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PurposeAlthough elective surgery is generally safe, some procedures remain associated with an increased risk of complications. Improved preoperative risk stratification and earlier recognition of these complications may ameliorate postoperative recovery and improve long-term outcomes. The perioperative longitudinal study of complications and long-term outcomes (PLUTO) cohort aims to establish a comprehensive biorepository that will facilitate research in this field. In this profile paper, we will discuss its design rationale and opportunities for future studies.ParticipantsPatients undergoing elective intermediate to high-risk non-cardiac surgery are eligible for enrolment. For the first seven postoperative days, participants are subjected to daily bedside visits by dedicated observers, who adjudicate clinical events and perform non-invasive physiological measurements (including handheld spirometry and single-channel electroencephalography). Blood samples and microbiome specimens are collected at preselected time points. Primary study outcomes are the postoperative occurrence of nosocomial infections, major adverse cardiac events, pulmonary complications, acute kidney injury and delirium/acute encephalopathy. Secondary outcomes include mortality and quality of life, as well as the long-term occurrence of psychopathology, cognitive dysfunction and chronic pain.Findings to dateEnrolment of the first participant occurred early 2020. During the inception phase of the project (first 2 years), 431 patients were eligible of whom 297 patients consented to participate (69%). Observed event rate was 42% overall, with the most frequent complication being infection.Future plansThe main purpose of the PLUTO biorepository is to provide a framework for research in the field of perioperative medicine and anaesthesiology, by storing high-quality clinical data and biomaterials for future studies. In addition, PLUTO aims to establish a logistical platform for conducting embedded clinical trials.Trial registration numberNCT05331118.

Background Functional capacity is used as an indicator for cardiac testing before non-cardiac surgery and is often performed subjectively. However, the value of subjectively estimated functional capacity in predicting cardiac complications is under debate. We determined the predictive value of subjectively assessed functional capacity on postoperative cardiac complications and mortality. Design An observational cohort study in patients aged 60 years and over undergoing elective inpatient non-cardiac surgery in a tertiary referral hospital. Methods Subjective functional capacity was determined by anaesthesiologists. The primary outcome was postoperative myocardial injury. Secondary outcomes were postoperative inhospital myocardial infarction and one year mortality. Logistic regression analysis and area under the receiver operating curves were used to determine the added value of functional capacity. Results A total of 4879 patients was included; 824 (17%) patients had a poor subjective functional capacity. Postoperative myocardial injury occurred in 718 patients (15%). Poor functional capacity was associated with myocardial injury (relative risk (RR) 1.7, 95% confidence interval (CI) 1.5–2.0; P Conclusions Subjectively assessed functional capacity is a predictor of postoperative myocardial injury and death, but had no added value on top of other preoperative predictors.

BACKGROUND Major surgery is associated with negative postoperative outcomes such as complications and delayed or poor recovery. Multimodal prehabilitation can help to reduce the negative effects of major surgery. Offering prehabilitation by means of mobile health (mHealth) could be an effective new approach. OBJECTIVE The objectives of this pilot study were to (1) evaluate the usability of the Be Prepared mHealth app prototype for people undergoing major surgery, (2) explore whether the app was capable of bringing about a change in risk behaviors, and (3) estimate a preliminary effect of the app on functional recovery after major surgery. METHODS A mixed-methods pilot randomized controlled trial was conducted in two Dutch academic hospitals. In total, 86 people undergoing major surgery participated. Participants in the intervention group received access to the Be Prepared app, a smartphone app using behavior change techniques to address risk behavior prior to surgery. Both groups received care as usual. Usability (System Usability Scale), change in risk behaviors 3 days prior to surgery, and functional recovery 30 days after discharge from hospital (Patient-Reported Outcomes Measurement Information System physical functioning 8-item short form) were assessed using online questionnaires. Quantitative data were analyzed using descriptive statistics, chi-square tests, and multivariable linear regression. Semistructured interviews about the usability of the app were conducted with 12 participants in the intervention group. Thematic analysis was used to analyze qualitative data. RESULTS Seventy-nine people—40 in the intervention group and 39 in the control group—were available for further analysis. Participants had a median age of 61 (interquartile range 51.0-68.0) years. The System Usability Scale showed that patients considered the Be Prepared app to have acceptable usability (mean 68.2 [SD 18.4]). Interviews supported the usability of the app. The major point of improvement identified was further personalization of the app. Compared with the control group, the intervention group showed an increase in self-reported physical activity and muscle strengthening activities prior to surgery. Also, 2 of 2 frequent alcohol users in the intervention group versus 1 of 9 in the control group drank less alcohol in the run-up to surgery. No difference was found in change of smoking cessation. Between-group analysis showed no meaningful differences in functional recovery after correction for baseline values (β=–2.4 [95% CI –5.9 to 1.1]). CONCLUSIONS The Be Prepared app prototype shows potential in terms of usability and changing risk behavior prior to major surgery. No preliminary effect of the app on functional recovery was found. Points of improvement have been identified with which the app and future research can be optimized. CLINICALTRIAL Netherlands Trial Registry NL8623; https://www.trialregister.nl/trial/8623

Background Thoracic epidural analgesia is the standard postoperative pain management strategy in esophageal cancer surgery. However, paravertebral block analgesia may achieve comparable pain control while inducing less side effects, which may be beneficial for postoperative recovery. This study primarily aims to compare the postoperative quality of recovery between paravertebral catheter versus thoracic epidural analgesia in patients undergoing minimally invasive esophagectomy. Methods This study represents a randomized controlled superiority trial. A total of 192 patients will be randomized in 4 Dutch high-volume centers for esophageal cancer surgery. Patients are eligible for inclusion if they are at least 18 years old, able to provide written informed consent and complete questionnaires in Dutch, scheduled to undergo minimally invasive esophagectomy with two-field lymphadenectomy and an intrathoracic anastomosis, and have no contra-indications to either epidural or paravertebral analgesia. The primary outcome is the quality of postoperative recovery, as measured by the Quality of Recovery-40 (QoR-40) questionnaire on the morning of postoperative day 3. Secondary outcomes include the QoR-40 questionnaire score Area Under the Curve on postoperative days 1–3, the integrated pain and systemic opioid score and patient satisfaction and pain experience according to the International Pain Outcomes (IPO) questionnaire, and cost-effectiveness. Furthermore, the groups will be compared regarding the need for additional rescue medication on postoperative days 0–3, technical failure of the pain treatment, duration of anesthesia, duration of surgery, total postoperative fluid administration day 0–3, postoperative vasopressor and inotrope use, length of urinary catheter use, length of hospital stay, postoperative complications, chronic pain at six months after surgery, and other adverse effects. Discussion In this study, it is hypothesized that paravertebral analgesia achieves comparable pain control while causing less side-effects such as hypotension when compared to epidural analgesia, leading to shorter postoperative length of stay on a monitored ward and superior quality of recovery. If this hypothesis is confirmed, the results of this study can be used to update the relevant guidelines on postoperative pain management for patients undergoing minimally invasive esophagectomy. Trial registration Netherlands Trial Registry, NL8037. Registered 19 September 2019.

Purpose Many studies report on outcomes of analgesic therapy for (suspected) traumatic rib fractures. However, the literature is inconclusive and diverse regarding the management of pain and its effect on pain relief and associated complications. This systematic review and meta-analysis summarizes and compares reduction of pain for the different treatment modalities and as secondary outcome mortality during hospitalization, length of mechanical ventilation, length of hospital stay, length of intensive care unit stay (ICU) and complications such as respiratory, cardiovascular, and/or analgesia-related complications, for four different types of analgesic therapy: epidural analgesia, intravenous analgesia, paravertebral blocks and intercostal blocks. Methods PubMed, EMBASE and CENTRAL databases were searched to identify comparative studies investigating epidural, intravenous, paravertebral and intercostal interventions for traumatic rib fractures, without restriction for study type. The search strategy included keywords and MeSH or Emtree terms relating blunt chest trauma (including rib fractures), analgesic interventions, pain management and complications. Results A total of 19 papers met our inclusion criteria and were finally included in this systematic review. Significant differences were found in favor of epidural analgesia for the reduction of pain. No significant differences were observed between epidural analgesia, intravenous analgesia, paravertebral blocks and intercostal blocks, for the secondary outcomes. Conclusions Results of this study show that epidural analgesia provides better pain relief than the other modalities. No differences were observed for secondary endpoints like length of ICU stay, length of mechanical ventilation or pulmonary complications. However, the quality of the available evidence is low, and therefore, preclude strong recommendations.

SUMMARY Adequate postoperative pain management is essential to facilitate uneventful recovery after esophagectomy. Although epidural analgesia is the gold standard, it is not satisfactory in all patients. The aim of this study is to describe the efficacy and complication profile of epidural analgesia after minimally invasive esophagectomy (MIE). A total of 108 patients who underwent a robot-assisted (McKeown) MIE for esophageal cancer were included from a single center prospective database (2012–2015). The number of patients that could receive epidural analgesia, the sensory block range per day, the number of epidural top-ups, the need for escape pain mediation (i.e. intravenous opioids), the highest pain score per day (numeric rating scale: 0–10), and epidural-related complications were assessed until postoperative day (POD) 4. Epidural catheter placement was achieved in 101 patients (94%). A complete sensory block was found in 49% (POD1), 42% (POD 2), 20% (POD3), and 30% (POD4) of patients. An epidural top-up was performed in 26 patients (24%), which was successful in 22 patients. Escape pain medication in the form of intravenous opioids was given at least once in 49 out of 108 patients (45%) on POD 1, 2, 3, or 4. Overall median highest pain scores on the corresponding days were 2.0 (range: 0–10), 3.5 (range: 0–9), 3.0 (range: 0–8), and 4.0 (range: 0–9). Epidural related complications occurred in 20 patients (19%) and included catheter problems (n = 11), hypotension (n = 6), bradypnea (n = 2), and reversible tingling in the legs (n = 1). In conclusion, in this study epidural analgesia was insufficient and escape pain medication was necessary in nearly half of patients undergoing MIE.

Background. Adequate pain control is essential in the treatment of patients with traumatic rib fractures. Although epidural analgesia is recommended in international guidelines, the use remains debatable and is not undisputed. The aim of this study was to describe the efficacy and safety of epidural analgesia in patients with multiple traumatic rib fractures.Methods. A retrospective cohort study was performed. Patients with ≥3 rib fractures following blunt chest trauma who received epidural analgesia between January 2015 and January 2018 were included. The main outcome parameters were the success rate of epidural analgesia and the incidence of medication-related side effects and catheter-related complications.Results. A total of 76 patients were included. Epidural analgesia was successful in a total of 45 patients (59%), including 22 patients without and in 23 patients with an additional analgesic intervention. In 14 patients (18%), epidural analgesia was terminated early without intervention due to insufficient sensory blockade (n=4), medication-related side effects (n=4), and catheter-related complications (n=6). In 17 patients (22%), the epidural catheter was removed after one or multiple additional interventions due to insufficient pain control. Minor epidural-related complications or side effects were encountered in 36 patients (47%). One patient had a major complication (opioid intoxication).Conclusion. Epidural analgesia was successful in 59% of patients; however, 30% needed additional analgesic interventions. As about half of the patients had epidural-related complications, it remains debatable whether epidural analgesia is a sufficient treatment modality in patients with multiple rib fractures.

Background Major surgery is associated with negative postoperative outcomes such as complications and delayed or poor recovery. Multimodal prehabilitation can help to reduce the negative effects of major surgery. Offering prehabilitation by means of mobile health (mHealth) could be an effective new approach. Objective The objectives of this pilot study were to (1) evaluate the usability of the Be Prepared mHealth app prototype for people undergoing major surgery, (2) explore whether the app was capable of bringing about a change in risk behaviors, and (3) estimate a preliminary effect of the app on functional recovery after major surgery. Methods A mixed-methods pilot randomized controlled trial was conducted in two Dutch academic hospitals. In total, 86 people undergoing major surgery participated. Participants in the intervention group received access to the Be Prepared app, a smartphone app using behavior change techniques to address risk behavior prior to surgery. Both groups received care as usual. Usability (System Usability Scale), change in risk behaviors 3 days prior to surgery, and functional recovery 30 days after discharge from hospital (Patient-Reported Outcomes Measurement Information System physical functioning 8-item short form) were assessed using online questionnaires. Quantitative data were analyzed using descriptive statistics, chi-square tests, and multivariable linear regression. Semistructured interviews about the usability of the app were conducted with 12 participants in the intervention group. Thematic analysis was used to analyze qualitative data. Results Seventy-nine people—40 in the intervention group and 39 in the control group—were available for further analysis. Participants had a median age of 61 (interquartile range 51.0-68.0) years. The System Usability Scale showed that patients considered the Be Prepared app to have acceptable usability (mean 68.2 [SD 18.4]). Interviews supported the usability of the app. The major point of improvement identified was further personalization of the app. Compared with the control group, the intervention group showed an increase in self-reported physical activity and muscle strengthening activities prior to surgery. Also, 2 of 2 frequent alcohol users in the intervention group versus 1 of 9 in the control group drank less alcohol in the run-up to surgery. No difference was found in change of smoking cessation. Between-group analysis showed no meaningful differences in functional recovery after correction for baseline values (β=–2.4 [95% CI –5.9 to 1.1]). Conclusions The Be Prepared app prototype shows potential in terms of usability and changing risk behavior prior to major surgery. No preliminary effect of the app on functional recovery was found. Points of improvement have been identified with which the app and future research can be optimized. Trial Registration Netherlands Trial Registry NL8623; https://www.trialregister.nl/trial/8623

Background Adequate postoperative pain management is essential to facilitate uneventful recovery after esophagectomy. Although epidural analgesia is the gold standard, it is not satisfactory in all patients. The aim of this study was to describe the efficacy and complication profile of epidural analgesia after minimally invasive esophagectomy (MIE). Methods A total of 108 patients who underwent a robot-assisted (McKeown) MIE for esophageal cancer were included from a single center prospective database (2012–2015). The number of patients that could receive epidural analgesia, the sensory block range per day, the number of epidural top-ups, the need for escape pain mediation (i.e. intravenous opioids), the highest pain score per day (numeric rating scale, 0–10), and epidural-related complications were assessed until postoperative day (POD) 4. Results Epidural catheter placement was achieved in 101 patients (94%). A complete sensory block was found in 49% (POD1), 42% (POD 2), 20% (POD3), and 30% (POD4) of patients. An epidural top-up was performed in 26 patients (24%), which was successful in 22 patients. Escape pain medication in the form of intravenous opioids were given at least once in 49 out of 108 patients (45%) on POD 1, 2, 3, or 4. Overall median highest pain scores on the corresponding days were 2.0 (range 0–10), 3.5 (range 0–9), 3.0 (range 0–8), and 4.0 (range 0–9). Epidural related complications occurred in 20 patients (19%) and included catheter problems (n = 11), hypotension (n = 6), bradypnea (n = 2), and reversible tingling in the legs (n = 1). Conclusion In conclusion, epidural analgesia is insufficient and escape pain medication is necessary in nearly half of patients undergoing MIE. Disclosure All authors have declared no conflicts of interest.

TNF family member CD70 is the ligand of CD27, a costimulatory receptor that shapes effector and memory T cell pools. Tight control of CD70 expression is required to prevent lethal immunodeficiency. By selective transcription, CD70 is largely confined to activated lymphocytes and dendritic cells (DC). We show here that, in addition, specific intracellular routing controls its plasma membrane deposition. In professional antigen-presenting cells, such as DC, CD70 is sorted to late endocytic vesicles, defined as MHC class II compartments (MIIC). In cells lacking the machinery for antigen presentation by MHC class II, CD70 travels by default to the plasma membrane. Introduction of class II transactivator sufficed to reroute CD70 to MIIC. Vesicular trafficking of CD70 and MHC class II is coordinately regulated by the microtubule-associated dynein motor complex. We show that when maturing DC make contact with T cells in a cognate fashion, newly synthesized CD70 is specifically delivered via MIIC to the immunological synapse. Therefore, we propose that routing of CD70 to MIIC serves to coordinate delivery of the T cell costimulatory signal in time and space with antigen recognition.

Small GTPases of the Rab family control timing of vesicle fusion. Fusion of two vesicles can only occur when they have been brought into close contact. Transport by microtubule- or actin-based motor proteins will facilitate this process in vivo. Ideally, transport and vesicle fusion are linked activities. Active, GTP-bound Rab proteins dock on specific compartments and are therefore perfect candidates to control transport of the different compartments. Recently, a number of Rab proteins were identified that control motor protein recruitment to their specific target membranes. By cycling through inactive and active states, Rab proteins are able to control motor protein-mediated transport and subsequent fusion of intracellular structures in both spatial and timed manners.

Salmonella typhimurium survives and replicates intracellular in a membrane-bound compartment, the Salmonella-containing vacuole (SCV). In HeLa cells, the SCV matures through interactions with the endocytic pathway, but Salmonella avoids fusion with mature lysosomes. The exact mechanism of the inhibition of phagolysosomal fusion is not understood. Rab GTPases control several proteins involved in membrane fusion and vesicular transport. The small GTPase Rab7 regulates the transport of and fusion between late endosomes and lysosomes and associates with the SCV. We show that the Rab7 GTPase cycle is not affected on the SCV. We then manipulated a pathway downstream of the small GTPase Rab7 in HeLa cells infected with Salmonella. Expression of the Rab7 effector RILP induces recruitment of the dynein/dynactin motor complex to the SCV. Subsequently, SCV fuse with lysosomes. As a result, the intracellular replication of Salmonella is inhibited. Activation of dynein-mediated vesicle transport can thus control intracellular survival of Salmonella.

Many intracellular compartments, including MHC class II-containing lysosomes [1], melanosomes [2], and phagosomes [3], move along microtubules in a bidirectional manner and in a stop-and-go fashion due to the alternating activities of a plus-end directed kinesin motor and a minus-end directed dynein-dynactin motor [4]. It is largely unclear how motor proteins are targeted specifically to different compartments. Rab GTPases recruit and/or activate several proteins involved in membrane fusion and vesicular transport [5, 6]. They associate with specific compartments after activation, which makes Rab GTPases ideal candidates for controlling motor protein binding to specific membranes. We and others [7] have identified a protein, called RILP (for Rab7-interacting lysosomal protein), that interacts with active Rab7 on late endosomes and lysosomes. Here we show that RILP prevents further cycling of Rab7. RILP expression induces the recruitment of functional dynein-dynactin motor complexes to Rab7-containing late endosomes and lysosomes. Consequently, these compartments are transported by these motors toward the minus end of microtubules, effectively inhibiting their transport toward the cell periphery. This signaling cascade may be responsible for timed and selective dynein motor recruitment onto late endosomes and lysosomes.

With the emergence of multidrug resistant (MDR) bacteria, it is imperative to develop new intervention strategies. Current antibiotics typically target pathogen rather than host-specific biochemical pathways. Here we have developed kinase inhibitors that prevent intracellular growth of unrelated pathogens such as Salmonella typhimurium and Mycobacterium tuberculosis. An RNA interference screen of the human kinome using automated microscopy revealed several host kinases capable of inhibiting intracellular growth of S. typhimurium. The kinases identified clustered in one network around AKT1 (also known as PKB). Inhibitors of AKT1 prevent intracellular growth of various bacteria including MDR-M. tuberculosis. AKT1 is activated by the S. typhimurium effector SopB, which promotes intracellular survival by controlling actin dynamics through PAK4, and phagosome-lysosome fusion through the AS160 (also known as TBC1D4)-RAB14 pathway. AKT1 inhibitors counteract the bacterial manipulation of host signalling processes, thus controlling intracellular growth of bacteria. By using a reciprocal chemical genetics approach, we identified kinase inhibitors with antibiotic properties and their host targets, and we determined host signalling networks that are activated by intracellular bacteria for survival.

Small GTPases of the Rab family control timing of vesicle fusion. Fusion of two vesicles can only occur when they have been brought into close contact. Transport by microtubule- or actin-based motor proteins will facilitate this process in vivo. Ideally, transport and vesicle fusion are linked activities. Active, GTP-bound Rab proteins dock on specific compartments and are therefore perfect candidates to control transport of the different compartments. Recently, a number of Rab proteins were identified that control motor protein recruitment to their specific target membranes. By cycling through inactive and active states, Rab proteins are able to control motor protein-mediated transport and subsequent fusion of intracellular structures in both spatial and timed manners.

SummaryMajor Histocompatibility Complex (MHC) class II molecules, including Human Leukocyte Antigen (HLA)-DR, present peptide fragments from proteins degraded in the endocytic pathway. HLA-DR is targeted to late-endocytic structures named MHC class II-containing Compartments (MIIC), where it interacts with HLA-DM. This chaperone stabilizes HLA-DR during peptide exchange and is critical for successful peptide loading. To follow this process in living cells, we have generated cells containing HLA-DR3/Cyan Fluorescent Protein (CFP), HLA-DM/Yellow Fluorescent Protein (YFP), and invariant chain. HLA-DR/DM interactions were observed by Fluorescence Resonance Energy Transfer (FRET). These interactions were pH insensitive, yet occurred only in internal structures and not at the limiting membrane of MIIC. In a cellular model of infection, phagosomes formed a limiting membrane surrounding internalized Salmonella. HLA-DR and HLA-DM did not interact in Salmonella-induced vacuoles, and HLA-DR was not loaded with antigens. The absence of HLA-DR/DM interactions at the limiting membrane prevents local loading of MHC class II molecules in phagosomes. This may allow these bacteria to successfully evade the immune system.