Comorbidities in adults with asthma: Population-based cross-sectional analysis of 1.4 million adults in Scotland.

BACKGROUND: Comorbidity in people with asthma can significantly increase asthma morbidity and lower adherence to asthma guidelines. OBJECTIVE: The objective of this study was to comprehensively measure the prevalence of physical and mental health comorbidities in adults with asthma using a large nationally representative population. METHODS: Cross-sectional analysis of routine primary care electronic medical records for 1 424 378 adults in the UK, examining the prevalence of 39 comorbidities in people with and without asthma, before and after adjustment for age, sex, social deprivation and smoking status using logistic regression. RESULTS: Of 39 comorbidities measured, 36 (92%) were significantly more common in adults with asthma; 62.6% of adults with asthma had ≥1 comorbidity vs 46.2% of those without, and 16.3% had ≥4 comorbidities vs 8.7% of those without. Comorbidities with the largest absolute increase in prevalence in adults with asthma were as follows: chronic obstructive pulmonary disease (COPD) (13.4% vs 3.1%), depression (17.3% vs 9.1%), painful conditions (15.4% vs 8.4%) and dyspepsia (10.9% vs 5.2%). Comorbidities with the largest relative difference in adults with asthma compared to those without were as follows: COPD (adjusted odds ratio [aOR] 5.65, 95% CI 5.52-5.79), bronchiectasis (aOR 4.65, 95% CI 4.26-5.08), eczema/psoriasis (aOR 3.30, 95% CI 3.14-3.48), dyspepsia (aOR 2.20, 95% CI 2.15-2.25) and chronic sinusitis (aOR 2.12, 95% CI 1.99-2.26). Depression and anxiety were more common in adults with asthma (aOR 1.60, 95% CI 1.57-1.63, and aOR 1.53, 95% CI 1.48-1.57, respectively). CONCLUSIONS AND CLINICAL RELEVANCE: Physical and mental health comorbidities are the norm in adults with asthma. Appropriate recognition and management should form part of routine asthma care.

Multiple myeloma causes clonal T-cell immunosenescence: identification of potential novel targets for promoting tumour immunity and implications for checkpoint blockade.

Tumour-induced dysfunction of cytotoxic T cells in patients with multiple myeloma (MM) may contribute to immune escape and be responsible for the lack of therapeutic efficacy of immune checkpoint blockade. We therefore investigated dysfunctional clonal T cells in MM and demonstrated immunosenescence but not exhaustion as a predominant feature. T-cell clones were detected in 75% of MM patients and their prognostic significance was revalidated in a new post-immunomodulatory drug cohort. The cells exhibited a senescent secretory effector phenotype: KLRG-1+/CD57+/CD160+/CD28-. Normal-for-age telomere lengths indicate that senescence is telomere independent and potentially reversible. p38-mitogen-activated protein kinase, p16 and p21 signalling pathways known to induce senescence were not elevated. Telomerase activity was found to be elevated and this may explain how normal telomere lengths are maintained in senescent cells. T-cell receptor signalling checkpoints were normal but elevated SMAD levels associated with T-cell inactivation were detected and may provide a potential target for the reversal of clonal T-cell dysfunction in MM. Low programmed death 1 and cytotoxic T-lymphocyte-associated antigen 4 expression detected on T-cell clones infers that these cells are not exhausted but suggests that there would be a suboptimal response to immune checkpoint blockade in MM. Our data suggest that other immunostimulatory strategies are required in MM.

Phospho-flow detection of constitutive and cytokine-induced pSTAT3/5, pAKT and pERK expression highlights novel prognostic biomarkers for patients with multiple myeloma.

Identifying check points in cell signal transduction pathways has led to the development of new cancer therapies; however, relatively few studies have determined the diagnostic and prognostic significance of analysing phosphorylated signaling proteins in patient blood and bone marrow (BM) samples. This is the first comprehensive phospho-flow study of both constitutive and cytokine-induced pSTAT3, pSTAT5, pAKT and phosphorylated extracellular signal-regulated kinase (pERK) expression in malignant plasma cells of patients with monoclonal gammopathies. In diagnostic BM samples from 65 patients with multiple myeloma (MM), interleukin (IL)-6-induced pSTAT3 proved to be a new and independent prognostic biomarker for improved survival. When combined with the International Staging System, 6 subgroups demonstrated stratified median survivals from 9 to 72 months (χ(2)=34.3; P<0.0001). In contrast, constitutive expression of pSTAT3, pSTAT5, pAKT and pERK did not assist the differential diagnosis nor determine prognosis. High pSTAT3 expression was dependent on existing CD45 expression and pSTAT5 appeared to regulate IgG production. Phospho-flow cytometry could be used to screen for personalized therapy, although the lack of clinical significance of constitutive pSTAT3 levels suggests that pSTAT3 blockade may not be clinically relevant in MM. This study has revealed novel prognostic biomarkers and insights into the biology of signaling pathways in patients with MM.

The use of FEIBA® in the correction of coagulation abnormalities induced by dabigatran.

INTRODUCTION: Studies have shown dabigatran to be an effective anticoagulant with an acceptable bleeding profile. None the less, these patients do suffer from bleeding complications. Unfortunately, there are currently no direct reversal agents to dabigatran or established guidelines on the management of bleeding in these circumstances. METHODS: We examined the effects on thrombin generation parameters, after ex-vivo spiking the plasma of patients on dabigatran (n = 8) with FEIBA(®). These parameters were measured using the calibrated automated thrombography (CAT) machine. RESULTS: In our study, we showed the ability of FEIBA(®) to improve the abnormal thrombin generation parameters caused by dabigatran in these patients. CONCLUSION: This provides evidence, lacking in the literature, that this agent may be able to provide haemostatic support in situations where dabigatran induced coagulopathy exists.

The impact of bispectral index monitoring on sedation administration in mechanically ventilated patients.

The aim of this prospective randomised controlled trial was to assess the effectiveness of the Bispectral Index (BIS) monitor in supporting clinical sedation management decisions in mechanically ventilated intensive care unit patients. Fifty adult mechanically ventilated surgical and general intensive care unit patients receiving sedative infusions of morphine and midazolam were randomly allocated to receive BIS monitoring (n=25) or standard sedation management (n=25). In the BIS group, sedation was titrated to maintain a BIS value of greater than 70. In the standard management group, sedative needs were titrated based on subjective assessment and clinical signs. There was no statistically significant difference in the amount of sedation administered (morphine P = 0.67 and midazolam P = 0.85). However, there was a statistically significant difference in sedation administration over time. Patients in the BIS group received increasing amounts of sedation over time whilst those in the control group received decreasing amounts of sedation over time. The same inverse relationship existed for both sedative agents (morphine P = 0.005, midazolam P = 0.03). Duration of mechanical ventilation was comparable in the two groups. We conclude that the use of BIS monitoring did not reduce the amount of sedation used, the length of mechanical ventilation time or the length of ICU stay.