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New Pharmacological Tools to Target Leukocyte Trafficking in Lung Disease.
No full textInfection and inflammation of the lung results in the recruitment of non-resident immune cells, including neutrophils, eosinophils and monocytes. This swift response should ensure clearance of the threat and resolution of stimuli which drive inflammation. However, once the threat is subdued this influx of immune cells should be followed by clearance of recruited cells through apoptosis and subsequent efferocytosis, expectoration or retrograde migration back into the circulation. This cycle of cell recruitment, containment of threat and then clearance of immune cells and repair is held in exquisite balance to limit host damage. Advanced age is often associated with detrimental changes to the balance described above. Cellular functions are altered including a reduced ability to traffic accurately towards inflammation, a reduced ability to clear pathogens and sustained inflammation. These changes, seen with age, are heightened in lung disease, and most chronic and acute lung diseases are associated with an exaggerated influx of immune cells, such as neutrophils, to the airways as well as considerable inflammation. Indeed, across many lung diseases, pathogenesis and progression has been associated with the sustained presence of trafficking cells, with examples including chronic diseases such as Chronic Obstructive Pulmonary Disease and Idiopathic Pulmonary Fibrosis and acute infections such as Pneumonia and Pneumonitis. In these instances, there is evidence that dysfunctional and sustained recruitment of cells to the airways not only increases host damage but impairs the hosts ability to effectively respond to microbial invasion. Targeting leukocyte migration in these instances, to normalise cellular responses, has therapeutic promise. In this review we discuss the current evidence to support the trafficking cell as an immunotherapeutic target in lung disease, and which potential mechanisms or pathways have shown promise in early drug trials, with a focus on the neutrophil, as the quintessential trafficking immune cell
Validation of COPDPredict™: Unique Combination of Remote Monitoring and Exacerbation Prediction to Support Preventative Management of COPD Exacerbations.
No full textBackground
COPDPredict™ is a novel digital application dedicated to providing early warning of imminent COPD (chronic obstructive pulmonary disease) exacerbations for prompt intervention. Exacerbation prediction algorithms are based on a decision tree model constructed from percentage thresholds for disease state changes in patient-reported wellbeing, forced expiratory volume in one second (FEV) and C-reactive protein (CRP) levels. Our study determined the validity of COPDPredict™ to identify exacerbations and provide timely notifications to patients and clinicians compared to clinician-defined episodes.
Methods
In a 6-month prospective observational study, 90 patients with COPD and frequent exacerbations registered wellbeing self-assessments daily using COPDPredict™ App and measured FEV using connected spirometers. CRP was measured using finger-prick testing.
Results
Wellbeing self-assessment submissions showed 98% compliance. Ten patients did not experience exacerbations and treatment was unchanged. A total of 112 clinician-defined exacerbations were identified in the remaining 80 patients: 52 experienced 1 exacerbation; 28 had 2.2±0.4 episodes. Sixty-two patients self-managed using prescribed rescue medication. In 14 patients, exacerbations were more severe but responded to timely escalated treatment at home. Four patients attended the emergency room; with 2 hospitalised for <72 hours. Compared to the 6 months pre-COPDPredict™, hospitalisations were reduced by 98% (90 vs 2, p<0.001). COPDPredict™ identified COPD-related exacerbations at 7, 3 days (median, IQR) prior to clinician-defined episodes, sending appropriate alerts to patients and clinicians. Cross-tabulation demonstrated sensitivity of 97.9% (95% CI 95.7-99.2), specificity of 84.0% (95% CI 82.6-85.3), positive and negative predictive value of 38.4% (95% CI 36.4-40.4) and 99.8% (95% CI 99.5-99.9), respectively.
Conclusion
High sensitivity indicates that if there is an exacerbation, COPDPredict™ informs patients and clinicians accurately. The high negative predictive value implies that when an exacerbation is not indicated by COPDPredict™, risk of an exacerbation is low. Thus, COPDPredict™ provides safe, personalised, preventative care for patients with COPD
COVID-19 admission risk tools should include multiethnic age structures, multimorbidity and deprivation metrics for air pollution, household overcrowding, housing quality and adult skills.
No full textBACKGROUND
Ethnic minorities account for 34% of critically ill patients with COVID-19 despite constituting 14% of the UK population. Internationally, researchers have called for studies to understand deterioration risk factors to inform clinical risk tool development.
METHODS
Multicentre cohort study of hospitalised patients with COVID-19 (n=3671) exploring determinants of health, including Index of Multiple Deprivation (IMD) subdomains, as risk factors for presentation, deterioration and mortality by ethnicity. Receiver operator characteristics were plotted for CURB65 and ISARIC4C by ethnicity and area under the curve (AUC) calculated.
RESULTS
Ethnic minorities were hospitalised with higher Charlson Comorbidity Scores than age, sex and deprivation matched controls and from the most deprived quintile of at least one IMD subdomain: indoor living environment (LE), outdoor LE, adult skills, wider barriers to housing and services. Admission from the most deprived quintile of these deprivation forms was associated with multilobar pneumonia on presentation and ICU admission. AUC did not exceed 0.7 for CURB65 or ISARIC4C among any ethnicity except ISARIC4C among Indian patients (0.83, 95% CI 0.73 to 0.93). Ethnic minorities presenting with pneumonia and low CURB65 (0-1) had higher mortality than White patients (22.6% vs 9.4%; p<0.001); Africans were at highest risk (38.5%; p=0.006), followed by Caribbean (26.7%; p=0.008), Indian (23.1%; p=0.007) and Pakistani (21.2%; p=0.004).
CONCLUSIONS
Ethnic minorities exhibit higher multimorbidity despite younger age structures and disproportionate exposure to unscored risk factors including obesity and deprivation. Household overcrowding, air pollution, housing quality and adult skills deprivation are associated with multilobar pneumonia on presentation and ICU admission which are mortality risk factors. Risk tools need to reflect risks predominantly affecting ethnic minorities
Corrigendum to "European Resuscitation Council Guidelines 2021: Cardiac arrest in special circumstances" [Resuscitation 161 (2021) 152-219].
No full textThe effect of young and old ex vivo human serum on cellular protein synthesis and growth in an in vitro model of aging.
No full textIn vitro models of muscle aging are useful for understanding mechanisms of age-related muscle loss and aiding the development of targeted therapies. To investigate mechanisms of age-related muscle loss in vitro utilizing ex vivo human serum, fasted blood samples were obtained from four old (72 ± 1 yr) and four young (26 ± 3 yr) men. Older individuals had elevated levels of plasma CRP, IL-6, HOMA-IR, and lower concentric peak torque and work-per-repetition compared with young participants ( < 0.05). C2C12 myotubes were serum and amino acid starved for 1 h and conditioned with human serum (10%) for 4 h or 24 h. After 4 h, C2C12 cells were treated with 5 mM leucine for 30 min. Muscle protein synthesis (MPS) was determined through the surface sensing of translation (SUnSET) technique and regulatory signaling pathways were measured via Western blot. Myotube diameter was significantly reduced in myotubes treated with serum from old, in comparison to young donors (84%, < 0.001). MPS was reduced in myotubes treated with old donor serum, compared with young serum before leucine treatment (32%, < 0.01). MPS and the phosphorylation of Akt, p70S6K, and eEF2 were increased in myotubes treated with young serum in response to leucine treatment, with a blunted response identified in cells treated with old serum ( < 0.05). Muscle protein breakdown signaling pathways did not differ between groups. In summary, we show that myotubes conditioned with serum from older individuals had decreased myotube diameter and MPS compared with younger individuals, potentially driven by low-grade systemic inflammation
Mismatch between Tissue Partial Oxygen Pressure and Near-Infrared Spectroscopy Neuromonitoring of Tissue Respiration in Acute Brain Trauma: The Rationale for Implementing a Multimodal Monitoring Strategy.
No full textThe brain tissue partial oxygen pressure (PbtO) and near-infrared spectroscopy (NIRS) neuromonitoring are frequently compared in the management of acute moderate and severe traumatic brain injury patients; however, the relationship between their respective output parameters flows from the complex pathogenesis of tissue respiration after brain trauma. NIRS neuromonitoring overcomes certain limitations related to the heterogeneity of the pathology across the brain that cannot be adequately addressed by local-sample invasive neuromonitoring (e.g., PbtO neuromonitoring, microdialysis), and it allows clinicians to assess parameters that cannot otherwise be scanned. The anatomical co-registration of an NIRS signal with axial imaging (e.g., computerized tomography scan) enhances the optical signal, which can be changed by the anatomy of the lesions and the significance of the radiological assessment. These arguments led us to conclude that rather than aiming to substitute PbtO with tissue saturation, multiple types of NIRS should be included via multimodal systemic- and neuro-monitoring, whose values then are incorporated into biosignatures linked to patient status and prognosis. Discussion on the abnormalities in tissue respiration due to brain trauma and how they affect the PbtO and NIRS neuromonitoring is given
Tetraspanin 6 is a regulator of carcinogenesis in colorectal cancer.
No full textEarly stages of colorectal cancer (CRC) development are characterized by a complex rewiring of transcriptional networks resulting in changes in the expression of multiple genes. Here, we demonstrate that the deletion of a poorly studied tetraspanin protein Tspan6 in Apc mice, a well-established model for premalignant CRC, resulted in increased incidence of adenoma formation and tumor size. We demonstrate that the effect of Tspan6 deletion results in the activation of EGF-dependent signaling pathways through increased production of the transmembrane form of TGF-α (tmTGF-α) associated with extracellular vesicles. This pathway is modulated by an adaptor protein syntenin-1, which physically links Tspan6 and tmTGF-α. In support of this, the expression of Tspan6 is frequently decreased or lost in CRC, and this correlates with poor survival. Furthermore, the analysis of samples from the epidermal growth factor receptor (EGFR)-targeting clinical trial (COIN trial) has shown that the expression of Tspan6 in CRC correlated with better patient responses to EGFR-targeted therapy involving Cetuximab. Importantly, Tspan6-positive patients with tumors in the proximal colon (right-sided) and those with KRAS mutations had a better response to Cetuximab than the patients that expressed low Tspan6 levels. These results identify Tspan6 as a regulator of CRC development and a potential predictive marker for EGFR-targeted therapies in CRC beyond RAS pathway mutations
Impact of SARS-CoV-2 pandemic on pancreatic cancer services and treatment pathways: United Kingdom experience.
No full textINTRODUCTION
The SARS-CoV-2 pandemic presented healthcare providers with an extreme challenge to provide cancer services. The impact upon the diagnostic and treatment capacity to treat pancreatic cancer is unclear. This study aimed to identify national variation in treatment pathways during the pandemic.
METHODS
A survey was distributed to all United Kingdom pancreatic specialist centres, to assess diagnostic, therapeutic and interventional services availability, and alterations in treatment pathways. A repeating methodology enabled assessment over time as the pandemic evolved.
RESULTS
Responses were received from all 29 centres. Over the first six weeks of the pandemic, less than a quarter of centres had normal availability of diagnostic pathways and a fifth of centres had no capacity whatsoever to undertake surgery. As the pandemic progressed services have gradually improved though most centres remain constrained to some degree. One third of centres changed their standard resectable pathway from surgery-first to neoadjuvant chemotherapy. Elderly patients, and those with COPD were less likely to be offered treatment during the pandemic.
CONCLUSION
The COVID-19 pandemic has affected the capacity of the NHS to provide diagnostic and staging investigations for pancreatic cancer. The impact of revised treatment pathways has yet to be realised
