Acute lung injury associated with thoracic surgery

Lung cancer is the most common cause of cancer death in the UK. In suitable cases, the best chance of cure is surgical resection. Due to high levels of co-morbidity seen in this population, lung resection is associated with high cardio-respiratory complication rates. One such complication is the development of Acute Lung Injury / Acute Respiratory Distress Syndrome (ALI/ARDS). ALI/ARDS is reported to occur in four to 11% of patients undergoing lung resection and is the major cause of hospital mortality following lung resection. ALI/ARDS occurring following lung resection is widely interpreted to be a variant of ALI/ARDS and follows an identical clinical and pathophysiological course to that seen in the wider critical care environment. The pathophysiology of lung injury following lung resection is complex and can be broadly conceptualised as occurring secondary to insults specific to both the ipsilateral (surgical) lung, the contralateral (anaesthetic) lung in addition to those insults common to both lungs. Increased recognition of the role of ventilator induced lung injury, and peri-operative fluid prescribing in the pathogenesis of lung injury in this population has brought the prevention of lung injury to the attention of the thoracic anaesthetist. Though high quality evidence is lacking, expert opinion widely favours the adoption of lung protective ventilatory strategies and restriction of peri-operative fluids in patients undergoing lung resection. This thesis presents the rationale, methodology and results of four discrete studies concerning the development of lung injury in the thoracic surgical population undergoing resection of primary lung cancer. Investigation I is a survey of contemporary UK thoracic anaesthetic practice when anaesthetising for thoracic surgery and lung resection, with specific reference to strategies designed to prevent lung injury. Though implementation of the techniques described is far from universal, the survey results suggest that aspects of lung protective ventilation are widespread within UK thoracic anaesthetic practice. Investigation II seeks to examine the impact of increased adoption of such strategies over time. A random effects meta-analysis and meta-regression analysis was performed to examine the trends in the incidence of and mortality from ALI and/or ARDS over time. The main findings of this study are that whilst there is no evidence to suggest the incidence of ALI and/or ARDS post-lung resection is falling, mortality due to ARDS (but not ALI) does appear to be falling over time. Investigations III and IV examine the utility of two clinical monitoring methodologies which have potential to provide bedside clinical monitoring of lung injury development in the thoracic surgical population in order to guide clinical decision making, monitor patient progress and serve as a surrogate end point in future clinical studies. Investigation III examines the utility of a single lung injury biomarker (long chain Pentraxin 3 – PTX3) and a panel of multiple lung injury biomarkers in the early post-operative period following lung resection. The properties of the ‘ideal’ lung injury biomarker are defined, against which PTX3 and the multiple biomarker panel are compared. PTX3 compared favourably to properties of the ‘ideal’ lung injury biomarker and appeared to identify a population of patients with elevated post-operative Lung Injury Score with high sensitivity. Conversely there is no evidence from the results presented that a ‘risk of lung injury score’ derived from a panel of 7 candidate lung injury biomarkers (as previously defined in a cohort of critically ill patients with ALI/ARDS) has any utility in the lung resection population. Investigation IV tests the reproducibility and construct validity of transpulmonary thermodilution derived measurements of extravascular lung water and pulmonary vascular permeability index in patients undergoing lung resection. The study’s findings are largely supportive of the reproducibility and construct validity of extravascular lung water measurement and pulmonary vascular permeability measurements after lung resection. In combination, it is hoped that the studies presented provide greater insight into the syndrome of post lung resection lung injury. More accurate definition of standard anaesthetic practice and the incidence of and mortality from ALI/ARDS following lung resection should serve to inform future clinical studies seeking to prevent, treat, or better understand this important clinical syndrome. The biomarker PTX3 and transpulmonary thermodilution derived measurement of extravascular lung water and pulmonary vascular permeability index are presented as surrogate endpoints suitable for use in such studies

A High-Throughput Screen Indicates Gemcitabine and JAK Inhibitors May be Useful for Treating Pediatric AML

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates \u3c 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML

The impact of a hybrid social marketing intervention on inequities in access, ownership and use of insecticide-treated nets

BACKGROUND: An ITN intervention was initiated in three predominantly rural districts of Eastern Province, Zambia, that lacked commercial distribution and communication infrastructures. Social marketing techniques were used for product and message development. Public sector clinics and village-based volunteers promoted and distributed subsidized ITNs priced at $2.5 per net. A study was conducted to assess the effects of the intervention on inequities in knowledge, access, ownership and use of ITNs. METHODS: A post-test only quasi-experimental study design was used to compare intervention and comparison districts. A total of 2,986 respondents were interviewed. Survey respondents were grouped into four socio-economic (SES) categories: low, medium-low, medium and high. Knowledge, access, ownership and use indicators are compared. Concentration index scores are calculated. Interactions between intervention status and SES help determine how different SES groups benefited from the intervention. RESULTS: Although overall use of nets remained relatively low, post-test data show that knowledge, access, ownership and use of mosquito nets was higher in intervention districts. A decline in SES inequity in access to nets occurred in intervention districts, resulting from a disproportionately greater increase in access among the low SES group. Declines in SES inequities in net ownership and use of nets were associated with the intervention. The largest increases in net ownership and use occurred among medium and high SES categories. CONCLUSION: Increasing access to nets among the poorest respondents in rural areas may not lead to increases in net use unless the price of nets is no longer a barrier to their purchase

Genome-Wide Association Scan for Diabetic Nephropathy Susceptibility Genes in Type 1 Diabetes

OBJECTIVE—Despite extensive evidence for genetic susceptibility to diabetic nephropathy, the identification of susceptibility genes and their variants has had limited success. To search for genes that contribute to diabetic nephropathy, a genome-wide association scan was implemented on the Genetics of Kidneys in Diabetes collection. RESEARCH DESIGN AND METHODS—We genotyped 360,000 single nucleotide polymorphisms (SNPs) in 820 case subjects (284 with proteinuria and 536 with end-stage renal disease) and 885 control subjects with type 1 diabetes. Confirmation of implicated SNPs was sought in 1,304 participants of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, a long-term, prospective investigation of the development of diabetes- associated complications. RESULTS—A total of 13 SNPs located in four genomic loci were associated with diabetic nephropathy with P1105. The strongest association was at the FRMD3 (4.1 protein ezrin, radixin, moesin [FERM] domain containing 3) locus (odds ratio [OR]1.45, P5.0107). A strong association was also identified at the CARS (cysteinyl-tRNA synthetase) locus (OR 1.36, P3.1106). Associations between both loci and time to onset of diabetic nephropathy were supported in the DCCT/EDIC study (hazard ratio [HR]1.33, P0.02, and HR1.32, P 0.01, respectively). We demonstrated expression of both FRMD3 and CARS in human kidney. CONCLUSIONS—We identified genetic associations for susceptibility to diabetic nephropathy at two novel candidate loci near the FRMD3 and CARS genes. Their identification implicates previously unsuspected pathways in the pathogenesis of this important late complication of type 1 diabetes

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Does a Screening Trial for Spinal Cord Stimulation in Patients with Chronic Pain of Neuropathic Origin have Clinical Utility and Cost-Effectiveness? (TRIAL-STIM Study): study protocol for a randomised controlled trial

Abstract Background The TRIAL-STIM Study aims to assess the diagnostic performance, clinical outcomes and cost-effectiveness of a screening trial prior to full implantation of a spinal cord stimulation (SCS) device. Methods/design The TRIAL-STIM Study is a superiority, parallel-group, three-centre, randomised controlled trial in patients with chronic neuropathic pain with a nested qualitative study and economic evaluation. The study will take place in three UK centres: South Tees Hospitals NHS Foundation Trust (The James Cook University Hospital); Basildon and Thurrock University Hospitals NHS Foundation Trust; and Leeds Teaching Hospitals NHS Trust. A total of 100 adults undergoing SCS implantation for the treatment of neuropathy will be included. Subjects will be recruited from the outpatient clinics of the three participating sites and randomised to undergo a screening trial prior to SCS implant or an implantation-only strategy in a 1:1 ratio. Allocation will be stratified by centre and minimised on patient age (≥ 65 or < 65 years), gender, presence of failed back surgery syndrome (or not) and use of high frequency (HF10™) (or not). The primary outcome measure is the numerical rating scale (NRS) at 6 months compared between the screening trial and implantation strategy and the implantation-only strategy. Secondary outcome measures will include diagnostic accuracy, the proportion of patients achieving at least 50% and 30% pain relief at 6 months as measured on the NRS, health-related quality-of-life (EQ-5D), function (Oswestry Disability Index), patient satisfaction (Patients’ Global Impression of Change) and complication rates. A nested qualitative study will be carried out in parallel for a total of 30 of the patients recruited in each centre (10 at each centre) to explore their views of the screening trial, implantation and overall use of the SCS device. The economic evaluation will take the form of a cost–utility analysis. Discussion The TRIAL-STIM Study is a randomised controlled trial with a nested qualitative study and economic evaluation aiming to determine the clinical utility of screening trials of SCS as well as their cost-effectiveness. The nested qualitative study will seek to explore the patient’s view of the screening trials, implantation and overall use of SCS. Trial registration ISRCTN, ISRCTN60778781. Registered on 15 August 2017

Multiple energy sources and metabolic strategies sustain microbial diversity in Antarctic desert soils

Numerous diverse microorganisms reside in the cold desert soils of continental Antarctica, though we lack a holistic understanding of the metabolic processes that sustain them. Here, we profile the composition, capabilities, and activities of the microbial communities in 16 physicochemically diverse mountainous and glacial soils. We assembled 451 metagenome-assembled genomes from 18 microbial phyla and inferred through Bayesian divergence analysis that the dominant lineages present are likely native to Antarctica. In support of earlier findings, metagenomic analysis revealed that the most abundant and prevalent microorganisms are metabolically versatile aerobes that use atmospheric hydrogen to support aerobic respiration and sometimes carbon fixation. Surprisingly, however, hydrogen oxidation in this region was catalyzed primarily by a phylogenetically and structurally distinct enzyme, the group 1l [NiFe]-hydrogenase, encoded by nine bacterial phyla. Through gas chromatography, we provide evidence that both Antarctic soil communities and an axenic Bacteroidota isolate (Hymenobacter roseosalivarius) oxidize atmospheric hydrogen using this enzyme. Based on ex situ rates at environmentally representative temperatures, hydrogen oxidation is theoretically sufficient for soil communities to meet energy requirements and, through metabolic water production, sustain hydration. Diverse carbon monoxide oxidizers and abundant methanotrophs were also active in the soils. We also recovered genomes of microorganisms capable of oxidizing edaphic inorganic nitrogen, sulfur, and iron compounds and harvesting solar energy via microbial rhodopsins and conventional photosystems. Obligately symbiotic bacteria, including Patescibacteria, Chlamydiae, and predatory Bdellovibrionota, were also present. We conclude that microbial diversity in Antarctic soils reflects the coexistence of metabolically flexible mixotrophs with metabolically constrained specialists.DATA AVAILABILTY: All amplicon sequencing data, raw metagenomes, metagenomic assemblies, and metagenome-assembled genomes were deposited to the National Center for Biotechnology Information (NCBI) Sequence Read Archive under the BioProject accession no. PRJNA630822. All other study data are included in the article and/or supporting information.An Australian Research Council Discovery Early Career Researcher Award (ARC DECRA) Fellowship, an Australian Antarctic Division grant, a South African National Antarctic Program grant, a National Health & Medical Research Council Emerging Leadership 2 (NHMRC EL2) Fellowship, an Australian Government Research Training Stipend Scholarship, a Monash International Tuition Scholarship, a Monash Postgraduate Publications Award, a South African National Antarctic Programme (SANAP) postdoctoral grant.https://www.pnas.orghj2022BiochemistryGeneticsMicrobiology and Plant Patholog

Vera Lynn on Screen: Popular Music and the ‘People's War’

By the outbreak of the Second World War in Britain, critics had spent several decades negotiating the supposed distinctions between highbrow and lowbrow culture, as recent scholarship has shown. What has received comparatively little attention is how the demands of wartime living changed the stakes of the debate. This article addresses this lacuna, exploring how war invited a reassessment of the relative merits of art and popular music. Perhaps the most iconic British singer of the period, Vera Lynn provides a case study. Focusing on her first film vehicle, We'll Meet Again (1942), I explore how Lynn's character mediated the highbrow/lowbrow conflict-for example, by presenting popular music as a site of community, while disparaging art music for its minority appeal. In so doing, I argue, the film not only promoted Lynn's star persona, but also intervened in a broader debate about the value of entertainment for a nation at war.</p

Sex difference and intra-operative tidal volume: Insights from the LAS VEGAS study

BACKGROUND: One key element of lung-protective ventilation is the use of a low tidal volume (VT). A sex difference in use of low tidal volume ventilation (LTVV) has been described in critically ill ICU patients.OBJECTIVES: The aim of this study was to determine whether a sex difference in use of LTVV also exists in operating room patients, and if present what factors drive this difference.DESIGN, PATIENTS AND SETTING: This is a posthoc analysis of LAS VEGAS, a 1-week worldwide observational study in adults requiring intra-operative ventilation during general anaesthesia for surgery in 146 hospitals in 29 countries.MAIN OUTCOME MEASURES: Women and men were compared with respect to use of LTVV, defined as VT of 8 ml kg-1 or less predicted bodyweight (PBW). A VT was deemed 'default' if the set VT was a round number. A mediation analysis assessed which factors may explain the sex difference in use of LTVV during intra-operative ventilation.RESULTS: This analysis includes 9864 patients, of whom 5425 (55%) were women. A default VT was often set, both in women and men; mode VT was 500 ml. Median [IQR] VT was higher in women than in men (8.6 [7.7 to 9.6] vs. 7.6 [6.8 to 8.4] ml kg-1 PBW, P &lt; 0.001). Compared with men, women were twice as likely not to receive LTVV [68.8 vs. 36.0%; relative risk ratio 2.1 (95% CI 1.9 to 2.1), P &lt; 0.001]. In the mediation analysis, patients' height and actual body weight (ABW) explained 81 and 18% of the sex difference in use of LTVV, respectively; it was not explained by the use of a default VT.CONCLUSION: In this worldwide cohort of patients receiving intra-operative ventilation during general anaesthesia for surgery, women received a higher VT than men during intra-operative ventilation. The risk for a female not to receive LTVV during surgery was double that of males. Height and ABW were the two mediators of the sex difference in use of LTVV.TRIAL REGISTRATION: The study was registered at Clinicaltrials.gov, NCT01601223