Epigenetic inheritance of diet-induced and sperm-borne mitochondrial RNAs.

Spermatozoa harbour a complex and environment-sensitive pool of small non-coding RNAs (sncRNAs)1, which influences offspring development and adult phenotypes1-7. Whether spermatozoa in the epididymis are directly susceptible to environmental cues is not fully understood8. Here we used two distinct paradigms of preconception acute high-fat diet to dissect epididymal versus testicular contributions to the sperm sncRNA pool and offspring health. We show that epididymal spermatozoa, but not developing germ cells, are sensitive to the environment and identify mitochondrial tRNAs (mt-tRNAs) and their fragments (mt-tsRNAs) as sperm-borne factors. In humans, mt-tsRNAs in spermatozoa correlate with body mass index, and paternal overweight at conception doubles offspring obesity risk and compromises metabolic health. Sperm sncRNA sequencing of mice mutant for genes involved in mitochondrial function, and metabolic phenotyping of their wild-type offspring, suggest that the upregulation of mt-tsRNAs is downstream of mitochondrial dysfunction. Single-embryo transcriptomics of genetically hybrid two-cell embryos demonstrated sperm-to-oocyte transfer of mt-tRNAs at fertilization and suggested their involvement in the control of early-embryo transcription. Our study supports the importance of paternal health at conception for offspring metabolism, shows that mt-tRNAs are diet-induced and sperm-borne and demonstrates, in a physiological setting, father-to-offspring transfer of sperm mitochondrial RNAs at fertilization.

Ubiquitous atmospheric production of organic acids mediated by cloud droplets.

Atmospheric acidity is increasingly determined by carbon dioxide and organic acids1-3. Among the latter, formic acid facilitates the nucleation of cloud droplets4 and contributes to the acidity of clouds and rainwater1,5. At present, chemistry-climate models greatly underestimate the atmospheric burden of formic acid, because key processes related to its sources and sinks remain poorly understood2,6-9. Here we present atmospheric chamber experiments that show that formaldehyde is efficiently converted to gaseous formic acid via a multiphase pathway that involves its hydrated form, methanediol. In warm cloud droplets, methanediol undergoes fast outgassing but slow dehydration. Using a chemistry-climate model, we estimate that the gas-phase oxidation of methanediol produces up to four times more formic acid than all other known chemical sources combined. Our findings reconcile model predictions and measurements of formic acid abundance. The additional formic acid burden increases atmospheric acidity by reducing the pH of clouds and rainwater by up to 0.3. The diol mechanism presented here probably applies to other aldehydes and may help to explain the high atmospheric levels of other organic acids that affect aerosol growth and cloud evolution.

Combined regression score predicts outcome after neoadjuvant treatment of oesophageal cancer.

BACKGROUND: Histopathologic regression following neoadjuvant treatment (NT) of oesophageal cancer is a prognostic factor of survival, but the nodal status is not considered. Here, a score combining both to improve prediction of survival after neoadjuvant therapy is developed. METHODS: Seven hundred and fifteen patients with oesophageal squamous cell (SCC) or adenocarcinoma (AC) undergoing NT and esophagectomy were analysed. Histopathologic response was classified according to percentage of vital residual tumour cells (VRTC): complete response (CR) without VRTC, major response with <10% VRTC, minor response with >10% VRTC. Nodal stage was classified as ypN0 and ypN+. Kaplan-Meier and Cox regression were used for survival analysis. RESULTS: Survival analysis identified three groups with significantly different mortality risks: (1) low-risk group for CR (ypT0N0) with 72% 5-year overall survival (5y-OS), (2) intermediate-risk group for minor/major responders and ypN0 with 59% 5y-OS, and (3) high-risk group for minor/major responders and ypN+ with 20% 5y-OS (p < 0.001). Median survival in AC and SCC cohorts were comparable (3.8 (CI 95%: 3.1, 5.3) vs. 4.6 years (CI 95%: 3.3, not reached), p = 0.3). CONCLUSIONS: Histopathologic regression and nodal status should be combined for estimating AC and SCC prognosis. Poor survival in the high-risk group highlights need for adjuvant therapy.

TEsoNet: knowledge transfer in surgical phase recognition from laparoscopic sleeve gastrectomy to the laparoscopic part of Ivor-Lewis esophagectomy.

BACKGROUND: Surgical phase recognition using computer vision presents an essential requirement for artificial intelligence-assisted analysis of surgical workflow. Its performance is heavily dependent on large amounts of annotated video data, which remain a limited resource, especially concerning highly specialized procedures. Knowledge transfer from common to more complex procedures can promote data efficiency. Phase recognition models trained on large, readily available datasets may be extrapolated and transferred to smaller datasets of different procedures to improve generalizability. The conditions under which transfer learning is appropriate and feasible remain to be established. METHODS: We defined ten operative phases for the laparoscopic part of Ivor-Lewis Esophagectomy through expert consensus. A dataset of 40 videos was annotated accordingly. The knowledge transfer capability of an established model architecture for phase recognition (CNN + LSTM) was adapted to generate a "Transferal Esophagectomy Network" (TEsoNet) for co-training and transfer learning from laparoscopic Sleeve Gastrectomy to the laparoscopic part of Ivor-Lewis Esophagectomy, exploring different training set compositions and training weights. RESULTS: The explored model architecture is capable of accurate phase detection in complex procedures, such as Esophagectomy, even with low quantities of training data. Knowledge transfer between two upper gastrointestinal procedures is feasible and achieves reasonable accuracy with respect to operative phases with high procedural overlap. CONCLUSION: Robust phase recognition models can achieve reasonable yet phase-specific accuracy through transfer learning and co-training between two related procedures, even when exposed to small amounts of training data of the target procedure. Further exploration is required to determine appropriate data amounts, key characteristics of the training procedure and temporal annotation methods required for successful transferal phase recognition. Transfer learning across different procedures addressing small datasets may increase data efficiency. Finally, to enable the surgical application of AI for intraoperative risk mitigation, coverage of rare, specialized procedures needs to be explored.

The ISCON-trial protocol: laparoscopic ischemic conditioning prior to esophagectomy in patients with esophageal cancer and arterial calcifications.

BACKGROUND: Anastomotic leakage is the most important surgical complication following esophagectomy. A major cause of leakage is ischemia of the gastric tube that is used for reconstruction of the gastrointestinal tract. Generalized cardiovascular disease, expressed by calcifications of the aorta and celiac axis stenosis on a pre-operative CT scan, is associated with an increased risk of anastomotic leakage. Laparoscopic ischemic conditioning (ISCON) aims to redistribute blood flow and increase perfusion at the anastomotic site by occluding the left gastric, left gastroepiploic and short gastric arteries prior to esophagectomy. This study aims to assess the safety and feasibility of laparoscopic ISCON in selected patients with esophageal cancer and concomitant arterial calcifications. METHODS: In this prospective single-arm safety and feasibility trial based upon the IDEAL recommendations for surgical innovation, a total of 20 patients will be included recruited in 2 European high-volume centers for esophageal cancer surgery. Patients with resectable esophageal carcinoma (cT1-4a, N0-3, M0) with "major calcifications" of the thoracic aorta accordingly to the Uniform Calcification Score (UCS) or a stenosis of the celiac axis accordingly to the modified North American Symptomatic Carotid Endarterectomy Trial (NASCET) score on preoperative CT scan, who are planned to undergo esophagectomy are eligible for inclusion. The primary outcome variables are complications grade 2 and higher (Clavien-Dindo classification) occurring during or after laparoscopic ISCON and before esophagectomy. Secondary outcomes include intra- and postoperative complications of esophagectomy and the induction of angiogenesis by biomarkers of microcirculation and redistribution of blood flow by measurement of indocyanine green (ICG) fluorescence angiography. DISCUSSION: We hypothesize that in selected patients with impaired vascularization of the gastric tube, laparoscopic ISCON is feasible and can be safely performed 12-18 days prior to esophagectomy. Depending on the results, a randomized controlled trial will be needed to investigate whether ISCON leads to a lower percentage and less severe course of anastomotic leakage in selected patients. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03896399 . Registered 4 January 2019.

Improved Tissue Processing in Esophageal Adenocarcinoma After Ivor Lewis Esophagectomy Allows Histological Analysis of All Surgically Removed Lymph Nodes with Significant Effects on Nodal UICC Stages.

BACKGROUND: In esophageal carcinoma, the numbers of metastatic and total removed lymph nodes (LN) are well-established variables of long-term prognosis. The overall rate of retrieved LN depends on neoadjuvant treatment, the extent of surgical lymphadenectomy, and the modality of the pathological workup. The question in this study is whether technically extended histopathological preparation can increase the number of detected (metastatic) LN with an impact on nodal UICC staging. PATIENTS AND METHODS: A cohort of 77 patients with esophageal adenocarcinoma was treated with Ivor Lewis esophagectomy including standardized two-field lymphadenectomy. The specimens were grossed, and all manually detectable LN were retrieved. The remaining tissue was completely embedded by the advanced "acetone compression" retrieval technique. The primary outcome parameter was the total number of detected lymph nodes before and after acetone workup. RESULTS: A mean number of 23,1 LN was diagnosed after standard manual LN preparation. With complete embedding of the fatty tissue using acetone compression, the number increased to 40.5 lymph nodes (p < 0.0001). The mean number of metastatic LN increased from 3.2 to 4.2 nodal metastases following acetone compression (p < 0.0001). Additional LN metastases which caused a change in the primary (y)pN stage were found in ten patients (13.0%). CONCLUSIONS: Advanced lymph node retrieval by acetone compression allows a reliable statement on the real number of removed LN. Results demonstrate an impact on the nodal UICC stage. A future multicenter study will examine the prognostic impact of improved lymph node retrieval on long-term oncologic outcome.

Experimental and theoretical study on the impact of a nitrate group on the chemistry of alkoxy radicals.

The chemistry of nitrated alkoxy radicals, and its impact on RO2 measurements using the laser induced fluorescence (LIF) technique, is examined by a combined theoretical and experimental study. Quantum chemical and theoretical kinetic calculations show that the decomposition of ß-nitrate-alkoxy radicals is much slower than ß-OH-substituted alkoxy radicals, and that the spontaneous fragmentation of the α-nitrate-alkyl radical product to a carbonyl product + NO2 prevents other ß-substituents from efficiently reducing the energy barrier. The systematic series of calculations is summarized as an update to the structure-activity relationship (SAR) by Vereecken and Peeters (2009), and shows increasing decomposition rates with higher degrees of substitution, as in the series ethene to 2,3-dimethyl-butene, and dominant H-migration for sufficiently large alkoxy radicals such as those formed from 1-pentene or longer alkenes. The slow decomposition allows other reactions to become competitive, including epoxidation in unsaturated nitrate-alkoxy radicals; the decomposition SAR is likewise updated for ß-epoxy substituents. A set of experiments investigating the NO3-initiated oxidation of ethene, propene, cis-2-butene, 2,3-dimethyl-butene, 1-pentene, and trans-2-hexene, were performed in the atmospheric simulation chamber SAPHIR with measurements of HO2 and RO2 radicals performed with a LIF instrument. Comparisons between modelled and measured HO2 radicals in all experiments, performed in excess of carbon monoxide to avoid OH radical chemistry, suggest that the reaction of HO2 with ß-nitrate alkylperoxy radicals has a channel forming OH and an alkoxy radical in yields of 15-65%, compatible with earlier literature data on nitrated isoprene and α-pinene radicals. Model concentrations of RO2 radicals when including the results of the theoretical calculations described here, agreed within 10% with the measured RO2 radicals for all species investigated when the alkene oxidation is dominated by NO3 radicals. The formation of NO2 in the decomposition of ß-nitrate alkoxy radicals prevents detection of the parent RO2 radical in a LIF instrument, as it relies on formation of HO2. The implications for measurements of RO2 in ambient and experimental conditions, such as for the NO3-dominated chemistry during nighttime, is discussed. The current results appear in disagreement with an earlier indirect experimental study by Yeh et al. on pentadecene.

Theoretical and experimental study of peroxy and alkoxy radicals in the NO3-initiated oxidation of isoprene.

The initial stages of the nitrate radical (NO3) initiated oxidation of isoprene, in particular the fate of the peroxy (RO2) and alkoxy (RO) radicals, are examined by an extensive set of quantum chemical and theoretical kinetic calculations. It is shown that the oxidation mechanism is highly complex, and bears similarities to its OH-initiated oxidation mechanism as studied intensively over the last decade. The nascent nitrated RO2 radicals can interconvert by successive O2 addition/elimination reactions, and potentially have access to a wide range of unimolecular reactions with rate coefficients as high as 35 s-1; the contribution of this chemistry could not be ascertained experimentally. The chemistry of the alkoxy radicals derived from these peroxy radicals is affected by the nitrate moiety, and can lead to the formation of nitrated epoxy peroxy radicals in competition with isomerisation and decomposition channels that terminate the organic radical chain by NO2 elimination. The theoretical predictions are implemented in the FZJ-NO3-isoprene mechanism for NO3-initiated atmospheric oxidation of isoprene. The model predictions are compared against peroxy radical (RO2) and methyl vinyl ketone (MVK) measurements in a set of experiments on the isoprene + NO3 reaction system performed in the SAPHIR environmental chamber (IsopNO3 campaign). It is shown that the formation of NO2 from the peroxy radicals can prevent a large fraction of the peroxy radicals from being measured by the laser-induced fluorescence (ROxLIF) technique that relies on a quantitative conversion of peroxy radicals to hydroxyl radicals. Accounting for the relative conversion efficiency of RO2 species in the experiments, the agreement between observations and the theory-based FZJ-NO3-isoprene model predictions improves significantly. In addition, MVK formation in the NO3-initiated oxidation was found to be suppressed by the epoxidation of the unsaturated RO radical intermediates, allowing the model-predicted MVK concentrations to be in good agreement with the measurements. The FZJ-NO3-isoprene mechanism is compared against the MCM v3.3.1 and Wennberg et al. (2018) mechanisms.

Two-stage hybrid Ivor-Lewis esophagectomy as surgical strategy to reduce postoperative morbidity for high-risk patients.

BACKGROUND: Ivor-Lewis esophagectomy (ILE) is the standard surgical care for esophageal cancer patients but postoperative morbidity impairs quality of life and reduces long-term oncological outcome. Two-stage ILE separating the abdominal and thoracic phase into two distinct surgical procedures has proven to enhance microcirculation of the gastric conduit and therefore most likely reduces complications. However, two-stage ILE has not been evaluated systematically in selected groups of patients scheduled for this procedure. This investigation aims to demonstrate the feasibility of two-stage ILE in high-risk patients. PATIENTS AND METHODS: In this retrospective analysis of data obtained from a prospective database, a consecutive series of 275 hybrid ILE (hILE) were included. Patients were divided into two groups based on one- or two-stage hILE. Postoperative complications were assessed according to ECCG (Esophageal Complication Consensus Group) criteria and compared using the Clavien-Dindo score. Indication for two-stage esophagectomy was classified as pre- or intraoperative decision. RESULTS: 34 out of 275 patients (12.7%) underwent two-stage hILE. Patients of the two-stage group were significantly older. In 21 of 34 patients (61.8%) the decision for a two-stage procedure was made prior to esophagectomy, in 13 (38.2%) patients intraoperatively after completion of the laparoscopic gastric mobilization. The most frequent preoperative reason to select the two-stage procedure was a stenosis of the coeliac trunc and superior mesenteric artery (n = 10). The predominant cause for an intraoperative change of strategy was a laparoscopically diagnosed hepatic fibrosis/cirrhosis (n = 5).Overall morbidity and major' complications (CD > IIIa) were comparable for both groups (11.7% in both groups). The overall anastomotic leak rate was 12.4% and was non-significant lower for the two-stage procedure. CONCLUSION: Two-stage hILE is a feasible concept to individualize the surgical treatment of patients with well-defined clinical risk factors for postoperative morbidity. It can also be applied after completion of the abdominal phase of IL esophagectomy without compromising the patient safety.

Navigated laparoscopic microwave ablation of tumour mimics in pig livers: a randomized ex-vivo experimental trial.

BACKGROUND: In order to efficiently perform laparoscopic microwave ablation of liver tumours precise positioning of the ablation probe is mandatory. This study evaluates the precision and ablation accuracy using the innovative laparoscopic stereotactic navigation system CAS-One-SPOT in comparison to 2d ultrasound guided laparoscopic ablation procedures. METHODS: In a pig liver ablation model four surgeons, experienced (n = 2) and inexperienced (n = 2) in laparoscopic ablation procedures, were randomized for 2d ultrasound guided laparoscopic or stereotactic navigated laparoscopic ablation procedures. Each surgeon performed a total of 20 ablations. Total attempts of needle placements, time from tumor localization till beginning of ablation and ablation accuracy were analyzed. RESULTS: The use of the laparoscopic stereotactic navigation system led to a significant reduction in total attempts of needle placement. The experienced group of surgeons reduced the mean number of attempts from 2.75 ± 2.291 in the 2d ultrasound guided ablation group to 1.45 ± 1.191 (p = 0.0302) attempts in the stereotactic navigation group. Comparable results could be observed in the inexperienced group with a reduction of 2.5 ± 1.50 to 1.15 ± 0.489 (p = 0.0005). This was accompanied by a significant time saving from 101.3 ± 112.1 s to 48.75 ± 27.76 s (p = 0.0491) in the experienced and 165.5 ± 98.9 s to 66.75 ± 21.96 s (p < 0.0001) in the inexperienced surgeon group. The accuracy of the ablation process was hereby not impaired as postinterventional sectioning of the ablation zone revealed. CONCLUSION: The use of a stereotactic navigation system for laparoscopic microwave ablation procedures of liver tumors significantly reduces the attempts and time of predicted correct needle placement for novices and experienced surgeons without impairing the accuracy of the ablation procedure.

Citrin deficiency mimicking mitochondrial depletion syndrome.

BACKGROUND: Neonatal intrahepatic cholestasis caused by citrin deficiency (CD) is a rare inborn error of metabolism due to variants in the SLC25A13 gene encoding the calcium-binding protein citrin. Citrin is an aspartate-glutamate carrier located within the inner mitochondrial membrane. CASE PRESENTATION: We report on two siblings of Romanian-Vietnamese ancestry with citrin deficiency. Patient 1 is a female who presented at age 8 weeks with cholestasis, elevated lactate levels and recurrent severe hypoglycemia. Diagnosis was made by whole exome sequencing and revealed compound heterozygosity for the frameshift variant c.852_855del, p.Met285Profs*2 and a novel deletion c.(69 + 1_70-1)_(212 + 1_231-1)del in SLC25A13. The girl responded well to dietary treatment with a lactose-free, MCT-enriched formula. Her younger brother (Patient 2) was born 1 year later and also found to be carrying the same gene variants. Dietary treatment from birth was able to completely prevent clinical manifestation until his current age of 4.5 months. CONCLUSIONS: As CD is a well-treatable disorder it should be ruled out early in the differential diagnosis of neonatal cholestasis. Due to the combination of hepatopathy, lactic acidosis and recurrent hypoglycemia the clinical presentation of CD may resemble hepatic mitochondrial depletion syndrome.

[Personal Factors of the Bio-Psycho-Social Model (WHO): A Revised Classification by the German Society for Social Medicine and Prevention (DGSMP)]. / Personbezogene Faktoren im bio-psycho-sozialen Modell der WHO: Systematik der Deutschen Gesellschaft für Sozialmedizin und Prävention (DGSMP).

BACKGROUND: In 2010, the ICF working group of Faculty II "Applied Social Medicine and Rehabilitation" of the German Society for Social Medicine and Prevention, DGSMP proposed a classification of personal factors (PF) for the German-speaking area. Meanwhile, the International Classification of Functioning, Disability and Health (ICF) and WHO's bio-psycho-social model were increasingly integrated into the German Social Code (Book IX for Rehabilitation and Participation). It was a legislative decision that the needs assessment for the rehabilitation process must be "comprehensive". AIM: This publication aims to present an updated classification of PF to support the socio-medical assessment. For this purpose other published papers proposing a classification of PF were analyzed, especially the publication of Geyh et al. METHODS: The multiprofessional working group re-examined the basic structure, consistency and selection of factors of the 2010 classification using a qualitative approach and modified them if meaningful and necessary. The principles for the selection of factors were the same as in the 2010 publication (comprehensive, manageable, universal, impartial, relevant, unambiguous, focusing on finality, not regarding causality and non-discriminatory). RESULTS: A fundamental revision was not necessary; the basic structure remained primarily unchanged. Some items were included, excluded, summarized, shifted and editorially or content-related altered. Legal expertise shows that the classification of PF and their individual use for the socio-medical assessment, if necessary for the individual rehabilitation allocation, incur no problems with regard to data-protection regulations. PERSPECTIVES: The revised classification is ready to support users to describe and document relevant influences of the life background of individuals in a structured manner. Thus, influences on functioning and participation can be described comprehensively and transparently based on the bio-psycho-social model. A justiciable allocation of benefits for persons with disabilities is facilitated.

IL-4 receptor α blockade prevents sensitization and alters acute and long-lasting effects of allergen-specific immunotherapy of murine allergic asthma.

BACKGROUND: Allergen-specific immunotherapy (AIT) is the only causal treatment for allergy. However, success rates vary depending on the type of allergy and disease background of the patient. Hence, strategies targeting an increased therapeutic efficacy are urgently needed. Here, the effects of blockade of IL-4 and IL-13 signaling on different phases of AIT were addressed. METHODS: The impact of the recombinantly produced IL-4 and IL-13 antagonist IL-4 mutein (IL-4M) on allergic sensitization and AIT outcome in experimental allergic asthma were analyzed in a murine model. The effects of IL-4M administration were assessed prior/during sensitization, immediately after AIT under allergen challenge, and two weeks post-treatment. RESULTS: Intervention with IL-4M prior/during sensitization led to strong induction of IgG1, IgG2a, IgG2b, and IgG3, decrease of specific and total IgE, as well as of IL-5 in serum. Similar effects on the serum immunoglobulin levels were observed immediately after IL4M-supplemented AIT during allergen challenge. Additionally, IL4M markedly suppressed type-2 cytokine secretion of splenocytes beyond the effect of AIT alone. These effects were equaled to those of AIT alone two weeks post-treatment. Intriguingly, here, IL-4M induced a sustained decrease of Th2-biased Tregs (ST2+ FOXP3+ GATA3intermediate ). CONCLUSIONS: IL-4 and IL-13 blockade during experimental AIT demonstrates beneficial effects on immunological key parameters such as immunoglobulin and cytokine secretion immediately after AIT. Although two weeks later these effects were dropped to those of AIT alone, the number of potentially disease-triggering Th2-biased Tregs was further significantly decreased by IL-4M treatment. Hence, IL-4/IL13-targeting therapies prime the immune memory in therapy success-favoring manner.

A paternal methyl donor-rich diet altered cognitive and neural functions in offspring mice.

Dietary intake of methyl donors, such as folic acid and methionine, shows considerable intra-individual variation in human populations. While it is recognized that maternal departures from the optimum of dietary methyl donor intake can increase the risk for mental health issues and neurological disorders in offspring, it has not been explored whether paternal dietary methyl donor intake influences behavioral and cognitive functions in the next generation. Here, we report that elevated paternal dietary methyl donor intake in a mouse model, transiently applied prior to mating, resulted in offspring animals (methyl donor-rich diet (MD) F1 mice) with deficits in hippocampus-dependent learning and memory, impaired hippocampal synaptic plasticity and reduced hippocampal theta oscillations. Gene expression analyses revealed altered expression of the methionine adenosyltransferase Mat2a and BK channel subunit Kcnmb2, which was associated with changes in Kcnmb2 promoter methylation in MD F1 mice. Hippocampal overexpression of Kcnmb2 in MD F1 mice ameliorated altered spatial learning and memory, supporting a role of this BK channel subunit in the MD F1 behavioral phenotype. Behavioral and gene expression changes did not extend into the F2 offspring generation. Together, our data indicate that paternal dietary factors influence cognitive and neural functions in the offspring generation.

[Prolonged Weaning - S2k-Guideline Published by the German Respiratory Society]. / Prolongiertes Weaning.

Mechanical ventilation (MV) is an essential part of modern intensive care medicine. MV is performed in patients with severe respiratory failure caused by insufficiency of respiratory muscles and/or lung parenchymal disease when/after other treatments, (i. e. medication, oxygen, secretion management, continuous positive airway pressure or nasal highflow) have failed.MV is required to maintain gas exchange and to buy time for curative therapy of the underlying cause of respiratory failure. In the majority of patients weaning from MV is routine and causes no special problems. However, about 20 % of patients need ongoing MV despite resolution of the conditions which precipitated the need for MV. Approximately 40 - 50 % of time spent on MV is required to liberate the patient from the ventilator, a process called "weaning."There are numberous factors besides the acute respiratory failure that have an impact on duration and success rate of the weaning process such as age, comorbidities and conditions and complications acquired in the ICU. According to an international consensus conference "prolonged weaning" is defined as weaning process of patients who have failed at least three weaning attempts or require more than 7 days of weaning after the first spontaneous breathing trial (SBT). Prolonged weaning is a challenge, therefore, an inter- and multi-disciplinary approach is essential for a weaning success.In specialised weaning centers about 50 % of patients with initial weaning failure can be liberated from MV after prolonged weaning. However, heterogeneity of patients with prolonged weaning precludes direct comparisons of individual centers. Patients with persistant weaning failure either die during the weaning process or are discharged home or to a long term care facility with ongoing MV.Urged by the growing importance of prolonged weaning, this Sk2-guideline was first published in 2014 on the initiative of the German Respiratory Society (DGP) together with other scientific societies involved in prolonged weaning. Current research and study results, registry data and experience in daily practice made the revision of this guideline necessary.The following topics are dealt with in the guideline: Definitions, epidemiology, weaning categories, the underlying pathophysiology, prevention of prolonged weaning, treatment strategies in prolonged weaning, the weaning unit, discharge from hospital on MV and recommendations for end of life decisions.Special emphasis in the revision of the guideline was laid on the following topics:- A new classification of subgroups of patients in prolonged weaning- Important aspects of pneumological rehabilitation and neurorehabilitation in prolonged weaning- Infrastructure and process organization in the care of patients in prolonged weaning in the sense of a continuous treatment concept- Therapeutic goal change and communication with relativesAspects of pediatric weaning are given separately within the individual chapters.The main aim of the revised guideline is to summarize current evidence and also expert based- knowledge on the topic of "prolonged weaning" and, based on the evidence and the experience of experts, make recommendations with regard to "prolonged weaning" not only in the field of acute medicine but also for chronic critical care.Important addressees of this guideline are Intensivists, Pneumologists, Anesthesiologists, Internists, Cardiologists, Surgeons, Neurologists, Pediatricians, Geriatricians, Palliative care clinicians, Rehabilitation physicians, Nurses in intensive and chronic care, Physiotherapists, Respiratory therapists, Speech therapists, Medical service of health insurance and associated ventilator manufacturers.

Endoscopic and histopathologic reflux-associated mucosal damage in the remnant esophagus following transthoracic esophagectomy for cancer-5-year long-term follow-up.

Gastroesophageal reflux is a common problem following esophagectomy and reconstruction with gastric interposition. Despite a routine prescription of proton pump inhibitors, reflux-associated mucosal damage in the remnant esophagus is frequently observed. Purpose of this study is to evaluate mucosal damage in the esophageal remnant during long-term follow-up and to compare the prevalence of this damage between the subgroups of esophageal squamous cell and adenocarcinoma. All patients undergoing transthoracic Ivor-Lewis esophagectomy were prospectively entered in our IRB approved database. All patients underwent a routine check-up program with yearly surveillance endoscopies following esophagectomy. Only patients with a complete follow-up were included into this study. Endoscopic and histopathologic mucosal changes of the remnant esophagus were analyzed in close intervals. A total of 50 patients met the inclusion criteria, consisting of 31 adenocarcinomas (AC) and 19 squamous cell carcinomas (SCC). Mucosal damage was already seen 1 year after surgery in 20 patients macroscopically (43%) and in 21 patients microscopically (45%). At 5-year follow-up the prevalence for macroscopic and microscopic damage was 55% and 60%, respectively. The prevalence of mucosal damage was higher in AC patients than in SCC patients (1y-FU: 51% [AC] vs. 28% [SCC]; 5y-FU: 68% [AC] vs. 35% [SCC], P < 0.05). Newly acquired Barrett's esophagus was seen in 10 patients (20%) with two of those patients (20%) showing histopathologic proof of neoplasia. This study shows a high prevalence of reflux-associated mucosal damage in the remnant esophagus one year out of surgery and only a moderate increase in prevalence in the following years. Mucosal damage was more frequently seen in AC patients and the occurrence of de-novo Barrett's esophagus and de-novo neoplasia was high. Endoscopic surveillance with targeted biopsies seems to be an indispensable tool to follow patients after esophagectomy appropriately.

Simultaneous laryngopharyngeal pH monitoring (Restech) and conventional esophageal pH monitoring-correlation using a large patient cohort of more than 100 patients with suspected gastroesophageal reflux disease.

24-hour esophageal pH-metry is not designed to detect laryngopharyngeal reflux (LPR). The new laryngopharyngeal pH-monitoring system (Restech) may detect LPR better. There is no established correlation between these two techniques as only small case series exist. The aim of this study is to examine the correlation between the two techniques with a large patient cohort. All patients received a complete diagnostic workup for gastroesophageal reflux including symptom evaluation, endoscopy, 24-hour pH-metry, high resolution manometry, and Restech. Consecutive patients with suspected gastroesophageal reflux and disease-related extra-esophageal symptoms were evaluated using 24-hour laryngopharyngeal and concomitant esophageal pH-monitoring. Subsequently, the relationship between the two techniques was evaluated subdividing the different reflux scenarios into four groups. A total of 101 patients from December 2013 to February 2017 were included. All patients presented extra-esophageal symptoms such as cough, hoarseness, asthma symptoms, and globus sensation. Classical reflux symptoms such as heartburn (71%), regurgitation (60%), retrosternal pain (54%), and dysphagia (32%) were also present. Esophageal 24-hour pH-metry was positive in 66 patients (65%) with a mean DeMeester Score of 66.7 [15-292]. Four different reflux scenarios were detected (group A-D): in 39% of patients with abnormal esophageal pH-metry, Restech evaluation was normal (group A, n = 26, mean DeMeester-score = 57.9 [15-255], mean Ryan score = 2.6 [2-8]). In 23% of patients with normal pH-metry (n = 8, group B), Restech evaluation was abnormal (mean DeMeester-score 10.5 [5-13], mean Ryan score 63.5 [27-84]). The remaining groups C and D showed corresponding results. Restech evaluation was positive in 48% of cases in this highly selective patient cohort. As demonstrated by four reflux scenarios, esophageal pH-metry and Restech do not necessarily need to correspond. Especially in patients with borderline abnormal 24-hour pH-metry, Restech may help to support the decision for or against laparoscopic anti-reflux surgery.

Foregut symptoms, somatoform tendencies, and the selection of patients for antireflux surgery.

A large variety of foregut symptoms can occur in patients with gastroesophageal reflux disease (GERD), which can overlap with other disorders such as somatoform disorders and dyspepsia. Due to unclear diagnostic situations, these patients are often not adequately treated. The aim of this study was the evaluation of patients with foregut symptoms, referred for possible antireflux surgery, regarding their relationship with GERD and somatization tendencies based on control data from an unselected population. Symptom evaluation and somatization screening were initiated both in volunteers and in patients with foregut symptoms and GERD. Unselected volunteers from a village population were also evaluated by symptom analysis and for somatisation tendency. In addition, patients with foregut symptoms were diagnosed for GERD, and symptom analysis and psychodiagnostic evaluation were performed. There is no major significant difference in the symptom-spectrum in patients with foregut symptoms, whether they have a proven pathologic acid exposure from GERD or not. The probability for the risk of somatization was 5.6% in the unselected population of nonpatient volunteers (n = 267). In patients with foregut symptoms (n = 750), the probability for the presence of somatoform tendencies was approximately 20%, independent whether these patients had a documented GERD or a normal esophageal acid exposure, implicating further diagnostic work-up for the selection of patients for antireflux surgery. There is a remarkable symptom load and variety in patients with GERD, in patients with foregut symptoms, and in an unselected population of volunteers. There is no difference in the risk for somatization between patients with foregut symptoms and those with documented GERD. Therapeutic decision making especially prior to antireflux surgery requires an awareness of mental and emotional challenges.

Simple preoperative risk scale accurately predicts perioperative mortality following esophagectomy for malignancy.

Surgery remains one of the major treatment options available to patients with esophageal cancer, with high mortality in certain cohorts. The aim of this study was to develop a simple preoperative risk scale based on patient factors, hospital factors, and tumor pathology to predict the risk of perioperative mortality following esophagectomy for malignancy. The Nationwide Inpatient Sample database was used to create the risk scale. Patients who underwent open or laparoscopic transhiatal and transthoracic esophageal resection were identified using International Classification of Diseases, 9th edition codes. Patients <18 years and those with peritoneal disease were excluded. Multivariate logistic regressions were used to define a predictive model of perioperative mortality and to create a simple risk scale. From 1998 to 2011, a total of 23 751 patients underwent esophagectomy. The observed overall perioperative mortality rate for this cohort was 7.7%. Minimally invasive techniques, and operations performed in higher volume centers were protective, whereas increasing age, comorbidities and diagnosis of squamous cell carcinoma were independent predictors of mortality. Based on this population, a risk scale from 0-16 was created. The calibration revealed a good agreement between the observed and risk scale-predicted probabilities. A set of sensitivity/specificity analyses was then performed to define normal (score 0-7) and high risk (score 8-16) patients for clinical practice. Mortality in patients with a score of 0-7 ranged from 1.3-7.6%, compared with 10.5-34.5% in patients with a score of 8-16. This simple preoperative risk scale may accurately predict the risk of perioperative mortality following esophagectomy for malignancy and can be used as a clinical tool for preoperative counseling.

[Noninvasive ventilation in pediatric acute respiratory failure]. / Nichtinvasive Beatmung bei Kindern mit akuter respiratorischer Insuffizienz.

Noninvasive ventilation (NIV) may be used to treat pediatric acute respiratory failure. Recent improvements in ventilator technology and availability of nasal and full face masks for infants and children have simplified the use of NIV even in the smallest children. Mainly patients with hypercapnic respiratory failure may benefit from noninvasive ventilation. There is some evidence available that supports the use of NIV in viral bronchiolitis, asthma and acute on chronic respiratory failure in patients with neuromuscular or chronic pulmonary disease. Furthermore, noninvasive ventilation is beneficial during prolonged weaning from invasive ventilation and to treat upper airway obstructions. Children suffering from hypoxic respiratory failure, such as community-acquired pneumonia and acute respiratory distress syndrome do not benefit from NIV. Due to possibly relevant side effects and the possibility of rapid deterioration in gas exchange in failure of NIV, invasive ventilation should be readily available; therefore, treatment with noninvasive ventilation for acute respiratory failure in children should be initiated on the pediatric intensive care ward.