Factores asociados a mortalidad intrahospitalaria en pacientes adultos mayores con asistencia ventilatoria mecánica invasiva en el servicio de urgencias / In-hospital mortality associated factors in elderly patients with invasive mechanical ventilation in the emergency department

Objetivos Identificar los factores asociados a mortalidad intrahospitalaria, estimar la tasa de intubación y describir la mortalidad intrahospitalaria de mayores de 65 años que requirieron ventilación mecánica invasiva (VMI) en el servicio de urgencias. Métodos Estudio de cohorte retrospectiva con pacientes mayores de 65 años, intubados en la central de emergencias del adulto entre 2016 y 2018 en un hospital de alta complejidad. Se consignaron datos demográficos, comorbilidades y scores de severidad al ingreso. Se realizaron análisis bivariado y multivariado con regresión logística en relación a mortalidad hospitalaria y posibles confundidores. Resultados Un total de 285 pacientes con media de 80 años requirieron VMI en urgencias durante una mediana de 3 días, y con media de 20 puntos de severidad según APACHE II. La tasa de VMI resultó 0,48% (IC95% 0,43-0,54), y 55,44% (158) fallecieron. Los factores asociados a mortalidad tras el ajuste por edad y sexo fueron: accidente cerebrovascular (OR 2,13; IC95%1,21-3,76), insuficiencia renal crónica (OR 4,38; IC95%1,91-10,04), índice de Charlson (OR 1,19; IC95%1,02-1,38), APACHE II (OR 1,07; IC95%1,02-1,12) y SOFA (OR 1,14; IC95%1,03-1,27). Discusión Nuestra tasa de VMI fue inferior a la declarada por Johnson et al. en Estados Unidos en 2018 (0,59%). La mortalidad intrahospitalaria de nuestro estudio superó la predicha por el score de APACHE II (40%) y de SOFA (33%), sin embargo fue consistente con la reportada por Lieberman et al. en Israel y Esteban et al. en Estados Unidos. Conclusiones Si bien la tasa de requerimiento de VMI en el servicio de emergencias fue baja, más de la mitad fallecieron durante su hospitalización. Las enfermedades cerebrovasculares y renales preexistentes y los altos puntajes en el índice de comorbilidades y en los scores de gravedad al ingreso fueron predictores independientes para mortalidad intrahospitalaria. (AU)

Aims To identify factors associated with in-hospital mortality, to estimate the intubation rate and to describe in-hospital mortality in patients over 65 years old with invasive mechanical ventilation (IMV) in the emergency department (ED). Methods Retrospective cohort study of patients over 65 years old, who were intubated in an ED of a high complexity hospital between 2016 and 2018. Demographic data, comorbidities, and severity scores on admission were described. Bivariate and multivariate analyses were performed with logistic regression according to mortality and possible confounders. Results A total of 285 patients with a mean age of 80 years required IMV in the emergency department, for a median of 3 days, and with a mean APACHE II score of 20 points of severity. The IMV rate was .48% (95% CI .43-.54), and 55.44% (158) died. Mortality-associated factors after age and sex adjustment were stroke (OR 2.13; 95%CI 1.21-3.76), chronic kidney failure, (OR 4.,38; 95%CI 1.91-10.04), Charlson index (OR 1.19; 95%CI 1.02-1.38), APACHE II score (OR 1.07; 95%CI 1.02-1.12), and SOFA score (OR 1.14; 95%CI 1.03-1.27). Discussion Our IMV rate was lower than that stated by Johnson et al. in the United States in 2018 (.59%). In-hospital mortality in our study exceeded that predicted by the APACHE II score (40%) and SOFA (33%). However it was consistent with that reported by Lieberman et al. in Israel and Esteban et al. in the United States. Conclusions Although the IMV rate was low in the ED, more than half the patients died during hospitalization. Pre-existing cerebrovascular and renal diseases and high results in the comorbidities index and severity scores on admission were independent factors associated with in-hospital mortality. (AU)

In-hospital mortality associated factors in elderly patients with invasive mechanical ventilation in the emergency department.

AIMS: To identify factors associated with in-hospital mortality, to estimate the intubation rate and to describe in-hospital mortality in patients over 65 years old with invasive mechanical ventilation (IMV) in the emergency department (ED). METHODS: Retrospective cohort study of patients over 65 years old, who were intubated in an ED of a high complexity hospital between 2016 and 2018. Demographic data, comorbidities, and severity scores on admission were described. Bivariate and multivariate analyses were performed with logistic regression according to mortality and possible confounders. RESULTS: A total of 285 patients with a mean age of 80 years required IMV in the emergency department, for a median of 3 days, and with a mean APACHE II score of 20 points of severity. The IMV rate was .48% (95% CI .43-.54), and 55.44% (158) died. Mortality-associated factors after age and sex adjustment were stroke (OR 2.13; 95% CI 1.21-3.76), chronic kidney failure, (OR 4.,38; 95% CI 1.91-10.04), Charlson index (OR 1.19; 95% CI 1.02-1.38), APACHE II score (OR 1.07; 95% CI 1.02-1.12), and SOFA score (OR 1.14; 95% CI 1.03-1.27). DISCUSSION: Our IMV rate was lower than that stated by Johnson et al. in the United States in 2018 (.59%). In-hospital mortality in our study exceeded that predicted by the APACHE II score (40%) and SOFA (33%). However it was consistent with that reported by Lieberman et al. in Israel and Esteban et al. in the United States. CONCLUSIONS: Although the IMV rate was low in the ED, more than half the patients died during hospitalization. Pre-existing cerebrovascular and renal diseases and high results in the comorbidities index and severity scores on admission were independent factors associated with in-hospital mortality.

Consistent skin α-synuclein positivity in REM sleep behavior disorder - A two center two-to-four-year follow-up study.

OBJECTIVE/METHODS: Phosphorylated alpha-synuclein (p-syn) in dermal nerves of patients with isolated REM sleep behavior disorder (iRBD) is detectable by immunofluorescence-labeling. Skin-biopsy-p-syn-positivity was recently postulated to be a prodromal marker of Parkinson's disease (PD) or related synucleinopathies. Here, we provide two-to four-year clinical and skin biopsy follow-up data of 33 iRBD patients, whose skin biopsy findings at baseline were reported in 2017. RESULTS: Follow-up biopsies were available from 25 patients (18 positive at baseline) and showed consistent findings over time in 24 patients. One patient converted from skin-biopsy-negativity to -positivity. P-syn-positivity was observed in iRBD patients who still had a normal FP-CIT-SPECT two years later. Clinically, five of the 23 at baseline skin-biopsy-positive patients (21.7%) had converted to PD or dementia with Lewy bodies at follow-up, but none of the skin-biopsy-negative patients. CONCLUSIONS: Dermal p-syn in iRBD is most probably an early consistent marker of synucleinopathy and may support other indicators of conversion to manifest disease state.

Aptamers as Therapeutic Agents: Has the Initial Euphoria Subsided?

Aptamers are synthetic DNA or RNA oligonucleotide ligands with great potential for therapeutic applications. A vast number of disease-related targets have been used to identify agonistic, antagonistic, or inhibitory aptamers, or aptamer-based targeting ligands. However, only a few aptamers have reached late-stage clinical trials so far and the commercial infrastructure is still far behind that of other therapeutic agents such as monoclonal antibodies. The desirable properties of aptamers such as selectivity, chemical flexibility, or cost-efficiency are faced by challenges, including a short half-life in vivo, immunogenicity, and entrapment in cellular organelles. Aptamer research is still in an early stage, and a deeper understanding of their structure, target interactions, and pharmacokinetics is necessary to catch up to the clinical market. In this review, we will discuss the benefits and limitations in the development of therapeutic aptamers, as well as the advances and future directions of aptamer research. The progress towards effective therapies seems to be slow, but it has not stopped and the best is yet to come.

Abnormal α-synuclein deposits in skin nerves: intra- and inter-laboratory reproducibility.

BACKGROUND AND PURPOSE: Visualization of phosphorylated α-synuclein at serine 129 (p-syn) in skin nerves is a promising test for the in vivo diagnosis of synucleinopathies. Here the aim was to establish the intra- and inter-laboratory reproducibility of measurement of intraneural p-syn immunoreactivity in two laboratories with major expertise (Würzburg and Bologna). METHODS: In total, 43 patients affected by Parkinson's disease (PD 21 patients), dementia with Lewy bodies (DLB 1), rapid eye movement sleep behaviour disorder (RBD 11), multiple system atrophy (MSA-P 4) and small fibre neuropathy (SFN 6) were enrolled. Skin biopsy was performed at the C7 paravertebral spine region and distal skin sites (thigh or leg). The analysis was standardized in both laboratories and carried out blinded on a single skin section double stained with antibodies to p-syn and the pan-axonal marker protein gene product 9.5. Fifty skin sections were randomly selected for the analysis: 25 from C7 and 25 from distal sites. Differently classified sections were re-evaluated to understand the reasons for the discrepancy. RESULTS: The intra-laboratory analysis showed an excellent reproducibility both in Würzburg (concordance of classification 100% of sections; K = 1; P < 0.001) and Bologna (96% of sections; K = 0.92; P < 0.001). Inter-laboratory analysis showed reproducibility in 45 sections (90%; K = 0.8; P < 0.001) and a different classification in five sections, which was mainly due to fragmented skin samples or weak fluorescent signals. CONCLUSIONS: Analysis of p-syn showed excellent inter- and intra-laboratory reproducibility supporting the reliability of this technique. The few ascertained discordances were important to further improve the standardization of this technique.

Basic clinical features do not predict dopamine transporter binding in idiopathic REM behavior disorder.

REM sleep behavior disorder (RBD) is strongly associated with development of Parkinson's Disease and other α-synuclein-related disorders. Dopamine transporter (DAT) binding deficit predicts conversion to α-synuclein-related disorders in individuals with RBD. In turn, identifying which individuals with RBD have the highest likelihood of having abnormal DAT binding would be useful. The objective of this analysis was to examine if there are basic clinical predictors of DAT deficit in RBD. Participants referred for inclusion in the RBD cohort of the Parkinson Progression Markers Initiative were included. Assessments at the screening visit including DAT SPECT imaging, physical examination, cognitive function screen, and questionnaire-based non-motor assessment. The group with DAT binding deficit (n = 49) was compared to those without (n = 26). There were no significant differences in demographic or clinical features between the two groups. When recruiting RBD cohorts enriched for high risk of neurodegenerative disorders, our data support the need for objective biomarker assessments.

Validation of semiautomatic scoring of REM sleep without atonia in patients with RBD.

OBJECTIVE/BACKGROUND: To evaluate REM sleep without atonia (RSWA) in REM sleep behavior disorder (RBD) several automatic algorithms have been developed. We aimed to validate our algorithm (Mayer et al., 2008) in order to assess the following: (1). capability of the algorithm to differentiate between RBD, night terror (NT), somnambulism (SW), Restless legs syndrome (RLS), and obstructive sleep apnea (OSA), (2). the cut-off values for short (SMI) and long muscle activity (LMI), (3). which muscles qualify best for differential diagnosis, and (4). the comparability of RSWA and registered movements between automatic and visual analysis of videometry. PATIENTS/METHODS: RSWA was automatically scored according to Mayer et al., 2008 in polysomnographies of 20 RBD, 10 SW/NT, 10 RLS and 10 OSA patients. Receiver operating characteristic (ROC) curves were used to determine the sensitivity and specificity of SMI and LMI. Independent samples were calculated with t-tests. Boxplots were used for group comparison. The comparison between motor events by manual scoring and automatic analysis were performed with "Visual Basic for Applications" (VBA) for every hundredth second. RESULTS: Our method discriminates RBD from SW/NT, OSA and RLS with a sensitivity of 72.5% and a specificity of 86.7%. Automatic scoring identifies more movements than visual video scoring. Mentalis muscle discriminates the sleep disorders best, followed by FDS, which was only recorded in SW/NT. Cut-off values for RSWA are comparable to those found by other groups. CONCLUSION: The semi-automatic RSWA scoring method is capable to confirm RBD and to discriminate it with moderate sensitivity from other sleep disorders.

Detection of cell proliferation in adults of the water bear Hypsibius dujardini (Tardigrada) via incorporation of a thymidine analog.

The taxon Tardigrada, commonly called "water bears", consists of microscopic, eight-legged invertebrates that are well known for their ability to tolerate extreme environmental conditions. Their miniscule body size means that tardigrades possess a small total number of cells, the number and arrangement of which may be highly conserved in some organs. Although mitoses have been observed in several organs, the rate and pattern of cell divisions in adult tardigrades has never been characterized. In this study, we incubated live tardigrades over a period of several days with a thymidine analog in order to visualize all cells that had divided during this time. We focus on the midgut, the largest part of the digestive system. Our results show that new cells in the midgut arise from the anterior and posterior ends of this organ and either migrate or divide toward its middle. These cells divide at a constant rate and all cells of the midgut epithelium are replaced in approximately one week. On the other hand, we found no cell divisions in the nervous system or any other major organs, suggesting that the cell turnover of these organs may be extremely slow or dependent on changing environmental conditions.

A rare case of Epstein-Barr virus-associated hepatosplenic smooth muscle tumors after kidney transplantation.

A 27-year old caucasian male was diagnosed 2.7 years after kidney transplantation with Epstein-Barr virus (EBV)-associated smooth muscle tumors in liver and spleen. The reduction in immunosuppression and conversion from tacrolimus to sirolimus did not lead to a regression of the tumors. Additionally, the patient developed a cellular rejection of his renal allograft, which was successfully treated. A combined approach with stereotactic radiofrequency ablation (SRFA) and surgical resection was effective in the treatment of the tumors.

Cationic switchable lipids: pH-triggered molecular switch for siRNA delivery.

A pH-sensitive molecular switch able to change its conformation upon protonation at endosomal pH values is embedded into the structure of cationic lipidoid materials, thus conferring endosomal escape properties. Involvement of the conformational switch in the endosomal escape process was confirmed and leading material identified was able to induce efficient gene knockdown both in vitro and in vivo. The lipid nanoparticles reported here are promising for therapeutic applications and this work could serve as a template for future design of stimulus-responsive (ionic, redox, light) molecular switch for drug and gene delivery.

[Sleep and neurological diseases]. / Schlaf und neurologische Erkrankungen.

Knowledge of the physiology of sleep-wake regulation can contribute to an understanding of the pathophysiology and symptoms of neurological diseases and is helpful for initiating specific therapies for sleep-wake cycle stabilization. Based on historically important observations on the close relationship between sleep and neurological diseases, new insights and developments in selected neurological entities are presented in this review article.

Dysautonomia in prodromal α-synucleinopathy: peripheral versus central autonomic degeneration.

BACKGROUND AND PURPOSE: There is an urgent need for early predictive markers for the course of disease in prodromal α-synucleinopathies such as idiopathic rapid eye movement (REM) sleep behaviour disorder. Autonomic cardiac/vascular dysfunction is a prominent feature in advanced α-synucleinopathies, but its diagnostic value as an early neurodegenerative marker remains unclear. The latter may be complicated since synuclein-mediated neurodegeneration may involve central and peripheral components of the autonomic nervous system. METHODS: The diagnostic value of autonomic symptoms and central and peripheral autonomic markers of blood pressure and heart rate regulation were prospectively evaluated in 20 subjects with idiopathic REM sleep behaviour disorder and 20 age-matched healthy controls. RESULTS: Although subjects with REM sleep behaviour disorder showed no clinical autonomic symptoms, blood pressure (P ≤ 0.035) and heart rate response (P ≤ 0.065) were slightly diminished during orthostatic challenge. Autonomic dysregulation was distinctively reflected in lower resting heart rate (all components, P ≤ 0.05) and blood pressure variability (low frequency component, P ≤ 0.024) indicating peripheral cardiac/vascular denervation. In contrast, baroreflex sensitivity and central cardiac autonomic outflow (sympathovagal balance) were well preserved indicating intact central autonomic regulation. Heart rate variability [very low frequency component, receiver operating characteristic (ROC) area under the curve (AUC) 0.80, P ≤ 0.001] and blood pressure variability (low frequency component ROC AUC 0.73, P ≤ 0.01) but not baroreflex sensitivity and sympathovagal balance showed an excellent diagnostic accuracy in identifying subjects with REM sleep behaviour disorder and healthy controls. CONCLUSIONS: Cardiac/vascular dysfunction in prodromal α-synucleinopathy arises from peripheral rather than from central autonomic degeneration. Autonomic indices encoded in heart rate and blood pressure variability are precise functional markers of early synuclein-mediated neurodegeneration.

The presence of biofilm structures in atherosclerotic plaques of arteries from legs amputated as a complication of diabetic foot ulcers.

OBJECTIVE: Atherosclerosis, rather than microcirculatory impairment caused by endothelial cell dysfunction, is the main driver of circulatory compromise in patients with diabetic limbs. The presence of atherosclerotic plaque at the trifurcation is a significant contributor to amputation of diabetic legs. The presence of bacteria and other microorganisms in atherosclerotic plaque has long been known, however, the cause of chronic inflammation and the role of bacteria/viruses in atherosclerosis have not been studied in detail. The objective of this study was to clarify the cause of the chronic inflammation within atherosclerotic plaques, and determine if any bacteria and/or viruses are involved in the inflammatory pathway. METHOD: This study uses fluorescence microscopy and fluorescence in-situ hybridisation (FISH) to identify components of biofilm in atherosclerotic arteries. These tools are also used to identify individual bacteria, and determine the architectural spatial location within the atherosclerotic plaque where the bacteria can be found. RESULTS: The results indicate that the presence of biofilms in grossly involved arteries may be an important factor in chronic inflammatory pathways of atherosclerotic progression, in the amputated limbs of patients with diabetic foot ulcers and vascular disease. CONCLUSION: While the presence of bacterial biofilm structures in atherosclerotic plaque does not prove that biofilm is the proximate cause of atherosclerosis, it could contribute to the persistent inflammation associated with it. Second, the synergistic relationship between the atherosclerotic infection and the diabetic foot ulcer may ultimately contribute to higher amputation rates in diabetics. DECLARATION OF INTEREST: RAW and RDW have equity interest in PathoGenius, a clinical laboratory using DNA to identify microbes.

[Challenges of aging skin: Care and therapy using the example of venous ulcers]. / Herausforderungen der alternden Haut : Versorgung und Therapie am Beispiel des Ulcus cruris.

BACKGROUND: One of the most significant, and growing, challenges in modern medicine, i.e. the treatment of chronic wounds, is marked by nonuniform data. This concerns both prevalence and incidence of chronic dermatosis, in particular venous ulcers (ulcus cruris), as well as the impact on the health-related quality of life, and practical and economic parameters of the success of different therapies. PURPOSE: The aim of this work is to examine the epidemiology of chronic wounds, in particular age-associated venous ulcers, their impact on health-related quality of life, the treatment regimen, and practical and economic parameters of the success of different therapies. MATERIALS AND METHODS: Performed were analysis of data on the care of venous ulcers in Germany, based on secondary data of Barmer GEK from 2009 and 2012, comparison with data of a NHS Kent Community Health Trust study, and analysis of studies concerning structures, processes and critical success factors for the treatment of chronic wounds, including economic effects. CONCLUSION: Early causal therapy with treatment based on the stage of the wound, consequent goal-oriented interdisciplinary care, and relapse prophylaxis is critical for successful healing of venous ulcers. The costs of treatment significantly correlate with the duration of treatment which can be reduced by up to 60% using guideline-based concepts for the treatment of chronic wounds. Treatment success, in particular with regard to cost-benefit considerations, can be optimized by telemedicine networks of key players who treat chronic wounds.

Seasonality in communication and collective decision-making in ants.

The ability of animals to adjust their behaviour according to seasonal changes in their ecology is crucial for their fitness. Eusocial insects display strong collective behavioural seasonality, yet the mechanisms underlying such changes are poorly understood. We show that nest preference by emigrating Temnothorax albipennis ant colonies is influenced by a season-specific modulatory pheromone that may help tune decision-making according to seasonal constraints. The modulatory pheromone triggers aversion towards low-quality nests and enhances colony cohesion in summer and autumn, but not after overwintering-in agreement with reports that field colonies split in spring and reunite in summer. Interestingly, we show that the pheromone acts by downgrading the perceived value of marked nests by informed and naive individuals. This contrasts with theories of collective intelligence, stating that accurate collective decision-making requires independent evaluation of options by individuals. The violation of independence highlighted here was accordingly shown to increase error rate during emigrations. However, this is counterbalanced by enhanced cohesion and the transmission of valuable information through the colony. Our results support recent claims that optimal decisions are not necessarily those that maximize accuracy. Other criteria-such as cohesion or reward rate-may be more relevant in animal decision-making.

[Consensus paper on the diagnosis and treatment of sleep disordered breathing]. / Konsensuspapier zur Diagnostik und Therapie schlafbezogener Atmungsstörungen bei Erwachsenen.

Diagnosis and treatment of sleep disordered breathing (SDB) undergo substantial changes, both in terms of increasing scientific knowledge and also in terms of patient provision and socio-economic aspects. Increasing evidence shows the relevance of SDB on morbidity and mortality of affected patients. The precise differentiation of different phenotypes of SDBs has improved substantially in recent years. These proceedings influence the approach to the patients suspected of suffering from SDB. The scientific advances on the one hand are facing intentions to simplify diagnostical processes and treatment initiation and intentions to translate duties of physicians to non-medical personnel on the other hand. This consensus paper presents the principals of diagnosis, treatment initiation and provision, including the role of different participants of the healthcare system, and compares different treatment options. Major aspects include the differentiation of the diagnostical process in screening, affirmation of diagnosis and differential diagnosis. In addition, it focusses on the relevance of the pretest probability and describes a therapeutical algorithm.

[REM sleep behavior disorder as a prodromal stage of α-synucleinopathies: symptoms, epidemiology, pathophysiology, diagnosis and therapy]. / REM-Schlaf-Verhaltensstörung als prodromales Stadium von α-Synukleinopathien: Klinik, Epidemiologie, Pathophysiologie, Diagnose und Behandlung.

Rapid eye movement (REM) sleep behavior disorder (RBD) is defined as a parasomnia characterized by loss of REM sleep-associated atonia and the presence of motor activity during dreaming typically presenting with an aggressive dream content. Epidemiological data on the prevalence of RBD are insufficient but it can be idiopathic or symptomatic. A video-audio polysomnography is essential for diagnosis. Clonazepam and melatonin are available as pharmaceutical treatment. Recent studies demonstrated that individuals suffering from idiopathic RBD carry a high specific risk (up to 80 %) for developing a neurodegenerative disorder of the α-synucleinopathy type (e.g. Parkinson's disease, dementia with Lewy bodies and multiple system atrophy) within 10-20 years. The current article provides a short overview of symptoms, epidemiology, pathophysiology, diagnosis and therapy of RBD.

[Narcolepsy]. / Narkolepsie.

Narcolepsy is a rare sleep disorder. The classical presentation includes the four symptoms excessive daytime sleepiness, cataplexy, sleep paralysis and hypnagogic hallucinations. As a model disease with all the transitions from awake to sleeping conditions, non-rapid eye movement (NREM) and rapid eye movement (REM), it plays an important role in neurology and sleep medicine. Patients with narcolepsy possess a reduced number of hypocretin-producing neurons in the hypothalamus and accordingly the hypocretin level in the cerebrospinal fluid is low. The neuropeptide hypocretin (orexin) has functions, such as the regulation of the sleep-wake cycle, the autonomous nerve system, motor system and metabolic processes. The delay in diagnosing narcolepsy is difficult to comprehend in modern medicine. The frequent association with other sleep-wake disorders may be responsible for the delay. Genomewide association studies have subsequently been able to prove that autoimmune mechanisms are responsible for the manifestation of narcolepsy with the HLA association being the most important for susceptibility and protection. Imaging studies have revealed neurodegenerative changes, making a multifactorial etiopathogenesis probable. The frequent occurrence of metabolic disorders has not yet been clarified. Early diagnosis of narcolepsy has the possibility to offer affected persons an adequate medication to lead an almost normal life and the future possibility to cure narcolepsy through immunomodulation therapy.