Impact of Opioid Use on Duration of Therapy and Overall Survival for Patients with Advanced Non-Small Cell Lung Cancer Treated with Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICI) have significantly improved outcomes in advanced non-small cell lung cancer (NSCLC). We evaluated the effect of opioid use on outcomes in patients receiving ICI either alone or with chemotherapy. We conducted a retrospective review of 209 patients with advanced NSCLC who received an ICI at the University of Virginia between 1 February 2015 and 1 January 2020. We performed univariate and multivariate analyses to evaluate the impact of opioid use on duration of therapy (DOT) and overall survival (OS). Patients with no or low opioid use (n = 172) had a median DOT of 12.2 months (95% CI: 6.9-17.4) compared to 1.9 months (95% CI: 1.8-2.0) for those with high opioid use (n = 37, HR 0.26 95% CI: 0.17-0.40, p < 0.001). Patients with no or low opioid use had a median OS of 22.6 months (95% CI: 14.8-30.4) compared to 3.8 months (95% CI: 2.7-4.9) for those with high opioid use (HR 0.26 95% CI: 0.17-0.40 p < 0.001). High opioid use was associated with a shorter DOT and worse OS. This difference remained significant when accounting for possible confounding variables. These data warrant investigation of possible mechanistic interactions between opioids, tumor progression, and ICIs, as well as prospective evaluation of opioid-sparing pain management strategies, where possible.

Phase I/II Trial of Carboplatin, Nab-paclitaxel, and Pembrolizumab for Advanced Non-Small Cell Lung Cancer: Hoosier Cancer Research Network LUN13-175.

BACKGROUND: Combination chemotherapy and immunotherapy regimens have significantly improved survival for patients with previously untreated advanced non-small cell lung cancer (NSCLC). Improvements in overall survival (OS) in two separate pembrolizumab trials have demonstrated survival improvements over chemotherapy alone, regardless of PD-L1 status. The optimal chemotherapy backbone for combination with immunotherapy is unknown. We hypothesized nab-paclitaxel may be a well-suited platinum partner to use in combination with checkpoint inhibitor therapy for both adenocarcinoma and squamous histology and conducted a phase I/II trial to assess the efficacy of this regimen in advanced NSCLC. METHODS: Adult patients with previously untreated, stage IIIB/IV NSCLC (any histology) with an Eastern Cooperative Oncology Group performance status of 0-1, any PD-L1 expression, and no EGFR mutations or ALK translocations, received carboplatin area under the curve (AUC) 6 day 1, nab-paclitaxel 100 mg/m2 days 1, 8, 15, and pembrolizumab 200 mg day 1 q21 days for 4 cycles followed by maintenance pembrolizumab q3w. Co-primary endpoints were progression-free survival (PFS) and overall response rate (ORR). RESULTS: Forty-six evaluable patients enrolled, 14 in phase I and 32 in phase II, from June 2015 to July 2018 with a median duration of follow-up of 35.4 months. Median time from enrollment to data lock was 42 months. In the ITT population, the ORR was 35%, median PFS was 5.6 months (95% CI, 4.6-8.2), and median OS was 15.4 months (CI, 12.4-28.1). There were no statistical differences in PFS or OS by PD-L1 status. The 2- and 3-year landmark OS rates were 33% and 24%, respectively. CONCLUSION: Carboplatin, nab-paclitaxel, and pembrolizumab are a safe and effective regimen for patients with both squamous and nonsquamous NSCLC. Although this study did not meet the prespecified endpoints, the median and landmark OS results are consistent with durable benefit of this regimen as seen in phase III trials for first-line treatment of advanced NSCLC.

Replicative Instability Drives Cancer Progression.

In the past decade, defective DNA repair has been increasingly linked with cancer progression. Human tumors with markers of defective DNA repair and increased replication stress exhibit genomic instability and poor survival rates across tumor types. Seminal studies have demonstrated that genomic instability develops following inactivation of BRCA1, BRCA2, or BRCA-related genes. However, it is recognized that many tumors exhibit genomic instability but lack BRCA inactivation. We sought to identify a pan-cancer mechanism that underpins genomic instability and cancer progression in BRCA-wildtype tumors. Methods: Using multi-omics data from two independent consortia, we analyzed data from dozens of tumor types to identify patient cohorts characterized by poor outcomes, genomic instability, and wildtype BRCA genes. We developed several novel metrics to identify the genetic underpinnings of genomic instability in tumors with wildtype BRCA. Associated clinical data was mined to analyze patient responses to standard of care therapies and potential differences in metastatic dissemination. Results: Systematic analysis of the DNA repair landscape revealed that defective single-strand break repair, translesion synthesis, and non-homologous end-joining effectors drive genomic instability in tumors with wildtype BRCA and BRCA-related genes. Importantly, we find that loss of these effectors promotes replication stress, therapy resistance, and increased primary carcinoma to brain metastasis. Conclusions: Our results have defined a new pan-cancer class of tumors characterized by replicative instability (RIN). RIN is defined by the accumulation of intra-chromosomal, gene-level gain and loss events at replication stress sensitive (RSS) genome sites. We find that RIN accelerates cancer progression by driving copy number alterations and transcriptional program rewiring that promote tumor evolution. Clinically, we find that RIN drives therapy resistance and distant metastases across multiple tumor types.

Association of sarcopenia with survival in advanced NSCLC patients receiving concurrent immunotherapy and chemotherapy.

Background: Frailty, sarcopenia and malnutrition are powerful predictors of clinical outcomes that are not routinely measured in patients with non-small cell lung cancer (NSCLC). The primary aim of this study was to investigate the association of sarcopenia, determined by the psoas muscle index (PMI) with overall survival (OS) in patients with advanced NSCLC treated with concurrent immune checkpoint inhibitor (ICI) and chemotherapy (CTX). Methods: We retrospectively reviewed data from a cohort of patients with locally advanced or metastatic NSCLC who were treated between 2015 and 2021 at the University of Virginia Medical Center. The cross-sectional area of the psoas muscle was assessed on CT or PET/CT imaging prior to treatment initiation. Multivariate analysis was performed using Cox proportional hazards regression models. Results: A total of 92 patients (median age: 64 years, range 36-89 years), 48 (52.2%) men and 44 (47.8%) women, were included in the study. The median follow-up was 29.6 months. The median OS was 17.8 months. Sarcopenia, defined by a PMI below the 25th percentile, was associated with significantly lower OS (9.1 months in sarcopenic patients vs. 22.3 months in non-sarcopenic patients, P = 0.002). Multivariate analysis revealed that sarcopenia (HR 2.12, P = 0.0209), ECOG ≥ 2 (HR 2.88, P = 0.0027), prognostic nutritional index (HR 3.02, P = 0.0034) and the absence of immune related adverse events (HR 2.04, P = 0.0185) were independently associated with inferior OS. Conclusions: Sarcopenia is independently associated with poor OS in patients with advanced NSCLC undergoing concurrent ICI and CTX.

Racial and Treatment Center Differences on Time to Treatment Initiation for Nonsmall Cell Lung Cancer Patients Receiving Radiation Therapy As an Initial Treatment.

Objective: Because time to treatment has been shown to be associated with increase in the risk of death for Non Small Cell Lung Cancer (NSCLC) patients, we examined the prevalence and magnitude of racial disparities in mean time to radiation therapy (TTRT) for Stage I-III non-small cell lung cancer patients across a variety of treatment facilities. Methods: Utilizing the United States National Cancer Database (NCDB), we determined differences in TTRT between different races and different treatment facilities. Results: Concordant with past research, we found that non-White patients and patients treated at academic facilities, regardless of race, have longer mean TTRT, and that racial disparities in TTRT extend across all treatment facilities (all p<0.05). Conclusions: These findings shed light on the potential presence of and impact of structural racism on patients seeking cancer treatment, and the need for further investigation behind the reasonings behind longer TTI for non-White patients. To elucidate the real-world applicability of these results, further investigation into the societal determinants that perpetuate disparity in time to radiation therapy, and potential interventions in the clinical setting to improve cultural and racial sensitivity among healthcare professionals is recommended.

Dental Pulp Cell Conditioning through Polyinosinic-Polycytidylic Acid Activation of Toll-like Receptor 3 for Amplification of Trophic Factors.

INTRODUCTION: Regeneration of the pulp-dentin complex hinges on functionally diverse growth factors, cytokines, chemokines, signaling molecules, and other secreted factors collectively referred to as trophic factors. The delivery of exogenous factors and the induced release of endogenous dentin-bound factors by conditioning agents have been explored toward these goals. The aim of this study was to investigate a promising regeneration strategy based on the conditioning of dental pulp cells (DPCs) with polyinosinic-polycytidylic acid (poly[I:C]) for the amplification of endogenous trophic factors. METHODS: DPCs were isolated from human dental pulps, propagated in culture, and treated with an optimized dose of poly(I:C). The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay and metabolite analysis were conducted to monitor the cytotoxicity of poly(I:C). Enzyme-linked immunosorbent assays and quantitative polymerase chain reaction assays were performed to quantify the induction of trophic factors in response to DPC conditioning. Statistical significance was P < .05. RESULTS: The analysis of 32 trophic factors involved in Wnt signaling, cell migration and chemotaxis, cell proliferation and differentiation, extracellular matrix remodeling and angiogenesis, and immunoregulation revealed that DPCs abundantly express many trophic factors including AMF, BDNF, BMP2, FGF1, FGF2, FGF5, HGF, MCP1, NGF, SDF1, TGFß1, TIMP1, TIMP2, TIMP3, and VEGFA, many of which were further induced by DPC conditioning; induction was significant for BDNF, EGF, HGF, LIF, MCP1, SDF1, IL6, IL11, MMP9, and TIMP1. Both DPC proliferation and lactate production (P < .05) were inhibited by 8 µg/mL poly(I:C) relative to the control. CONCLUSIONS: In vitro DPC conditioning through poly(I:C) activation of toll-like receptor 3 led to the amplification of trophic factors involved in tissue repair. The strategy offers promise for endodontic regeneration and tooth repair and warrants further investigation.

S100B as a biomarker of blood-brain barrier disruption after thoracoabdominal aortic aneurysm repair: a secondary analysis from a prospective cohort study.

PURPOSE: The objective of this study was to determine whether the magnitude of the peripheral inflammatory response to cardiovascular surgery is associated with increases in blood-brain barrier (BBB) permeability as reflected by changes in cerebrospinal fluid (CSF)/plasma S100B concentrations. METHODS: We conducted a secondary analysis from a prospective cohort study of 35 patients undergoing elective thoracoabdominal aortic aneurysm repair with (n = 17) or without (n = 18) cardiopulmonary bypass (CPB). Plasma and CSF S100B, interleukin-6 (IL-6), and albumin concentrations were measured at baseline (C0) and serially for up to five days. RESULTS: Following CPB, the median [interquartile range] plasma S100B concentration increased from 58 [32-88] pg·mL-1 at C0 to a maximum concentration (Cmax) of 1,131 [655-1,875] pg·mL-1 over a median time (tmax) of 6.3 [5.9-7.0] hr. In the non-CPB group, the median plasma S100B increased to a lesser extent. There was a delayed increase in CSF S100B to a median Cmax of 436 [406-922] pg·mL-1 in the CPB group at a tmax of 23.7 [18.5-40.2] hr. In the non-CPB group, the CSF concentrations were similar at all time points. In the CPB group, we did not detect significant correlations between plasma and CSF S100B with plasma IL-6 [r = 0.52 (95% confidence interval [CI], -0.061 to 0.84)] and CSF IL-6 [r = 0.53 (95% CI, -0.073 to 0.85)] concentrations, respectively. Correlations of plasma or CSF S100B levels with BBB permeability were not significant. CONCLUSION: The lack of parallel increases in plasma and CSF S100B following CPB indicates that S100B may not be a reliable biomarker for BBB disruption after thoracoabdominal aortic aneurysm repair employing CPB. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT00878371); registered 7 April 2009.

RéSUMé: OBJECTIF: L'objectif de cette étude était de déterminer si l'intensité de la réponse inflammatoire périphérique à la chirurgie cardiovasculaire était associée à une augmentation de la perméabilité de la barrière hémato-encéphalique (BHE), telle que reflétée par des changements dans les concentrations de S100B dans le liquide céphalorachidien (LCR) et le plasma. MéTHODE: Nous avons mené une analyse secondaire à partir d'une étude de cohorte prospective portant sur 35 patients bénéficiant d'une réparation élective d'un anévrisme aortique thoraco-abdominal avec (n = 17) ou sans (n = 18) circulation extracorporelle (CEC). Les concentrations plasmatiques et dans le LCR de S100B, d'interleukine-6 (IL-6) et d'albumine ont été mesurées au départ (C0) et en série jusqu'à cinq jours. RéSULTATS: Après la CEC, la concentration médiane [écart interquartile] plasmatique de S100B est passée de 58 [32­88] pg·mL-1 au départ (C0) à une concentration maximale (Cmax) de 1131 [655­1875] pg·mL-1 sur une période médiane (tmax) de 6,3 [5,9­7,0] h. Dans le groupe sans CEC, la concentration plasmatique médiane de S100B a augmenté dans une moindre mesure. Il y a eu une augmentation retardée de S100B dans le LCR à une Cmax médiane de 436 [406­922] pg·mL-1 dans le groupe CEC à une tmax de 23,7 [18,5­40,2] h. Dans le groupe sans CEC, les concentrations dans le LCR étaient similaires à tous les moments. Dans le groupe CEC, nous n'avons pas détecté de corrélations significatives entre la concentration de S100B dans le plasma et le LCR avec les concentrations plasmatiques d'IL-6 [r = 0,52 (intervalle de confiance [IC] à 95 %, -0,061 à 0,84)] et d'IL-6 dans le LCR [r = 0,53 (IC 95 %, -0,073 à 0,85)], respectivement. Les corrélations entre les taux plasmatiques ou dans le LCR de S100B et la perméabilité de la BHE n'étaient pas significatives. CONCLUSION: L'absence d'augmentations parallèles de la concentration de S100B dans le plasma et le LCR après la CEC indique que la S100B pourrait ne pas être un biomarqueur fiable de la perturbation de la BHE après une réparation d'anévrisme aortique thoraco-abdominal sous CEC. ENREGISTREMENT DE L'éTUDE: www.clinicaltrials.gov (NCT00878371); enregistrée le 7 avril 2009.

Patient understanding and experience of non-invasive imaging diagnostic techniques and the liver patient pathway.

BACKGROUND: Clinical and patient-reported outcomes are positively affected when efforts to increase patient understanding of underlying diseases and foster patient participation are part of care pathways. The prevalence of liver diseases is increasing globally, and successful communication of results from liver diagnostic tests will be important for physicians to ensure patient engagement and encourage adherence to lifestyle changes and therapy. Here, we aimed to explore the impact of non-invasive liver tests on patient experience and patient comprehension of liver disease in chronic liver disease diagnostic pathways typically managed with liver biopsies. RESULTS: 101 participants diagnosed with a range of liver disease aetiologies (90 patients, 11 caregivers) underwent a multiparametric magnetic resonance imaging (MRI) test. A subset of 33 participants was subjected to transient elastography (TE) with FibroScan® in addition to multiparametric MRI. MRI results were analysed using LiverMultiScan™. Participants received results on their liver-health status followed by a semi-structured interview to assess the scan procedure experience, comprehension of the results, and experiences of liver disease. A subset of participants (N = 5) was also engaged in the design, execution, and thematic analysis of the interview transcripts of the study. Analysis of semi-structured interviews revealed: (1) Presentation and discussion of the LiverMultiScan visual report by a physician was an effective contributor to better patient experience and increased comprehension of liver disease. (2) Patients demonstrated preference for non-invasive tests over biopsy for management of liver disease. (3) Patients reported positive experiences with the MRI test during the path for liver disease management. CONCLUSIONS: Patients presented with visual reports of liver test results developed increased understanding of liver disease care which may have contributed to an overall more positive experience. Patients reported that clinical information obtained through non-invasive methods and transmitted through visual reports contributed to clarity, understanding and overall increased satisfaction. We conclude that a shift toward non-invasive testing and visual reporting of clinical information (e.g. picture of liver with visual scale) when possible are likely to contribute to improved physician engagement with patients and lead to better outcomes in the management of chronic liver diseases. Evidence suggests that patient experience and understanding can affect several aspects of clinical care and patient well-being. In this study, 101 patients and patient caregivers affected by liver diseases were recruited to determine how patient experiences of liver disease were affected with the introduction of non-invasive evaluation of the liver with an MRI or ultrasound-based elastography. All 101 participants received an MRI followed by a LiverMultiScan report. 33 participants received an additional FibroScan and report. Following the reports, participants were interviewed and asked to reflect on factors which affected their experience of the procedure and the understanding of their results. We focused on factors related to the layout of the standardised report and the delivery of its results. The interviews were transcribed and analysed for common themes and patterns. Patients and patient advocacy groups were involved in the design and conduct of the study, and analysis of the interview transcripts. Here, we report the perception of patients and patient caregivers on the quality of care and diagnostic experience. Trial registration ClinicalTrials.gov identifier-NCT02877602.

Drug-induced immune-mediated thrombocytopenia secondary to durvalumab use.

Immunotherapy is an expanding area of cancer treatment with significant promise. Despite their efficacy, checkpoint inhibitors are associated with a number of immune-related adverse events; here, we described thrombocytopenia secondary todurvalumab.

Do Patients Regret Having Received Systemic Treatment for Advanced Non-Small Cell Lung Cancer: A Prospective Evaluation.

BACKGROUND: Thousands of patients annually receive treatment for advanced non-small cell lung cancer (NSCLC), but little is known about their views on the decision to receive that treatment, or regret. This trial prospectively evaluated the incidence of regret and whether baseline characteristics, patient decision-making parameters, or clinical progress early in the treatment course predicts regret. MATERIALS AND METHODS: Patients receiving systemic treatment for advanced NSCLC completed every 3-week patient reported outcome (PRO) assessment using the electronic Lung Cancer Symptom Scale (eLCSS-QL), including the 3-Item Global Index (3-IGI; assessing overall distress, activities, and quality of life [QL]). A prespecified secondary aim was to determine the frequency of regret evaluated at 3 months after starting treatment. Patients were randomized to usual care or enhanced care (which included use of the DecisionKEYS decision aid). RESULTS: Of 164 patients entered, 160 received treatment and 142 were evaluable for regret. In total, 11.5% of patients and 9% of their supporters expressed regret. Baseline characteristics did not predict regret; regret was rarely expressed by those who had a less than 20% decline or improvement in the 3-IGI PRO score after two treatment cycles. In contrast, when asked if they would make the same decision again, only 1% not having a 20% 3-IGI decline expressed regret, versus 14% with a 3-IGI decline (p = .01). CONCLUSION: The majority of patients having regret were identified early using the PRO 3-IGI of the eLCSS-QL measure. Identifying patients at risk for regret allows for interventions, including frank discussions of progress and goals early in the treatment course, which could address regret in patients and their supporters. IMPLICATIONS FOR PRACTICE: This report documents prospectively, for the first time, the incidence of treatment-related regret in patients with advanced lung cancer and outlines that risk of regret is associated with patient-determined worsening health status early in the course of treatment. Identifying patients at risk for regret early in treatment (before the third cycle of treatment) appears to be crucial. Counseling at that time should include a discussion of consideration of treatment change and the reason for this change.

Intracranial disease control for EGFR-mutant and ALK-rearranged lung cancer with large volume or symptomatic brain metastases.

PURPOSE/OBJECTIVE(S): Tyrosine kinase inhibitors (TKIs) are commonly employed for patients with brain metastases from lung cancer and specific driver mutations. We sought to identify the correlation between intracranial tumor burden and outcomes in patients with brain metastases treated with TKIs. MATERIALS/METHODS: We identified and retrospectively reviewed cases of EGFR-mutant or ALK-rearranged lung cancer with brain metastases at any time during their cancer course. Clinical characteristics and treatment information were abstracted from the medical records. Brain metastases were contoured to calculate total volume of disease at diagnosis and after initial therapy. High intracranial burden was defined as either > 10 brain metastases, volume of brain metastases > 15 cc, or largest lesion > 3 cm. Intracranial response was determined according to Response Assessment in Neuro-Oncology (RANO) criteria on the patient level. We determined the correlation between clinical and imaging characteristics and intracranial progression free survival (IC-PFS) and overall survival (OS). RESULTS: Fifty-seven patients with EGFR (n = 49) and ALK (n = 8) alterations were identified. Median follow-up from initial brain metastasis diagnosis was 17 months. Neurological symptoms were present in 54% at brain metastasis diagnosis. For those receiving TKIs alone or TKIs with radiation, at least a partial intracranial response (≥ 65% volume reduction) at 3 months from starting therapy was achieved in 94% and 58%. Progressive intracranial disease at 3 months occurred in 6.3% and 8.3%. Patients with high intracranial burden (n = 21) had a median 17 brain metastases, 6.5 cc volume, and 1.9 cm maximal tumor diameter. Median IC-PFS and OS for patients with high intracranial burden was 13.9 and 35.4 months. Patients with high intracranial burden and neurological symptoms at diagnosis had similar IC-PFS and OS compared to those with low burden and absence of neurological symptoms (p > 0.05 for each). CONCLUSION: Most patients receiving TKIs as part of their initial therapy achieve an early and durable volumetric intracranial response, irrespective of presenting disease burden or neurologic symptoms.

Fragment-based drug discovery: opportunities for organic synthesis.

This Review describes the increasing demand for organic synthesis to facilitate fragment-based drug discovery (FBDD), focusing on polar, unprotected fragments. In FBDD, X-ray crystal structures are used to design target molecules for synthesis with new groups added onto a fragment via specific growth vectors. This requires challenging synthesis which slows down drug discovery, and some fragments are not progressed into optimisation due to synthetic intractability. We have evaluated the output from Astex's fragment screenings for a number of programs, including urokinase-type plasminogen activator, hematopoietic prostaglandin D2 synthase, and hepatitis C virus NS3 protease-helicase, and identified fragments that were not elaborated due, in part, to a lack of commercially available analogues and/or suitable synthetic methodology. This represents an opportunity for the development of new synthetic research to enable rapid access to novel chemical space and fragment optimisation.

MYBL2-Driven Transcriptional Programs Link Replication Stress and Error-prone DNA Repair With Genomic Instability in Lung Adenocarcinoma.

It has long been recognized that defects in cell cycle checkpoint and DNA repair pathways give rise to genomic instability, tumor heterogeneity, and metastasis. Despite this knowledge, the transcription factor-mediated gene expression programs that enable survival and proliferation in the face of enormous replication stress and DNA damage have remained elusive. Using robust omics data from two independent studies, we provide evidence that a large cohort of lung adenocarcinomas exhibit significant genome instability and overexpress the DNA damage responsive transcription factor MYB proto-oncogene like 2 (MYBL2). Across two studies, elevated MYBL2 expression was a robust marker of poor overall survival and disease-free survival outcomes, regardless of disease stage. Clinically, elevated MYBL2 expression identified patients with aggressive early onset disease, increased lymph node involvement, and increased incidence of distant metastases. Analysis of genomic sequencing data demonstrated that MYBL2 High lung adenocarcinomas had elevated somatic mutation burden, widespread chromosomal alterations, and alterations in single-strand DNA break repair pathways. In this study, we provide evidence that impaired single-strand break repair, combined with a loss of cell cycle regulators TP53 and RB1, give rise to MYBL2-mediated transcriptional programs. Omics data supports a model wherein tumors with significant genomic instability upregulate MYBL2 to drive genes that control replication stress responses, promote error-prone DNA repair, and antagonize faithful homologous recombination repair. Our study supports the use of checkpoint kinase 1 (CHK1) pharmacological inhibitors, in targeted MYBL2 High patient cohorts, as a future therapy to improve lung adenocarcinoma patient outcomes.

Cardiac Surgery and the Blood-Brain Barrier.

Neurologic abnormality after cardiac surgery is common, and neurologic complications after cardiac surgery are among the most devastating problems that can occur in the postoperative period. Disruption of the blood-brain barrier (BBB) plays an important role in these complications. Assessment of the BBB integrity relies on cognitive testing, MRI, and measurement of brain biomarkers. In applying these methods, up to 50% of cardiac patients show some degree of BBB disruption and most of these abnormalities are short lived. To date there is no single test or measure that can predict BBB disruption in cardiac surgery.

Expansion of Thaumarchaeota habitat range is correlated with horizontal transfer of ATPase operons.

Thaumarchaeota are responsible for a significant fraction of ammonia oxidation in the oceans and in soils that range from alkaline to acidic. However, the adaptive mechanisms underpinning their habitat expansion remain poorly understood. Here we show that expansion into acidic soils and the high pressures of the hadopelagic zone of the oceans is tightly linked to the acquisition of a variant of the energy-yielding ATPases via horizontal transfer. Whereas the ATPase genealogy of neutrophilic Thaumarchaeota is congruent with their organismal genealogy inferred from concatenated conserved proteins, a common clade of V-type ATPases unites phylogenetically distinct clades of acidophilic/acid-tolerant and piezophilic/piezotolerant species. A presumptive function of pumping cytoplasmic protons at low pH is consistent with the experimentally observed increased expression of the V-ATPase in an acid-tolerant thaumarchaeote at low pH. Consistently, heterologous expression of the thaumarchaeotal V-ATPase significantly increased the growth rate of E. coli at low pH. Its adaptive significance to growth in ocean trenches may relate to pressure-related changes in membrane structure in which this complex molecular machine must function. Together, our findings reveal that the habitat expansion of Thaumarchaeota is tightly correlated with extensive horizontal transfer of atp operons.

A randomized controlled feasibility trial of paracetamol during febrile neutropenia in hemato-oncology patients.

The efficacy of paracetamol (acetaminophen) as an antipyretic during febrile neutropenia (FN) has not previously been established. We conducted a randomized double-blind placebo-controlled feasibility trial: hemato-oncology patients at high FN risk were randomly assigned to six hourly oral paracetamol (1 g) or placebo during the first 42 hours of FN. Fifty-three participants were screened, thirty-seven enrolled; 22 developed FN and commenced treatment (13 paracetamol; 9 placebo); recruitment rates were below, and retention rates met, pre-defined feasibility criteria. During the first 24 hours of FN, paracetamol recipients had significantly lower peak temperature than placebo: mean 38.2 (standard deviation 0.8) °C versus 38.9 (0.4) °C; difference -0.78 °C (95% CI -1.38 to -0.18); p = .013. Bacterial load measurement was not informative. Paracetamol lowers body temperature during FN, and definitive trials to determine its impact on FN outcomes are needed. Australian New Zealand Clinical Trials Registry reference ACTRN12613000601730; funded by Health Research Council of New Zealand.