motif representation, the k-mer set memory (KSM), which consists of a set of aligned k-mers that are overrepresented at TF binding sites, and a new method called KMAC for de novo discovery of KSMs. We find that KSMs more accurately predict in vivo binding sites than position weight matrix (PWM) models and other more complex motif models across a large set of ChIP-seq experiments. Furthermore, KSMs outperform PWMs and more complex motif models in predicting in vitro binding sites. KMAC also identifies correct motifs in more experiments than five state-of-the-art motif discovery methods. In addition, KSM-derived features outperform both PWM and deep learning model derived sequence features in predicting differential regulatory activities of expression quantitative trait loci (eQTL) alleles. Finally, we have applied KMAC to 1600 ENCODE TF ChIP-seq data sets and created a public resource of KSM and PWM motifs. We expect that the KSM representation and KMAC method will be valuable in characterizing TF binding specificities and in interpreting the effects of noncoding genetic variations.

Predicting gene expression in massively parallel reporter assays: A comparative study.

In many human diseases, associated genetic changes tend to occur within noncoding regions, whose effect might be related to transcriptional control. A central goal in human genetics is to understand the function of such noncoding regions: given a region that is statistically associated with changes in gene expression (expression quantitative trait locus [eQTL]), does it in fact play a regulatory role? And if so, how is this role "coded" in its sequence? These questions were the subject of the Critical Assessment of Genome Interpretation eQTL challenge. Participants were given a set of sequences that flank eQTLs in humans and were asked to predict whether these are capable of regulating transcription (as evaluated by massively parallel reporter assays), and whether this capability changes between alternative alleles. Here, we report lessons learned from this community effort. By inspecting predictive properties in isolation, and conducting meta-analysis over the competing methods, we find that using chromatin accessibility and transcription factor binding as features in an ensemble of classifiers or regression models leads to the most accurate results. We then characterize the loci that are harder to predict, putting the spotlight on areas of weakness, which we expect to be the subject of future studies.

Procedure-specific outcomes following gastrectomy for cancer compared by hospital volume and service capability.

BACKGROUND: International literature recommends centralising gastric cancer surgery, however, with volumes that define 'high-volume resection' being higher than those in most major centres in Australia and New Zealand. These reports rarely focus on the difference between total (TG) and partial gastrectomy (PG). We assessed the impact of resection volume and service capability on operative mortality, morbidity and surgical quality in patients who had a PG and TG. METHODS: Patients who had gastrectomy for adenocarcinoma, between 2001 and 2015, were collected from the Queensland Oncology Repository. Hospitals were characterised by cases-per-annum (high-volume [HV] ≥ 5 and low-volume [LV] < 5) and hospital service capability as (high-service [HS] and low-service [LS]), giving three hospital groups: HVHS, LVHS and LVLS. Chi-squared tests were used to compare post-operative mortality, morbidity, failure to rescue (FTR) from complications and surgical quality between these three groups. RESULTS: There were 426 patients who had a TG and 827 having PG. HVHS centres performed 59% of PG with high surgical quality rates of: HVHS = 53%, LVHS = 34% and LVLS = 46% (p < 0.01). Surgical complications were highest in LVLS (LVLS = 19%, LVHS = 11%, HVHS = 11%; p = 0.02). There was no difference in 30-day mortality nor in FTR. For TG, HVHS performed 67% of these procedures, with lower 30-day mortality (2%) and FTR rates (5%) compared with LVHS (7%, 22%) and LVLS (12%, 28%; p < 0.01). There was no difference in operative morbidity and surgical quality between hospital groups. CONCLUSION: Despite the 'high-volume' threshold for gastrectomy being the lowest described in the literature, we have shown that centralisation to HVHS centres was associated with lower operative mortality for TG and improved quality of surgery for PG.

Hospital characteristics associated with better 'quality of surgery' and survival following oesophagogastric cancer surgery in Queensland: a population-level study.

BACKGROUND: The impact of hospital characteristics on the quality of surgery and survival following oesophagogastric cancer surgery has not been well established in Australia. We assessed the interaction between hospital volume, service capability and surgical outcomes, with the hypothesis that both the quality of surgery and survival are better following treatment in high-volume, high service capability hospitals. METHODS: All patients undergoing oesophagectomy and gastrectomy for cancer in Queensland, between 2001 and 2015, were included. Demographic, pathology and outcome data were collected. Hospitals were categorized into high (HV) (≥5 gastrectomies; ≥6 oesophagectomies) and low volume (LV). Hospital service capability was defined as high (HS) and low (LS), and then linked to hospital volume: HVHS, LVHS and LVLS. Higher quality surgery was defined using six perioperative parameters. Univariable comparisons of quality of surgery between hospital groups used chi-squared tests. The 5-year overall survival was compared using log-rank tests and Cox proportional hazard models. RESULTS: For both gastrectomy and oesophagectomy, higher quality surgery occurred more frequently in HVHS hospitals (gastrectomy: HVHS = 44.2%, LVHS = 23.1%, LVLS = 29.1% (P < 0.01); oesophagectomy: HVHS = 34.5%, LVHS = 24.4%, LVLS = 21.7% (P = 0.01)). Following oesophagectomy, the 3- and 5-year overall survival was better following treatment in HVHS (P < 0.01). There was no difference between the groups following gastrectomy. CONCLUSION: In Queensland, the quality of surgery was higher in HVHS hospitals performing gastrectomy and oesophagectomy; however, the impact on cancer survival was only seen following oesophagectomy.

Chemically Coupled Interfacial Adhesion in Multimaterial Printing of Hydrogels and Elastomers.

Functional devices that use hydrogels as ionic conductors and elastomers as dielectrics have the advantage of being soft, stretchable, transparent, and biocompatible, making them ideal for biomedical applications. These devices are typically fabricated by manual assembly. Techniques for the manufacturing of soft materials have generally not looked at integrating multiple dissimilar materials. Silane coupling agents have recently shown promise for creating strong bonds between hydrogels and elastomers but have yet to be used in the extrusion printing of complex devices that integrate both hydrogels and elastomers. Here, we demonstrate the viability of silane coupling agents in a system with the rheology and functional composition necessary for three-dimensional (3D) extrusion printing of hydrogel-elastomer materials, specifically polyacrylamide (PAAm) hydrogel and poly(dimethylsiloxane) (PDMS) hydrophobic elastomer. By introducing a charge-neutral surfactant in the PDMS and adjusting silane concentrations in the PAAm, cast material samples demonstrate strong adhesion. We were also able to achieve an interfacial toughness of up to Γ = 193 ± 6.3 J/m2 for a fully extrusion printed PAAm hydrogel-on-PDMS bilayer. This result demonstrates that an integration strategy based on silane coupling agents makes it possible for extrusion printing of a wide variety of hydrogel and silicone elastomers.

Adhesion between Hydrophobic Elastomer and Hydrogel through Hydrophilic Modification and Interfacial Segregation.

Recent progress in the printing of soft materials has made it possible to fabricate soft stretchable devices for a range of engineering applications. These devices tend to be heterogeneous systems, and their reliability depends to a large extent on the integrity of the interfaces between the various materials in the system. Previous studies on the printing of hydrogels have highlighted the need to investigate the adhesion between extrusion printable dielectric elastomers and hydrogels. Here we consider polydimethylsiloxane (PDMS) and a polyacrylamide hydrogel that contains lithium chloride and a nonionic rheological modifier. We show that the adhesion between oxygen plasma-treated PDMS and the hydrogel increases with time to reach a stable value of 15 J m-2 after ∼6 days. During that time, the contact angle of water on the PDMS interface remains constant at ∼30°, suggesting that hydrophobic recovery of plasma-treated PDMS is suppressed by the presence of the hydrogel. It is further observed that a thin viscous layer develops at the interface between PDMS and hydrogel, which results in energy dissipation upon debonding and which allows full recovery of the adhesion after debonding and rejoining. This viscous layer develops only in the presence of the rheological modifier in the hydrogel and the hydrophilic surface treatment of the PDMS.

Sustainable Animal Protein-Intermeshed Epoxy Hybrid Polymers: From Conquering Challenges to Engineering Properties.

The presence of highly modifiable chemical functional groups, abundance of functional groups, and their biological origin make proteins an important class of biomaterials from a fundamental science and applied engineering perspective. Hence, the utilization of proteins from the animal rendering industry (animal protein, AP) for high-value, nonfeed, and nonfertilizer applications is intensely pursued. Although this leads to the exploration of protein-derived plastics as a plausible alternative, the proposed methods are energy-intensive and not based on protein in its native form, which leads to high processing and production costs. Here, we propose, for the first time, novel pathways to develop engineered hybrid systems utilizing AP in its native form and epoxy resins with mechanical properties ranging from toughened thermosets to elastic epoxy-based systems. Furthermore, we demonstrate the capability to engineer the properties of epoxy-AP hybrids from high-strength hybrids to elastic films through controlling the interaction, hydrophilicity, as well as the extent of cross-linking and network density. Through the facile introduction of cochemicals, a sevenfold increase in the mechanical properties of the conventional epoxy-AP hybrid is achieved. Similarly, because of better compatibility afforded by the similar hydrophilicity, AP demonstrated higher cross-linking capability with a water-soluble epoxy (WEP) matrix, resulting in an elastic WEP-AP hybrid without any external aid.

Highly Stretchable and Tough Hydrogels below Water Freezing Temperature.

Hydrogels consist of hydrophilic polymer networks dispersed in water. Many applications of hydrogels rely on their unique combination of solid-like mechanical behavior and water-like transport properties. If the temperature is lowered below 0 °C, however, hydrogels freeze and become rigid, brittle, and non-conductive. Here, a general class of hydrogels that do not freeze at temperatures far below 0 °C, while retaining high stretchability and fracture toughness, is demonstrated. These hydrogels are synthesized by adding a suitable amount of an ionic compound to the hydrogel. The present study focuses on tough polyacrylamide-alginate double network hydrogels equilibrated with aqueous solutions of calcium chloride. The resulting hydrogels can be cooled to temperatures as low as -57 °C without freezing. In this temperature range, the hydrogels can still be stretched more than four times their initial length and have a fracture toughness of 5000 J m-2 . It is anticipated that this new class of hydrogels will prove useful in developing new applications operating under a broad range of environmental and atmospheric conditions.

3D Printing of Transparent and Conductive Heterogeneous Hydrogel-Elastomer Systems.

A hydrogel-dielectric-elastomer system, polyacrylamide and poly(dimethylsiloxane) (PDMS), is adapted for extrusion printing for integrated device fabrication. A lithium-chloride-containing hydrogel printing ink is developed and printed onto treated PDMS with no visible signs of delamination and geometrically scaling resistance under moderate uniaxial tension and fatigue. A variety of designs are demonstrated, including a resistive strain gauge and an ionic cable.

Detecting Character Dependencies in Stochastic Models of Evolution.

Stochastic models of biological evolution generally assume that different characters (runs of the stochastic process) are independent and identically distributed. In this article we determine the asymptotic complexity of detecting dependence for some fairly general models of evolution, but simple models of dependence. A key difference from much of the previous work is that our algorithms work without knowledge of the tree topology. Specifically, we consider various stochastic models of evolution ranging from the common ones used by biologists (such as Cavender-Farris-Neyman and Jukes-Cantor models) to very general ones where evolution of different characters can be governed by different transition matrices on each edge of the evolutionary tree (phylogeny). We also consider several models of dependence between two characters. In the most specific model, on each edge of the phylogeny the joint distribution of the dependent characters undergoes a perturbation of a fixed magnitude, in a fixed direction from what it would be if the characters were evolving independently. More general dependence models don't require such a strong "signal." Instead they only require that on each edge, the perturbation of the joint distribution has a significant component in a specific direction. Our main results are nearly tight bounds on the induced or operator norm of the transition matrices that would allow us to detect dependence efficiently for most models of evolution and dependence that we consider. We make essential use of a new concentration result for multistate random variables of a Markov random field on arbitrary trivalent trees: We show that the random variable counting the number of leaves in any particular state has variance that is subquadratic in the number of leaves.