Extracellular RNA Sensing Mediates Inflammation and Organ Injury in a Murine Model of Polytrauma.

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma-bone fracture, muscle crush injury, and bowel ischemia-induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential expression of numerous miRNAs after severe trauma. Plasma exRNA isolated from trauma mice induced a dose-dependent cytokine production in macrophages, which was almost abolished in TLR7-deficient cells but unchanged in TLR3-deficient cells. Moreover, RNase or specific miRNA inhibitors against the selected proinflammatory miRNAs (i.e., miR-7a-5p, miR-142, let-7j, miR-802, and miR-146a-5p) abolished or attenuated trauma plasma exRNA-induced cytokine production, respectively. Bioinformatic analyses of a group of miRNAs based on cytokine readouts revealed that high uridine abundance (>40%) is a reliable predictor in miRNA mimic-induced cytokine and complement production. Finally, compared with the wild-type, TLR7-knockout mice had attenuated plasma cytokine storm and reduced lung and hepatic injury after polytrauma. These data suggest that endogenous plasma exRNA of severely injured mice and ex-miRNAs with high uridine abundance prove to be highly proinflammatory. TLR7 sensing of plasma exRNA and ex-miRNAs activates innate immune responses and plays a role in inflammation and organ injury after trauma.

Common Data Elements for Disorders of Consciousness: Recommendations from the Working Group on Physiology and Big Data.

BACKGROUND: The implementation of multimodality monitoring in the clinical management of patients with disorders of consciousness (DoC) results in physiological measurements that can be collected in a continuous and regular fashion or even at waveform resolution. Such data are considered part of the "Big Data" available in intensive care units and are potentially suitable for health care-focused artificial intelligence research. Despite the richness in content of the physiological measurements, and the clinical implications shown by derived metrics based on those measurements, they have been largely neglected from previous attempts in harmonizing data collection and standardizing reporting of results as part of common data elements (CDEs) efforts. CDEs aim to provide a framework for unifying data in clinical research and help in implementing a systematic approach that can facilitate reliable comparison of results from clinical studies in DoC as well in international research collaborations. METHODS: To address this need, the Neurocritical Care Society's Curing Coma Campaign convened a multidisciplinary panel of DoC "Physiology and Big Data" experts to propose CDEs for data collection and reporting in this field. RESULTS: We report the recommendations of this CDE development panel and disseminate CDEs to be used in physiologic and big data studies of patients with DoC. CONCLUSIONS: These CDEs will support progress in the field of DoC physiologic and big data and facilitate international collaboration.

Overlapping Physiologic Signs of Sepsis and Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury: Exploring A Clinical Conundrum.

BACKGROUND: Paroxysmal sympathetic hyperactivity (PSH) occurs in a subset of patients with traumatic brain injury (TBI) and is associated with worse outcomes. Sepsis is also associated with worse outcomes after TBI and shares several physiologic features with PSH, potentially creating diagnostic confusion and suboptimal management of each. This is the first study to directly investigate the interaction between PSH and infection using robust diagnostic criteria. METHODS: We performed a retrospective cohort study of patients with TBI admitted to a level I trauma center intensive care unit with hospital length of stay of at least 2 weeks. From January 2016 to July 2018, 77 patients diagnosed with PSH were 1:1 matched by age and Glasgow Coma Scale to 77 patients without PSH. Trauma infectious diseases subspecialists prospectively documented assessments corroborating diagnoses of infection. Extracted data including incidence, timing, classification, and anatomical source of infections were compared according to PSH diagnosis. We also evaluated daily PSH clinical feature severity scores and systemic inflammatory response syndrome (SIRS) criteria and compared values for patients with and without confirmed infection, stratified by PSH diagnosis. RESULTS: During the first 2 weeks of hospitalization, there were no differences in rates of suspected (62%) nor confirmed (48%) infection between patients with PSH and controls. Specific treatments for PSH were initiated on median hospital day 7 and for confirmed infections on median hospital day 8. SIRS criteria could identify infection only in patients who were not diagnosed with PSH. CONCLUSIONS: In the presence of brain injury-induced autonomic nervous system dysregulation, the initiation and continuation of antimicrobial therapy is a challenging clinical decision, as standard physiologic markers of sepsis do not distinguish infected from noninfected patients with PSH, and these entities often present around the same time. Clinicians should be aware that PSH is a potential driver of SIRS, and familiarity with its diagnostic criteria as proposed by the PSH assessment measure is important. Management by a multidisciplinary team attentive to these issues may reduce rates of inappropriate antibiotic usage and misdiagnoses.

Leveraging Continuous Vital Sign Measurements for Real-Time Assessment of Autonomic Nervous System Dysfunction After Brain Injury: A Narrative Review of Current and Future Applications.

Subtle and profound changes in autonomic nervous system (ANS) function affecting sympathetic and parasympathetic homeostasis occur as a result of critical illness. Changes in ANS function are particularly salient in neurocritical illness, when direct structural and functional perturbations to autonomic network pathways occur and may herald impending clinical deterioration or intervenable evolving mechanisms of secondary injury. Sympathetic and parasympathetic balance can be measured quantitatively at the bedside using multiple methods, most readily by extracting data from electrocardiographic or photoplethysmography waveforms. Work from our group and others has demonstrated that data-analytic techniques can identify quantitative physiologic changes that precede clinical detection of meaningful events, and therefore may provide an important window for time-sensitive therapies. Here, we review data-analytic approaches to measuring ANS dysfunction from routine bedside physiologic data streams and integrating this data into multimodal machine learning-based model development to better understand phenotypical expression of pathophysiologic mechanisms and perhaps even serve as early detection signals. Attention will be given to examples from our work in acute traumatic brain injury on detection and monitoring of paroxysmal sympathetic hyperactivity and prediction of neurologic deterioration, and in large hemispheric infarction on prediction of malignant cerebral edema. We also discuss future clinical applications and data-analytic challenges and future directions.

Dynamic Intracranial Pressure Waveform Morphology Predicts Ventriculitis.

BACKGROUND: Intracranial pressure waveform morphology reflects compliance, which can be decreased by ventriculitis. We investigated whether morphologic analysis of intracranial pressure dynamics predicts the onset of ventriculitis. METHODS: Ventriculitis was defined as culture or Gram stain positive cerebrospinal fluid, warranting treatment. We developed a pipeline to automatically isolate segments of intracranial pressure waveforms from extraventricular catheters, extract dominant pulses, and obtain morphologically similar groupings. We used a previously validated clinician-supervised active learning paradigm to identify metaclusters of triphasic, single-peak, or artifactual peaks. Metacluster distributions were concatenated with temperature and routine blood laboratory values to create feature vectors. A L2-regularized logistic regression classifier was trained to distinguish patients with ventriculitis from matched controls, and the discriminative performance using area under receiver operating characteristic curve with bootstrapping cross-validation was reported. RESULTS: Fifty-eight patients were included for analysis. Twenty-seven patients with ventriculitis from two centers were identified. Thirty-one patients with catheters but without ventriculitis were selected as matched controls based on age, sex, and primary diagnosis. There were 1590 h of segmented data, including 396,130 dominant pulses in patients with ventriculitis and 557,435 pulses in patients without ventriculitis. There were significant differences in metacluster distribution comparing before culture-positivity versus during culture-positivity (p < 0.001) and after culture-positivity (p < 0.001). The classifier demonstrated good discrimination with median area under receiver operating characteristic 0.70 (interquartile range 0.55-0.80). There were 1.5 true alerts (ventriculitis detected) for every false alert. CONCLUSIONS: Intracranial pressure waveform morphology analysis can classify ventriculitis without cerebrospinal fluid sampling.

Admission Features Associated With Paroxysmal Sympathetic Hyperactivity After Traumatic Brain Injury: A Case-Control Study.

OBJECTIVES: Paroxysmal sympathetic hyperactivity occurs in a subset of critically ill traumatic brain injury patients and has been associated with worse outcomes after traumatic brain injury. The goal of this study was to identify admission risk factors for the development of paroxysmal sympathetic hyperactivity in traumatic brain injury patients. DESIGN: Retrospective case-control study of age- and Glasgow Coma Scale-matched traumatic brain injury patients. SETTING: Neurotrauma ICU at the R. Adams Cowley Shock Trauma Center of the University of Maryland Medical System, January 2016 to July 2018. PATIENTS: Critically ill adult traumatic brain injury patients who underwent inpatient monitoring for at least 14 days were included. Cases were identified based on treatment for paroxysmal sympathetic hyperactivity with institutional first-line therapies and were confirmed by retrospective tabulation of established paroxysmal sympathetic hyperactivity diagnostic and severity criteria. Cases were matched 1:1 by age and Glasgow Coma Scale to nonparoxysmal sympathetic hyperactivity traumatic brain injury controls, yielding 77 patients in each group. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Admission characteristics independently predictive of paroxysmal sympathetic hyperactivity included male sex, higher admission systolic blood pressure, and initial CT evidence of diffuse axonal injury, intraventricular hemorrhage/subarachnoid hemorrhage, complete cisternal effacement, and absence of contusion. Paroxysmal sympathetic hyperactivity cases demonstrated significantly worse neurologic outcomes upon hospital discharge despite being matched for injury severity at admission. CONCLUSIONS: Several anatomical, epidemiologic, and physiologic risk factors for clinically relevant paroxysmal sympathetic hyperactivity can be identified on ICU admission. These features help characterize paroxysmal sympathetic hyperactivity as a clinical-pathophysiologic phenotype associated with worse outcomes after traumatic brain injury.

Enhanced Training Benefits of Video Recording Surgery With Automated Hand Motion Analysis.

BACKGROUND: Hand motion analysis by video recording during surgery has potential for evaluation of surgical performance. The aim was to identify how technical skill during open surgery can be measured unobtrusively by video recording during a surgical procedure. We hypothesized that procedural-step timing, hand movements, instrument use and Shannon entropy differ with expertise and training and are concordant with a performance-based validated individual procedure score. METHODS: Surgeon and non-surgeon participants with varying training and levels of expertise were video recorded performing axillary artery exposure and control (AA) on un-preserved cadavers. Color-coded gloves permitted motion-tracking and automated extraction of entropy data from recordings. Timing and instrument-use metrics were obtained through observational video reviews. Shannon entropy measured speed, acceleration and direction by computer-vision algorithms. Findings were compared with individual procedure score for AA performance RESULTS: Experts had lowest entropy values, idle time, active time and shorter time to divide pectoralis minor, using fewer instruments. Residents improved with training, without reaching expert levels, and showed deterioration 12-18 months later. Individual procedure scores mirrored these results. Non-surgeons differed substantially. CONCLUSIONS: Hand motion entropy and timing metrics discriminate levels of surgical skill and training, and these findings are congruent with individual procedure score evaluations. These measures can be collected using consumer-level cameras and analyzed automatically with free software. Hand motion with video timing data may have widespread application to evaluate resident performance and can contribute to the range of evaluation and testing modalities available to educators, training course designers and surgical quality assurance programs.

Comparison of efficacy from two different dosing regimens of bortezomib: an exposure-response analysis.

Bortezomib is a first-in-class proteasome inhibitor, approved for the treatment of multiple myeloma. The originally approved dosing schedule of bortezomib results in significant toxicities that require dose interruptions and discontinuations. Consequentially, less frequent dosing has been explored to optimise bortezomib's benefit-risk profile. Here, we performed exposure-response analysis to compare the efficacy of the original bortezomib dosing regimen with less frequent dosing of bortezomib over nine 6-week treatment cycles using data from the VISTA clinical trial and the control arm of the ALCYONE clinical trial. The relationship between cumulative bortezomib dose and clinical response was evaluated with a univariate logit model. The median cumulative bortezomib dose was higher in ALCYONE versus VISTA (42·2 vs. 38·5 mg/m2 ) and ALCYONE patients stayed on treatment longer (mean: 7·2 vs. 5·8 cycles). For all endpoints and regimens, probability of clinical response correlated with cumulative bortezomib dose. Similar to results observed for VISTA, overall survival was longer in ALCYONE patients with ≥ 39·0 versus < 39·0 mg/m2 cumulative dose (hazard ratio, 0·119; P < 0·0001). Less frequent bortezomib dosing results in comparable efficacy, and a higher cumulative dose than the originally approved bortezomib dosing schedule, which may be in part be due to reduced toxicity and fewer dose reductions/interruptions.

The gap between what patients know and desire to learn about their cardiac implantable electronic devices.

BACKGROUND: Advancement of digital technology now allows patients to have access to data from their cardiac implantable electronic devices (CIEDs). However, patients' understanding regarding CIED data and perceived personal usability remain unclear. The present study is a prospective survey to examine patients' understanding of their CIEDs and their perception of what is important. METHODS: We screened 400 patients between July and December 2018 who presented to our outpatient clinic for a CIED interrogation. Patients received a one-page questionnaire asking baseline demographics, their perception about their own knowledge about their device, and multiple-choice questions in seven basic categories: type of CIED, original indication, functionality, manufacturer, number of active leads, estimated battery life, and number of shocks received. We compared these answers to their interrogation reports to assess accuracy. We also asked participants what they would like to be aware of regarding their CIED. RESULTS: From this cohort, 344 of 400 (86%) (62.9 ± 12.8 years and 64 % males) agreed to take the survey and were included in the analysis. At baseline, 63.2% agreed or strongly agreed that they were knowledgeable about their devices. The overwhelming majority of patients demonstrated CIED knowledge deficits in at least one content area (n = 294, 86%), or more than two content areas (n = 176, 51%). Patients agreed or strongly agreed that they had a desire to have information regarding each of the following: battery life (84%), activity level (79%), heart rate trend (75%), and ventricular arrhythmias (74%). CONCLUSION: There is a large discrepancy in patients' level of knowledge regarding their CIEDs and their wish to know more details. Future technologies should satisfy providers' goals to educate their patients with basic information and fulfill patients' desire to obtain more data from their CIEDs.

A novel method of calculating stroke volume using point-of-care echocardiography.

BACKGROUND: Point-of-care transthoracic echocardiography (POC-TTE) is essential in shock management, allowing for stroke volume (SV) and cardiac output (CO) estimation using left ventricular outflow tract diameter (LVOTD) and left ventricular velocity time integral (VTI). Since LVOTD is difficult to obtain and error-prone, the body surface area (BSA) or a modified BSA (mBSA) is sometimes used as a surrogate (LVOTDBSA, LVOTDmBSA). Currently, no models of LVOTD based on patient characteristics exist nor have BSA-based alternatives been validated. METHODS: Focused rapid echocardiographic evaluations (FREEs) performed in intensive care unit patients over a 3-year period were reviewed. The age, sex, height, and weight were recorded. Human expert measurement of LVOTD (LVOTDHEM) was performed. An epsilon-support vector regression was used to derive a computer model of the predicted LVOTD (LVOTDCM). Training, testing, and validation were completed. Pearson coefficient and Bland-Altman were used to assess correlation and agreement. RESULTS: Two hundred eighty-seven TTEs with ideal images of the LVOT were identified. LVOTDCM was the best method of SV measurement, with a correlation of 0.87. LVOTDmBSA and LVOTDBSA had correlations of 0.71 and 0.49 respectively. Root mean square error for LVOTDCM, LVOTDmBSA, and LVOTDBSA respectively were 13.3, 37.0, and 26.4. Bland-Altman for LVOTDCM demonstrated a bias of 5.2. LVOTDCM model was used in a separate validation set of 116 ideal images yielding a linear correlation of 0.83 between SVHEM and SVCM. Bland Altman analysis for SVCM had a bias of 2.3 with limits of agreement (LOAs) of - 24 and 29, a percent error (PE) of 34% and a root mean square error (RMSE) of 13.9. CONCLUSIONS: A computer model may allow for SV and CO measurement when the LVOTD cannot be assessed. Further study is needed to assess the accuracy of the model in various patient populations and in comparison to the gold standard pulmonary artery catheter. The LVOTDCM is more accurate with less error compared to BSA-based methods, however there is still a percentage error of 33%. BSA should not be used as a surrogate measure of LVOTD. Once validated and improved this model may improve feasibility and allow hemodynamic monitoring via POC-TTE once it is validated.

Early T precursor acute lymphoblastic leukaemia/lymphoma shows differential immunophenotypic characteristics including frequent CD33 expression and in vitro response to targeted CD33 therapy.

The differential immunophenotypic characteristics of early T precursor (ETP) acute lymphoblastic leukaemia/lymphoma (ALL) remain incompletely characterized. The study group (n = 142) included 106 (74·7%) men and 36 (25·3%) women with a median age of 34·9 years (range, 2-79) at diagnosis. Patients were subtyped by flow cytometry immunophenotyping as follows: 33 (23·2%) ETP; 32 (22·5%) early non-ETP; 60 (42·2%) thymic; and 17 (12·1%) mature. Excepting definitional markers, there was a significant differential expression of the markers CD2, CD10, CD33 and TdT between ETP-ALL and non-ETP-ALL. Positive CD33 expression (≥20% of leukaemic blasts) was detected in 21/33 (63%) ETP-ALL compared with 17/95 (17·9%) non-ETP-ALL (P < 0·001). Notably, targeted anti-CD33 therapy with IMGN779 resulted in significant growth inhibition and increased apoptosis in ETP-ALL cells in vitro. An 11-marker T-ALL immunophenotype score discriminated reliably between ETP and non-ETP ALL. Longitudinal analysis of ETP-ALL cases in this study demonstrated that the immunophenotype may be occasionally dynamic but is largely stable over the disease course. In summary, identification of ETP-ALL might be enhanced by using an 11-marker T-ALL immunophenotype score. CD33 expression is frequent in ETP-ALL, and in vitro data suggest that exploring anti-CD33 therapy in ETP-ALL is warranted.

Linking Big Data and Prediction Strategies: Tools, Pitfalls, and Lessons Learned.

OBJECTIVES: Modern critical care amasses unprecedented amounts of clinical data-so called "big data"-on a minute-by-minute basis. Innovative processing of these data has the potential to revolutionize clinical prognostics and decision support in the care of the critically ill but also forces clinicians to depend on new and complex tools of which they may have limited understanding and over which they have little control. This concise review aims to provide bedside clinicians with ways to think about common methods being used to extract information from clinical big datasets and to judge the quality and utility of that information. DATA SOURCES: We searched the free-access search engines PubMed and Google Scholar using the MeSH terms "big data", "prediction", and "intensive care" with iterations of a range of additional potentially associated factors, along with published bibliographies, to find papers suggesting illustration of key points in the structuring and analysis of clinical "big data," with special focus on outcomes prediction and major clinical concerns in critical care. STUDY SELECTION: Three reviewers independently screened preliminary citation lists. DATA EXTRACTION: Summary data were tabulated for review. DATA SYNTHESIS: To date, most relevant big data research has focused on development of and attempts to validate patient outcome scoring systems and has yet to fully make use of the potential for automation and novel uses of continuous data streams such as those available from clinical care monitoring devices. CONCLUSIONS: Realizing the potential for big data to improve critical care patient outcomes will require unprecedented team building across disparate competencies. It will also require clinicians to develop statistical awareness and thinking as yet another critical judgment skill they bring to their patients' bedsides and to the array of evidence presented to them about their patients over the course of care.

Targeted next-generation sequencing of endometrial cancer and matched circulating tumor DNA: identification of plasma-based, tumor-associated mutations in early stage patients.

There is currently no blood-based marker in routine use for endometrial cancer patients. Such a marker could potentially be used for early detection, but it could also help to track tumor recurrence following hysterectomy. This is important, as extra-vaginal recurrence of endometrial endometrioid adenocarcinoma is usually incurable. This proof-of-principle study was designed to determine if tumor-associated mutations could be detected in cell-free DNA from the peripheral blood of early and late stage endometrial endometrioid carcinoma patients. Approximately 90% of endometrioid carcinomas have at least one mutation in the genes CTNNB1, KRAS, PTEN, or PIK3CA. Using a custom panel targeting 30 hotspot amplicons in these four genes, next-generation sequencing was performed on cell-free DNA extracted from plasma obtained from a peripheral blood draw at the time of hysterectomy and the matching tumor DNA from 48 patients with endometrioid endometrial carcinomas. At least one mutation in the tumor was detected in 45/48 (94%) of patients. Fifteen of 45 patients (33%) had a mutation in the plasma that matched a mutation in the tumor. These same mutations were not detected in the matched negative control buffy coat. Presence of a plasma mutation was significantly associated with advanced stage at hysterectomy, deep myometrial invasion, lymphatic/vascular invasion, and primary tumor size. Detecting a plasma-based mutation was independent of the amount of cell-free DNA isolated from the plasma. Overall, 18% of early stage patients had a mutation detected in the plasma. These results demonstrate that mutations in genes relevant to endometrial cancer can be identified in the peripheral blood of patients at the time of surgery. Future studies can help to determine the post-operative time course of mutation clearance from the peripheral blood and if mutation re-emergence is predictive of recurrence.

Safety and Efficacy of Low-dose Domperidone for Treating Nausea and Vomiting Due to Acute Gastroenteritis in Children.

BACKGROUND: This study was conducted based on a request from the European Medicines Agency to generate robust data on domperidone efficacy in children in the relief of symptoms of nausea and vomiting by assessing the effect of a low-dose and short treatment duration. METHODS: In this randomized, double-blind, phase 3 study, children ages 6 months to 12 years with acute gastroenteritis randomly (1:1) received oral domperidone 0.25 mg/kg with oral rehydration therapy (ORT) or matching placebo thrice daily for 2 to 7 days. The proportion of patients with no vomiting episodes (primary endpoint) and patients ages ≥4 years with no nausea episodes (key secondary endpoint) within 48 hours of first treatment administration were evaluated. RESULTS: The study was terminated early following futility analysis. At early termination, 292 patients randomly received domperidone (n = 147) or placebo (n = 145). The proportion of patients with no vomiting episodes within 48-hours of first treatment administration was similar between domperidone (32.0%) and placebo groups (33.8%). Similarly, there was no significant difference in proportion of patients ages ≥4 years with no nausea episodes within 48 hours of first treatment administration between domperidone (35.7%) and placebo (38.6%). Total 13 patients (domperidone, 3.4% [5/147] vs placebo, 5.5% [8/145]) reported ≥1 treatment-emergent adverse events. No deaths or adverse events of special interest (extrapyramidal symptoms and QT prolongation) were reported. CONCLUSIONS: Low-dose of domperidone with ORT did not significantly differ from placebo in reducing vomiting and nausea episodes in pediatric patients with acute gastroenteritis (AG), and the safety profile was similar between both groups.

Handheld Tissue Oximetry for the Prehospital Detection of Shock and Need for Lifesaving Interventions: Technology in Search of an Indication?

Improved prehospital methods for assessing the need for lifesaving interventions (LSIs) are needed to gain critical lead time in the care of the injured. We hypothesized that threshold values using prehospital handheld tissue oximetry would detect occult shock and predict LSI requirements. This was a prospective observational study of adult trauma patients emergently transported by helicopter. Patients were monitored with a handheld tissue oximeter (InSpectra Spot Check; Hutchinson Technology Inc, Hutchinson, MN), continuous vital signs, and 21 laboratory measurements obtained both in the field with a portable analyzer and at the time of admission. Shock was defined as base excess ≥ 4 or lactate > 3 mmol/L. Eighty-eight patients were enrolled with a median Injury Severity Score of 16 (interquartile range, 5-29). The median hemoglobin saturation in the capillaries, venules, and arterioles (StO2) value for all patients was 82% (interquartile range, 76%-87%; range, 42%-98%). StO2 was abnormal (< 75%) in 18 patients (20%). Eight were hypotensive (9%) and had laboratory-confirmed evidence of occult shock. StO2 correlated poorly with shock threshold laboratory values (r = -0.17; 95% confidence interval, -0.33 to 1.0; P = .94). The area under the receiver operating curve was 0.51 (95% confidence interval, 0.39-0.63) for StO2 < 75% and laboratory-confirmed shock. StO2 was not associated with LSI need on admission when adjusted for multiple covariates, nor was it independently associated with death. Handheld tissue oximetry was not sensitive or specific for identifying patients with prehospital occult shock. These results do not support prehospital StO2 monitoring despite its inclusion in several published guidelines.

Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study.

BACKGROUND: In the LYM-3002 study, the efficacy and safety of frontline bortezomib plus rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were compared in transplant-ineligible patients with untreated, newly diagnosed, mantle cell lymphoma. We report the final overall survival and safety outcomes for patients in the long-term follow-up phase after the primary progression-free-survival endpoint was met. METHODS: LYM-3002 was a randomised, open-label, phase 3 study done at 128 clinical centres in 28 countries in Asia, Europe, North America, and South America. Adult patients with confirmed stage II-IV previously untreated mantle cell lymphoma, Eastern Cooperative Oncology Group performance status score of 2 or less, who were ineligible for bone marrow transplantation, were randomly assigned (1:1) to receive six or eight 21-day cycles of VR-CAP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and bortezomib 1·3 mg/m2, plus oral prednisone 100 mg/m2) or R-CHOP (intravenous vincristine 1·4 mg/m2 [2 mg maximum], rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, plus oral prednisone 100 mg/m2). Randomisation was done according to a computer-generated randomisation schedule prepared by the sponsor; permuted blocks central randomisation was used (block size of 4), and was stratified by International Prognostic Index score and disease stage at diagnosis. The primary endpoint of this final analysis was overall survival, which was analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00722137, and is closed to new participants with follow-up completed. FINDINGS: Between May 22, 2008, and Dec 5, 2011, 487 patients were enrolled and randomly assigned. 268 patients (140 in the VR-CAP group and 128 in the R-CHOP group) were included in the follow-up analysis, which included patients with data available after the primary analysis clinical cutoff date of Dec 2, 2013. After median follow-up of 82·0 months (IQR 74·1-94·2), median overall survival was significantly longer in the VR-CAP group than in the R-CHOP group (90·7 months [95% CI 71·4 to not estimable] vs 55·7 months [47·2 to 68·9]; hazard ratio 0·66 [95% CI 0·51-0·85]; p=0·001). Three new adverse events were reported since the primary analysis cutoff (one each of grade 4 lung adenocarcinoma and grade 4 gastric cancer in the VR-CAP group, and one case of grade 2 pneumonia in the R-CHOP group). 103 (42%) of 243 patients in the VR-CAP group, and 138 (57%) of 244 in the R-CHOP group died; the most common cause of death was progressive disease. INTERPRETATIONS: Compared with R-CHOP, VR-CAP was associated with significantly longer survival, and had a manageable and expected safety profile. Our results support further assessment of VR-CAP in patients with previously untreated mantle cell lymphoma. FUNDING: Janssen Research & Development.

Resuscitative Endovascular Balloon Occlusion of the Aorta Improves Cardiac Compression Fraction Versus Resuscitative Thoracotomy in Patients in Traumatic Arrest.

STUDY OBJECTIVE: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is emerging as an alternative to resuscitative thoracotomy for proximal aortic control in select patients with exsanguinating hemorrhage below the diaphragm. The purpose of this study is to compare interruptions in closed chest compression or open chest cardiac massage during REBOA versus resuscitative thoracotomy. METHODS: From May 2014 to December 2016, patients in arrest who received aortic occlusion with REBOA or resuscitative thoracotomy were included. Total cardiac compression time was defined as the total time that closed chest compression was performed for REBOA patients and the total time that closed chest compression (before resuscitative thoracotomy) and open chest cardiac massage (after thoracotomy) were performed for resuscitative thoracotomy patients. Cardiac compression fraction was defined as the time compressions occurred during the entire resuscitation phase. All resuscitations were captured by multiview, time-stamped videography. RESULTS: Fifty patients with aortic occlusion after arrest were enrolled: 22 REBOA and 28 resuscitative thoracotomy. Most were men (86%) (median age 30.2 years, interquartile range [IQR] 24.9 to 42.3; median Injury Severity Score 27, IQR 16 to 42; neither differed between groups). The median duration of total cardiac compression time was 945 seconds (IQR 697 to 1,357) for REBOA versus 496 seconds (IQR 375 to 933) for resuscitative thoracotomy. During initial resuscitation, compressions occurred 86.5% of the time (SD 9.7%) during resuscitation with REBOA versus 35.7% of the time (SD 16.4%) in patients receiving resuscitative thoracotomy. Cardiac compression fraction improved after open cross clamp in resuscitative thoracotomy patients to 73.2% of the time (SD 18.0%) but remained significantly less than the same period for REBOA (86.7%; SD 9.4%). Mean cardiac compression fraction for REBOA was significantly improved over that for resuscitative thoracotomy (86.2% [SD 9.1%] versus 55.3 [SD 17.1%]; mean difference 31.0%; 95% confidence interval for difference 22.7% to 39.23%; P<.001). Median pause in resuscitation related to procedural tasks was 0 seconds (IQR 0 to 13) for REBOA and 148 seconds (IQR 118 to 223) in resuscitative thoracotomy. CONCLUSION: Total duration of interruptions of cardiac compressions is shorter for patients receiving REBOA versus resuscitative thoracotomy before and during resuscitation with aortic occlusion. Markers for perfusion during resuscitation must be examined to understand the effects of cardiac compressions and aortic occlusion on patients in arrest because of hemorrhagic shock.

Repeat lactate level predicts mortality better than rate of clearance.

BACKGROUND: Lactate clearance has been developed into a marker of resuscitation in trauma, but no study has compared the predictive power of the various clearance calculations. Our objective was to determine which method of calculating lactate clearance best predicted 24-hour and in-hospital mortality after injury. STUDY DESIGN: Retrospective chart review of patients admitted to a Level-1 trauma center directly from the scene of injury from 2010 to 2013 who survived >15min, had an elevated lactate at admission (≥3mmol/L), followed by another measurement within 24h of admission. Lactate clearance was calculated using five models: actual value of the repeat level, absolute clearance, relative clearance, absolute rate, and relative rate. Models were compared using the areas under the respective receiver operating curves (AUCs), with an endpoint of death at 24h and in-hospital mortality. RESULTS: 3910 patients had an elevated admission lactate concentration on admission (mean=5.6±3.0mmol/L) followed by a second measurement (2.7±1.8mmol/L). Repeat absolute measurement best predicted 24-hour (AUC=0.85, 95% CI: 0.84-0.86) and in-hospital death (AUC=0.77; 95% CI, 0.76-0.78). Relative clearance was the best model of lactate clearance (AUC=0.77, 95% CI: 0.75-0.78 and AUC=0.705, 95% CI: 0.69-72, respectively) (p<0.0001 for each). A sensitivity analysis using a range of initial lactate measures yielded similar results. CONCLUSIONS: The absolute value of the repeat lactate measurement had the greatest ability to predict mortality in injured patients undergoing resuscitation.

The use of modified and non-natural nucleotides provide unique insights into pro-mutagenic replication catalyzed by polymerase eta.

This report evaluates the pro-mutagenic behavior of 8-oxo-guanine (8-oxo-G) by quantifying the ability of high-fidelity and specialized DNA polymerases to incorporate natural and modified nucleotides opposite this lesion. Although high-fidelity DNA polymerases such as pol δ and the bacteriophage T4 DNA polymerase replicating 8-oxo-G in an error-prone manner, they display remarkably low efficiencies for TLS compared to normal DNA synthesis. In contrast, pol η shows a combination of high efficiency and low fidelity when replicating 8-oxo-G. These combined properties are consistent with a pro-mutagenic role for pol η when replicating this DNA lesion. Studies using modified nucleotide analogs show that pol η relies heavily on hydrogen-bonding interactions during translesion DNA synthesis. However, nucleobase modifications such as alkylation to the N2 position of guanine significantly increase error-prone synthesis catalyzed by pol η when replicating 8-oxo-G. Molecular modeling studies demonstrate the existence of a hydrophobic pocket in pol η that participates in the increased utilization of certain hydrophobic nucleotides. A model is proposed for enhanced pro-mutagenic replication catalyzed by pol η that couples efficient incorporation of damaged nucleotides opposite oxidized DNA lesions created by reactive oxygen species. The biological implications of this model toward increasing mutagenic events in lung cancer are discussed.