Streamlined Clinical Management Pathways May Reduce Major Amputations in Patients with Chronic Limb Threatening Ischaemia: A Prospective Cohort Study with Historical Controls.

OBJECTIVE: Patient characteristics and patterns of disease in chronic limb threatening ischaemia (CLTI) have changed markedly in recent years. Urgent specialist referral and timely revascularisation are recommended in international guidelines. UK guidelines now recommend revascularisation within 5 days of referral for inpatients and 2 weeks in outpatients. This study compared the contemporary one year major amputation incidence in patients with CLTI with a historical cohort at a single UK centre. METHODS: This was a single centre, observational cohort study with historical controls. A prospective cohort was recruited between May 2019 and March 2022. A historical cohort presenting between 2013 and 2015 inclusive was identified retrospectively. Significant changes in management pathways, including establishing a rapid access limb salvage clinic, occurred between these periods aiming to expedite time from referral to revascularisation. The one year primary outcome was major amputation, and the secondary outcome was death. Major amputation was analysed by Fine-Gray competing risks models (death as the competing risk), presented as subdistribution hazard ratios (SHRs). One year mortality was analysed by Cox regression, presented as hazard ratios. Analyses were adjusted for propensity score. RESULTS: A total of 928 patients were included (432 prospective and 496 historical). Proportions of patients presenting with tissue loss (72.2% vs. 71.6%; p = .090) were similar in both cohorts. At one year, 48 patients (11.1%) in the prospective cohort and 124 patients (25.0%) in the historical cohort had undergone a major amputation (p < .001). Risk of major amputation was 57.0% lower in the prospective cohort compared with the historical cohort after adjustment for propensity score (SHR 0.43, 95% confidence interval 0.29 - 0.63; p < .001). CONCLUSION: An encouraging reduction in major amputation incidence was observed after improvements to CLTI management pathways, but residual confounding is likely. The generalisability of these results is uncertain.

Gender-affirming hormone therapy, mental health, and surgical considerations for aging transgender and gender diverse adults.

As the transgender and gender diverse (TGD) population ages, more transfeminine and transmasculine individuals present to clinic to initiate or continue their gender-affirming care at older ages. Currently available guidelines on gender-affirming care are excellent resources for the provision of gender-affirming hormone therapy (GAHT), primary care, surgery, and mental health care but are limited in their scope as to whether recommendations require tailoring to older TGD adults. Data that inform guideline-recommended management considerations, while informative and increasingly evidence-based, mainly come from studies of younger TGD populations. Whether results from these studies, and therefore recommendations, can or should be extrapolated to aging TGD adults remains to be determined. In this perspective review, we acknowledge the lack of data in older TGD adults and discuss considerations for evaluating cardiovascular disease, hormone-sensitive cancers, bone health and cognitive health, gender-affirming surgery, and mental health in the older TGD population on GAHT.

The Impact of the COVID-19 Pandemic on a Dedicated Vascular Emergency Clinic.

BACKGROUND: Vascular Emergency Clinics (VEC) improve patient outcomes in chronic limb-threatening ischemia (CLTI). They provide a "1 stop" open access policy, whereby "suspicion of CLTI" by a healthcare professional or patient leads to a direct review. We assessed the resilience of the outpatient VEC model to the first year of the coronavirus disease (COVID-19) pandemic. METHODS: A retrospective review of a prospectively maintained database of all patients assessed in our VEC for lower limb pathologies between March 2020 and April 2021 was performed. This was cross-referenced to national and loco-regional Governmental COVID-19 data. Individuals with CLTI were further analysed to determine Peripheral Arterial Disease-Quality Improvement Framework compliance. RESULTS: Seven hundred and ninety one patients attended for 1,084 assessments (Male n = 484, 61%; Age 72.5 ± standard deviation 12.2 years; White British n = 645, 81.7%). In total, 322 patients were diagnosed with CLTI (40.7%). A total of 188 individuals (58.6%) underwent a first revascularization strategy (Endovascular n = 128, 39.8%; Hybrid n = 41, 12.7%; Open surgery n = 19, 5.9%; Conservative n = 134, 41.6%). Major lower limb amputation rate was 10.9% (n = 35) and mortality rate was 25.8% (n = 83) at 12 months of follow-up. Median referral to assessment time was 3 days (interquartile range: 1-5). For the nonadmitted patient with CLTI, the median assessment to intervention was 8 days (interquartile range: 6-15) and median referral to intervention time of 11 days (11-18). CONCLUSIONS: The VEC model has demonstrated strong resilience to the COVID-19 pandemic with rapid treatment timelines maintained for patients with CLTI.

The Role of High-Fidelity Simulation in the Acquisition of Endovascular Surgical Skills: A Systematic Review.

BACKGROUND: The widespread introduction of minimally invasive endovascular techniques in cardiovascular surgery has necessitated a transition in the psychomotor skillset of trainees and surgeons. Simulation has previously been used in surgical training; however, there is limited high-quality evidence regarding the role of simulation-based training on the acquisition of endovascular skills. This systematic review aimed to systematically appraise the currently available evidence regarding endovascular high-fidelity simulation interventions, to describe the overarching strategies used, the learning outcomes addressed, the choice of assessment methodology, and the impact of education on learner performance. METHODS: A comprehensive literature review was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement using relevant keywords to identify studies evaluating simulation in the acquisition of endovascular surgical skills. References of review articles were screened for additional studies. RESULTS: A total of 1,081 studies were identified (474 after removal of duplicates). There was marked heterogeneity in methodologies and reporting of outcomes. Quantitative analysis was deemed inappropriate due to the risk of serious confounding and bias. Instead, a descriptive synthesis was performed, summarizing key findings and quality components. Eighteen studies were included in the synthesis (15 observational, 2 case-control and 1 randomized control studies). Most studies measured procedure time, contrast usage, and fluoroscopy time. Other metrics were recorded to a lesser extent. Significant reductions were noted in both procedure and fluoroscopy times with the introduction of simulation-based endovascular training. CONCLUSIONS: The evidence regarding the use of high-fidelity simulation in endovascular training is very heterogeneous. The current literature suggests simulation-based training leads to improvements in performance, mostly in terms of procedure and fluoroscopy time. High-quality randomized control trials are needed to establish the clinical benefits of simulation training, sustainability of improvements, transferability of skills and its cost-effectiveness.

Time to Load Up-Resistance Training Can Improve the Health of Women with Polycystic Ovary Syndrome (PCOS): A Scoping Review.

BACKGROUND: Guidelines for the management of polycystic ovary syndrome (PCOS) focus on lifestyle changes, incorporating exercise. Whilst evidence suggests that aerobic exercise may be beneficial, less is known about the effectiveness of resistance training (RT), which may be more feasible for those that have low fitness levels and/or are unable to tolerate/participate in aerobic exercise. OBJECTIVES: To identify the available evidence on RT in women with PCOS and to summarise findings in the context of a scoping review. ELIGIBILITY CRITERIA: Studies utilising pre-post designs to assess the effectiveness of RT in PCOS; all outcomes were included. SOURCES OF EVIDENCE: Four databases (PubMed, CENTRAL, CINAHL and SportDiscus) were searched and supplemented by hand searching of relevant papers/reference lists. CHARTING METHODS: Extracted data were presented in tables and qualitatively synthesised. RESULTS: Searches returned 42 papers; of those, 12 papers were included, relating to six studies/trials. Statistical changes were reported for multiple pertinent outcomes relating to metabolic (i.e., glycaemia and fat-free mass) and hormonal (i.e., testosterone and sex hormone-binding globulin) profiles. CONCLUSIONS: There is a striking lack of studies in this field and, despite the reported statistical significance for many outcomes, the documented magnitude of changes are small and the quality of the evidence questionable. This highlights an unmet need for rigorously designed/reported and sufficiently powered trials.

Editor's Choice - Covered vs. Bare Metal Stents in the Reconstruction of the Aortic Bifurcation: Early and Midterm Outcomes from the COBRA European Multicentre Registry.

OBJECTIVE: To report outcomes following endovascular revascularisation for severe aorto-iliac occlusive disease (AIOD) using covered (CS) or bare metal (BMS) stent(s). METHODS: This was a retrospective cohort study including patients who underwent treatment with CS or BMS for AIOD between November 2012 and March 2020 in 12 European centres. Outcome measures included death, freedom from target lesion revascularisation (TLR), major amputation, and major adverse cardiac and cerebrovascular events (MACCE). RESULTS: Overall, 252 patients (53% males; mean age 65 ± 10 years) were included (102 with a bare metal and 150 with a covered aortic stent); 122 (48%) presented with chronic limb threatening ischaemia (CLTI). Severe arterial calcification was noted in > 65% of patients, 70% presented with Trans-Atlantic Societies Consensus (TASC) D lesions, 32% and 46% had aortic or iliac chronic total occlusion (CTO), respectively. Median follow up was 17 months (range 6 - 40; none lost to follow up). Median inpatient stay was two days (range two to four). During the first 30 days, two patients died (both with covered aortic stents, because of cardiovascular events), none required TLR, two (1%) patients had a major amputation (all presented with CLTI), and three (1%) had a MACCE. At 17 months, mortality (BMS 14% vs. CS 7%, hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.42 - 2.26, p = .94, log rank test) and TLR (11% vs. 10%, HR 1.98, 95% CI 0.89 - 4.43, p = .095) did not differ statistically significantly between the two groups; only three patients had a major limb amputation during late follow up (all with a covered stent). In a multivariable model, the use of an aortic CS did not influence TLR. In a conditional Cox regression, however, the concomitant use of aortic and iliac CSs was associated with improved freedom from TLR. CONCLUSION: Endovascular reconstruction with aortic CSs or BMSs for severe AIOD showed comparable midterm performance. The use of both aortic and iliac CSs seems to be associated with reduced TLR.

The Impact of Anemia on One-Year Amputation-Free Survival in Patients Undergoing Revascularization for Chronic Limb-Threatening Ischemia: A Retrospective Cohort Study.

BACKGROUND: Anemia is potentially associated with increased morbidity and mortality following vascular surgery procedures. This study investigated whether peri-procedural anemia is associated with reduced 1-year amputation-free survival (AFS) in patients undergoing revascularization for chronic limb-threatening ischemia (CLTI). METHODOLOGY: A retrospective analysis of patients diagnosed with CLTI between February 2018-February 2019, who subsequently underwent revascularization, was conducted. Hemoglobin concentration measured at index assessment was recorded and stratified by WHO criteria. Subsequent peri-procedural red blood cell transfusions (RBC) were also recorded. The primary outcome was 1-year AFS. Kaplan Meier survival analysis and Cox's proportional hazard modelling were conducted to assess the effect of anemia and peri-procedure transfusion on outcomes. RESULTS: 283 patients were analyzed, of which 148 (52.3%) were anemic. 53 patients (18.7%) underwent RBC transfusion. Patients with anemia had a significantly lower 1-year AFS (64.2% vs. 78.5%, P = 0.009). A significant difference in 1-year AFS was also observed based upon anemia severity (P = 0.008) and for patients who received RBC transfusion (45.3% vs 77.0%, P < 0.001). On multivariable analysis, moderately severe anemia was independently associated with increased risk of major amputation/death (aHR 1.90, 95% CI 1.06-3.38, P = 0.030). After adjusting for severity of baseline anemia, peri-procedural RBC transfusion was associated with a significant increase in the combined risk of major amputation/death (aHR 3.15, 95% CI 1.91-5.20, P < 0.001). CONCLUSION: Moderately severe peri-procedural anemia and subsequent RBC transfusion are independently associated with reduced 1-year AFS in patients undergoing revascularization for CLTI. Future work should focus on investigating alternative measures to managing anemia in this cohort.

The Relationship Between Obesity and Amputation-free Survival in Patients Undergoing Lower-limb Revascularisation for Chronic Limb-threatening Ischaemia: A Retrospective Cohort Study.

BACKGROUND: The obesity paradox is a well-documented phenomenon in cardiovascular disease, however it remains poorly understood. We aimed to investigate the relationship between body mass (as measured by body mass index [BMI]) and 1-year amputation-free survival (AFS) for patients undergoing lower limb revascularisation for chronic limb-threatening ischaemia (CLTI). METHODS: A retrospective analysis was undertaken of all consecutive patients undergoing lower limb revascularisation for CLTI at the Leicester Vascular Institute between February 2018-19. Baseline demographics and outcomes were collected using electronic records. BMI was stratified using the World Health Organization criteria. One-year AFS (composite of major amputation/death) was the primary outcome. Kaplan-Meier survival analysis and adjusted Cox's proportional hazard models were used to compare groups to patients of normal mass. RESULTS: One-hundred and ninety patients were included. Overall, no difference was identified in 1-year AFS across all groups (pooled P = 0.335). Compared to patients with normal BMI (n = 66), obese patients (n = 43) had a significantly lower adjusted combined risk of amputation/death (aHR 0.39, 95% CI 0.16-0.92, P = 0.032), however no significant differences were observed for overweight (aHR 0.89, 95% CI 0.47-1.70, P = 0.741), morbidly obese (aHR 1.15, 95% CI 0.41-3.20, P = 0.797) and underweight individuals (aHR 1.86, 95% CI 0.56-6.20, P = 0.314). CONCLUSIONS: In the context of CLTI, obesity is potentially associated with favourable amputation-free survival at 1 year, compared to normal body mass. The results of this study support the notion of an obesity paradox existing within CLTI and question whether current guidance on weight management requires a more patient-specific approach.

Do patients fed enterally post-gastrointestinal surgery experience more complications when fed a fiber-enriched feed compared with a standard feed? A systematic review.

The role of enteral feeding with fiber-enriched feeds in minimizing infections, shortening length of hospital stay (LOHS), and preventing or treating feeding complications has been widely researched. However, there is limited evidence to evaluate the role of fiber-enriched enteral feeding in gastrointestinal surgery patients postoperatively. This systematic review aims to identify the role of fiber-enriched enteral feeds on postoperative feeding complications of diarrhea, nausea and vomiting, abdominal distension, flatulence, cramps, LOHS, and infection rates after gastrointestinal surgery. A systematic literature search was conducted using MEDLINE, CINAHL, and Cochrane Library. Manual reference lists were searched on identified studies and the SCOPUS database. Randomized controlled trials (RCTs) conducted on any gastrointestinal surgery type that included enteral nutrition with high-fiber enteral feeds and/or fiber supplements were included. All studies included were screened for risk of bias with Cochrane's risk-of-bias tool, and data were extracted with Cochrane Collaboration's data extraction tool. In total, 3 RCTs out of 231 screened citations including fiber-enriched feeds and probiotics were included in this review. No significant effect on LOHS or postoperative infections was found. No safety risks were identified. Limited, low-quality evidence suggests fiber-enriched feeds may minimize diarrhea incidence. The effects of fiber-enriched feeds postoperatively in gastrointestinal surgery remain under-researched. Studies evaluating fiber and probiotics were low quality and at high risk of bias because of the misreporting of outcomes and the lack of detailed outlines of probiotic strains utilized. However, fiber-enriched enteral feeding appears safe, may yield benefits, and is recommended in stable gastrointestinal surgical patients.

Associations of Clinical Frailty with Severity of Limb Threat and Outcomes in Chronic Limb-threatening Ischaemia.

OBJECTIVE: Investigate the relationship of frailty and severity of chronic limb-threatening ischaemia (CLTI), and their comparative associations with one-year outcomes, in patients presenting to a vascular limb salvage (VaLS) clinic. METHODS: This retrospective cohort study utilised data collected from a prospectively maintained VaLS clinic database. Patients aged ≥50 presenting to the VaLS clinic with CLTI between February 2018 and April 2019 were included. Frailty was measured using the Clinical Frailty Scale (CFS) and limb threat severity by the Wound, Ischaemia, and foot Infection (WIfI) score. Excessive polypharmacy was defined as ≥10 medications. Anticholinergic burden (ACB) score and Charlson comorbidity index (CCI) were calculated for all patients. The primary outcome measure was a composite endpoint of death or amputation at one-year. Associations with outcome were assessed using Cox regression and reported as hazards ratios (HR) with 95% confidence intervals (CI). RESULTS: A total of 198 patients were included, with CFS scores available for 190 patients. 98 patients (52%) were frail (CFS ≥5). 127 patients (67%) initially underwent endovascular revascularisation. Excessive polypharmacy was common (55 patients; 28%). Frailty was associated with increased WIfI stage (P = 0.025) as well as age, female sex, CCI score, number of medications, excessive polypharmacy but not ACB score. Frail patients were more frequently managed non-operatively (P = 0.017). Frailty (HR 1.91; 95% CI 1.09, 3.34; P = 0.024) and WIfI stage 4 (HR 3.29; 95%CI 1.23, 8.80; P = 0.018) were associated with death or amputation on univariable analysis. WIfI stage 4 (HR 2.80; 95%CI 1.04, 7.57; P = 0.042) and CCI score (HR 1.21; 95%CI 1.03, 1.41; P = 0.015), but not frailty (HR 1.25; 95%CI 0.67, 2.33; P = 0.474), were independently associated with death or amputation on multivariable analysis. CONCLUSIONS: Frailty is highly prevalent among CLTI patients and related to severity of limb threat. The CFS may be a useful adjunct to patient risk assessment in CLTI.

Does the Introduction of a Vascular Limb Salvage Service Improve One Year Amputation Outcomes for Patients with Chronic Limb-Threatening Ischaemia?

OBJECTIVE: Vascular limb salvage services are recommended by the Global Vascular Guidelines to help improve outcomes for patients with chronic limb-threatening ischaemia (CLTI), although their description within the literature is limited. This study reports the 12 month outcomes for an outpatient based vascular limb salvage (VaLS) clinic. METHODS: An analysis of a prospectively maintained database, involving all consecutive patients diagnosed with CLTI within the VaLS clinic from February 2018-February 2019, was undertaken. Data were compared with two comparator cohorts, identified from coding data: 1) patients managed prior to the clinic, between May 2017 and February 2018 (Pre-Clinic [PC]); and 2) patients managed outside of clinic, between February 2018 and February 2019 (Alternative Pathways [AP]). Freedom from major amputation at 12 months was the primary outcome. Kaplan-Meier plots and adjusted Cox's proportional hazard models (aHR) were used to compare outcomes. RESULTS: Five hundred and sixty-six patients (VaLS 158, AP 173, PC 235) were included (median age 74 years). Patients managed within the VaLS cohort were statistically significantly more likely to be free from major amputation (90.5%) compared with both the AP (82.1%, aHR 0.52, 95% confidence interval [CI] 0.28 - 0.98, p = .041) and the PC (80.0%; aHR 0.50, 95% CI 0.28 - 0.91, p = .022) cohorts at 12 months, after adjustment for age, disease severity, and presence of diabetes. CONCLUSION: This study supports the recommendations of the Global Vascular Guidelines that vascular limb salvage clinics may improve the rate of major amputation. Furthermore, the study provides a reproducible service model that delivers timely vascular assessment in an ambulatory setting. Further evaluation is required to assess longer term outcomes.

Replacing low-intensity cattle pasture with oil palm conserves dung beetle functional diversity when paired with forest protection.

Meeting rising demand for oil palm whilst minimizing the loss of tropical biodiversity and associated ecosystem functions is a core conservation challenge. One potential solution is focusing the expansion of high-yielding crops on presently low-yielding farmlands alongside protecting nearby tropical forests that can enhance provision of ecosystem functions. A key question is how this solution would impact invertebrate functional diversity. We focus on oil palm in the Colombian Llanos, where plantations are replacing improved cattle pastures and forest fragments, and on dung beetles, which play key functional roles in nutrient cycling and secondary seed dispersal. We show that functional richness and functional diversity of dung beetles is greater in oil palm than in cattle pasture, and that functional metrics did not differ between oil palm and remnant forest. The abundance-size class profile of dung beetles in oil palm was more similar to forest than to pasture, which had lower abundances of the smallest and largest dung beetles. The abundance of tunneling and rolling dung beetles did not differ between oil palm and forest, while higher forest cover increased the abundance of diurnal and generalist-feeding beetles in oil palm landscapes. This suggests that prioritizing agricultural development on low-yielding cattle pasture will have positive effects on functional diversity and highlights the need for forest protection to maintain ecosystem functioning within agricultural landscapes.

Evaluation of public and animal health risks in case of a delayed post-mortem inspection in ungulates.

The potential effects of a 24 or 72-h delay in post-mortem inspection (PMI) of ungulates on public health and monitoring of animal health and welfare was evaluated. The assessment used a survey of meat inspectors, expert opinion, literature search and a stochastic model for Salmonella detection sensitivity. Disease detection sensitivity at a delayed PMI is expected to reduce detection sensitivity to a variable extent, depending on the hazard and on the signs/lesions and organs involved. No reduction is expected for Trichinella detection in meat from susceptible animal species and any decrease in detection of transmissible spongiform encephalopathies (TSEs) will not exceed the current tolerance for fallen stock. A 24-h delay in PMI could result in a small reduction in sensitivity of detection for tuberculosis, echinococcosis and cysticercosis. A greater reduction is expected for the detection of pyaemia and Rift valley fever. For the detection of Salmonella, the median model estimates are a reduction of sensitivity of 66.5% (90% probability interval (PI) 0.08-99.75%) after 24-h delay and 94% (90% PI 0.83-100%) after 72-h delay of PMI. Laboratory testing for tuberculosis following a sampling delay of 24-72 h could result in no, or a moderate, decrease in detection depending on the method of confirmation used (PCR, culture, histopathology). For chemical contaminants, a delay in meat inspection of 24 or 72 h is expected to have no impact on the effectiveness of detection of persistent organic pollutants and metals. However, for certain pharmacologically active substances, there will be a reduced effectiveness to detect some of these substances due to potential degradation in the available matrices (tissues and organs) and the non-availability of specific preferred matrices of choice.

An in-vivo Intraoral Defect Model for Assessing the Use of P11-4 Self-Assembling Peptide in Periodontal Regeneration.

Periodontal disease is one of the most common diseases worldwide. It has a significant impact on oral health and subsequently the individual's quality of life. However, optimal regeneration of periodontal tissues, using current treatments, has yet to be achieved. Peptide self-assembly has provided a step-change in nanobiotechnology and regenerative medicine fields. Our aim was to investigate the effects of a self-assembling peptide (SAP; P11-4) on periodontal regeneration in a preclinical model. Twenty-six bilateral maxillary critical-sized periodontal defects were created surgically in 13 rats. Defects on one side of the mouth were filled with P11-4 hydrogel; the contra-lateral defect was untreated (control). Rats were sacrificed immediately post-surgery (time 0) and after 2 and 4 weeks. Retrieved maxillae were processed for histological, immunohistochemical, and histomorphometric assessments. The results of histological analysis showed greater organization of periodontal fibers in defects treated with P11-4, at both time points, when compared to untreated defects. Histomorphometry showed that treated defects had both a significant increase in functional periodontal ligament length and a reduction in epithelial down growth after 4 weeks. At 2 weeks, treated defects showed a significant increase in expression of osteocalcin and osteoprotegerin as judged by immunohistochemistry. Also, a significantly higher osteoprotegerin/RANKL ratio was shown in treated defects. In conclusion, the results demonstrated enhanced regeneration of periodontal tissues when SAP P11-4 was used to fill periodontal defects in rats. The findings of this study suggest that SAP P11-4 is a promising novel candidate for periodontal regenerative therapy. Further investigations are required for optimization before clinical use.

Differentiated ovine tracheal epithelial cells support the colonisation of pathogenic and non-pathogenic strains of Mannheimia haemolytica.

Mannheimia haemolytica is the primary bacterial species associated with respiratory disease of ruminants. A lack of cost-effective, reproducible models for the study of M. haemolytica pathogenesis has hampered efforts to better understand the molecular interactions governing disease progression. We employed a highly optimised ovine tracheal epithelial cell model to assess the colonisation of various pathogenic and non-pathogenic M. haemolytica isolates of bovine and ovine origin. Comparison of single representative pathogenic and non-pathogenic ovine isolates over ten time-points by enumeration of tissue-associated bacteria, histology, immunofluorescence microscopy and scanning electron microscopy revealed temporal differences in adhesion, proliferation, bacterial cell physiology and host cell responses. Comparison of eight isolates of bovine and ovine origin at three key time-points (2 h, 48 h and 72 h), revealed that colonisation was not strictly pathogen or serotype specific, with isolates of serotype A1, A2, A6 and A12 being capable of colonising the cell layer regardless of host species or disease status of the host. A trend towards increased proliferative capacity by pathogenic ovine isolates was observed. These results indicate that the host-specific nature of M. haemolytica infection may result at least partially from the colonisation-related processes of adhesion, invasion and proliferation at the epithelial interface.

Missed Opportunities for Timely Recognition of Chronic Limb Threatening Ischaemia in Patients Undergoing a Major Amputation: A Population Based Cohort Study Using the UK's Clinical Practice Research Datalink.

OBJECTIVE: Opportunities for timely recognition of chronic limb-threatening ischaemia (CLTI) within primary care, such as performing cardiovascular assessment during clinical consultation, are possibly being missed. This study aimed to investigate for potential "missed opportunities" within primary care. METHODS: This was a population based cohort study, using the UK's Clinical Practice Research Datalink (CPRD). Patients undergoing a major amputation for CLTI between 1 January 2000 and 31 December 2016 were included. Primary care consultation and patient clinical data within the one year period prior to amputation were extracted from the CPRD. Dates of last primary care consultation and cardiovascular assessment prior to amputation were evaluated. Timings of latest cardiovascular assessments were stratified into "recent" (7-90 days before amputation) and "late" (> 91 days). RESULTS: In total, 3 260 patients were included. In the year prior to amputation, patients attended a median of 19 (range 9-32) primary care consultations; however, prescription of secondary preventive medications was poor (antiplatelet 49.7%; lipid lowering agent 40.7%). Overall, 2 175 patients (66.7%) attended a primary care consultation 7-30 days before their amputation. However, only 416 (12.8%) underwent a cardiovascular assessment within this period, with 2 073 (63.6%) undergoing no assessment within 90 days of their amputation. Of these 2 073 patients, 1 230 (59.3%) had a primary care consultation 7-30 days before their procedure. Patients undergoing "late" assessment were younger (p = .003), with higher systolic (p = .008) and diastolic (p = .001) blood pressures than those undergoing "recent" assessment. Differences were also observed between assessment timings by deprivation (p = .003) and ethnicity (p = .006). CONCLUSION: Missed opportunities for timely recognition potentially exist and may be related to age, deprivation, and ethnicity. Further work is required to investigate these factors, as well as individual amputations to identify the causes precipitating amputation. Greater emphasis on the medical management of peripheral arterial disease and identifying cardiovascular risk factors in patients who may not fit the "at risk" stereotype, are also required.

Paclitaxel and Mortality Following Peripheral Angioplasty: An Adjusted and Case Matched Multicentre Analysis.

OBJECTIVE: Paclitaxel based drug coated balloons (DCBs) and drug eluting stents (DESs) may be associated with increased mortality in patients with peripheral arterial occlusive disease (PAOD), based on a recent meta-analysis. This study, however, had a number of limitations, which have been discussed at great length among the vascular community. The aim of this research was to assess the association between paclitaxel based endovascular treatment (PTX) in the femoropopliteal (F-P) segment and mortality, adjusting for relevant risk factors and including patients with chronic limb threatening ischaemia (CLTI). METHODS: This was a retrospective cohort study of a prospectively maintained multicentre (three sites) database of patients with claudication or CLTI. Patients having F-P angioplasty between 1 January 2014 and 30 May 2019 with or without PTX were included. Survival was compared in Cox regression analyses adjusted for parameters of the Charlson comorbidity index. A separate nested case matched (based on each individual's Charlson index) analysis was performed to compare mortality rates between those who received PTX and those who did not. RESULTS: A total of 2 071 patients were analysed: 966 patients (46.6%) were treated with PTX (952 [46%] had CLTI and 1 119 [54%] severe claudication [Rutherford stage 3]). Over a 24 month median follow up, 456 (22.1%) patients died. Using multivariable Cox regression, PTX was not associated with mortality (HR 0.94, p = .46), even when assessed separately for those with intermittent claudication (HR 1.30, p = .15) or CLTI (HR 0.81, p = .060). In the case matched analysis (885 matched pairs of patients), PTX was not associated with mortality (HR 0.89, p = .17). Paclitaxel dose and use of a DCB or DES were not associated with mortality in any subanalysis. CONCLUSION: When relevant risk factors were taken into account, there were no associations between PTX and mid term mortality in patients with PAOD.

Internalization of Metal-Organic Framework Nanoparticles in Human Vascular Cells: Implications for Cardiovascular Disease Therapy.

Abstract: Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality worldwide. Alteration of endothelial cells and the underlying vasculature plays a central role in the pathogenesis of various CVDs. The application of nanoscale materials such as nanoparticles in biomedicine has opened new horizons in the treatment of CVDs. We have previously shown that the iron metal-organic framework nanoparticle, Materials Institut Lavoisier-89 (nanoMIL-89) represents a viable vehicle for future drug delivery of pulmonary arterial hypertension. In this study, we have assessed the cellular uptake of nanoMIL-89 in pulmonary artery endothelial and smooth muscle cells using microscopy imaging techniques. We also tested the cellular responses to nanoMIL-89 using molecular and cellular assays. Microscopic images showed cellular internalization of nanoMIL-89, packaging into endocytic vesicles, and passing to daughter cells during mitosis. Moreover, nanoMIL-89 showed anti-inflammatory activity without any significant cytotoxicity. Our results indicate that nanoMIL-89 formulation may offer promising therapeutic opportunities and set forth a new prototype for drug delivery not only in CVDs, but also for other diseases yet incurable, such as diabetes and cancer.

A systematic review investigating the identification, causes, and outcomes of delays in the management of chronic limb-threatening ischemia and diabetic foot ulceration.

OBJECTIVE: Patients presenting with chronic limb-threatening ischemia and diabetic foot ulceration (DFU) are at high risk of major lower limb amputation. Long-standing concern exists regarding late presentation and delayed management contributing to increased amputation rates. Despite multiple guidelines existing on the management of both conditions, there is currently no accepted time frame in which to enact specialist care and treatment. This systematic review aimed to investigate potential time delays in the identification, referral, and management of both chronic limb-threatening ischemia and DFU. METHODS: A systematic review conforming to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement standards was performed searching MEDLINE, Embase, The Cochrane Library, and Cumulative Index to Nursing and Allied Health Literature from inception to November 14, 2018. All English-language qualitative and quantitative articles investigating or reporting the identification, causes, and outcomes of time delays within "high-income" countries (annual gross domestic product per person >$15,000) were included. Data were extracted independently by the investigators. Given the clinical crossover, both conditions were investigated together. A study protocol was designed and registered at the International Prospective Register of Systematic Reviews. RESULTS: A total of 4780 articles were screened, of which 32 articles, involving 71,310 patients and 1388 health care professionals, were included. Twenty-three articles focused predominantly on DFU. Considerable heterogeneity was noted, and only 12 articles were deemed of high quality. Only four articles defined a delay, but this was not consistent between studies. Median times from symptom onset to specialist health care assessment ranged from 15 to 126 days, with subsequent median times from assessment to treatment ranging from 1 to 91 days. A number of patient and health care factors were consistently reported as potentially causative, including poor symptom recognition by the patient, inaccurate health care assessment, and difficulties in accessing specialist services. Twenty articles reported outcomes of delays, namely, rates of major amputation, ulcer healing, and all-cause mortality. Although results were heterogeneous, they allude to delays being associated with detrimental outcomes for patients. CONCLUSIONS: Time delays exist in all aspects of the management pathway, which are in some cases considerable in length. The causes of these are complex but reflect poor patient health-seeking behaviors, inaccurate health care assessment, and barriers to referral and treatment within the care pathway. The adoption of standardized limits for referral and treatment times, exploration of missed opportunities for diagnosis, and investigation of novel strategies for providing specialist care are required to help reduce delays.