Delirium in trauma patients: a 1-year prospective cohort study of 2026 patients.

BACKGROUND: Delirium in trauma surgery is common, especially post-operatively, but medical characteristics, risk factors and residence post-discharge have not comprehensively been investigated in all trauma patients. METHODS: Over 1 year, 2026 trauma patients were prospectively screened for delirium with the following tools: Delirium Observation screening scale (DOS), Intensive Care Delirium Screening Checklist (ICDSC) and a DSM (Diagnostic and Statistical Manual)-5, nursing tool (ePA-AC) construct. Risk factors-predisposing und precipitating-for delirium were assessed via multiple regression analysis. RESULTS: Of 2026 trauma patients, 440 (21.7%) developed delirium, which was associated with an increased risk of assisted living (OR 6.42, CI 3.92-10.49), transfer to nursing home (OR 4.66, CI 3.29-6.6), rehabilitation (OR 3.96, CI 3.1-5.1), or death (OR 70.72, CI 22-227.64). Intensive care management (OR 18.62, CI 14.04-24.68), requirement of ventilation (OR 32.21, CI 21.27-48.78), or its duration (OR 67.22, CI 33.8-133.71) all increased the risk for developing delirium. Relevant predisposing risk factors were dementia (OR 50.92, CI 15.12-171.45), cardiac insufficiency (OR 11.76, CI 3.6-38.36), and polypharmacy (OR 5.9, CI 4.01-8.68).Relevant precipitating risk factors were brain edema (OR 40.53, CI 4.81-341.31), pneumonia (OR 39.66, CI 8.89-176.93) and cerebral inflammation (OR 21.74, CI 2.34-202.07). CONCLUSION: Delirium in trauma patients is associated with poor outcome as well as with intensive care management and various predisposing and/or precipitating factors. Three quarters of patients who had undergone delirium were not able to live independently at home any more.

Death in delirious palliative-care patients occurs irrespective of age: A prospective, observational cohort study of 229 delirious palliative-care patients.

OBJECTIVES: Patients with terminal illness are at high risk of developing delirium, in particular, those with multiple predisposing and precipitating risk factors. Delirium in palliative care is largely under-researched, and few studies have systematically assessed key aspects of delirium in elderly, palliative-care patients. METHODS: In this prospective, observational cohort study at a tertiary care center, 229 delirious palliative-care patients stratified by age: <65 (N = 105) and ≥65 years (N = 124), were analyzed with logistic regression models to identify associations with respect to predisposing and precipitating factors. RESULTS: In 88% of the patients, the underlying diagnosis was cancer. Mortality rate and median time to death did not differ significantly between the two age groups. No inter-group differences were detected with respect to gender, care requirements, length of hospital stay, or medical costs. In patients ≥65 years, exclusively predisposing factors were relevant for delirium, including hearing impairment [odds ratio (OR) 3.64; confidence interval (CI) 1.90-6.99; P < 0.001], hypertension (OR 3.57; CI 1.84-6.92; P < 0.001), and chronic kidney disease (OR 4.84; CI 1.19-19.72; P = 0.028). In contrast, in patients <65 years, only precipitating factors were relevant for delirium, including cerebral edema (OR 0.02; CI 0.01-0.43; P = 0.012). SIGNIFICANCE OF RESULTS: The results of this study demonstrate that death in delirious palliative-care patients occurs irrespective of age. The multifactorial nature and adverse outcomes of delirium across all age in these patients require clinical recognition. Potentially reversible factors should be detected early to prevent or mitigate delirium and its poor survival outcomes.

Delirium at the end of life.

BACKGROUND: The general in-hospital mortality and interrelationship with delirium are vastly understudied. Therefore, this study aimed to assess the rates of in-hospital mortality and terminal delirium. METHOD: In this prospective cohort study of 28,860 patients from 37 services including 718 in-hospital deaths, mortality rates and prevalence of terminal delirium were determined with simple logistic regressions and their respective odds ratios (ORs). RESULTS: Although overall in-hospital mortality was low (2.5%), substantial variance between services became apparent: Across intensive care services the rate was 10.8% with a 5.8-fold increased risk, across medical services rates were 4.4% and 2.4-fold, whereas at the opposite end, across surgical services rates were 0.7% and 87% reduction, respectively. The highest in-hospital mortality rate occurred on the palliative care services (27.3%, OR 19.45). The general prevalence of terminal delirium was 90.7% and ranged from 83.2% to 100%. Only across intensive care services (98.1%, OR 7.48), specifically medical intensive care (98.1%, OR 7.48) and regular medical services (95.8%, OR 4.12) rates of terminal delirium were increased. In contrast, across medical services (86.4%, OR 0.32) and in particular oncology (73.9%, OR 0.25), pulmonology (72%, OR 0.31) and cardiology (63.2%, OR 0.4) rates were decreased. For the remaining services, rates of terminal delirium were the same. SIGNIFICANCE OF RESULTS: Although in-hospital mortality was low, the interrelationship with delirium was vast: most patients were delirious at the end of life. The implications of terminal delirium merit further studies.

The prevalence rates and sequelae of delirium at age older than 90 years.

OBJECTIVE: Although age and pre-existent dementia are robust risk factors for developing delirium, evidence for patients older than 90 years is lacking. Therefore, this study assesses the delirium prevalence rates and sequelae in this age group. METHOD: Based on a Diagnostic and Statistical Manual (DSM)-5, Delirium Observation screening scale (DOS), and Intensive Care Delirium Screening Checklist (ICDSC) construct, in this prospective cohort study, the prevalence rates and sequelae of delirium were determined in 428 patients older than 90 years by simple logistic regressions and corresponding odds ratios (ORs). RESULTS: The overall prevalence delirium rate was 45.2%, with a wide range depending upon specialty: intermediate and intensive care services (83.1%), plastic surgery and palliative care (75%), neurology (72%), internal medicine (69%) vs. dermatology (26.5%), and angiology (14.5%). Delirium occurred irrespective of age and gender; however, pre-existent dementia was the strongest delirium predictor (OR 36.05). Delirious patients were less commonly admitted from home (OR 0.47) than from assisted living (OR 2.24), indicating functional impairment. These patients were more severely ill, as indicated by emergency (OR 3.25) vs. elective admission (OR 0.3), requirement for intensive care management (OR 2.12) and ventilation (OR 5.56-8.33). At discharge, one-third did not return home (OR 0.22) and almost half were transferred to assisted living (OR 2.63), or deceased (OR 47.76). SIGNIFICANCE OF RESULTS: At age older than 90 years, the prevalence and sequelae of delirium are substantial. In particular, functional impairment and pre-existent dementia predicted delirium and subsequently, the loss of independence and death were imminent.

Tumour hypoxia promotes melanoma growth and metastasis via High Mobility Group Box-1 and M2-like macrophages.

Hypoxia is a hallmark of cancer that is strongly associated with invasion, metastasis, resistance to therapy and poor clinical outcome. Tumour hypoxia affects immune responses and promotes the accumulation of macrophages in the tumour microenvironment. However, the signals linking tumour hypoxia to tumour-associated macrophage recruitment and tumour promotion are incompletely understood. Here we show that the damage-associated molecular pattern High-Mobility Group Box 1 protein (HMGB1) is released by melanoma tumour cells as a consequence of hypoxia and promotes M2-like tumour-associated macrophage accumulation and an IL-10 rich milieu within the tumour. Furthermore, we demonstrate that HMGB1 drives IL-10 production in M2-like macrophages by selectively signalling through the Receptor for Advanced Glycation End products (RAGE). Finally, we show that HMGB1 has an important role in murine B16 melanoma growth and metastasis, whereas in humans its serum concentration is significantly increased in metastatic melanoma. Collectively, our findings identify a mechanism by which hypoxia affects tumour growth and metastasis in melanoma and depict HMGB1 as a potential therapeutic target.

IL-1ß drives inflammatory responses to propionibacterium acnes in vitro and in vivo.

Acne vulgaris is potentially a severe skin disease associated with colonization of the pilo-sebaceous unit by the commensal bacterium Propionibacterium acnes and inflammation. P. acnes is considered to contribute to inflammation in acne, but the pathways involved are unclear. Here we reveal a mechanism that regulates inflammatory responses to P. acnes. We show that IL-1ß mRNA and the active processed form of IL-1ß are abundant in inflammatory acne lesions. Moreover, we identify P. acnes as a trigger of monocyte-macrophage NLRP3-inflammasome activation, IL-1ß processing and secretion that is dependent on phagocytosis, lysosomal destabilization, reactive oxygen species, and cellular K+ efflux. In mice, inflammation induced by P. acnes is critically dependent on IL-1ß and the NLRP3 inflammasome of myeloid cells. These findings show that the commensal P. acnes-by activating the inflammasome-can trigger an innate immune response in the skin, thus establishing the NLRP3-inflammasome and IL-1ß as possible therapeutic targets in acne.

Carcinogen treatment in mouse selectively expressing activated N-Ras Q61K in melanocytes recapitulates metastatic cutaneous melanoma development.

The incidence of melanoma has significantly increased, and a better understanding of its pathogenesis and development of new therapeutic strategies are urgently needed. Here, we describe a murine model of metastatic cutaneous melanoma using C57BL/6 mice expressing a mutated human N-Ras gene under the control of a tyrosinase promoter (TyrRas). These mice were topically exposed to 7,12- dimethylbenzanthracene (DMBA) for brief exposure periods. Cutaneous melanoma developed at the site of exposure on average by 19 weeks of age and in 80% of mice. Importantly, as in humans, melanoma development was associated with subsequent metastasis to tumor-draining lymph nodes. Critically, such metastatic behavior is transplantable, as intradermal inoculation of melanoma cells from TyrRas-DMBA mice into non-transgenic mice led to the growth of melanoma and, again, metastasis to skin-draining lymph nodes. This metastatic melanoma model closely mimics human pathology and should be a useful tool for studying melanoma pathogenesis and developing new therapies.

Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization.

Efficient priming of adaptive immunity depends on danger signals provided by innate immune pathways. As an example, inflammasome-mediated activation of caspase-1 and IL-1beta is crucial for the development of reactive T cells targeting sensitizers like dinitrofluorobenzene (DNFB). Surprisingly, DNFB and dinitrothiocyanobenzene provide cross-reactive Ags yet drive opposing, sensitizing vs tolerizing, T cell responses. In this study, we show that, in mice, inflammasome-signaling levels can be modulated to turn dinitrothiocyanobenzene into a sensitizer and DNFB into a tolerizer, and that it correlates with the IL-6 and IL-12 secretion levels, affecting Th1, Th17, and regulatory T cell development. Hence, our data provide the first evidence that the inflammasome can define the type of adaptive immune response elicited by an Ag, and hint at new strategies to modulate T cell responses in vivo.