Transcatheter Arterialization of Deep Veins in Chronic Limb-Threatening Ischemia.

BACKGROUND: Approximately 20% of patients with chronic limb-threatening ischemia have no revascularization options, leading to above-ankle amputation. Transcatheter arterialization of the deep veins is a percutaneous approach that creates an artery-to-vein connection for delivery of oxygenated blood by means of the venous system to the ischemic foot to prevent amputation. METHODS: We conducted a prospective, single-group, multicenter study to evaluate the effect of transcatheter arterialization of the deep veins in patients with nonhealing ulcers and no surgical or endovascular revascularization treatment options. The composite primary end point was amputation-free survival (defined as freedom from above-ankle amputation or death from any cause) at 6 months, as compared with a performance goal of 54%. Secondary end points included limb salvage, wound healing, and technical success of the procedure. RESULTS: We enrolled 105 patients who had chronic limb-threatening ischemia and were of a median age of 70 years (interquartile range, 38 to 89). Of the patients enrolled, 33 (31.4%) were women and 45 (42.8%) were Black, Hispanic, or Latino. Transcatheter arterialization of the deep veins was performed successfully in 104 patients (99.0%). At 6 months, 66.1% of the patients had amputation-free survival. According to Bayesian analysis, the posterior probability that amputation-free survival at 6 months exceeded a performance goal of 54% was 0.993, which exceeded the prespecified threshold of 0.977. Limb salvage (avoidance of above-ankle amputation) was attained in 67 patients (76.0% by Kaplan-Meier analysis). Wounds were completely healed in 16 of 63 patients (25%) and were in the process of healing in 32 of 63 patients (51%). No unanticipated device-related adverse events were reported. CONCLUSIONS: We found that transcatheter arterialization of the deep veins was safe and could be performed successfully in patients with chronic limb-threatening ischemia and no conventional surgical or endovascular revascularization treatment options. (Funded by LimFlow; PROMISE II study ClinicalTrials.gov number, NCT03970538.).

Current Status and Principles for the Treatment and Prevention of Diabetic Foot Ulcers in the Cardiovascular Patient Population: A Scientific Statement From the American Heart Association.

Despite the known higher risk of cardiovascular disease in individuals with type 2 diabetes, the pathophysiology and optimal management of diabetic foot ulcers (DFUs), a leading complication associated with diabetes, is complex and continues to evolve. Complications of type 2 diabetes, such as DFUs, are a major cause of morbidity and mortality and the leading cause of major lower extremity amputation in the United States. There has recently been a strong focus on the prevention and early treatment of DFUs, leading to the development of multidisciplinary diabetic wound and amputation prevention clinics across the country. Mounting evidence has shown that, despite these efforts, amputations associated with DFUs continue to increase. Furthermore, due to increasing patient complexity of management secondary to comorbid conditions, such as cardiovascular disease, the management of peripheral artery disease associated with DFUs has become increasingly difficult, and care delivery is often episodic and fragmented. Although structured, process-specific approaches exist at individual institutions for the management of DFUs in the cardiovascular patient population, there is insufficient awareness of these principles in the general medicine communities. Furthermore, there is growing interest in better understanding the mechanistic underpinnings of DFUs to better define personalized medicine to improve outcomes. The goals of this scientific statement are to provide salient background information on the complex pathogenesis and current management of DFUs in cardiovascular patients, to guide therapeutic and preventive strategies and future research directions, and to inform public policy makers on health disparities and other barriers to improving and advancing care in this expanding patient population.

High-Sensitivity Troponin I after Cardiac Surgery and 30-Day Mortality.

BACKGROUND: Consensus recommendations regarding the threshold levels of cardiac troponin elevations for the definition of perioperative myocardial infarction and clinically important periprocedural myocardial injury in patients undergoing cardiac surgery range widely (from >10 times to ≥70 times the upper reference limit for the assay). Limited evidence is available to support these recommendations. METHODS: We undertook an international prospective cohort study involving patients 18 years of age or older who underwent cardiac surgery. High-sensitivity cardiac troponin I measurements (upper reference limit, 26 ng per liter) were obtained 3 to 12 hours after surgery and on days 1, 2, and 3 after surgery. We performed Cox analyses using a regression spline that explored the relationship between peak troponin measurements and 30-day mortality, adjusting for scores on the European System for Cardiac Operative Risk Evaluation II (which estimates the risk of death after cardiac surgery on the basis of 18 variables, including age and sex). RESULTS: Of 13,862 patients included in the study, 296 (2.1%) died within 30 days after surgery. Among patients who underwent isolated coronary-artery bypass grafting or aortic-valve replacement or repair, the threshold troponin level, measured within 1 day after surgery, that was associated with an adjusted hazard ratio of more than 1.00 for death within 30 days was 5670 ng per liter (95% confidence interval [CI], 1045 to 8260), a level 218 times the upper reference limit. Among patients who underwent other cardiac surgery, the corresponding threshold troponin level was 12,981 ng per liter (95% CI, 2673 to 16,591), a level 499 times the upper reference limit. CONCLUSIONS: The levels of high-sensitivity troponin I after cardiac surgery that were associated with an increased risk of death within 30 days were substantially higher than levels currently recommended to define clinically important periprocedural myocardial injury. (Funded by the Canadian Institutes of Health Research and others; VISION Cardiac Surgery ClinicalTrials.gov number, NCT01842568.).

DNA Nanostructures as Catalysts: Double Crossover Tile-Assisted 5' to 5' and 3' to 3' Chemical Ligation of Oligonucleotides.

Accessibility of synthetic oligonucleotides and the success of DNA nanotechnology open a possibility to use DNA nanostructures for building sophisticated enzyme-like catalytic centers. Here we used a double DNA crossover (DX) tile nanostructure to enhance the rate, the yield, and the specificity of 5'-5' ligation of two oligonucleotides with arbitrary sequences. The ligation product was isolated via a simple procedure. The same strategy was applied for the synthesis of 3'-3' linked oligonucleotides, thus introducing a synthetic route to DNA and RNA with a switched orientation that is affordable by a low-resource laboratory. To emphasize the utility of the ligation products, we synthesized a circular structure formed from intramolecular complementarity that we named "an impossible DNA wheel" since it cannot be built from regular DNA strands by enzymatic reactions. Therefore, DX-tile nanostructures can open a route to producing useful chemical products that are unattainable via enzymatic synthesis. This is the first example of the use of DNA nanostructures as a catalyst. This study advocates for further exploration of DNA nanotechnology for building enzyme-like reactive systems.

Multilevel thrombotic or embolic burden and its role in sex-related outcomes in acute limb ischemia.

OBJECTIVE: The impact of sex upon outcomes in acute limb ischemia (ALI) remains disputed. We aim to quantify the effect of sex upon amputation-free survival (AFS) after a percutaneous-first approach for ALI. METHODS: This was a two-center retrospective review of ALI managed via a percutaneous-first approach. Demographics, comorbidities, and clinical characteristics were analyzed. The Kaplan-Meier and Cox regression were used to estimate AFS, limb salvage, and overall survival. RESULTS: Over 9 years, 170 patients (n = 87, 51% males; median age, 67 [interquartile range (IQR), 59-77 years) presented with ALI. Rutherford classification was I in 56 (33%); IIa in 85 (50%); IIb in 20 (12%), and III in 9 (5%). Thirty-day mortality, major amputation rate, and fasciotomy rates were 8% (n = 13); 6.5% (n = 11), and 4.7% (n = 8), respectively. Among revascularized limbs, 92% were patent at 30 days. Length of stay was 7 days (IQR, 3-11 days). Complications included 13 bleeding episodes (8%), four cases of atrial fibrillation (2%), and three re-thrombosis/clot extension events (1.7%). No differences were noted in complication rates when stratified by sex. Females were older than males (median age, 70 [IQR, 62-79] vs 65 [IQR, 56-76 years]; P = .02) and more likely to present with atrial fibrillation (20.5% vs 8%; P = .02) and hyperlipidemia (72% vs 57%; P = .04). Females also more frequently presented with multi-level thrombotic/embolic burden compared with males (56% vs 43%; P = .03) and required both aspiration thrombectomy and thrombolysis (27% vs 14%; P = .02). Kaplan-Meier estimated median AFS, limb salvage, and overall survival were 425 days (IQR, 140-824 days); 314 days (IQR, 72-727 days); and 342 days (IQR, 112-762 days). When stratified by sex, females had worse survival (median, 270 days [IQR, 92-636 days] vs 406 days [IQR, 140-937 days]; P = .005) and limb salvage (median, 241 days [IQR, 88-636 days] vs 363 days [IQR, 49-822 days]; P = .04) compared with males. Univariate Cox regression showed female sex (hazard ratio [HR], 1.46; 95% confidence interval [CI], 1.04-2.05; P = .03), multi-level thrombotic/embolic burden (HR, 1.64; 95% CI, 1.17-2.31; P = .004), and Rutherford class (HR, 1.37; 95% CI, 1.08-1.73; P = .009) predicted major amputation/death. By multivariable Cox regression, multi-level thrombotic/embolic burden (HR, 1.54; 95% CI, 1.09-2.17; P = .01), Rutherford class (HR, 1.34; 95% CI, 1.07-1.69; P = .01), and female sex (HR, 1.45; 95% CI, 1.03-2.05; P = .03) were each independently predictive of major amputation/death. CONCLUSIONS: A percutaneous-first strategy is safe and efficacious in the overall ALI population. Similar to prior works, female vs male patients with ALI in our cohort have higher rates of mortality and major amputation. In our multivariable model, multi-level thrombotic/embolic burden was independently associated with a greater than 45% increased hazard of major amputation/death at last follow-up. Further prospective analysis is warranted to elucidate the underlying factors contributing to the higher prevalence of multi-level thrombotic/embolic burden in female patients with ALI, and to further define the optimal percutaneous-first approach for ALI in consideration of patient sex and extent of clot burden.

Guidelines on the classification of foot ulcers in people with diabetes (IWGDF 2023 update).

BACKGROUND: This publication represents a scheduled update of the 2019 guidelines of the International Working Group of the Diabetic Foot (IWGDF) addressing the use of systems to classify foot ulcers in people with diabetes in routine clinical practice. The guidelines are based on a systematic review of the available literature that identified 28 classifications addressed in 149 articles and, subsequently, expert opinion using the GRADE methodology. METHODS: First, we have developed a list of classification systems considered as being potentially adequate for use in a clinical setting, through the summary of judgements for diagnostic tests, focussing on the usability, accuracy and reliability of each system to predict ulcer-related complications as well as use of resources. Second, we have determined, following group debate and consensus, which of them should be used in specific clinical scenarios. Following this process, in a person with diabetes and a foot ulcer we recommend: (a) for communication among healthcare professionals: to use the SINBAD (Site, Ischaemia, Bacterial infection, Area and Depth) system (first option) or consider using WIfI (Wound, Ischaemia, foot Infection) system (alternative option, when the required equipment and level of expertise is available and it is considered feasible) and in each case the individual variables that compose the systems should be described rather than a total score; (b) for predicting the outcome of an ulcer in a specific individual: no existing system could be recommended; (c) for characterising a person with an infected ulcer: the use of the IDSA/IWGDF classification (first option) or consider using the WIfI system (alternative option, when the required equipment and level of expertise is available and it is considered as feasible); (d) for characterising a person with peripheral artery disease: consider using the WIfI system as a means to stratify healing likelihood and amputation risk; (e) for the audit of outcome(s) of populations: the use of the SINBAD score. CONCLUSIONS: For all recommendations made using GRADE, the certainty of evidence was judged, at best, as being low. Nevertheless, based on the rational application of current data this approach allowed the proposal of recommendations, which are likely to have clinical utility.

Classification of foot ulcers in people with diabetes: A systematic review.

BACKGROUND: Classification and scoring systems can help both clinical management and audit the outcomes of routine care. AIM: This study aimed to assess published systems used to characterise ulcers in people with diabetes to determine which should be recommended to (a) aid communication between health professionals, (b) predict clinical outcome of individual ulcers, (c) characterise people with infection and/or peripheral arterial disease, and (d) audit to compare outcomes in different populations. This systematic review is part of the process of developing the 2023 guidelines to classify foot ulcers from the International Working Group on Diabetic Foot. METHODS: We searched PubMed, Scopus and Web of Science for articles published up to December 2021 which evaluated the association, accuracy or reliability of systems used to classify ulcers in people with diabetes. Published classifications had to have been validated in populations of >80% of people with diabetes and a foot ulcer. RESULTS: We found 28 systems addressed in 149 studies. Overall, the certainty of the evidence for each classification was low or very low, with 19 (68%) of the classifications being assessed by ≤ 3 studies. The most frequently validated system was the one from Meggitt-Wagner, but the articles validating this system focused mainly on the association between the different grades and amputation. Clinical outcomes were not standardized but included ulcer-free survival, ulcer healing, hospitalisation, limb amputation, mortality, and cost. CONCLUSION: Despite the limitations, this systematic review provided sufficient evidence to support recommendations on the use of six particular systems in specific clinical scenarios.

Performance of non-invasive bedside vascular testing in the prediction of wound healing or amputation among people with foot ulcers in diabetes: A systematic review.

INTRODUCTION: The presence of peripheral artery disease (PAD) confers a significantly increased risk of failure to heal and major lower limb amputation for people with diabetes-related foot ulcer (DFU). Determining performance of non-invasive bedside tests for predicting likely DFU outcomes is therefore key to effective risk stratification of patients with DFU and PAD to guide management decisions. The aim of this systematic review was to determine the performance of non-invasive bedside tests for PAD to predict DFU healing, healing post-minor amputation, or need for minor or major amputation in people with diabetes and DFU or gangrene. METHODS: A database search of Medline and Embase was conducted from 1980 to 30 November 2022. Prospective studies that evaluated non-invasive bedside tests in patients with diabetes, with and without PAD and foot ulceration or gangrene to predict the outcomes of DFU healing, minor amputation, and major amputation with or without revascularisation, were eligible. Included studies were required to have a minimum 6-month follow-up period and report adequate data to calculate the positive likelihood ratio (PLR) and negative likelihood ratio for the outcomes of DFU healing, and minor and major amputation. Methodological quality was assessed using the Quality in Prognosis Studies tool. RESULTS: From 14,820 abstracts screened 28 prognostic studies met the inclusion criteria. The prognostic tests evaluated by the studies included: ankle-brachial index (ABI) in 9 studies; ankle pressures in 10 studies, toe-brachial index in 4 studies, toe pressure in 9 studies, transcutaneous oxygen pressure (TcPO2 ) in 7 studies, skin perfusion pressure in 5 studies, continuous wave Doppler (pedal waveforms) in 2 studies, pedal pulses in 3 studies, and ankle peak systolic velocity in 1 study. Study quality was variable. Common reasons for studies having a moderate or high risk of bias were poorly described study participation, attrition rates, and inadequate adjustment for confounders. In people with DFU, toe pressure ≥30 mmHg, TcPO2 ≥25 mmHg, and skin perfusion pressure of ≥40 mmHg were associated with a moderate to large increase in pretest probability of healing in people with DFU. Toe pressure ≥30 mmHg was associated with a moderate increase in healing post-minor amputation. An ABI using a threshold of ≥0.9 did not increase the pretest probability of DFU healing, whereas an ABI <0.5 was associated with a moderate increase in pretest probability of non-healing. Few studies investigated amputation outcomes. An ABI <0.4 demonstrated the largest increase in pretest probability of a major amputation (PLR ≥10). CONCLUSIONS: Prognostic capacity of bedside testing for DFU healing and amputation is variable. A toe pressure ≥30 mmHg, TcPO2 ≥25 mmHg, and skin perfusion pressure of ≥40 mmHg are associated with a moderate to large increase in pretest probability of healing in people with DFU. There are little data available evaluating the prognostic capacity of bedside testing for healing after minor amputation or for major amputation in people with DFU. Current evidence suggests that an ABI <0.4 may be associated with a large increase in risk of major amputation. The findings of this systematic review need to be interpreted in the context of limitations of available evidence, including varying rates of revascularisation, lack of post-revascularisation bedside testing, and heterogenous subpopulations.

Effectiveness of bedside investigations to diagnose peripheral artery disease among people with diabetes mellitus: A systematic review.

As a progressive disease process, early diagnosis and ongoing monitoring and treatment of lower limb peripheral artery disease (PAD) is critical to reduce the risk of diabetes-related foot ulcer (DFU) development, non-healing of wounds, infection and amputation, in addition to cardiovascular complications. There are a variety of non-invasive tests available to diagnose PAD at the bedside, but there is no consensus as to the most diagnostically accurate of these bedside investigations or their reliability for use as a method of ongoing monitoring. Therefore, the aim of this systematic review was to first determine the diagnostic accuracy of non-invasive bedside tests for identifying PAD compared to an imaging reference test and second to determine the intra- and inter-rater reliability of non-invasive bedside tests in adults with diabetes. A database search of Medline and Embase was conducted from 1980 to 30 November 2022. Prospective and retrospective investigations of the diagnostic accuracy of bedside testing in people with diabetes using an imaging reference standard and reliability studies of bedside testing techniques conducted in people with diabetes were eligible. Included studies of diagnostic accuracy were required to report adequate data to calculate the positive likelihood ratio (PLR) and negative likelihood ratio (NLR) which were the primary endpoints. The quality appraisal was conducted using the Quality Assessment of Diagnostic Accuracy Studies and Quality Appraisal of Reliability quality appraisal tools. From a total of 8517 abstracts retrieved, 40 studies met the inclusion criteria for the diagnostic accuracy component of the review and seven studies met the inclusion criteria for the reliability component of the review. Most studies investigated the diagnostic accuracy of ankle -brachial index (ABI) (N = 38). In people with and without DFU, PLRs ranged from 1.69 to 19.9 and NLRs from 0.29 to 0.84 indicating an ABI <0.9 increases the likelihood of disease (but the extent of the increase ranges from a small to large amount) and an ABI within the normal range (≥0.90 and <1.3) does not exclude PAD. For toe-brachial index (TBI), a threshold of <0.70 has a moderate ability to rule PAD in and out; however, this is based on limited evidence. Similarly, a small number of studies indicate that one or more monophasic Doppler waveforms in the pedal arteries is associated with the presence of PAD, whereas tri- or biphasic waveform suggests that PAD is less likely. Several forms of bedside testing may also be useful as adjunct tests and 7 studies were identified that investigated the reliability of bedside tests including ABI, toe pressure, TBI, transcutaneous oxygen pressure (TcPO2 ) and pulse palpation. Inter-rater reliability was poor for pulse palpation and moderate for TcPO2. The ABI, toe pressure and TBI may have good inter- and intra-rater reliability, but margins of error are wide, requiring a large change in the measurement for it to be considered a true change rather than error. There is currently no single bedside test or a combination of bedside tests that has been shown to have superior diagnostic accuracy for PAD in people with diabetes with or without DFU. However, an ABI <0.9 or >1.3, TBI of <0.70, and absent or monophasic pedal Doppler waveforms are useful to identify the presence of disease. The ability of the tests to exclude disease is variable and although reliability may be acceptable, evidence of error in the measurements means test results that are within normal limits should be considered with caution and in the context of other vascular assessment findings (e.g., pedal pulse palpation and clinical signs) and progress of DFU healing.

The intersocietal IWGDF, ESVS, SVS guidelines on peripheral artery disease in people with diabetes and a foot ulcer.

Diabetes related foot complications have become a major cause of morbidity and are implicated in most major and minor amputations globally. Approximately 50% of people with diabetes and a foot ulcer have peripheral artery disease (PAD) and the presence of PAD significantly increases the risk of adverse limb and cardiovascular events. The International Working Group on the Diabetic Foot (IWGDF) has published evidence based guidelines on the management and prevention of diabetes related foot complications since 1999. This guideline is an update of the 2019 IWGDF guideline on the diagnosis, prognosis and management of peripheral artery disease in people with diabetes mellitus and a foot ulcer. For this guideline the IWGDF, the European Society for Vascular Surgery and the Society for Vascular Surgery decided to collaborate to develop a consistent suite of recommendations relevant to clinicians in all countries. This guideline is based on three new systematic reviews. Using the Grading of Recommendations, Assessment, Development, and Evaluation framework clinically relevant questions were formulated, and the literature was systematically reviewed. After assessing the certainty of the evidence, recommendations were formulated which were weighed against the balance of benefits and harms, patient values, feasibility, acceptability, equity, resources required, and when available, costs. Through this process five recommendations were developed for diagnosing PAD in a person with diabetes, with and without a foot ulcer or gangrene. Five recommendations were developed for prognosis relating to estimating likelihood of healing and amputation outcomes in a person with diabetes and a foot ulcer or gangrene. Fifteen recommendations were developed related to PAD treatment encompassing prioritisation of people for revascularisation, the choice of a procedure and post-surgical care. In addition, the Writing Committee has highlighted key research questions where current evidence is lacking. The Writing Committee believes that following these recommendations will help healthcare professionals to provide better care and will reduce the burden of diabetes related foot complications.