[Sustainable waste management in general surgical operations]. / Nachhaltiges Abfallmanagement bei allgemeinchirurgischen Operationen.

BACKGROUND AND OBJECTIVE OF THE STUDY: Hospitals, especially surgical departments, are among the largest producers of waste in Germany. Data on waste management in the operating room (OR) are largely lacking. The aim of this study was to assess and discuss the possibilities of reducing waste and recovering recyclable materials in general surgery against the background of current practice. METHODOLOGY: Surgical departments throughout Germany were surveyed on waste management. First, the theoretical waste separation possibilities for laparoscopic appendectomy were determined. Subsequently, a simple system for the separation of recyclables was established and practically tested in 35 operations. These were compared with 35 appendectomies without separation. RESULTS: Only 25.7% of hospitals perform waste separation. Theoretically, 20.7% of waste can be recycled, in practice up to 18.9%. Paper, cardboard and plastics, especially polyethylene terephthalate (PET) and high-density polyethylene (HDPE) were separated. This leads to a significant reduction in residual waste without extending the operation time. DISCUSSION: Separation of recyclables can contribute to more sustainable waste management in the OR. High-value recyclables can be recycled and the residual waste mass can be significantly reduced. This is possible without special effort and does not delay the processes in the OR. The opportunities for this have hardly been used in Germany to date.

New Perianal Sepsis Risk Score Predicts Outcome of Elderly Patients with Perianal Abscesses.

Antibiotic therapy following surgical perianal abscess drainage is debated, but may be necessary for high-risk patients. Frailty has been shown to increase the risk of unfavorable outcomes in elderly surgical patients. This study aims to identify high-risk patients by retrospectively analyzing a single-center cohort and using a pretherapeutic score to predict the need for postoperative antibiotics and extended nursing care following perianal abscess drainage surgery. The perianal sepsis risk score was developed through univariable and multivariable analysis. Internal validation was assessed using the area under receiver-operating characteristic curve. Elderly, especially frail patients exhibited more severe perianal disease, higher frequency of antibiotic therapy, longer hospitalization, poorer clinical outcomes. Multivariable analysis revealed that scores in the 5-item modified frailty index, severity of local infection, and preoperative laboratory markers of infection independently predicted the need for prolonged hospitalization and anti-infective therapy after abscess drainage surgery. These factors were combined into the perianal sepsis risk score, which demonstrated better predictive accuracy for prolonged hospitalization and antibiotic therapy compared with chronological age or frailty status alone. Geriatric assessments are becoming increasingly important in clinical practice. The perianal sepsis risk score identifies high-risk patients before surgery, enabling early initiation of antibiotic therapy and allocation of additional nursing resources.

Activation of endothelial NO synthase and P2X7 receptor modification mediates the cholinergic control of ATP-induced interleukin-1ß release by mononuclear phagocytes.

Objective: The pro-inflammatory cytokine interleukin-1ß (IL-1ß) plays a central role in host defense against infections. High systemic IL-1ß levels, however, promote the pathogenesis of inflammatory disorders. Therefore, mechanisms controlling IL-1ß release are of substantial clinical interest. Recently, we identified a cholinergic mechanism inhibiting the ATP-mediated IL-1ß release by human monocytes via nicotinic acetylcholine receptor (nAChR) subunits α7, α9 and/or α10. We also discovered novel nAChR agonists that trigger this inhibitory function in monocytic cells without eliciting ionotropic functions at conventional nAChRs. Here, we investigate the ion flux-independent signaling pathway that links nAChR activation to the inhibition of the ATP-sensitive P2X7 receptor (P2X7R). Methods: Different human and murine mononuclear phagocytes were primed with lipopolysaccharide and stimulated with the P2X7R agonist BzATP in the presence or absence of nAChR agonists, endothelial NO synthase (eNOS) inhibitors, and NO donors. IL-1ß was measured in cell culture supernatants. Patch-clamp and intracellular Ca2+ imaging experiments were performed on HEK cells overexpressing human P2X7R or P2X7R with point mutations at cysteine residues in the cytoplasmic C-terminal domain. Results: The inhibitory effect of nAChR agonists on the BzATP-induced IL-1ß release was reversed in the presence of eNOS inhibitors (L-NIO, L-NAME) as well as in U937 cells after silencing of eNOS expression. In peripheral blood mononuclear leukocytes from eNOS gene-deficient mice, the inhibitory effect of nAChR agonists was absent, suggesting that nAChRs signal via eNOS to inhibit the BzATP-induced IL-1ß release. Moreover, NO donors (SNAP, S-nitroso-N-acetyl-DL-penicillamine; SIN-1) inhibited the BzATP-induced IL-1ß release by mononuclear phagocytes. The BzATP-induced ionotropic activity of the P2X7R was abolished in the presence of SIN-1 in both, Xenopus laevis oocytes and HEK cells over-expressing the human P2X7R. This inhibitory effect of SIN-1 was absent in HEK cells expressing P2X7R, in which C377 was mutated to alanine, indicating the importance of C377 for the regulation of the P2X7R function by protein modification. Conclusion: We provide first evidence that ion flux-independent, metabotropic signaling of monocytic nAChRs involves eNOS activation and P2X7R modification, resulting in an inhibition of ATP signaling and ATP-mediated IL-1ß release. This signaling pathway might be an interesting target for the treatment of inflammatory disorders.

Robotic operations in urgent general surgery: a systematic review.

Robotically assisted operations are the state of the art in laparoscopic general surgery. They are established predominantly for elective operations. Since laparoscopy is widely used in urgent general surgery, the significance of robotic assistance in urgent operations is of interest. Currently, there are few data on robotic-assisted operations in urgent surgery. The aim of this study was to collect and classify the existing studies. A two-stage, PRISMA-compliant literature search of PubMed and the Cochrane Library was conducted. We analyzed all articles on robotic surgery associated with urgent general surgery resp. acute surgical diseases of the abdomen. Gynecological and urological diseases so as vascular surgery, except mesenterial ischemia, were excluded. Studies and case reports/series published between 1980 and 2021 were eligible for inclusion. In addition to a descriptive synopsis, various outcome parameters were systematically recorded. Fifty-two studies of operations for acute appendicitis and cholecystitis, hernias and acute conditions of the gastrointestinal tract were included. The level of evidence is low. Surgical robots in the narrow sense and robotic camera mounts were used. All narrow-sense robots are nonautonomous systems; in 82%, the Da Vinci® system was used. The most frequently published emergency operations were urgent cholecystectomies (30 studies, 703 patients) followed by incarcerated hernias (9 studies, 199 patients). Feasibility of robotic operations was demonstrated for all indications. Neither robotic-specific problems nor extensive complication rates were reported. Various urgent operations in general surgery can be performed robotically without increased risk. The available data do not allow a final evidence-based assessment.

Drug resistant bacteria in perianal abscesses are frequent and relevant.

Perianal abscesses are frequent diseases in general surgery. Principles of standard patient care are surgical drainage with exploration and concomitant treatment of fistula. Antiinfective therapy is frequently applied in cases of severe local disease and perianal sepsis. However, the role of microbiologic testing of purulence from perianal abscesses is disputed and the knowledge concerning bacteriology and bacterial resistances is very limited. A retrospective cohort study was performed of consecutive patients (≥ 12 years of age) from a tertiary care hospital, who underwent surgical treatment for perianal abscess from 01/2008 to 12/2019. Subdividing the cohort into three groups regarding microbiological testing results: no microbiological testing of purulence (No_Swab, n = 456), no detection of drug resistant bacteria [DR(-), n = 141] or detection of bacteria with acquired drug resistances from purulence [DR(+), n = 220]. Group comparisons were performed using Kruskall-Wallis test and, if applicable, followed by Dunn´s multiple comparisons test for continuous variables or Fishers exact or Pearson's X2 test for categorical data. Fistula persistence was estimated by Kaplan Meier and compared between the groups using Log rank test. Corralation analysis between perioperative outcome parameters and bacteriology was performed using Spearman´s rho rank correlation. Higher pretherapeutic C-reactive protein (p < 0.0001) and white blood cell count (p < 0.0001), higher rates of supralevatoric or pararectal abscesses (p = 0.0062) and of complicated fistula-in-ano requiring drainage procedure during index surgery (p < 0.0001) reflect more severe diseases in DR(+) patients. The necessity of antibiotic therapy (p < 0.0001), change of antibiotic regimen upon microbiologic testing results (p = 0.0001) and the rate of re-debridements during short-term follow-up (p = 0.0001) were the highest, the duration until definitive fistula repair was the longest in DR(+) patients (p = 0.0061). Escherichia coli, Bacteroides, Streptococcus and Staphylococcus species with acquired drug resistances were detected frequently. High rates of resistances against everyday antibiotics, including perioperative antibiotic prophylaxis were alarming. In conclusion, the knowledge about individual bacteriology is relevant in cases of complex and severe local disease, including locally advanced infection with extended soft tissue affection and perianal sepsis, signs of systemic inflammatory response as well as the need of re-do surgery for local debridements during short-term and fistula repair during long-term follow-up. Higher rates of acquired antibiotic resistances are to be expected in patients with more severe diseases.

Two years later: Is the SARS-CoV-2 pandemic still having an impact on emergency surgery? An international cross-sectional survey among WSES members.

BACKGROUND: The SARS-CoV-2 pandemic is still ongoing and a major challenge for health care services worldwide. In the first WSES COVID-19 emergency surgery survey, a strong negative impact on emergency surgery (ES) had been described already early in the pandemic situation. However, the knowledge is limited about current effects of the pandemic on patient flow through emergency rooms, daily routine and decision making in ES as well as their changes over time during the last two pandemic years. This second WSES COVID-19 emergency surgery survey investigates the impact of the SARS-CoV-2 pandemic on ES during the course of the pandemic. METHODS: A web survey had been distributed to medical specialists in ES during a four-week period from January 2022, investigating the impact of the pandemic on patients and septic diseases both requiring ES, structural problems due to the pandemic and time-to-intervention in ES routine. RESULTS: 367 collaborators from 59 countries responded to the survey. The majority indicated that the pandemic still significantly impacts on treatment and outcome of surgical emergency patients (83.1% and 78.5%, respectively). As reasons, the collaborators reported decreased case load in ES (44.7%), but patients presenting with more prolonged and severe diseases, especially concerning perforated appendicitis (62.1%) and diverticulitis (57.5%). Otherwise, approximately 50% of the participants still observe a delay in time-to-intervention in ES compared with the situation before the pandemic. Relevant causes leading to enlarged time-to-intervention in ES during the pandemic are persistent problems with in-hospital logistics, lacks in medical staff as well as operating room and intensive care capacities during the pandemic. This leads not only to the need for triage or transferring of ES patients to other hospitals, reported by 64.0% and 48.8% of the collaborators, respectively, but also to paradigm shifts in treatment modalities to non-operative approaches reported by 67.3% of the participants, especially in uncomplicated appendicitis, cholecystitis and multiple-recurrent diverticulitis. CONCLUSIONS: The SARS-CoV-2 pandemic still significantly impacts on care and outcome of patients in ES. Well-known problems with in-hospital logistics are not sufficiently resolved by now; however, medical staff shortages and reduced capacities have been dramatically aggravated over last two pandemic years.

Neuropsychological Assessment of Cognitive Impairment in Kidney Transplantation (NAsKiT) and its related risk factors: a study protocol.

BACKGROUND: Association of cognitive impairment with chronic kidney disease has been reported over the last decade. Individuals show better cognitive performance after kidney transplantation than individuals on dialysis but are more likely to be affected by cognitive impairment than age-matched comparison groups. Better knowledge of the prevalence as well as course and profile of cognitive impairment is important for the design of future studies assessing the clinical impact of cognitive impairment and developing management strategies. The goal of our study is to examine the extent of cognitive impairment before and after transplantation and to derive a distinct profile of cognitive function using standard neurocognitive tests. Furthermore, we aim to assess whether transplantation per se leads to an improvement in cognitive performance. METHODS: We are conducting a prospective single-center cohort study involving 100 kidney transplant individuals. Individuals who are wait-listed to receive a kidney transplantation or have already received one will be included in this study. Individuals will undergo a battery of detailed neurocognitive tests at baseline (in part before surgery), and then 3 and 12 months afterwards. Furthermore, the enrolled patients will complete a validated German version of the Cognitive Failure Questionnaire for self-assessment (s-CFQ) as well as the Hospital Anxiety and Depression Scale -Deutsche (HADS-D), a self-report screening instrument with two scales that capture anxiety and depression. In addition, a hair sample will be taken at each measurement time point for the determination of hair cortisol levels as a parameter for the cumulative hypothalamic-pituitary-adrenocortical axis activity over the previous three months. The primary outcome measure will be (a) the effect of kidney transplantation on the cognitive performance up to 12 months after transplantation and (b) the course of cognitive performance following kidney transplantation over time. DISCUSSION: The results of our study have potentially important implications for the prevention and treatment of cognitive impairment in kidney transplant individuals. By increasing our knowledge of the neurocognitive profile and assigning the corresponding deficits, it might be possible to create an individualized training program to positively impact cognitive deficits in kidney transplant patients.

Comparison of the Anti-inflammatory Properties of Two Nicotinic Acetylcholine Receptor Ligands, Phosphocholine and pCF3-diEPP.

Activation of nicotinic acetylcholine receptors (nAChRs) expressed by innate immune cells can attenuate pro-inflammatory responses. Silent nAChR agonists, which down-modulate inflammation but have little or no ionotropic activity, are of outstanding clinical interest for the prevention and therapy of numerous inflammatory diseases. Here, we compare two silent nAChR agonists, phosphocholine, which is known to interact with nAChR subunits α7, α9, and α10, and pCF3-N,N-diethyl-N'-phenyl-piperazine (pCF3-diEPP), a previously identified α7 nAChR silent agonist, regarding their anti-inflammatory properties and their effects on ionotropic nAChR functions. The lipopolysaccharide (LPS)-induced release of interleukin (IL)-6 by primary murine macrophages was inhibited by pCF3-diEPP, while phosphocholine was ineffective presumably because of instability. In human whole blood cultures pCF3-diEPP inhibited the LPS-induced secretion of IL-6, TNF-α and IL-1ß. The ATP-mediated release of IL-1ß by LPS-primed human peripheral blood mononuclear leukocytes, monocytic THP-1 cells and THP-1-derived M1-like macrophages was reduced by both phosphocholine and femtomolar concentrations of pCF3-diEPP. These effects were sensitive to mecamylamine and to conopeptides RgIA4 and [V11L; V16D]ArIB, suggesting the involvement of nAChR subunits α7, α9 and/or α10. In two-electrode voltage-clamp measurements pCF3-diEPP functioned as a partial agonist and a strong desensitizer of classical human α9 and α9α10 nAChRs. Interestingly, pCF3-diEPP was more effective as an ionotropic agonist at these nAChRs than at α7 nAChR. In conclusion, phosphocholine and pCF3-diEPP are potent agonists at unconventional nAChRs expressed by monocytic and macrophage-like cells. pCF3-diEPP inhibits the LPS-induced release of pro-inflammatory cytokines, while phosphocholine is ineffective. However, both agonists signal via nAChR subunits α7, α9 and/or α10 to efficiently down-modulate the ATP-induced release of IL-1ß. Compared to phosphocholine, pCF3-diEPP is expected to have better pharmacological properties. Thus, low concentrations of pCF3-diEPP may be a therapeutic option for the treatment of inflammatory diseases including trauma-induced sterile inflammation.

Frailty in elderly patients with acute appendicitis.

PURPOSE: Acute appendicitis in the elderly is becoming increasingly recognized for its often severe course. For various elective and urgent operations in older patients, frailty is a risk factor for poor outcomes. However, there is a lack of data on frailty in elderly patients with acute appendicitis. METHODS: Patients over 65 years old who underwent surgery for acute appendicitis in three hospitals between January 2015 and September 2020 were assessed with the Hospital Frailty Risk Score (HFRS) and the modified Frailty Index (mFI). Outcomes of interest, including morbidity, mortality, and length of stay, were recorded. RESULTS: While frailty can be measured with both tests, the mFI has better applicability and takes significantly less time to implement compared to the HFRS (21.6 s vs. 80.3 s, p < 0.0001) while providing the same information value. Patients who exhibited frailty according to either assessment had a significantly higher rate of milder (OR 5.85/2.87, p < 0.0001/0.009) and serious (OR 4.92/3.61, p < 0.011/0.029) complications, more admissions to the intensive care unit (OR 5.16/7.36, p < 0.0001), and an almost doubled length of stay (12.7 days vs. 6.6 days, p < 0.005). Up to 31% of these patients required institutional care after discharge, which is significantly more than those without frailty (p < 0.0001). Furthermore, the mortality rate in frail patients was significantly elevated to 17%, compared to less than 1% in non-frail patients (p = 0.018). CONCLUSION: In elderly patients, frailty is a significant risk factor for negative outcomes. Frailty can be assessed more quickly and reliably with the mFI compared to the HFRS.

DIALAPP: a prospective validation of a new diagnostic algorithm for acute appendicitis.

PURPOSE: The management of patients with suspected appendicitis remains a challenge in daily clinical practice, and the optimal management algorithm is still being debated. Negative appendectomy rates (NAR) continue to range between 10 and 15%. This prospective study evaluated the accuracy of a diagnostic pathway in acute appendicitis using clinical risk stratification (Alvarado score), routine ultrasonography, gynecology consult for females, and selected CT after clinical reassessment. METHODS: Patients presenting with suspected appendicitis between November 2015 and September 2017 from age 18 years and above were included. Decision-making followed a clear management pathway. Patients were followed up for 6 months after discharge. The hypothesis was that the algorithm can reduce the NAR to a value of under 10%. RESULTS: A total of 183 patients were included. In 65 of 69 appendectomies, acute appendicitis was confirmed by histopathology, corresponding to a NAR of 5.8%. Notably, all 4 NAR appendectomies had other pathologies of the appendix. The perforation rate was 24.6%. Only 36 patients (19.7%) received a CT scan. The follow-up rate after 30 days achieved 69%, including no patients with missed appendicitis. The sensitivity and specificity of the diagnostic pathway was 100% and 96.6%, respectively. The potential saving in costs can be as much as 19.8 million €/100,000 cases presenting with the suspicion of appendicitis. CONCLUSION: The risk-stratified diagnostic algorithm yields a high diagnostic accuracy for patients with suspicion of appendicitis. Its implementation can safely reduce the NAR, simultaneously minimizing the use of CT scans and optimizing healthcare-related costs in the treatment of acute appendicitis. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02627781 (December 2015).

Hepatitis B Virus DNA is a Substrate for the cGAS/STING Pathway but is not Sensed in Infected Hepatocytes.

Hepatitis B virus (HBV) chronic infection is a critical risk factor for hepatocellular carcinoma. The innate immune response to HBV infection is a matter of debate. In particular, viral escape mechanisms are poorly understood. Our study reveals that HBV RNAs are not immunostimulatory in immunocompetent myeloid cells. In contrast, HBV DNA from viral particles and DNA replication intermediates are immunostimulatory and sensed by cyclic GMP-AMP Synthase (cGAS) and Stimulator of Interferon Genes (STING). We show that primary human hepatocytes express DNA sensors to reduced levels compared to myeloid cells. Nevertheless, hepatocytes can respond to HBV relaxed-circular DNA (rcDNA), when transfected in sufficient amounts, but not to HBV infection. Finally, our data suggest that HBV infection does not actively inhibit the DNA-sensing pathway. In conclusion, in infected hepatocytes, HBV passively evades recognition by cellular sensors of nucleic acids by (i) producing non-immunostimulatory RNAs, (ii) avoiding sensing of its DNAs by cGAS/STING without active inhibition of the pathway.

Redox Modulation and Induction of Ferroptosis as a New Therapeutic Strategy in Hepatocellular Carcinoma.

Ferroptosis, a newly discovered form of cell death mediated by reactive oxygen species (ROS) and lipid peroxidation, has recently been shown to have an impact on various cancer types; however, so far there are only few studies about its role in hepatocellular carcinoma (HCC). The delicate equilibrium of ROS in cancer cells has found to be crucial for cell survival, thus increased levels may trigger ferroptosis in HCC. In our study, we investigated the effect of different ROS modulators and ferroptosis inducers on a human HCC cell line and a human hepatoblastoma cell line. We identified a novel synergistic cell death induction by the combination of Auranofin and buthionine sulfoxime (BSO) or by Erastin and BSO at subtoxic concentrations. We found a caspase-independent, redox-regulated cell death, which could be rescued by different inhibitors of ferroptosis. Both cotreatments stimulated lipid peroxidation. All these findings indicated ferroptotic cell death. Both cotreatments affected the canonical ferroptosis pathway through GPX4 downregulation. We also found an accumulation of Nrf2 and HO-1, indicating an additional effect on the non-canonical pathway. Our results implicate that targeting these two main ferroptotic pathways simultaneously can overcome chemotherapy resistance in HCC.

Nonoperative Antibiotic Treatment of Appendicitis in Adults: A Survey among Clinically Active Surgeons.

BACKGROUND: As a result of well-publicized studies, the nonsurgical antibiotic therapy of uncomplicated acute appendicitis has been propagated since 2006. A final assessment regarding efficiency and long-term results is not possible; however, nonoperative therapy of acute appendicitis is actually being discussed more diversely and receives a lot of attention. It is still unknown how far this therapy has found its way into everyday clinical care. METHODS: An online questionnaire was sent to 1,400 randomly selected specialists for general/visceral surgery in Germany. Representativeness was achieved by a preselection according to the geographical origin and the care level of the hospitals. RESULTS: 14% of surgeons stated that they methodically treat appendicitis conservatively. 38.1% do so in exceptional cases, while 48.8% reject this therapy. For methodically use, sonography or computed tomography is demanded beforehand. Nonoperative therapy is performed more often in metropolitan areas and maximum-care/university hospitals. Patients' request for antibiotic therapy is an important factor for conservative treatment. The main argument against this therapy is "medical doubts." 26% of the surgeons would treat their own appendicitis conservatively. There are distinct associations between the application of conservative therapy, satisfaction with it, and expectations about future development. The response rate was 19.9%. CONCLUSION: The nonoperative antibiotic therapy of appendicitis is part of clinical practice in Germany. There are differences in preconditions as well as in the acceptance of this therapeutic option with a high proportion of general rejection.

Antibiotic-treated acute appendicitis-reception in social media.

PURPOSE: Social media, especially Twitter®, is becoming increasingly important for medical topics. Systematic analyses of the content of these tweets are rare. To date, no analysis of the reception of antibiotic/non-operative-treated acute appendicitis on Twitter® has been performed. METHODS: Tweets with the content "appendicitis," "appendix," and "appendectomy" from December 31, 2010, to September 27, 2017, were recorded. Further analysis was performed by secondary search strings related to antibiotic-treated acute appendicitis. Subsequent systematic analysis of content, author groups, and followers was performed. RESULTS: Out of 22,962 analyzed tweets, 3400 were applicable on all search strings, and 349 dealt meaningfully with antibiotic-treated acute appendicitis. 47.9% of the tweets were published by individuals, of which non-surgical consultants comprised the largest group. The tweets published by organizations and institutions were mostly published by publishing platforms. Half of the tweets were neutral, with an overall positive trend for antibiotic-treated acute appendicitis, but significant differences were noted among the authors. The number of followers showed a wide range, with an considerable numeric impact. CONCLUSION: The scientific discussion of antibiotic-treated acute appendicitis is reflected on Twitter®. Overall, antibiotic-treated acute appendicitis is presented in a neutral and differentiated manner on Twitter®, but this picture is exclusively derived from assessment of a variety of tweets. Individual tweets are partially undifferentiated in content and misrepresent antibiotic-treated acute appendicitis. In addition, content and intentions are significantly author dependent. Scientists should therefore use Twitter® to make sound medical information heard. If this policy is not implemented, the importance of inadequate and incorrect information transfer is indirectly increased.

Cotreatment with sorafenib and oleanolic acid induces reactive oxygen species-dependent and mitochondrial-mediated apoptotic cell death in hepatocellular carcinoma cells.

Hepatocellular carcinoma (HCC) is the most common liver malignancy, and the lack of effective chemotherapies underlines the need for novel therapeutic approaches for this disease. Recently, we discovered a novel synergistic induction of cell death by combining sorafenib, the only routinely used palliative chemotherapeutic agent, and the triterpenoid oleanolic acid (OA). However, the underlying mechanisms of action have remained obscure. Here, we report that sorafenib and OA acted in concert to trigger mitochondria-mediated apoptotic cell death, which is dependent on reactive oxygen species (ROS). Sorafenib/OA cotreatment significantly increased ROS production, which was prevented by the ROS scavengers α-tocopherol and MnTBAP. Importantly, rescue experiments showed that ROS were required for sorafenib/OA-induced apoptosis as ROS scavengers protected HCC cells against cell death. In addition, sorafenib and OA cotreatment cooperated to decrease myeloid cell leukaemia-1 expression and to activate Bak, two events that were prevented by ROS scavengers. Bak activation was accompanied by the loss of mitochondrial membrane potential, followed by PARP cleavage, DNA fragmentation and, finally, apoptotic cell death in HCC cells. By providing new insights into the molecular regulation of sorafenib/OA-mediated and ROS-dependent cell death, our study contributes toward the development of novel treatment strategies to overcome sorafenib resistance in HCC.

Influence of the recipient body mass index on the outcomes after kidney transplantation.

PURPOSE: The relationship between the body mass index (BMI) of kidney transplant recipients and outcomes after kidney transplantation (KT) is not fully understood and remains controversial. We studied the influence of BMI on clinically relevant outcomes in kidney transplant recipients. METHODS: In this retrospective single-centre study, all patients who underwent kidney transplantation at our institution between January 2007 and December 2012 were included. Demographic data and BMI were correlated with the clinical course of the disease, rejection rates, delayed graft function rates, and graft and patient survival. RESULTS: During the study period, 384 single KTs (130 women and 254 men) were performed. Seventeen percent of the transplants were transplanted within the Eurotransplant Senior Programme (ESP). Most of the transplants were performed using organs that were obtained from donors after brain death (DBD), and living donor kidney transplants were performed in 22.4% of all transplants. The median BMI of the recipients was 25.9 kg/m2. Additionally, 13.5% of the recipients had a BMI of 30-34.9 kg/m2 and 3.9% had a BMI >35 kg/m2. A BMI >30 kg/m2 was significantly associated with primary non-function of the kidney (p = 0.047), delayed graft function (p = 0.008), and a higher rate of loss of graft function (p = 0.015). The glomerular filtration rate 12 months after KT was significantly lower in recipients with a BMI >30 kg/m2. Multivariate analysis revealed that recipient BMI, among other factors, was an independent risk factor for delayed graft function and graft survival. Patients with a BMI >30 kg/m2 had an almost four times higher risk for surgical site infection than did recipients with a lower BMI. CONCLUSIONS: Increased BMI at kidney transplantation is a predictor of adverse outcomes, including delayed graft function. These findings demonstrate the importance of the careful selection of patients and pre-transplant weight reduction, although the role of weight reduction for improving graft function is not clear.

Bad bacteria in acute appendicitis: rare but relevant.

PURPOSE: Bacterial infections are a factor for morbidity in patients with acute appendicitis (AA). The spreading of multidrug-resistant (MDR) bacteria is a significant problem in surgery, and the most relevant MDR pathogens are summarized as Enterobacteriaceae, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterococci (ESKAPE) bacteria. Data regarding the species and distribution of bacteria in AA are available, but information about the resistances and their relevance is deficient. METHODS: In this retrospective study, we analyzed microbiological swabs of patients with AA. The outcome parameters of patients after laparoscopic appendectomy were analyzed against microbiological results, including antibiotic resistance testing. Positive swabs were compared with bacteria cultivated after alternative abdominal emergency surgery (AES). RESULTS: In total, 584 patients with AA were included and had a mean age of 35.5 years. In 216 patients (36.9%), a swab was taken, and in 128 (59.3%) swabs, bacteria could be cultivated. The most frequent organisms were Escherichia coli, Bacteroides species, and Pseudomonas. In 9.4% of the positive AA swabs, MDR germs were cultivated, and all of them were ESKAPE pathogens. Patients with MDR bacteria in AA suffered more infectious complications (p = 0.006) and needed longer hospitalizations (p < 0.009). In AES, aside from appendicitis, a different spectrum containing more MDR bacteria was cultivated (5.9 vs. 20.9%; p < 0.0001). CONCLUSIONS: Although they occur less frequently in appendectomy compared to emergency surgeries for other abdominal diseases, MDR bacteria are traceable in this common disease and contribute to additional morbidity.

The meteorological influence on seasonal alterations in the course of acute appendicitis.

BACKGROUND: Several diseases, including acute appendicitis (AA), have been known to undergo seasonal variations. Changes in the incidence and course of AA are attributed to seasonal weather differences, but this connection remains unproven. METHODS: In this retrospective, single-center analysis, we analyzed daily meteorological data over an 8-year period. A connection of day-by-day meteorological data with 680 consecutive appendectomies was performed. Patients' characteristics, intraoperative findings, and outcome parameters were analyzed. Seasons were classified meteorologically as 3-month periods (winter, spring, summer, and autumn). RESULTS: Nonambient temperature (unusual warm or cold weather) is correlated with a higher rate of complicated (gangrenous or perforated) AA (P = 0.018). In summer and winter, days with nonambient temperatures were more frequent (P < 0.0001). A higher rate of complicated AA was seen during summer and winter (P = 0.009). In addition, patients operated on in summer and accordingly after warm days suffer more complications (P < 0.0001), especially more superficial surgical site infections (P < 0.048). CONCLUSIONS: The concordant observation of more complicated AA and complications after AA with meteorological data and calendric seasonal variations makes it most likely that temperature is a cofactor in complicated AA and contributes to the seasonal variations in AA. Although an increase in the microbiome of the skin during warm seasons might explain the increase in surgical site infection, the functional connection between warmer temperatures and AA complications remains unclear.

Identification of a novel oxidative stress induced cell death by Sorafenib and oleanolic acid in human hepatocellular carcinoma cells.

The lack of effective chemotherapies in hepatocellular carcinoma (HCC) is still an unsolved problem and underlines the need for new strategies in liver cancer treatment. In this study, we present a novel approach to improve the efficacy of Sorafenib, today's only routinely used chemotherapeutic drug for HCC, in combination with triterpenoid oleanolic acid (OA). Our data show that cotreatment with subtoxic concentrations of Sorafenib and OA leads to highly synergistic induction of cell death. Importantly, Sorafenib/OA cotreatment triggers cell damage in a sustained manner and suppresses long-term clonogenic survival. Sorafenib/OA cotreatment induces DNA fragmentation and caspase-3/7 cleavage and the addition of the pan-caspase inhibitor zVAD.fmk shows the requirement of caspase activation for Sorafenib/OA-triggered cell death. Furthermore, Sorafenib/OA co-treatment stimulates a significant increase in reactive oxygen species (ROS) levels. Most importantly, the accumulation of intracellular ROS is required for cell death induction, since the addition of ROS scavengers (i.e. α-tocopherol, MnTBAP) that prevent the increase of intracellular ROS levels completely rescues cells from Sorafenib/OA-triggered cell death. In conclusion, OA represents a novel approach to increase the sensitivity of HCC cells to Sorafenib via oxidative stress.