Sarcopenia in Patients Undergoing Lower Limb Bypass Surgery is Associated with Higher Mortality and Major Amputation Rates.

BACKGROUND: Sarcopenia is adversely associated with survival in several diseases. Vasculopathy is often associated with multimorbidity and consequent deconditioning with poor long-term outcomes. This study examined the impact of sarcopenia on clinical outcome in patients with and without critical limb-threatening ischaemia who underwent infrainguinal bypass surgery. METHODS: All patients undergoing infra-inguinal surgical revascularisation in 2016-2018 were retrospectively reviewed. Sarcopenia was defined as a skeletal muscle area at the L3 vertebral level (defined as L3 muscle area < 114cm2 for men or <89.8cm2 for women) on CT angiography. The primary outcome was overall survival by analysed by time to event analysis. Secondary outcomes included ipsilateral major lower-limb amputation, length of hospital stay, myocardial infarction and surgical-site infection. RESULTS: A total of 116 patients with a mean age of 66.9 years were included, with a mean follow-up of 21 months. 14 (12%) of patients were sarcopenic; there were more patients with diabetes (40% vs 7%) in the sarcopenic group, p=0.018. Age, gender, Rutherford grade at presentation, other co-morbidities, other laboratory tests, conduit material and Rutherford grade at presentation were similar in those with and without sarcopenia and were statistically insignificant upon testing. Overall survival was worse for sarcopenic patients (Log Rank P=0.001) and Hazard Ratio for death 5.8; 95%CI 1.8-19.1; P=0.001. Major lower-limb amputation occurred more frequently in patients with sarcopenia (7/14 [50%] vs 23/102 [23%]; P=0.046). There was no difference in other secondary outcomes including rates of graft occlusion, myocardial infarction, surgical site infection and length of stay. Adding SMA measurement to a multivariate generalised linear model including age, sex, diabetes, and haemoglobin improved the AUROC from 0.75-0.85. CONCLUSION: In this cohort of patients undergoing vascular surgery, sarcopenia defined using L3 muscle area was significantly associated with overall mortality and major lower-limb amputation.

Dissecting the Management and Outcomes of Thoracic Aortovascular Disease During the COVID-19 Pandemic.

OBJECTIVE: The COVID-19 pandemic has forced the cancellation of planned surgery and led to significant surgical service reductions. Early intervention in aortovascular disease is often critical and cannot be deferred despite these reductions. There is urgent need to evaluate the provision and outcomes of thoracic aortovascular intervention during the peak of the pandemic. METHODS: Prospective data was collected for patients receiving open and endovascular thoracic aortovascular intervention over two-time points; January-May 2020 and January-May 2019 at three tertiary cardiovascular centres. Baseline demographics, cardiovascular risk and COVID-19 screening results were noted. Primary outcomes were median length of intensive care unit and hospital stay, intra-operative mortality, 30-day mortality, post-operative stroke, and spinal cord injury. RESULTS: Patients operated in 2020 (41) had significantly higher median EuroSCORE II than 2019 (53) (7.44 vs. 5.86, P = 0.032) and rates of previous cardiac (19.5% vs. 3.8%, P = 0.019), aortic (14.6% vs. 1.9%, P = 0.041), and endovascular (22.0% vs. 3.8%, P = 0.009) intervention. There was an increase in proportion of urgent cases in 2020 (31.7% vs. 18.9%). There were no intra-operative deaths in 2020 and 1 in 2019 (P = 1.00). There were no significant differences (P ≥ 0.05) in 30-day mortality (4.9% vs. 13.2%), median intensive care unit length of stay (72 vs. 70 hr), median hospital length of stay (8 vs. 9 days), post-operative stroke (3 vs. 6), or spinal cord injury (2 vs. 1) between 2020 and 2019 respectively. CONCLUSIONS: Despite the increased mortality risk of patients and urgency of cases during COVID-19, complicated by the introduction of cohorting and screening regimens, thoracic aortovascular intervention remained safe with comparable in outcomes to pre-COVID-19.

Fibrogenic Activity of MECP2 Is Regulated by Phosphorylation in Hepatic Stellate Cells.

BACKGROUND & AIMS: Methyl-CpG binding protein 2, MECP2, which binds to methylated regions of DNA to regulate transcription, is expressed by hepatic stellate cells (HSCs) and is required for development of liver fibrosis in mice. We investigated the effects of MECP2 deletion from HSCs on their transcriptome and of phosphorylation of MECP2 on HSC phenotype and liver fibrosis. METHODS: We isolated HSCs from Mecp2-/y mice and wild-type (control) mice. HSCs were activated in culture and used in array analyses of messenger RNAs and long noncoding RNAs. Kyoto Encyclopedia of Genes and Genomes pathway analyses identified pathways regulated by MECP2. We studied mice that expressed a mutated form of Mecp2 that encodes the S80A substitution, MECP2S80, causing loss of MECP2 phosphorylation at serine 80. Liver fibrosis was induced in these mice by administration of carbon tetrachloride, and liver tissues and HSCs were collected and analyzed. RESULTS: MECP2 deletion altered expression of 284 messenger RNAs and 244 long noncoding RNAs, including those that regulate DNA replication; are members of the minichromosome maintenance protein complex family; or encode CDC7, HAS2, DNA2 (a DNA helicase), or RPA2 (a protein that binds single-stranded DNA). We found that MECP2 regulates the DNA repair Fanconi anemia pathway in HSCs. Phosphorylation of MECP2S80 and its putative kinase, HAS2, were induced during transdifferentiation of HSCs. HSCs from MECP2S80 mice had reduced proliferation, and livers from these mice had reduced fibrosis after carbon tetrachloride administration. CONCLUSIONS: In studies of mice with disruption of Mecp2 or that expressed a form of MECP2 that is not phosphorylated at S80, we found phosphorylation of MECP2 to be required for HSC proliferation and induction of fibrosis. In HSCs, MECP2 regulates expression of genes required for DNA replication and repair. Strategies to inhibit MECP2 phosphorylation at S80 might be developed for treatment of liver fibrosis.

Significance of neoadjuvant downstaging in gastric adenocarcinoma.

BACKGROUND: Neoadjuvant chemotherapy is established in the treatment of gastric adenocarcinoma. Histopathological regression may have important prognostic implications. There are little data comparing clinical outcomes of patients with gastric adenocarcinoma that received neoadjuvant treatment and those neoadjuvant naive. The aim of this study is to determine the impact of neoadjuvant chemotherapy upon prognosis of patients being treated for gastric adenocarcinoma. METHODS: Consecutive patients with gastric cancer from a single center between 2007 and 2017 were evaluated. Patients were treated with either a subtotal or total gastrectomy with D2 lymphadenectomy. Stage-by-stage comparison of the extent of pathological downstaging was conducted for patients who received neoadjuvant treatment (ypTNM) and those who did not (pTNM) using the TNM eighth edition. RESULTS: Overall, 384 patients underwent gastrectomy, 141 patients received neoadjuvant chemotherapy, and 86 patients (58.1%) were downstaged. Downstaged patients had improved overall survival compared to patients who did not respond to neoadjuvant chemotherapy (not reported vs 66 months, P < .001). Downstaging by >3 stages was the strongest independent predictor of overall survival (hazard ratio: 0.17; 95% confidence interval 0.062-0.44). Overall survival was significantly better among patients in the ypTNM groups when a stage-by-stage comparison was performed with the pTNM group. CONCLUSION: Pathological stage is a more accurate predictor of prognosis compared clinical stage with downstaged patients benefiting from lower recurrence rates and improved overall survival. Patients downstaged due to neoadjuvant chemotherapy may potentially have more favorable clinical outcomes compared to stage-matched patients who did not receive this.

Methaemoglobinaemia Can Complicate Normothermic Machine Perfusion of Human Livers.

Background: Although liver normothermic machine perfusion is increasingly used clinically, there are few reports of complications or adverse events. Many centers perform liver NMP to viability test suboptimal grafts, often for prolonged periods. In addition, several researchers are investigating NMP as a drug delivery platform, which usually necessitates prolonged perfusion of otherwise non-viable liver grafts. We describe two instances of methaemoglobinaemia during NMP of suboptimal livers. Methods: The NMP of eight human livers rejected for transplantation is described. Methaemoglobinaeima developed in two; one perfused using generic Medtronic™ perfusion equipment and one using the OrganOx Metra®. Results: The first liver (53 years DBD) developed methaemoglobinaemia (metHb = 2.4%) after 13 h of NMP, increasing to metHb = 19% at 16 h. Another liver (45 years DBD) developed methaemoglobinaemia at 25 h (metHb = 2.8%), which increased to metHb = 28.2% at 38 h. Development of methaemoglobinaemia was associated with large reductions in oxygen delivery and oxygen extraction. Both livers were steatotic and showed several suboptimal features on viability testing. Delivery of methylene blue failed to reverse the methaemoglobinaemia. Compared to a matched cohort of steatotic organs, livers which developed methaemoglobinaemia showed significantly higher levels of hemolysis at 12 h (prior to development of methaemoglobinaemia). Conclusions: Methaemglobinaemia is a complication of NMP of suboptimal liver grafts, not limited to a single machine or perfusion protocol. It can occur within 13 h (a timepoint frequently surpassed when NMP is used clinically) and renders further perfusion futile. Therefore, metHb should be monitored during NMP visually and using blood gas analysis.

Acute Leg Ischaemia in a Child due to a Thrombosed Popliteal Aneurysm.

INTRODUCTION: The case of an idiopathic thrombosed popliteal aneurysm is described in an otherwise healthy 6 year old child. This is the fourth reported case and the second youngest patient to present with an idiopathic isolated popliteal aneurysm. REPORT: A 6 year old boy presented with an acutely ischaemic right foot. Computed tomography angiography confirmed a thrombosed popliteal aneurysm. A femoropopliteal bypass was performed with reversed long saphenous vein and ligation of the aneurysm. Yearly follow up is ongoing with ultrasound surveillance; the child's growth and development is unaffected, and the graft is patent. There was a readmission over six years later with claudication on the right side. There was evidence of thrombus in the graft with associated distal embolisation, which was managed conservatively with anticoagulation. DISCUSSION: Given the rarity of such presentations in the paediatric population, there is minimal good quality data to guide treatment. There have been three previous cases of idiopathic popliteal aneurysms all managed with a reversed long saphenous vein femoropopliteal bypass with resection of the aneurysm. Management should be guided based on the clinical picture and should be undertaken in specialised tertiary centres if possible. Surgical intervention is the treatment of choice in patients with an ischaemic limb.