[68Ga]Ga-Schizokinen, a Potential Radiotracer for Selective Bacterial Infection Imaging.

Gallium-68-labeled siderophores as radiotracers have gained interest for the development of in situ infection-specific imaging diagnostics. Here, we report radiolabeling, in vitro screening, and in vivo pharmacokinetics (PK) of gallium-68-labeled schizokinen ([68Ga]Ga-SKN) as a new potential radiotracer for imaging bacterial infections. We radiolabeled SKN with ≥95% radiochemical purity. Our in vitro studies demonstrated its hydrophilic characteristics, neutral pH stability, and short-term stability in human serum and toward transchelation. In vitro uptake of [68Ga]Ga-SKN by Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and S. epidermidis, but no uptake by Candida glabrata, C. albicans, or Aspergillus fumigatus, demonstrated its specificity to bacterial species. Whole-body [68Ga]Ga-SKN positron emission tomography (PET) combined with computerized tomography (CT) in healthy mice showed rapid renal excretion with no or minimal organ uptake. The subsequent ex vivo biodistribution resembled this fast PK with rapid renal excretion with minimal blood retention and no major organ uptake and showed some dissociation of the tracer in the urine after 60 min postinjection. These findings warrant further evaluation of [68Ga]Ga-SKN as a bacteria-specific radiotracer for infection imaging.

Supporting Employment Consultants to Implement Supported and Customized Employment.

Implementing supported and customized employment in all their components is essential for supporting job seekers with disabilities to achieve their career goals. We asked 42 employment consultants in nine employment programs to respond daily to three quick questions about their employment support activities, for 6 months. Through monthly coaching, we helped the managers of these organizations engage their teams of employment consultants to interpret the data, reflect, set goals, and take action for quality improvement. Based on the positive results of this pilot, we recommend that employment consultants be provided with data-enabled feedback that supports decision making and helps them fully implement supported and customized employment as a necessary step toward improving job seekers' employment outcomes.

HTATIP2 regulates arteriogenic activity in monocytes from patients with limb ischemia.

Use of autologous cells isolated from elderly patients with multiple comorbidities may account for the modest efficacy of cell therapy in patients with chronic limb threatening ischemia (CLTI). We aimed to determine whether proarteriogenic monocyte/macrophages (Mo/MΦs) from patients with CLTI were functionally impaired and to demonstrate the mechanisms related to any impairment. Proarteriogenic Mo/MΦs isolated from patients with CLTI were found to have an impaired capacity to promote neovascularization in vitro and in vivo compared with those isolated from healthy controls. This was associated with increased expression of human HIV-1 TAT interactive protein-2 (HTATIP2), a transcription factor known to suppress angiogenesis/arteriogenesis. Silencing HTATIP2 restored the functional capacity of CLTI Mo/MΦs, which was associated with increased expression of arteriogenic regulators Neuropilin-1 and Angiopoietin-1, and their ability to enhance angiogenic (endothelial tubule formation) and arteriogenic (smooth muscle proliferation) processes in vitro. In support of the translational relevance of our findings, silencing HTATIP2 in proarteriogenic Mo/MΦs isolated from patients with CLTI rescued their capacity to enhance limb perfusion in the ischemic hindlimb by effecting greater angiogenesis and arteriogenesis. Ex vivo modulation of HTATIP2 may offer a strategy for rescuing the functional impairment of pro-angio/arteriogenic Mo/MΦs prior to autologous delivery and increase the likelihood of clinical efficacy.

Mechanical aortic valve may no longer be a contraindication to inner branch aortic arch endografts.

OBJECTIVES: The presence of a mechanical aortic valve has been a contraindication to the use of an arch branch aortic endograft due to the risk of damaging the valve, resulting in acute aortic regurgitation, or a trapped endograft. METHODS: We present a 67-year-old woman, with a background of Marfan's syndrome and a previous Bentall's procedure, who presented with a symptomatic enlarging aortic arch and descending thoracic aortic aneurysm, with a type 1A endoleak. RESULTS: Using an inner branch arch endograft (Cook Medical, Bloomington, Indiana), the nose cone of the delivery system was passed laterally through the semi-circular aperture of the mechanical aortic valve to facilitate deployment just distal to the coronary buttons. CONCLUSIONS: With advancement of endovascular technology, techniques and experience, endovascular aortic arch repair in the presence of a mechanical aortic valve is feasible.

Radiometal chelators for infection diagnostics.

Infection of native tissues or implanted devices is common, but clinical diagnosis is frequently difficult and currently available noninvasive tests perform poorly. Immunocompromised individuals (for example transplant recipients, or those with cancer) are at increased risk. No imaging test in clinical use can specifically identify infection, or accurately differentiate bacterial from fungal infections. Commonly used [18F]fluorodeoxyglucose (18FDG) positron emission computed tomography (PET/CT) is sensitive for infection, but limited by poor specificity because increased glucose uptake may also indicate inflammation or malignancy. Furthermore, this tracer provides no indication of the type of infective agent (bacterial, fungal, or parasitic). Imaging tools that directly and specifically target microbial pathogens are highly desirable to improve noninvasive infection diagnosis and localization. A growing field of research is exploring the utility of radiometals and their chelators (siderophores), which are small molecules that bind radiometals and form a stable complex allowing sequestration by microbes. This radiometal-chelator complex can be directed to a specific microbial target in vivo, facilitating anatomical localization by PET or single photon emission computed tomography. Additionally, bifunctional chelators can further conjugate therapeutic molecules (e.g., peptides, antibiotics, antibodies) while still bound to desired radiometals, combining specific imaging with highly targeted antimicrobial therapy. These novel therapeutics may prove a useful complement to the armamentarium in the global fight against antimicrobial resistance. This review will highlight current state of infection imaging diagnostics and their limitations, strategies to develop infection-specific diagnostics, recent advances in radiometal-based chelators for microbial infection imaging, challenges, and future directions to improve targeted diagnostics and/or therapeutics.

Management of secondary aorto-enteric fistulae: a multi-centre study.

BACKGROUND: Secondary aorto-enteric fistulae (SAEF) are a rare, complex and life-threatening complication following aortic repair. Traditional treatment strategy has been with open aortic repair (OAR), with emergence of endovascular repair (EVAR) as a potentially viable initial treatment option. Controversy exists over optimal immediate and long-term management. METHODS: This was a retrospective, observational, multi-institutional cohort study. Patients who had been treated for SAEF between 2003 and 2020 were identified using a standardized database. Baseline characteristics, presenting features, microbiological, operative, and post-operative variables were recorded. The primary outcomes were short and mid-term mortality. Descriptive statistics, binomial regression, Kaplan-Meier and Cox age-adjusted survival analyses were performed. RESULTS: Across 5 tertiary centres, a total of 47 patients treated for SAEF were included, 7 were female and the median (range) age at presentation was 74 years (48-93). In this cohort, 24 (51%) patients were treated with initially with OAR, 15 (32%) with EVAR-first and 8 (17%) non-operatively. The 30-day and 1-year mortality for all cases that underwent intervention was 21% and 46% respectively. Age-adjusted survival analysis revealed no statistically significant difference in mortality in the EVAR-first group compared to the OAR-first group, HR 0.99 (95% CI 0.94-1.03, P = 0.61). CONCLUSION: In this study there was no difference in all-cause mortality in patients who had OAR or EVAR as first line treatment for SAEF. In the acute setting, alongside broad-spectrum antimicrobial therapy, EVAR can be considered as an initial treatment for patients with SAEF, as a primary treatment or a bridge to definitive OAR.

Carbon dioxide flushing versus saline flushing of thoracic aortic stents (INTERCEPTevar): protocol for a multicentre pilot randomised controlled trial.

INTRODUCTION: Thoracic endovascular aortic repair (TEVAR) carries a 3%-6.1% stroke risk, including risk of 'silent' cerebral infarction (SCI). Stent-grafts are manufactured in room air and retain air. Instructions for use recommend saline flushing to 'de-air' the system prior to insertion, but substantial amounts of air are released when deploying them, potentially leading to downstream neuronal injury and SCI. Carbon dioxide (CO2) is more dense and more soluble in blood than air, without risk of bubble formation, so could be used in addition to saline to de-air stents. This pilot trial aims to assess the feasibility of a full-scale randomised controlled trial (RCT) investigating the neuroprotective benefit against SCI with the use of CO2-flushed aortic stent-grafts. METHODS AND ANALYSIS: This is a multicentre pilot RCT, which is taking place in vascular centres in the UK, USA and New Zealand. Patients identified for TEVAR will be enrolled after informed written consent. 120 participants will be randomised (1:1) to TEVAR-CO2 or TEVAR-saline, stratified according to TEVAR landing zone. Participants will undergo preoperative neurocognitive tests and quality of life assessments, which will be repeated at 6 weeks, or first outpatient appointment, and 6 months. Inpatient neurological testing will be performed within 48 hours of return to level 1 care for clinical stroke or delirium. Diffusion-weighted MRI will be undertaken within 72 hours postoperatively (1-7 days) and at 6 months to look for evidence and persistence of SCI. Feasibility will be assessed via measures of recruitment and retention, informing the design of a full-scale trial. ETHICS AND DISSEMINATION: The study coordination centre has obtained approval from the London Fulham Research Ethics Committee (19/LO/0836) and Southern Health and Disability Ethics Committee (NZ) and UK's Health Regulator Authority (HRA). The study has received ethical approval for recruitment in the UK (Fulham REC, 19/LO/0836), New Zealand (21/STH/192) and the USA (IRB 019-264, Ref 378630). Consent for entering into the study will be taken using standardised consent forms by the local study team, led by a local PI. The results of the trial will be submitted for publication in an open access journal. TRIAL REGISTRATION NUMBER: NCT03886675.

Novel modification of a branched arch endograft with a retrograde left common carotid branch for acute pseudoaneurysm post type A repair.

OBJECTIVE: Pseudoaneurysm formation post type A aortic dissection repair is rare. Revision surgical repair is challenging, with a risk of death from haemorrhage. METHODS: We present a 56-year-old man who presented with a rapidly enlarging distal ascending aortic anastomotic pseudoaneurysm following a recent ascending and hemiarch replacement for acute type A aortic dissection. RESULTS: A tight kink in the ascending aortic graft precluded an endovascular repair utilizing two antegrade branches, and so a novel custom-made 3 inner branched aortic endograft was designed, with an antegrade brachiocephalic inner branch and retrograde left common carotid and subclavian artery inner branches. The patient required an angioplasty to dilate the kinked/coarcted surgical graft, but made an uneventful recovery. CONCLUSION: An aortic arch inner branch design with an antegrade brachiocephalic branch but retrograde left common carotid and left subclavian branches was feasible and may prove particularly useful when there is limited space in the ascending aorta.

The Benefits of Active, Person-Centered Job Placement: Results From Service Providers Undergoing Organizational Transformation Away From Sheltered Employment.

Recent national and state-level policy changes have created an imperative for service providers to transform from sheltered work to competitive integrated employment. The current study sought to understand the impact of participation in a 1-year, comprehensive technical assistance pilot designed to support service providers to transform away from sheltered workshops towards encouraging competitive integrated employment and delivering job development supports. Findings showed competitive integrated employment is attainable if given the appropriate organizational emphasis and when effective job development practices are implemented to a strategically identified group. Implications highlight the values of slowly preparing individuals for competitive integrated employment; facilitating an active, person-centered job placement process; engaging key stakeholders in job development; and focusing on individual job placement in the context of organizational transformation.

Predictors of percutaneous access-related complications in aortic endovascular procedures: 'real-world' insights and a comparison to open access.

BACKGROUND: Percutaneous endovascular aneurysm repair (PEVAR) is becoming increasingly popular due to fewer access-related complications, shorter procedural times and length of stay (LOS). Our aim was to explore factors associated with access-related complications and their impact on procedural time and LOS. METHODS: We retrospectively analyzed consecutive aorto-iliac endovascular procedures in a tertiary hub comprising 2 institutions and 18 consultant vascular surgeons and interventional radiologists between 2016-2017. Access-related complications were defined as: bleeding requiring cutdown or return to theatre, acute limb ischemia or common femoral artery (CFA) pseudoaneurysm requiring intervention and wound infection or dehiscence needing hospitalization. RESULTS: Of 511 patients, 354 (69%) had a percutaneous approach via 589 CFA access sites. In this percutaneous group, access-related complications occurred in 11% of sites (65/589); Their rate varied with procedure type ranging between 3.6% to 17.6%. The most common complication was bleeding due to closure device failure in 8.5% (50/589) of access sites. When uncomplicated, percutaneous interventions were faster compared to open surgical access (P<0.0001). Operation time and median LOS (3 vs. 2 days) were longer for elective standard EVAR patients experiencing access-related complications (P=0.033). In the percutaneous group, multivariate regression analysis demonstrated significant associations between access-related complications and eGFR (odds ratio (OR) 0.984 [0.972-0.997], P=0.014), CFA depth (OR 1.026 [1.008-1.045], P=0.005), device used (Prostar vs. Proglide (OR 2.177 [1.236-3.832], P=0.007) and procedural type (complex vs. standard EVAR) (OR 2.017 [1.122-3.627], P=0.019). We developed a risk score which had reasonably good predictive power (C-statistic 0.716 [0.646-0.787], P<0.0001) for avoiding access complications. CONCLUSIONS: Physiological (low eGFR level), anatomical (increased CFA depth) and technical factors (choice of device and complex procedures) were identified as predictors of access-related complications in this large retrospective series. These are important for safe selection of patients that would benefit from percutaneous access.

A systematic review of pharmacologic and cell-based therapies for treatment of lymphedema (2010-2021).

BACKGROUND: Lymphedema describes the accumulation of interstitial fluid that results from lymphatic failure. Lymphedema can be of primary or secondary origin and has been estimated to affect 200 million people worldwide. Secondary lymphedema is commonly due to damage to the lymphatic vessels after surgical procedures. Treatments include compression bandaging and exercise regimens. However, at present, no pharmacologic therapy has been approved. We performed a systematic review of randomized controlled trials (RCTs) that had investigated pharmacologic and cell-based therapies for secondary lymphedema. METHODS: We searched the databases MEDLINE, Embase, and ClinicalTrials.gov from January 2010 to May 2021. Only RCTs that had investigated pharmacologic and/or cell-based therapies for secondary lymphedema were eligible for inclusion. Those studies that had examined only active filarial infection were excluded. Two of us (J.W., S.T.) independently screened the studies for eligibility. RESULTS: We identified eight RCTs that met the inclusion criteria. Overall, the studies were of poor quality with a high risk of bias. Ketoprofen demonstrated promising improvements in skin thickness and tissue histopathologic scores. Some evidence was found to suggest that doxycycline might be beneficial for nonfilarial secondary lymphedema, and a single, small RCT demonstrated that selenium might also confer some benefit. Neither synbiotics nor platelet-rich plasma resulted in reduced lymphedema volumes or symptom severity. Also, although bone marrow-derived stem cells resulted in improved symptom scores, no significant volume reduction was detected. Although positive results were demonstrated in trials investigating benzopyrones, previous meta-analyses have cast doubt on their efficacy. No two studies assessed the same intervention; thus, we could not perform a meta-analysis. CONCLUSIONS: Although the results from some studies appeared promising, the available evidence at present is insufficient for any pharmacologic or cell-based therapy for patients with secondary lymphedema. Furthermore, large, high-quality RCTs are required before treatment recommendations will be possible.