The association of intraoperative low driving pressure ventilation and nonhome discharge: a historical cohort study.

PURPOSE: To evaluate whether intraoperative ventilation using lower driving pressure decreases the risk of nonhome discharge. METHODS: We conducted a historical cohort study of patients aged ≥ 60 yr who were living at home before undergoing elective, noncardiothoracic surgery at two tertiary healthcare networks in Massachusetts between 2007 and 2018. We assessed the association of the median driving pressure during intraoperative mechanical ventilation with nonhome discharge using multivariable logistic regression analysis, adjusted for patient and procedural factors. Contingent on the primary association, we assessed effect modification by patients' baseline risk and mediation by postoperative respiratory failure. RESULTS: Of 87,407 included patients, 12,584 (14.4%) experienced nonhome discharge. In adjusted analyses, a lower driving pressure was associated with a lower risk of nonhome discharge (adjusted odds ratio [aOR], 0.88; 95% confidence interval [CI], 0.83 to 0.93, per 10 cm H2O decrease; P < 0.001). This association was magnified in patients with a high baseline risk (aOR, 0.77; 95% CI, 0.73 to 0.81, per 10 cm H2O decrease, P-for-interaction < 0.001). The findings were confirmed in 19,518 patients matched for their baseline respiratory system compliance (aOR, 0.90; 95% CI, 0.81 to 1.00; P = 0.04 for low [< 15 cm H2O] vs high [≥ 15 cm H2O] driving pressures). A lower risk of respiratory failure mediated the association of a low driving pressure with nonhome discharge (20.8%; 95% CI, 15.0 to 56.8; P < 0.001). CONCLUSIONS: Intraoperative ventilation maintaining lower driving pressure was associated with a lower risk of nonhome discharge, which can be partially explained by lowered rates of postoperative respiratory failure. Future randomized controlled trials should target driving pressure as a potential intervention to decrease nonhome discharge.

RéSUMé: OBJECTIF: Évaluer si la ventilation peropératoire utilisant une pression motrice plus faible diminue le risque de congé hors domicile. MéTHODE: Nous avons réalisé une étude de cohorte historique de patients âgés de ≥ 60 ans vivant à la maison avant de bénéficier d'une chirurgie non cardiothoracique non urgente dans deux réseaux de soins de santé tertiaires du Massachusetts entre 2007 et 2018. Nous avons évalué l'association entre la pression motrice médiane pendant la ventilation mécanique peropératoire et le congé ailleurs qu'au domicile à l'aide d'une analyse de régression logistique multivariable, ajustée pour tenir compte des facteurs liés aux patients et à l'intervention. En fonction de l'association primaire, nous avons évalué la modification de l'effet par le risque initial des patients et la médiation par l'insuffisance respiratoire postopératoire. RéSULTATS: Sur les 87 407 patients inclus, 12 584 (14,4 %) ont reçu leur congé ailleurs qu'au domicile. Dans les analyses ajustées, une pression motrice plus faible était associée à un risque réduit de congé hors domicile (rapport de cotes ajusté [RCa], 0,88; intervalle de confiance [IC] à 95 %, 0,83 à 0,93, par diminution de 10 cm H2O; P < 0,001). Cette association a été amplifiée chez les patients présentant un risque initial élevé (RCa, 0,77; IC 95 %, 0,73 à 0,81, par diminution de 10 cm H2O, P-pour-interaction < 0,001). Les résultats ont été confirmés chez 19 518 patients appariés pour la compliance initiale de leur système respiratoire (RCa, 0,90; IC 95 %, 0,81 à 1,00; P = 0,04 pour des pressions motrices faibles [< 15 cm H2O] vs élevées [≥ 15 cm H2O]). Un risque plus faible d'insuffisance respiratoire a entraîné une association entre une faible pression motrice et un congé à l'extérieur du domicile (20,8 %; IC 95 %, 15,0 à 56,8 ; P < 0,001). CONCLUSION: La ventilation peropératoire maintenant une pression motrice plus faible a été associée à un risque plus faible de congé hors domicile, ce qui peut s'expliquer en partie par des taux réduits d'insuffisance respiratoire postopératoire. Les futures études randomisées contrôlées devraient cibler la pression motrice comme intervention potentielle pour réduire les congés hors domicile.

Supraglottic airway device versus tracheal intubation and the risk of emergent postoperative intubation after general anaesthesia in adults: a retrospective cohort study.

BACKGROUND: We examined the association between emergent postoperative tracheal intubation and the use of supraglottic airway devices (SGAs) vs tracheal tubes. METHODS: We included data from adult noncardiac surgical cases under general anaesthesia between 2008 and 2018. We only included cases (n=59 991) in which both airways were deemed to be feasible options. Multivariable logistic regression, instrumental variable analysis, propensity matching, and mediation analysis were used. RESULTS: Use of a tracheal tube was associated with a higher risk of emergent postoperative intubation (adjusted absolute risk difference [ARD]=0.80%; 95% confidence interval (CI), 0.64-0.97; P<0.001), and a higher risk of post-extubation hypoxaemia (ARD=3.9%; 95% CI, 3.4-4.4; P<0.001). The effect was modified by the use of non-depolarising neuromuscular blocking agents (NMBAs); mediation analyses revealed that 28.9% (95% CI, 14.4-43.4%; P<0.001) of the main effect was attributable to NMBA. Airway management modified the association of NMBA and risk of emergent postoperative intubation (Pinteraction=0.02). Patients managed with an SGA had higher odds of NMBA-associated reintubation compared to patients managed with a tracheal tube (adjusted odds ratio [aOR]=3.65, 95% CI, 1.99-6.67 vs aOR=1.68, 95% CI, 1.29-2.18 [P<0.001], respectively). CONCLUSIONS: In patients undergoing procedures under general anaesthesia that could be managed with either SGA or tracheal tube, use of an SGA was associated with lower risk of emergent postoperative intubation. The effect can partly be explained by use of NMBAs. Use of NMBAs in patients with an SGA appears to increase the risk of emergent postoperative intubation.

Outcomes after endoscopic retrograde cholangiopancreatography with general anaesthesia versus sedation.

BACKGROUND: We tested the primary hypothesis that use of general anaesthesia vs sedation increases vulnerability to adverse discharge (in-hospital mortality or new discharge to a nursing facility) after endoscopic retrograde cholangiopancreatography (ERCP). METHODS: In this retrospective cohort study, adult patients undergoing ERCP with general anaesthesia or sedation at a tertiary care hospital were included. We calculated adjusted absolute risk differences between patients receiving general anaesthesia vs sedation using provider preference-based instrumental variable analysis. We also used mediation analysis to determine whether intraoperative hypotension during general anaesthesia mediated its effect on adverse discharge. RESULTS: Among 17 538 patients undergoing ERCP from 2007 through 2018, 16 238 received sedation and 1300 received GA. Rates of adverse discharge were 5.8% (n=938) after sedation and 16.2% (n=210) after general anaesthesia. Providers' adjusted mean predicted probabilities of using general anaesthesia for ERCP ranged from 0.2% to 63.2% of individual caseloads. Utilising provider-related variability in the use of general anaesthesia for instrumental variable analysis resulted in an 8.6% risk increase (95% confidence interval, 4.5-12.6%; P<0.001) in adverse discharge among patients receiving general anaesthesia vs sedation. Intraoperative hypotensive events occurred more often during general anaesthesia and mediated 23.8% (95% confidence interval, 3.9-43.7%: P=0.019) of the primary association. CONCLUSIONS: These results suggest that use of sedation during ERCP facilitates reduced adverse discharge for patients for whom general anaesthesia is not clearly indicated. Intraoperative hypotension during general anaesthesia for ERCP partly mediates the increased vulnerability to adverse discharge.

Discharge Prediction for Patients Undergoing Inpatient Surgery: Development and validation of the DEPENDENSE score.

BACKGROUND: A substantial proportion of patients undergoing inpatient surgery each year is at risk for postoperative institutionalization and loss of independence. Reliable individualized preoperative prediction of adverse discharge can facilitate advanced care planning and shared decision making. METHODS: Using hospital registry data from previously home-dwelling adults undergoing inpatient surgery, we retrospectively developed and externally validated a score predicting adverse discharge. Multivariable logistic regression analysis and bootstrapping were used to develop the score. Adverse discharge was defined as in-hospital mortality or discharge to a skilled nursing facility. The model was subsequently externally validated in a cohort of patients from an independent hospital. RESULTS: In total, 106 164 patients in the development cohort and 92 962 patients in the validation cohort were included, of which 16 624 (15.7%) and 7717 (8.3%) patients experienced adverse discharge, respectively. The model was predictive of adverse discharge with an area under the receiver operating characteristic curve (AUC) of 0.87 (95% CI 0.87-0.88) in the development cohort and an AUC of 0.86 (95% CI 0.86-0.87) in the validation cohort. CONCLUSION: Using preoperatively available data, we developed and validated a prediction instrument for adverse discharge following inpatient surgery. Reliable prediction of this patient centered outcome can facilitate individualized operative planning to maximize value of care.

Succinylcholine and postoperative pulmonary complications: a retrospective cohort study using registry data from two hospital networks.

BACKGROUND: Neuromuscular blocking agents (NMBAs) with a non-depolarising mechanism of action carry the risk of postoperative residual paralysis and are associated with postoperative pulmonary complications (POPC). Owing to the shorter duration of action, the depolarising NMBA succinylcholine may be associated with less postoperative residual paralysis, and hence fewer POPC. We tested the association of succinylcholine administration during anaesthesia and POPC. METHODS: In a retrospective cohort study of registry data from two large US academic medical centres, 244 850 adult noncardiac surgical patients undergoing general anaesthesia were included. The primary outcome was POPC, defined as post-extubation haemoglobin oxygen de-saturation to <90%, or re-intubation requiring intensive care unit admission within 7 days after surgery. The association between succinylcholine and POPC and its dose-dependency were tested in a hierarchical fashion using a multivariable logistic regression model. RESULTS: A total of 13 206 patients (5.4%) experienced POPC. Use of succinylcholine was associated with increased risk of POPC (adjusted odds ratio [ORAdj]=1.11; 95% confidence interval [CI], 1.06-1.16; P<0.001; adjusted risk=5.18%; 95% CI, 5.06-5.30 without and 5.69%; 95% CI, 5.53-5.85 with succinylcholine), with a dose-dependent relationship (ORAdj=1.08; 95% CI, 1.05-1.11 per mg kg-1; P<0.001). In patients receiving non-depolarising NMBAs, succinylcholine further increased the risk of POPC (ORAdj=1.08; 95% CI, 1.03-1.14; P=0.001). The association between succinylcholine and POPC was modified (P=0.03 for interaction) by the duration of surgery with higher odds of POPC in patients undergoing surgeries of <2 vs ≥2 h (ORAdj=1.24; 95% CI, 1.15-1.33 and 1.05; 95% CI, 1.00-1.10, respectively). CONCLUSIONS: In contrast to our prediction, succinylcholine administration was associated with an increased risk of POPC. This association was dose-dependent and magnified in surgeries of shorter duration.

Effects of high neuromuscular blocking agent dose on post-operative respiratory complications in infants and children.

BACKGROUND: This study evaluated the association between neuromuscular blocking agent dose and post-operative respiratory complications in infants and children. METHODS: Data from 6507 general anaesthetics provided to children aged 0-10 years undergoing surgery were analysed to examine the effects of neuromuscular blocking agent dose on post-operative respiratory complications (primary endpoint) and secondary endpoints. Confounder-adjusted analyses addressed age, surgical duration, and comorbidity burden. RESULTS: In confounder-adjusted analyses, high doses of neuromuscular blocking agents were associated with higher risk of post-operative respiratory complications (OR 2.27; 95% CI 1.12-4.59; P = .022). The effect was modified by age (P-for-interaction = .016) towards a more substantial risk in infants ≤1 year (OR 3.84; 95% CI 1.35-10.94; P = .012), by duration of surgery (P-for-interaction = .006) towards a higher difference in odds for surgeries <90 minutes (OR 4.25; 95% CI 1.19-15.18; P = .026), and by ASA physical status (P-for-interaction = .015) with a greater effect among patients with higher operative risk (ASA >1: OR 3.17; 95% CI 1.43-7.04; P = .005). Neostigmine reversal did not modify the association between neuromuscular blocking agents and post-operative respiratory complications (P-for-interaction = .38). Instrumental variable analysis confirmed that high doses of neuromuscular blocking agents were associated with post-operative respiratory complications (probit coefficient 0.25; 95% CI 0.04-0.46; P = .022), demonstrating robust results regarding concerns of unobserved confounding. CONCLUSIONS: High dose of neuromuscular blocking agents is associated with post-operative respiratory complications. We have identified subcohorts of paediatric patients who are particularly vulnerable to the respiratory side-effects of neuromuscular blocking agents: infants, paediatric patients undergoing surgeries of short duration, and those with a high ASA risk score.

Multimodal Patient Blood Management Program Based on a Three-pillar Strategy: A Systematic Review and Meta-analysis.

OBJECTIVES: To determine whether a multidisciplinary, multimodal Patient Blood Management (PBM) program for patients undergoing surgery is effective in reducing perioperative complication rate, and thereby is effective in improving clinical outcome. BACKGROUND: PBM is a medical concept with the focus on a comprehensive anemia management, to minimize iatrogenic (unnecessary) blood loss, and to harness and optimize patient-specific physiological tolerance of anemia. METHODS: A systematic review and meta-analysis was performed. Eligible studies had to address each of the 3 PBM pillars with at least 1 measure per pillar, for example, preoperative anemia management plus cell salvage plus rational transfusion strategy. The study protocol has been registered with PROSPERO (CRD42017079217). RESULTS: Seventeen studies comprising 235,779 surgical patients were included in this meta-analysis (100,886 pre-PBM group and 134,893 PBM group). Implementation of PBM significantly reduced transfusion rates by 39% [risk ratio (RR) 0.61, 95% confidence interval (CI) 0.55-0.68, P < 0.00001], 0.43 red blood cell units per patient (mean difference -0.43, 95% CI -0.54 to -0.31, P < 0.00001), hospital length of stay (mean difference -0.45, 95% CI -0.65 to -0.25, P < 0,00001), total number of complications (RR 0.80, 95% CI 0.74-0.88, P <0.00001), and mortality rate (RR 0.89, 95% CI 0.80-0.98, P = 0.02). CONCLUSIONS: Overall, a comprehensive PBM program addressing all 3 PBM pillars is associated with reduced transfusion need of red blood cell units, lower complication and mortality rate, and thereby improving clinical outcome. Thus, this first meta-analysis investigating a multimodal approach should motivate all executives and health care providers to support further PBM activities.

Multicenter Real-World Analysis of Combined MET and EGFR Inhibition in Patients With Non-Small Cell Lung Cancer and Acquired MET Amplification or Polysomy After EGFR Inhibition.

PURPOSE: MET amplification is a common resistance mechanism to EGFR inhibition in EGFR-mutant non-small cell lung cancer (NSCLC). Several trials showed encouraging results with combined EGFR and MET inhibition (EGFRi/METi). However, MET amplification has been inconsistently defined and frequently included both polysomy and true amplification. METHODS: This is a multicenter, real-world analysis in patients with disease progression on EGFR inhibition and MET copy number gain (CNG), defined as either true amplification (MET to centromere of chromosome 7 ratio [MET-CEP7] ≥ 2) or polysomy (gene copy number ≥ 5, MET-CEP7 < 2). RESULTS: A total of 43 patients with MET CNG were included, 42 of whom were detected by FISH. Twenty-three, 7, and 14 received EGFRi/METi, METi, and SoC, respectively. Patients in the EGFRi/METi cohort exhibited a superior real-world clinical benefit rate, defined as stable disease or better, of 82% (95% confidence interval [CI], 60-95) compared to METi (29%, 4-71) and SoC (50%, 23-77). Median real-world progression-free survival was longer with EGFRi/METi with 9.8 vs. 4.3 months with METi (hazard ratio [HR], 0.19, 95% CI, 0.06-0.57) and 3.7 months with SoC (0.41, 0.18-0.91), respectively. Overall survival was numerically improved. Interaction analysis with treatment and type of CNG (amplification vs. polysomy) suggests that differences were exclusively driven by MET-amplified patients receiving EGFRi/METi (HR for OS, 0.09, 0.01-0.54). CONCLUSION: In this real-world study, EGFRi/METi showed clinical benefit over METi and SoC. Future studies should focus on the differential impact of the type of MET CNG with a focus on true MET amplification as predictor of response.

Sotorasib in KRAS G12C-mutated non-small cell lung cancer: A multicenter real-world experience from the compassionate use program in Germany.

BACKGROUND: Sotorasib is a first-in-class KRAS p.G12C-inhibitor that has entered clinical trials in pretreated patients with non-small cell lung cancer (NSCLC) in 2018. First response rates were promising in the CodeBreaK trials. It remains unclear whether response to sotorasib and outcomes differ in a real-world setting when including patients underrepresented in clinical trials. METHODS: Patients with KRAS p.G12C-mutated advanced or metastatic NSCLC received sotorasib within the German multicenter sotorasib compassionate use program between 2020 to 2022. Data on efficacy, tolerability, and survival were analyzed in the full cohort and in subgroups of special interest such as co-occurring mutations and across PD-L1 expression levels. RESULTS: We analyzed 163 patients who received sotorasib after a median of two treatment lines (range, 0 to 7). Every fourth patient had a poor performance status and 38% had brain metastases (BM). The objective response rate was 38.7%. The median overall survival was 9.8 months (95% CI, 6.5 to not reached). Median real-world (rw) progression-free survival was 4.8 months (9% CI, 3.9 to 5.9). Dose reductions and permanent discontinuation were necessary in 35 (21.5%) and 7 (4.3%) patients, respectively. Efficacy seems to be influenced by PD-L1 expression and a co-occurring KEAP1 mutation. KEAP1 was associated with an inferior survival. Other factors such as BM, STK11, and TP53 mutations had no impact on response and survival. CONCLUSION: First results from a real-world population confirm promising efficacy of sotorasib for the treatment of advanced KRAS p.G12C-mutated NSCLC. Patients with co-occurring KEAP1 mutations seem to derive less benefit.

Cell-type-specific TEV protease cleavage reveals cohesin functions in Drosophila neurons.

Cohesin is a highly conserved multisubunit complex that holds sister chromatids together in mitotic cells. At the metaphase to anaphase transition, proteolytic cleavage of the alpha kleisin subunit (Rad21) by separase causes cohesin's dissociation from chromosomes and triggers sister-chromatid disjunction. To investigate cohesin's function in postmitotic cells, where it is widely expressed, we have created fruit flies whose Rad21 can be cleaved by TEV protease. Cleavage causes precocious separation of sister chromatids and massive chromosome missegregation in proliferating cells, but not disaggregation of polytene chromosomes in salivary glands. Crucially, cleavage in postmitotic neurons is lethal. In mushroom-body neurons, it causes defects in axon pruning, whereas in cholinergic neurons it causes highly abnormal larval locomotion. These data demonstrate essential roles for cohesin in nondividing cells and also introduce a powerful tool by which to investigate protein function in metazoa.

Survival benefit with checkpoint inhibitors versus chemotherapy is modified by brain metastases in patients with recurrent small cell lung cancer.

Introduction: Small cell lung cancer (SCLC) is a rapidly growing malignancy with early distant metastases. Up to 70% will develop brain metastases, and the poor prognosis of these patients has not changed considerably. The potential of checkpoint inhibitors (CPI) in treating recurrent (r/r) SCLC and their effect on brain metastases remain unclear. Methods: In this retrospective multicenter study, we analyzed r/r SCLC patients receiving second or further-line CPI versus chemotherapy between 2010 and 2020. We applied multivariable-adjusted Cox regression analysis to test for differences in 1-year mortality and real-world progression. We then used interaction analysis to evaluate whether brain metastases (BM) and/or cranial radiotherapy (CRT) modified the effect of CPI versus chemotherapy on overall survival. Results: Among 285 patients, 99 (35%) received CPI and 186 (65%) patients received chemotherapy. Most patients (93%) in the CPI group received nivolumab/ipilimumab. Chemotherapy patients were entirely CPI-naïve and only one CPI patient had received atezolizumab for first-line treatment. CPI was associated with a lower risk of 1-year mortality (adjusted Hazard Ratio [HRadj] 0.59, 95% CI 0.42 to 0.82, p=0.002). This benefit was modified by BM and CRT, indicating a pronounced effect in patients without BM (with CRT: HRadj 0.34, p=0.003; no CRT: HRadj 0.50, p=0.05), while there was no effect in patients with BM who received CRT (HRadj 0.85, p=0.59). Conclusion: CPI was associated with a lower risk of 1-year mortality compared to chemotherapy. However, the effect on OS was significantly modified by intracranial disease and radiotherapy, suggesting the benefit was driven by patients without BM.

Multiparametric Evaluation of Radiomics Features and Dual-Energy CT Iodine Maps for Discrimination and Outcome Prediction of Thymic Masses.

RATIONALE AND OBJECTIVES: To investigate the diagnostic value of radiomics features and dual-source dual-energy CT (DECT) based material decomposition in differentiating low-risk thymomas, high-risk thymomas, and thymic carcinomas. MATERIALS AND METHODS: This retrospective study included 32 patients (16 males, mean age 66 ± 14 years) with pathologically confirmed thymic masses who underwent contrast-enhanced DECT between 10/2014 and 01/2023. Two experienced readers evaluated all patients regarding conventional radiomics features, as well as DECT-based features, including attenuation (HU), iodine density (mg/mL), and fat fraction (%). Data comparisons were performed using analysis of variance and chi-square statistic tests. Receiver operating characteristic curve analysis and Cox-regression tests were used to discriminate between low-risk/high-risk thymomas and thymic carcinomas. RESULTS: Of the 32 thymic tumors, 12 (38%) were low-risk thymomas, 11 (34%) were high-risk thymomas, and 9 (28%) were thymic carcinomas. Values differed significantly between low-risk thymoma, high-risk thymoma, and thymic carcinoma regarding DECT-based features (p ≤ 0.023) and 30 radiomics features (p ≤ 0.037). The area under the curve to differentiate between low-risk/high-risk thymomas and thymic cancer was 0.998 (95% CI, 0.915-1.000; p < 0.001) for the combination of DECT imaging parameters and radiomics features, yielding a sensitivity of 100% and specificity of 96%. During a follow-up of 60 months (IQR, 35-60 months), the multiparametric approach including radiomics features, DECT parameters, and clinical parameters showed an excellent prognostic power to predict all-cause mortality (c-index = 0.978 [95% CI, 0.958-0.998], p = 0.003). CONCLUSION: A multiparametric approach including conventional radiomics features and DECT-based features facilitates accurate, non-invasive discrimination between low-risk/high-risk thymomas and thymic carcinomas.

Detrimental incorporation of excess Cenp-A/Cid and Cenp-C into Drosophila centromeres is prevented by limiting amounts of the bridging factor Cal1.

Propagation of centromere identity during cell cycle progression in higher eukaryotes depends critically on the faithful incorporation of a centromere-specific histone H3 variant encoded by CENPA in humans and cid in Drosophila. Cenp-A/Cid is required for the recruitment of Cenp-C, another conserved centromere protein. With yeast three-hybrid experiments, we demonstrate that the essential Drosophila centromere protein Cal1 can link Cenp-A/Cid and Cenp-C. Cenp-A/Cid and Cenp-C interact with the N- and C-terminal domains of Cal1, respectively. These Cal1 domains are sufficient for centromere localization and function, but only when linked together. Using quantitative in vivo imaging to determine protein copy numbers at centromeres and kinetochores, we demonstrate that centromeric Cal1 levels are far lower than those of Cenp-A/Cid, Cenp-C and other conserved kinetochore components, which scale well with the number of kinetochore microtubules when comparing Drosophila with budding yeast. Rather than providing a stoichiometric link within the mitotic kinetochore, Cal1 limits centromeric deposition of Cenp-A/Cid and Cenp-C during exit from mitosis. We demonstrate that the low amount of endogenous Cal1 prevents centromere expansion and mitotic kinetochore failure when Cenp-A/Cid and Cenp-C are present in excess.

Study Design and Rationale for the PACE-LUNG Trial: A Multicenter, Single-Arm, Phase II Clinical Trial Evaluating the Efficacy of Additional Chemotherapy for Patients with EGFRm NSCLC with the Continued Presence of Plasma ctDNA EGFRm at Week 3 After Start of Osimertinib First-Line Treatment.

BACKGROUND: Tyrosine kinase inhibitors (TKI) targeting the epidermal growth factor receptor (EGFR) like the third-generation TKI osimertinib have substantially improved the treatment of patients with advanced non-small cell lung cancer (NSCLC) harboring sensitizing EGFR mutations. However, there is a subset of patients that do not benefit from these therapies in terms of response rate or progression-free-survival (PFS). It has been shown that persistence of EGFR mutations in circulating tumor DNA (ctDNA) at weeks 3 and 6 after start of osimertinib predicts shorter PFS. These patients may benefit from additional chemotherapy. While combination therapies with older TKI have been demonstrated effective in improving outcome, they are associated with a significant increase in toxicity. PATIENTS AND METHODS: PACE-LUNG is a multicenter, single-arm, investigator initiated, phase II trial conducted with the German national Network Genomic Medicine (nNGM). Patients with stage IIIB or IV NSCLC and exon 19 deletion or p.L858R EGFR mutation not amenable to curative treatment with persisting ctDNA after 3 to 4 weeks of first-line osimertinib monotherapy will receive additional chemotherapy (4 cycles of either cisplatin/pemetrexed or carboplatin/pemetrexed). Afterwards, osimertinib will be continued as standard of care until disease progression or intolerable toxicity. The primary endpoint is PFS. Secondary endpoints include overall survival, response rate, safety, and quality of life. Concomitant translational research will be performed to identify patterns of mutational evolution in ctDNA upon disease progression or ctDNA persistence. Enrollment started in December 2021. DISCUSSION: The PACE-LUNG trial is designed to evaluate the efficacy and safety of a biomarker-driven strategy for therapy escalation in patients at high risk for early treatment failure. This approach aims not only to improve treatment outcomes, but also to limit the anticipated additional toxicity to high-risk patients. TRIAL REGISTRATION NUMBER: 2019-004757-88 (EudraCT).

Dual-energy CT based material decomposition to differentiate intrahepatic cholangiocarcinoma from hepatocellular carcinoma.

PURPOSE: To assess the potential of material decomposition in dual-energy CT (DECT) to differentiate intrahepatic cholangiocarcinoma (iCCA) from hepatocellular carcinoma (HCC). METHOD: In this retrospective study, we included 94 patients (26 female (27.7 %), median age 64.5 (interquartile range 55.5-74.5) years) with either iCCA or HCC who underwent abdominal contrast-enhanced DECT in arterial phase. To test for differences between iCCA (n = 47) and HCC (n = 47), we evaluated mean attenuation and DECT material density values including iodine density (ID), normalized iodine uptake (NIU), fat fraction, and lesion-to-liver parenchyma ratio. Histopathology served as reference standard for all lesions. We used univariate logistic regression models for the outcome iCCA versus HCC. ROC curve analysis was applied to assess discriminative ability of the model. Model accuracy was evaluated by calculating the Brier score. Youden index was applied to establish thresholds to differentiate between iCCA and HCC. RESULTS: Comparison of quantitative image parameters revealed significant differences between iCCA and HCC for ID (1.6 ± 0.5 mg/ml vs 2.8 ± 0.8 mg/ml, p < 0.001), NIU (14.5 ± 4.8 vs 24.8 ± 10.3, p < 0.001), attenuation (41.9 ± 10.1 HU vs 47.9 ± 8.9 HU, p = 0.003), and fat fraction (12.0 ± 7.8 % vs 9.0 ± 6.4 %, p = 0.045). ROC curve analysis revealed highest ability to differentiate iCCA from HCC for ID (AUC = 0.93, 95 % CI 0.89-0.98). For ID, an optimal threshold of 2.33 mg/dl was determined to discriminate between iCCA and HCC (sensitivity 89.4 %, specificity 76.6 %). CONCLUSIONS: DECT-based iodine quantification can serve as a tool for the differentiation of iCCA and HCC in contrast-enhanced CT. ID yielded the highest diagnostic performance and may assist in clinical routine CT diagnostics.

Provider variability in the intraoperative use of neuromuscular blocking agents: a retrospective multicentre cohort study.

OBJECTIVE: To assess variability in the intraoperative use of non-depolarising neuromuscular blocking agents (NMBAs) across individual anaesthesia providers, surgeons and hospitals. DESIGN: Retrospective observational cohort study. SETTING: Two major tertiary referral centres, Boston, Massachusetts, USA. PARTICIPANTS: 265 537 adult participants undergoing non-cardiac surgery between October 2005 and September 2017. MAIN OUTCOME MEASURES: We analysed the variances in NMBA use across 958 anaesthesia and 623 surgical providers, across anaesthesia provider types (anaesthesia residents, certified registered nurse anaesthetists, attendings) and across hospitals using multivariable-adjusted mixed effects logistic regression. Intraclass correlations (ICC) were calculated to further quantify the variability in NMBA use that was unexplained by other covariates. Procedure-specific subgroup analyses were performed. RESULTS: NMBAs were used in 183 242 (69%) surgical cases. Variances in NMBA use were significantly higher among individual surgeons than among anaesthesia providers (variance 1.32 (95% CI 1.06 to 1.60) vs 0.24 (95% CI 0.19 to 0.28), p<0.001). Procedure-specific subgroup analysis of hernia repairs, spine surgeries and mastectomies confirmed our findings: the total variance in NMBA use that was unexplained by the covariate model was higher for surgeons versus anaesthesia providers (ICC 37.0% vs 13.0%, 69.7% vs 25.5%, 69.8% vs 19.5%, respectively; p<0.001). Variances in NMBA use were also partially explained by the anaesthesia provider's hospital network (Massachusetts General Hospital: variance 0.35 (95% CI 0.27 to 0.43) vs Beth Israel Deaconess Medical Center: 0.15 (95% CI 0.12 to 0.19); p<0.001). Across provider types, surgeons showed the highest variance, and anaesthesia residents showed the lowest variance in NMBA use. CONCLUSIONS: There is wide variability across individual surgeons and anaesthesia providers and institutions in the use of NMBAs, which could not sufficiently be explained by a large number of patient-related and procedure-related characteristics, but may instead be driven by preference. Surgeons may have a stronger influence on a key aspect of anaesthesia management than anticipated.

Effects of night surgery on postoperative mortality and morbidity: a multicentre cohort study.

BACKGROUND: Surgery at night (incision time 17:00 to 07:00 hours) may lead to increased postoperative mortality and morbidity. Mechanisms explaining this association remain unclear. METHODS: We conducted a multicentre retrospective cohort study of adult patients undergoing non-cardiac surgery with general anaesthesia at two major, competing tertiary care hospital networks. In primary analysis, we imputed missing data and determined whether exposure to night surgery affects 30-day mortality using a mixed-effects model with individual anaesthesia and surgical providers as random effects. Secondary outcomes were 30-day morbidity and the mediating effect of blood transfusion rates and provider handovers on the effect of night surgery on outcomes. We further tested for effect modification by surgical setting. RESULTS: Among 350 235 participants in the primary imputed cohort, the mortality rate was 0.9% (n=2804/322 327) after day and 3.4% (n=940/27 908) after night surgery. Night surgery was associated with an increased risk of mortality (ORadj 1.26, 95% CI 1.15 to 1.38, p<0.001). In secondary analyses, night surgery was associated with increased morbidity (ORadj 1.41, 95% CI 1.33 to 1.48, p<0.001). The proportion of patients receiving intraoperative blood transfusion and anaesthesia handovers were higher during night-time, mediating 9.4% (95% CI 4.7% to 14.2%, p<0.001) of the effect of night surgery on 30-day mortality and 8.4% (95% CI 6.7% to 10.1%, p<0.001) of its effect on morbidity. The primary association was modified by the surgical setting (p-for-interaction<0.001), towards a greater effect in patients undergoing ambulatory/same-day surgery (ORadj 1.81, 95% CI 1.39 to 2.35) compared with inpatients (ORadj 1.17, 95% CI 1.02 to 1.34). CONCLUSIONS: Night surgery was associated with an increased risk of postoperative mortality and morbidity. The effect was independent of case acuity and was mediated by potentially preventable factors: higher blood transfusion rates and more frequent provider handovers.

Drosophila Cyclin J is a mitotically stable Cdk1 partner without essential functions.

Cyclin J is a cyclin family member that appears to have evolved before the metazoan radiation. Its evolutionary conservation argues for an important role but functional characterizations of Cyclin J have remained very limited. In Drosophila, Cyclin J is expressed only in females. Using transgenic Drosophila lines expressing Cyclin J versions with N- or C-terminal GFP extensions, we demonstrate that it is expressed exclusively in the germline. After low level expression in all nuclei within the germarium, it gets highly enriched in the germinal vesicle within the oocyte until stage 12 of oogenesis, followed by disappearance after germinal vesicle breakdown before the first meiotic division. Surprisingly, Cyclin J is not required for female fertility. Chromosome segregation during female meiosis, as well as the rapid early embryonic cell cycles after fertilization, occurs normally in the complete absence of Cyclin J. Cyclin J with EGFP fused at either N- or C-terminus binds to Cdk1 and not to Cdk2. However, in contrast to the other known Cdk1 partners, the A- and B-type cyclins, Cyclin J is not degraded during mitosis.

Study protocol for a randomised controlled trial evaluating the effects of the orexin receptor antagonist suvorexant on sleep architecture and delirium in the intensive care unit.

INTRODUCTION: Insomnia frequently occurs in patients admitted to an intensive care unit (ICU). Sleep-promoting agents may reduce rapid eye movement sleep and have deliriogenic effects. Suvorexant (Belsomra) is an orexin receptor antagonist with Food and Drug Administration (FDA) approval for the treatment of adult insomnia, which improves sleep onset and maintenance as well as subjective measures of quality of sleep. This trial will evaluate the efficacy of postoperative oral suvorexant treatment on night-time wakefulness after persistent sleep onset as well as the incidence and duration of delirium among adult cardiac surgical patients. METHODS AND ANALYSIS: In this single-centre, randomised, double-blind, placebo-controlled trial, we will enrol 120 patients, aged 60 years or older, undergoing elective cardiac surgery with planned postoperative admission to the ICU. Participants will be randomised to receive oral suvorexant (20 mg) or placebo one time a day starting the night after extubation. The primary outcome will be wakefulness after persistent sleep onset. The secondary outcome will be total sleep time. Exploratory outcomes will include time to sleep onset, incidence of postoperative in-hospital delirium, number of delirium-free days and subjective sleep quality. ETHICS AND DISSEMINATION: Ethics approval was obtained through the 'Committee on Clinical Investigations' at Beth Israel Deaconess Medical Center (protocol number 2019P000759). The findings will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: This trial has been registered at clinicaltrials.gov on 17 September 2019 (NCT04092894).