Safety, tolerability, and pharmacokinetics of Aurora kinase B inhibitor AZD2811: a phase 1 dose-finding study in patients with advanced solid tumours.

BACKGROUND: AZD2811 is a potent, selective Aurora kinase B inhibitor. We report the dose-escalation phase of a first-in-human study assessing nanoparticle-encapsulated AZD2811 in advanced solid tumours. METHODS: AZD2811 was administered in 12 dose-escalation cohorts (2-h intravenous infusion; 15‒600 mg; 21-/28-day cycles) with granulocyte colony-stimulating factor (G-CSF) at higher doses. The primary objective was determining safety and maximum tolerated/recommended phase 2 dose (RP2D). RESULTS: Fifty-one patients received AZD2811. Drug exposure was sustained for several days post-dose. The most common AZD2811-related adverse events (AEs) were fatigue (27.3%) at ≤200 mg/cycle and neutropenia (37.9%) at ≥400 mg/cycle. Five patients had dose-limiting toxicities: grade (G)4 decreased neutrophil count (n = 1, 200 mg; Days 1, 4; 28-day cycle); G4 decreased neutrophil count and G3 stomatitis (n = 1 each, both 400 mg; Day 1; 21-day cycle); G3 febrile neutropenia and G3 fatigue (n = 1 each, both 600 mg; Day 1; 21-day cycle +G-CSF). RP2D was 500 mg; Day 1; 21-day cycle with G-CSF on Day 8. Neutropenia/neutrophil count decrease were on-target AEs. Best overall responses were partial response (n = 1, 2.0%) and stable disease (n = 23, 45.1%). CONCLUSIONS: At RP2D, AZD2811 was tolerable with G-CSF support. Neutropenia was a pharmacodynamic biomarker. CLINICAL TRIAL REGISTRATION: NCT02579226.

One Health security lessons from a year-long webinar series on international COVID-19 response.

Following the principles outlined by the Global Outbreak Alert and Response Network, the Federal Bureau of Investigation's International Biosecurity and Prevention Forum, the European Commission's Joint Research Centre, and the Middlebury Institute of International Studies' James Martin Center for Nonproliferation Studies cohosted a webinar series from April 2020 to January 2021 on COVID-19 management across Africa, Europe, and North America. We provide here an overview of the webinar series and discuss how lessons learned during the COVID-19 pandemic and debated during the webinars can be used to bridge One Health with biological threat-driven health security. This report can be used to inform recommendations for future One Health security approaches to strengthen global capacity and multidisciplinary cooperation.

A simulated single ventilator/dual patient ventilation strategy for acute respiratory distress syndrome during the COVID-19 pandemic.

The potential for acute shortages of ventilators at the peak of the COVID-19 pandemic has raised the possibility of needing to support two patients from a single ventilator. To provide a system for understanding and prototyping designs, we have developed a mathematical model of two patients supported by a mechanical ventilator. We propose a standard set-up where we simulate the introduction of T-splitters to supply air to two patients and a modified set-up where we introduce a variable resistance in each inhalation pathway and one-way valves in each exhalation pathway. Using the standard set-up, we demonstrate that ventilating two patients with mismatched lung compliances from a single ventilator will lead to clinically significant reductions in tidal volume in the patient with the lowest respiratory compliance. Using the modified set-up, we demonstrate that it could be possible to achieve the same tidal volumes in two patients with mismatched lung compliances, and we show that the tidal volume of one patient can be manipulated independently of the other. The results indicate that, with appropriate modifications, two patients could be supported from a single ventilator with independent control of tidal volumes.

Monitoring for proteinuria in patients with type 2 diabetes mellitus.

OBJECTIVE: The UK National Institute for Health and Care Excellence (NICE) guideline on diabetes recommends at least annual monitoring of patients with type 2 diabetes mellitus (T2DM) for proteinuria. To date, little has been published on the frequency of proteinuria monitoring in T2DM, and its association with risk factors for renal complications. We aimed to describe proteinuria monitoring in patients with T2DM. DESIGN: This study identified patients with T2DM aged 40 years or older with the first antidiabetic drug use in 2007-2012 (cohort entry) in the UK Clinical Practice Research Datalink. At least 1 year of registration before and after cohort entry was required. A test was considered undertaken if a medical or laboratory code indicated a urinary albumin or protein test. The percentage of patients with at least one test performed was obtained in 1 year after cohort entry and any time during follow-up. A Cox proportional hazards model was used to estimate the HRs of patients having the first screening test while adjusting for baseline covariates. RESULTS: 65 790 patients (mean age 63.0 years, men 57.5%, mean follow-up 41.0 months) were included, of whom 49 707 (75.6%) patients had at least one test in 1 year after antidiabetic drug initiation and 59 400 (90.3%) had at least one test any time during follow-up. Proteinuria monitoring decreased with time since initiation of antidiabetic drug therapy and with number of treatment changes and was independently associated with age, sex, smoking status, and year of antidiabetic drug initiation. 12.3% of patients with T2DM tested had a positive proteinuria test for the first screening performed in 1 year after initiation of antidiabetic drug therapy. CONCLUSIONS: The findings suggested suboptimal compliance with the NICE guideline on proteinuria monitoring in patients with T2DM and that level of monitoring appeared to depend on multiple clinical factors.

Lung function abnormalities in infants developing bronchopulmonary dysplasia.

OBJECTIVE: To determine if infants developing bronchopulmonary dysplasia (BPD), particularly mild BPD, initially had minimal lung function abnormalities, which then worsened throughout the neonatal period. DESIGN: Prospective observational study. SETTING: Tertiary neonatal intensive care unit. PATIENTS: 74 infants with a median gestational age of 30 weeks (24-32) and birth weight of 1200 g (474-2000) were studied; 35 had no BPD, 12 developed mild BPD and 23 developed moderate/severe BPD. INTERVENTIONS: BPD was diagnosed in infants who were oxygen dependent beyond 28 days after birth. MAIN OUTCOME MEASURES: Lung function was assessed by measurement of functional residual capacity (FRC) by helium gas dilution and compliance and resistance of the respiratory system. Measurements were attempted on days 3, 5, 7, 14, 21 and 28. RESULTS: Infants developing BPD, particularly moderate/severe BPD, had lower mean FRC (p=0.009) and mean compliance (p=0.005) throughout the 28-day period than those who did not develop BPD. Lung function improved over the neonatal period in all three groups, but the rate of improvement in FRC (p=0.004) and compliance (p=0.002) results over the first 28 days varied by BPD status, being greatest in infants developing moderate/severe BPD (all p values <0.05). CONCLUSIONS: Overall, in infants who did and did not develop BPD, lung function improved throughout the neonatal period. Infants with more severe initial lung disease were more likely to develop moderate/severe BPD.

Prediction of bronchopulmonary dysplasia.

OBJECTIVE: To determine whether elevation of a biological marker of inflammation would be a better predictor of bronchopulmonary dysplasia (BPD) development than lung function measurement results. DESIGN: Prospective study. SETTING: Tertiary neonatal intensive care unit. PATIENTS: 78 prematurely born infants (median gestational age 29 (range 24-32) weeks) were studied; 39 developed BPD. INTERVENTIONS: BPD was diagnosed as oxygen dependence at 28 days. MAIN OUTCOME MEASURES: Levels of a biological marker of inflammation (carbon monoxide) were assessed by measurement of end-tidal carbon monoxide (ETCO) and lung function by measurement of functional residual capacity (FRC) and compliance (Crs) and resistance (Rrs) of the respiratory system on days 3 and 14 after birth. Possible predictive factors were modelled for BPD and for BPD severity. RESULTS: Gestational age, birth weight, ETCO, FRC and Crs results on days 3 and 14 differed significantly between infants who did and did not develop BPD. In multifactorial logistic regression, only birth weight and ETCO results (on day 14) remained significant predictors of BPD with an area under the curve of 0.97. The final multifactorial model for the severity of BPD included those two factors, plus septic episodes. CONCLUSION: These results emphasise the importance of ongoing inflammation in the development of BPD; ETCO levels, rather than lung function test results, were the more accurate predictor of BPD development.

Self-assessment of acute mountain sickness in adolescents: a pilot study.

OBJECTIVE: To perform a pilot study exploring the prevalence of acute mountain sickness (AMS) in adolescents on ascent to altitude and evaluating whether this age group is capable of self-assessment of AMS using the Lake Louise scoring system. METHODS: Twelve teenagers aged 15 to 18 years old (5 girls) traveled for 21 days between 2400 and 5500 m. Each member of the expedition completed a Lake Louise self-assessment questionnaire on a daily basis. Group leaders (nonmedical) were informed about any subject with a score of 3 or more. Appropriate treatments were then initiated. Detailed analysis of data was undertaken on return to the UK. RESULTS: There was 100% completion of 252 questionnaires. Eleven of the 12 subjects (91.7%) had symptom scores greater than or equal to 3, consistent with a diagnosis of AMS, on at least one day (range, 0-8). Symptoms of AMS were more common in the female group members (P = .041). CONCLUSIONS: AMS is a common problem among adolescents. There are increasing numbers of adolescents traveling to high altitudes, and there appears to be a lack of information about the prevalence of AMS in this age group. Motivated adolescents seemed capable of self-monitoring for AMS using the Lake Louise questionnaire. Combined with an appropriate ascent profile and support, we feel this approach may contribute to safety in the mountains and merits further study.

Pond tadpoles with generalized morphology: is it time to reconsider their functional roles in aquatic communities?

With rare exceptions, anuran larvae have traditionally been considered to occupy lower trophic levels in aquatic communities where they function as microphagous suspension feeders. This view is being challenged by studies showing that tadpoles with generalized morphology often function as macrophagous predators. Here, we review the literature concerning macrophagy by tadpoles and provide two additional examples involving generalized tadpoles. In the first, we demonstrate with laboratory and field experiments that wood frog (Rana sylvatica) tadpoles are major predators of macroinvertebrates in ponds. In the second, we show that green frog (R. clamitans) tadpoles can cause catastrophic reproductive failure of the wood frog via egg predation. These results and data from other studies challenge the assumption that generalized tadpoles function as filter-feeding omnivores, and question the general applicability of community organization models which assume that predation risk increases with pond permanence. We suggest that predation risk is greater in temporary ponds than in more permanent ponds for many organisms that are vulnerable to predation by tadpoles. This being so, a conditional model based upon interactions that are species-specific, life-stage-specific, and context-dependent may better explain community organization along hydrological gradients than models which assume that temporary ponds have few or no predators.