Mortality in Amputees with Peripheral Artery Disease during the Post-COVID Era: A Three-Year Analysis.

BACKGROUND: Patients with peripheral artery disease (PAD) have 40-70% higher three-year mortality after lower limb amputation compared to non-amputees. In this study, we examined the consequences of delayed treatment for patients with PAD during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This study employed a retrospective single-centre cohort design at a large tertiary care hospital. We compared amputees with PAD during the initial COVID-19 outbreak period in 2020 with a control group of amputees from 2019 after a three-year follow-up. RESULTS: In total, 134 amputees with PAD were included due to unsuccessful revascularization (n = 84 in 2020 vs. n = 50 in 2019). Patients in 2020 were significantly younger than those in 2019 (p = 0.01) and mostly admitted with advanced stages of PAD (p < 0.03). The proportion of major limb amputations increased significantly in 2020 (p = 0.03). Non-COVID-19-related deaths among patients in 2020 were more than twice as many as those in 2019, and long-term mortality in 2020 was 49% compared to 39% in 2019 (p = 0.04). Diabetes and renal insufficiency had a significantly negative impact on the survival of amputees with PAD (p < 0.01). CONCLUSIONS: Delayed treatment in patients with PAD leads to high long-term mortality risk after amputation, especially in PAD patients with diabetes and renal insufficiency. Therefore, in future pandemics, continuously monitoring patients with PAD will be crucial to prevent delayed treatment and severe short-term and long-term consequences.

Technical and functional outcome after sacral neuromodulation using the "H" technique.

BACKGROUND: Sacral neuromodulation (SNM) is a widely accepted treatment for pelvic floor disorders, including constipation and fecal incontinence (FI). In 2017, a standardized electrode placement method, the H technique, was introduced to minimize failure rates and improve clinical outcomes. We aimed to investigate the technical feasibility and functional outcome of the procedure. METHODS: In this prospective study, we evaluated the first 50 patients who underwent SNM according to the H technique between 2017 and 2020 at a tertiary care hospital. Patient demographic and clinical data were collected, and the impact of various factors on patients' postoperative quality of life (QoL) was assessed after a follow-up of 40 months. Functional outcome was monitored prospectively using a standardized questionnaire. RESULTS: Of 50 patients, 36 (72%) reported greater than 50% symptom relief and received a permanent implant (95% CI: 58.3-82.5). We observed 75% success in relieving FI (95% CI: 58.9-86.3) and 64% in constipation (95% CI: 38.8-83.7). Complication occurred in five (10%) patients. Preoperative vs. postoperative physical and psychological QoL, Vaizey score, and obstructed defecation syndrome (ODS) scores revealed significant improvements (all p < 0.01). Male gender was significantly associated with postoperative complications (p = 0.035). CONCLUSION: We provide evidence for the technical feasibility and efficacy of the SNM implantation using the H technique. The medium-term results are promising for patients with FI and constipation. Male patients and those with a BMI > 25 are more prone to perioperative complications.

Peripheral Artery Disease Causes More Harm to Patients than COVID-19.

Background: To optimize our strategic planning, we aimed to investigate the impact of the COVID-19 pandemic on the treatment of patients with peripheral artery disease (PAD) at our tertiary care hospital. Methods: We performed a retrospective single-center cohort study. In total, 1210 patients were included: 611 patients admitted between March and December 2020, compared to retrospective data from 599 patients from the same period in 2019. Results: Emergency admissions involving patients with advanced stage PAD increased significantly during the pandemic period of 2020, compared to the same period in 2019 (p < 0.0098). This increase was accompanied by increased limb amputations performed during the first lockdown, post-lockdown and the second lockdown in 2020, compared to respective time periods in 2019 (p < 0.0003, p < 0.0004, p = 1). No SARS-CoV-2 infection was observed among patients with PAD during the observation period. Conclusions: Strict lockdown protocols adversely affected the care of PAD patients, with persisting aftereffects, including increased emergency admission with unsuccessful revascularization attempts leading to limb amputation, even after the peak of the pandemic had passed. We believe that providing continuous care to PAD patients, even in times of global pandemics, will prevent the unfavorable outcomes observed during the COVID-19 pandemic in 2020.

Safety and tolerability of topically administered autologous, apoptotic PBMC secretome (APOSEC) in dermal wounds: a randomized Phase 1 trial (MARSYAS I).

Developing effective therapies against chronic wound healing deficiencies is a global priority. Thus we evaluated the safety of two different doses of topically administered autologous APOSEC, the secretome of apoptotic peripheral blood mononuclear cells (PBMCs), in healthy male volunteers with artificial dermal wounds. Ten healthy men were enrolled in a single-center, randomized, double-blinded, placebo-controlled phase 1 trial. Two artificial wounds at the upper arm were generated using a 4-mm punch biopsy. Each participant was treated with both topically applied APOSEC and placebo in NuGel for 7 consecutive days. The volunteers were randomized into two groups: a low-dose group (A) receiving the supernatant of 12.5 × 106 PBMCs and a high-dose group (B) receiving an equivalent of 25 × 106 PBMCs resuspended in NuGel Hydrogel. Irradiated medium served as placebo. The primary outcome was the tolerability of the topical application of APOSEC. All adverse events were recorded until 17 days after the biopsy. Local tolerability assessment was measured on a 4-point scale. Secondary outcomes were wound closure and epithelization at day 7. No therapy-related serious adverse events occurred in any of the participants, and both low- and high-dose treatments were well tolerated. Wound closure was not affected by APOSEC therapy.

Dying blood mononuclear cell secretome exerts antimicrobial activity.

BACKGROUND: Several activities are attributed to antimicrobial peptides (AMPs), including bacterial killing, leucocyte recruitment and angiogenesis. Despite promises of advanced cellular therapies for treatment of diabetic foot ulcer, it is currently accepted that paracrine factors rather than cellular components are causative for the observed effects. Whether AMPs are present in the mononuclear cell (MNC) secretome (MNC-sec) of white blood cells that are beneficial in experimental wound healing is not known. MATERIALS AND METHODS: Antimicrobial activity of the secretomes of nonirradiated (MNC-sec) and γ-irradiated MNCs (MNC-sec rad) was analysed by microdilution assay. AMPs were determined by quantitative real-time PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). Whether human MNC-sec rad causes AMP secretion in vivo was examined in an experimental rat model. Image flow cytometry was used to determine the type of cell death induced in MNCs after exposure to γ-radiation. RESULTS: The antimicrobial activity assay revealed a bactericidal activity of MNC-sec rad and to a lesser degree also of MNC-sec. Image flow cytometry showed that γ-irradiation of MNCs induced early apoptosis followed mainly by necroptosis. RT-PCR and ELISA revealed a high abundance of different AMPs in the secretome of MNCs. In addition, human MNC-sec elicited an increase in de novo endogenous AMP production in rats in vivo. CONCLUSION: We provide evidence that the secretome of MNCs has direct and indirect positive effects on the immune defence system, including augmentation of antibacterial properties. Our data further suggest that necroptosis could play a key role for the release of paracrine factors and the therapeutic action of MNC-sec rad.

High dose ionizing radiation regulates micro RNA and gene expression changes in human peripheral blood mononuclear cells.

BACKGROUND: High dose ionizing radiation (IR) induces potent toxic cell effects mediated by either direct DNA damage or the production of reactive oxygen species (ROS). IR-induced modulations in multiple biological processes have been proposed to be partly regulated by radiosensitive microRNA (miRNA). In order to gain new insights into the role of miRNAs in the regulation of biological processes after IR, we have investigated changes in mRNA and miRNA expression after high dose IR. RESULTS: IR induced changes in the mRNA and miRNA profiles of human peripheral blood mononuclear cells (PBMCs). When comparing non-irradiated and irradiated samples, we detected a time-dependent increase in differentially expressed mRNAs and miRNAs, with the highest differences detectable 20 hours after exposure. Gene ontology analysis revealed that very early events (up to 4 hours) after irradiation were specifically associated with p53 signaling and apoptotic pathways, whereas a large number of diverse cellular processes were deregulated after 20 hours. Transcription factor analysis of all up-regulated genes confirmed the importance of p53 in the early post-irradiation phase. When analyzing miRNA expression, we found 177 miRNAs that were significantly regulated in the late post-irradiation phase. Integrating miRNA and target gene expression data, we found a significant negative correlation between miRNA-mRNA and identified hepatic leukemia factor (HLF) as a transcription factor down-regulated in the response to IR. These regulated miRNAs and the HLF target genes were involved in modulating radio-responsive pathways, such as apoptosis, the MAKP signaling pathway, endocytosis, and cytokine-cytokine interactions. CONCLUSION: Using a large dataset of mRNA and miRNA expression profiles, we describe the interplay of mRNAs and miRNAs in the regulation of gene expression in response to IR at a posttranscriptional level and their involvement in the modulation of radiation-induced biological pathways.

Antimicrobial peptides are highly abundant and active in postoperative pleural drainage fluids.

BACKGROUND: The human lung is considered a nonsterile organ, and surgical interventions therefore take place in a more or less contaminated operating field. Nevertheless, infectious complications of the pleural cavity are low after major lung resections. Antimicrobial peptides (AMPs) are part of the innate immunity and display a broad capacity to kill pathogens. We hypothesized that the pleural space must have a high natural antimicrobial barrier and that AMPs might effectively protect the pleural cavity. METHODS: Pleural effusions were collected after lung operations. Antimicrobial activity of the fluids against gram-positive and gram-negative pathogens was analyzed by microdilution assays. AMPs were determined by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), and immunohistochemical analysis. The impact of proinflammatory triggers on AMP release from pleural mesothelial cells was evaluated. RESULTS: Antimicrobial activity assays revealed high bactericidal properties of postoperative pleural drainage fluids. They effectively killed gram-negative pathogens (Escherichia coli, Pseudomonas aeruginosa) as well as gram-positive pathogens (Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes). A variety of AMPs was detected at constantly high concentrations in the pleural fluids. They mainly derived from leukocytes and pleural epithelium. Although proinflammatory cytokine levels were elevated in the postoperative pleural fluids, AMP expression could not be augmented by Toll-like receptor (TLR) triggering or by the proinflammatory cytokines interleukin (IL)-1ß and tumor necrosis factor (TNF)α. CONCLUSIONS: We provide the first evidence of a high abundance of AMPs in postoperative pleural fluids. Our findings might explain the broad protection against infectious complications of the pleural space after major lung operations.