Association between anaesthetic technique and unplanned admission to intensive care after thoracic lung resection surgery: the second Association of Cardiothoracic Anaesthesia and Critical Care (ACTACC) National Audit

Unplanned intensive care admission is a devastating complication of lung resection and is associated with significantly increased mortality. We carried out a two‐year retrospective national multicentre cohort study to investigate the influence of anaesthetic and analgesic technique on the need for unplanned postoperative intensive care admission. All patients undergoing lung resection surgery in 16 thoracic surgical centres in the UK in the calendar years 2013 and 2014 were included. We defined critical care admission as the unplanned need for either tracheal intubation and mechanical ventilation or renal replacement therapy, and sought an association between mode of anaesthesia (total intravenous anaesthesia vs. volatile) and analgesic technique (epidural vs. paravertebral) and need for intensive care admission. A total of 253 out of 11,208 patients undergoing lung resection in the study period had an unplanned admission to intensive care in the postoperative period, giving an incidence of intensive care unit admission of 2.3% (95%CI 2.0–2.6%). Patients who had an unplanned admission to intensive care unit had a higher mortality (29.00% vs. 0.03%, p < 0.001), and hospital length of stay was increased (26 vs. 6 days, p < 0.001). Across univariate, complete case and multiple imputation (multivariate) models, there was a strong and significant effect of both anaesthetic and analgesic technique on the need for intensive care admission. Patients receiving total intravenous anaesthesia (OR 0.50 (95%CI 0.34–0.70)), and patients receiving epidural analgesia (OR 0.56 (95%CI 0.41–0.78)) were less likely to have an unplanned admission to intensive care after thoracic surgery. This large retrospective study suggests a significant effect of both anaesthetic and analgesic technique on outcome in patients undergoing lung resection. We must emphasise that the observed association does not directly imply causation, and suggest that well‐conducted, large‐scale randomised controlled trials are required to address these fundamental questions

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Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76293/1/AIAA-1992-2724-750.pd

Fish prey of sub-Antarctic fur seals Arctocephalus tropicalis at the Tristan da Cunha Islands, South Atlantic Ocean

Some top predator populations in the South Atlantic and South Indian oceans are in decline, presumably contingent upon reduced food availability, precipitated by climate change. This phenomenon impacts on the positions of major ocean frontal zones which are hypothesised to act as natural dispersal borders for fish in the Southern Ocean. We investigate this hypothesis by establishing the fish diet of sub-Antarctic fur seals, Arctocephalus tropicalis, at Tristan da Cunha Island (37°15′S, 12°25′W) and Gough Island (40°19′S, 9°57′W), South Atlantic Ocean. The diets of these island populations, located on either side of the Subtropical Convergence, are compared with published dietary information from populations further south on islands located within the Polar Frontal Zone. To this end, fur seal scats were collected and analysed for remains of hard parts from prey in 2012–2013. The myctophid fish Gymnoscopelus piabilis, Protomyctophum tenisoni and Symbolophorus barnardi predominated in the diet. Lampichthys gemellarii, Myctophum aurolaternatum, S. barnardi and the Diaphus genus are recorded for the first time in the diet of A. tropicalis. Sub-Antarctic fur seal populations clustered around the Subtropical Convergence (~ 41°40′S), compared with those in the Polar Frontal Zone (~ 47°25′S to ~ 50°47′S), showed a considerable difference in the myctophid fish prey taken. The latitudinal differences in the fish diet of sub-Antarctic fur seals support suggestions that major frontal zones act as natural dispersal borders for fish in the Southern Ocean.http://link.springer.com/journal/3002022-03-10hj2022Mammal Research InstituteZoology and Entomolog

Reversible maps and composites of involutions in groups of piecewise linear homeomorphisms of the real line

An element of a group is reversible if it is conjugate to its own inverse, and it is strongly reversible if it is conjugate to its inverse by an involution. A group element is strongly reversible if and only if it can be expressed as a composite of two involutions. In this paper the reversible maps, the strongly reversible maps, and those maps that can be expressed as a composite of involutions are determined in certain groups of piecewise linear homeomorphisms of the real line

Microanatomy of the Human Atherosclerotic Plaque by Single-Cell Transcriptomics

Rationale:Atherosclerotic lesions are known for their cellular heterogeneity, yet the molecular complexity within the cells of human plaques has not been fully assessed.Objective:Using single-cell transcriptomics and chromatin accessibility, we gained a better understanding of the pathophysiology underlying human atherosclerosis.Methods and Results:We performed single-cell RNA and single-cell ATAC sequencing on human carotid atherosclerotic plaques to define the cells at play and determine their transcriptomic and epigenomic characteristics. We identified 14 distinct cell populations including endothelial cells, smooth muscle cells, mast cells, B cells, myeloid cells, and T cells and identified multiple cellular activation states and suggested cellular interconversions. Within the endothelial cell population, we defined subsets with angiogenic capacity plus clear signs of endothelial to mesenchymal transition. CD4(+) and CD8(+) T cells showed activation-based subclasses, each with a gradual decline from a cytotoxic to a more quiescent phenotype. Myeloid cells included 2 populations of proinflammatory macrophages showing IL (interleukin) 1B or TNF (tumor necrosis factor) expression as well as a foam cell-like population expressing TREM2 (triggering receptor expressed on myeloid cells 2) and displaying a fibrosis-promoting phenotype. ATACseq data identified specific transcription factors associated with the myeloid subpopulation and T cell cytokine profiles underlying mutual activation between both cell types. Finally, cardiovascular disease susceptibility genes identified using public genome-wide association studies data were particularly enriched in lesional macrophages, endothelial, and smooth muscle cells.Conclusions:This study provides a transcriptome-based cellular landscape of human atherosclerotic plaques and highlights cellular plasticity and intercellular communication at the site of disease. This detailed definition of cell communities at play in atherosclerosis will facilitate cell-based mapping of novel interventional targets with direct functional relevance for the treatment of human disease

Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS

BACKGROUND Tofersen is an antisense oligonucleotide that mediates the degradation of superoxide dismutase 1 (SOD1) messenger RNA to reduce SOD1 protein synthesis. Intrathecal administration of tofersen is being studied for the treatment of amyotrophic lateral sclerosis (ALS) due to SOD1 mutations. METHODS We conducted a phase 1–2 ascending-dose trial evaluating tofersen in adults with ALS due to SOD1 mutations. In each dose cohort (20, 40, 60, or 100 mg), participants were randomly assigned in a 3:1 ratio to receive five doses of tofersen or placebo, administered intrathecally for 12 weeks. The primary outcomes were safety and pharmacokinetics. The secondary outcome was the change from baseline in the cerebrospinal fluid (CSF) SOD1 concentration at day 85. Clinical function and vital capacity were measured. RESULTS A total of 50 participants underwent randomization and were included in the analyses; 48 participants received all five planned doses. Lumbar puncture–related adverse events were observed in most participants. Elevations in CSF white-cell count and protein were reported as adverse events in 4 and 5 participants, respectively, who received tofersen. Among participants who received tofersen, one died from pulmonary embolus on day 137, and one from respiratory failure on day 152; one participant in the placebo group died from respiratory failure on day 52. The difference at day 85 in the change from baseline in the CSF SOD1 concentration between the tofersen groups and the placebo group was 2 percentage points (95% confidence interval [CI], −18 to 27) for the 20-mg dose, −25 percentage points (95% CI, −40 to −5) for the 40-mg dose, −19 percentage points (95% CI, −35 to 2) for the 60-mg dose, and −33 percentage points (95% CI, −47 to −16) for the 100-mg dose. CONCLUSIONS In adults with ALS due to SOD1 mutations, CSF SOD1 concentrations decreased at the highest concentration of tofersen administered intrathecally over a period of 12 weeks. CSF pleocytosis occurred in some participants receiving tofersen. Lumbar puncture–related adverse events were observed in most participants. (Funded by Biogen; ClinicalTrials.gov number, NCT02623699. opens in new tab; EudraCT number, 2015-004098-33. opens in new tab.

Association of variants in the SPTLC1 gene with juvenile amyotrophic lateral sclerosis

IMPORTANCE Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.OBJECTIVE To identify the genetic variants associated with juvenile ALS.DESIGN, SETTING, AND PARTICIPANTS In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.MAIN OUTCOMES AND MEASURES De novo variants present only in the index case and not in unaffected family members.RESULTS Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p. Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.CONCLUSIONS AND RELEVANCE These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.Genetics of disease, diagnosis and treatmen

Large-scale analyses of CAV1 and CAV2 suggest their expression is higher in post-mortem ALS brain tissue and affects survival

Introduction: Caveolin-1 and Caveolin-2 (CAV1 and CAV2) are proteins associated with intercellular neurotrophic signalling. There is converging evidence that CAV1 and CAV2 (CAV1/2) genes have a role in amyotrophic lateral sclerosis (ALS). Disease-associated variants have been identified within CAV1/2 enhancers, which reduce gene expression and lead to disruption of membrane lipid rafts. Methods: Using large ALS whole-genome sequencing and post-mortem RNA sequencing datasets (5,987 and 365 tissue samples, respectively), and iPSC-derived motor neurons from 55 individuals, we investigated the role of CAV1/2 expression and enhancer variants in the ALS phenotype. Results: We report a differential expression analysis between ALS cases and controls for CAV1 and CAV2 genes across various post-mortem brain tissues and three independent datasets. CAV1 and CAV2 expression was consistently higher in ALS patients compared to controls, with significant results across the primary motor cortex, lateral motor cortex, and cerebellum. We also identify increased survival among carriers of CAV1/2 enhancer mutations compared to non-carriers within Project MinE and slower progression as measured by the ALSFRS. Carriers showed a median increase in survival of 345 days. Discussion: These results add to an increasing body of evidence linking CAV1 and CAV2 genes to ALS. We propose that carriers of CAV1/2 enhancer mutations may be conceptualised as an ALS subtype who present a less severe ALS phenotype with a longer survival duration and slower progression. Upregulation of CAV1/2 genes in ALS cases may indicate a causal pathway or a compensatory mechanism. Given prior research supporting the beneficial role of CAV1/2 expression in ALS patients, we consider a compensatory mechanism to better fit the available evidence, although further investigation into the biological pathways associated with CAV1/2 is needed to support this conclusion

The impact of age on genetic testing decisions in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, a family history is observed. Although Mendelian disease gene variants are found in apparently sporadic ALS, genetic testing is usually restricted to those with a family history or younger patients with sporadic disease. With the advent of therapies targeting genetic ALS, it is important that everyone treatable is identified. We therefore sought to determine the probability of a clinically actionable ALS genetic test result by age of onset, globally, but using the UK as an exemplar. Blood-derived DNA was sequenced for ALS genes, and the probability of a clinically actionable genetic test result estimated. For a UK subset, age- and sex-specific population incidence rates were used to determine the number of such results missed by restricting testing by age of onset according to UK’s National Genomic Test Directory criteria. There were 6274 people with sporadic ALS, 1551 from the UK. The proportion with a clinically actionable genetic test result ranged between 0.21 [95% confidence interval (CI) 0.18–0.25] in the youngest age group to 0.15 (95% CI 0.13–0.17) in the oldest age group for a full gene panel. For the UK, the equivalent proportions were 0.23 (95% CI 0.13–0.33) in the youngest age group to 0.17 (95% CI 0.13–0.21) in the oldest age group. By limiting testing in those without a family history to people with onset below 40 years, 115 of 117 (98% of all, 95% CI 96%–101%) clinically actionable test results were missed. There is a significant probability of a clinically actionable genetic test result in people with apparently sporadic ALS at all ages. Although some countries limit testing by age, doing so results in a significant number of missed pathogenic test results. Age of onset and family history should not be a barrier to genetic testing in ALS