Shock volume: Patient-specific cumulative hypoperfusion predicts organ dysfunction in a prospective cohort of multiply injured patients

BACKGROUND: Multiply injured patients are at risk of developing hemorrhagic shock and organ dysfunction. We determined how cumulative hypoperfusion predicted organ dysfunction by integrating serial Shock Index measurements. METHODS: In this study, we calculated shock volume (SHVL) which is a patient-specific index that quantifies cumulative hypoperfusion by integrating abnormally elevated Shock Index (heart rate/systolic blood pressure ≥ 0.9) values acutely after injury. Shock volume was calculated at three hours (3 hr), six hours (6 hr), and twenty-four hours (24 hr) after injury. Organ dysfunction was quantified using Marshall Organ Dysfunction Scores averaged from days 2 through 5 after injury (aMODSD2–D5). Logistic regression was used to determine correspondence of 3hrSHVL, 6hrSHVL, and 24hrSHVL to organ dysfunction. We compared correspondence of SHVL to organ dysfunction with traditional indices of shock including the initial base deficit (BD) and the lowest pH measurement made in the first 24 hr after injury (minimum pH). RESULTS: SHVL at all three time intervals demonstrated higher correspondence to organ dysfunction (R2 = 0.48 to 0.52) compared to initial BD (R2 = 0.32) and minimum pH (R2 = 0.32). Additionally, we compared predictive capabilities of SHVL, initial BD and minimum pH to identify patients at risk of developing high-magnitude organ dysfunction by constructing receiver operator characteristic curves. SHVL at six hours and 24 hours had higher area under the curve compared to initial BD and minimum pH. CONCLUSION: SHVL is a non-invasive metric that can predict anticipated organ dysfunction and identify patients at risk for high-magnitude organ dysfunction after injury. LEVEL OF EVIDENCE: Prognostic study, level III

SHOCK VOLUME: A PRECISION MEDICINE BASED INDEX THAT PREDICTS TRANSFUSION REQUIREMENTS AND ORGAN DYSFUNCTION IN MULTIPLY INJURED PATIENTS

poster abstractIntroduction: Multiply injured patients (MIPs) in hemorrhagic shock develop oxygen debt, which causes organ dysfunction and can lead to death. Clinicians monitor hypoperfusion by interpreting progression of traditional hemodynamic measures along with serum markers of hypoperfusion, which reflect current hemodynamic and metabolic status. However, these indices are sampled at discrete time points and poorly reflect cumulative hypoperfusion. Shock Volume (SV) is a novel, non-invasive, patient-specific index developed to quantify cumulative hypoperfusion. SV integrates the time and magnitude of shock index (Heart Rate/Systolic Blood Pressure) values above 0.9 (known threshold of hypoperfusion) using serial individual vital sign data. SV can be monitored in real time to assess ongoing hypoperfusion. The goal of this study was to determine how SV corresponded to transfusion requirements and organ dysfunction. Methods: SV was measured in six hour increments for 48 hours after injury in a retrospective cohort of 74 MIPs (18-65; Injury Severity Score > 18). SV was compared to base deficit (BD) in predicting mass transfusions (MT) and critical administration transfusions (CATs). Presence of multiple organ failure (MOF) was determined using the Denver Organ Failure assessment score, while Sequential Organ Failure Assessment scores were used to determine magnitude of organ dysfunction. Results: Patients who had accumulated 40 units of SV within six hours of injury and 100 units of SV within twelve hours of injury were at high risk for requiring MT or multiple CATs. SV measurements were equally sensitive and specific as compared to BD values in predicting transfusions. SV measurements at six hours after injury stratified patients at risk for MOF and corresponded to the magnitude of organ failure. Conclusions: SV is a patient-specific index that can be quantified in real-time in critically injured patients. SV is a non-invasive surrogate for cumulative hypoperfusion and predicts high volume transfusions and organ dysfunction

The Incidence and Incubation Period of False Positive Cultures in Shoulder Surgery

Background Postoperative shoulder infection (PSI) is a significant complication requiring timely identification and treatment. Indolent infections such as those involving Cutibacterium acnes (C. acnes, recently reclassified from Propionibacterium acnes 1) provide a diagnostic dilemma as they present differently without the acute symptoms associated with most postoperative bone and joint infections. Furthermore, C. acnes is thought to be a common contaminant isolated from intraoperative cultures. With no consensus algorithm, long hold cultures play a major role in guiding management decisions in potential PSI. Our study seeks to determine the incidence of positive cultures in both open and arthroscopic procedures in non-infected patients as well as clarify whether or not an increase in the incubation time frame leads to an increased rate of culture growth. Method ology: One hundred patients were prospectively enrolled into either an open and arthroscopic procedure group. Patients with abnormal inflammatory labs, history of previous shoulder surgery, or corticosteroid injection within six months of surgery were excluded from the study. Three cultures were obtained for each patient (1superficial tissue culture, 2- tissue culture, and 3- “sterile” control swab). Cultures were held for 28 days and checked on regular intervals. All patients were followed clinically for 6 months to ensure no signs of postoperative infection. Results Ultimately ninety-five patients were included in the final analysis. The false-positive rate in open shoulder surgery was 17.02% and arthroscopic shoulder surgery was 10.4%. The incidence of positive C. acnes cultures was 6.4% in the open group while C. acnes was not isolated in the arthroscopic group. All positive bacterial cultures were reported within seven days of collection. One culture was positive for “mold” at 26 days. Conclusion A relatively high false-positive culture rate occurred in both open and arthroscopic shoulder surgery. C. acnes was the most commonly identified bacteria in cultures in the open surgery group. Knowledge of one’s own institutional false-positive culture rate could be important in avoiding potentially inappropriate treatment. Additionally, we found that holding cultures longer than 14 days did not lead to an increased rate of false positive culture results

Insights into the association between coagulopathy and inflammation: abnormal clot mechanics are a warning of immunologic dysregulation following major injury

Background: Severe injury initiates a complex physiologic response encompassing multiple systems and varies phenotypically between patients. Trauma-induced coagulopathy may be an early warning of a poorly coordinated response at the molecular level, including a deleterious immunologic response and worsening of shock states. The onset of trauma-induced coagulopathy (TIC) may be subtle however. In previous work, we identified an early warning sign of coagulopathy from the admission thromboelastogram, called the MAR ratio. We hypothesized that a low MAR ratio would be associated with specific derangements in the inflammatory response. Methods: In this prospective, observational study, 88 blunt trauma patients admitted to the intensive care unit (ICU) were identified. Concentrations of inflammatory mediators were recorded serially over the course of a week and the MAR ratio was calculated from the admission thromboelastogram. Correlation analysis was used to assess the relationship between MAR and inflammatory mediators. Dynamic network analysis was used to assess coordination of immunologic response. Results: Seventy-nine percent of patients were male and mean age was 37 years (SD 12). The mean ISS was 30.2 (SD 12) and mortality was 7.2%. CRITICAL patients (MAR ratio ≤14.2) had statistically higher shock volumes at three time points in the first day compared to NORMAL patients (MAR ratio >14.2). CRITICAL patients had significant differences in IL-6 (P=0.0065), IL-8 (P=0.0115), IL-10 (P=0.0316) and MCP-1 (P=0.0039) concentrations compared to NORMAL. Differences in degree of expression and discoordination of immune response continued in CRITICAL patients throughout the first day. Conclusions: The admission MAR ratio may be the earliest warning signal of a pathologic inflammatory response associated with hypoperfusion and TIC. A low MAR ratio is an early indication of complicated dysfunction of multiple molecular processes following trauma

A global reference for human genetic variation

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.We thank the many people who were generous with contributing their samples to the project: the African Caribbean in Barbados; Bengali in Bangladesh; British in England and Scotland; Chinese Dai in Xishuangbanna, China; Colombians in Medellin, Colombia; Esan in Nigeria; Finnish in Finland; Gambian in Western Division – Mandinka; Gujarati Indians in Houston, Texas, USA; Han Chinese in Beijing, China; Iberian populations in Spain; Indian Telugu in the UK; Japanese in Tokyo, Japan; Kinh in Ho Chi Minh City, Vietnam; Luhya in Webuye, Kenya; Mende in Sierra Leone; people with African ancestry in the southwest USA; people with Mexican ancestry in Los Angeles, California, USA; Peruvians in Lima, Peru; Puerto Ricans in Puerto Rico; Punjabi in Lahore, Pakistan; southern Han Chinese; Sri Lankan Tamil in the UK; Toscani in Italia; Utah residents (CEPH) with northern and western European ancestry; and Yoruba in Ibadan, Nigeria. Many thanks to the people who contributed to this project: P. Maul, T. Maul, and C. Foster; Z. Chong, X. Fan, W. Zhou, and T. Chen; N. Sengamalay, S. Ott, L. Sadzewicz, J. Liu, and L. Tallon; L. Merson; O. Folarin, D. Asogun, O. Ikpwonmosa, E. Philomena, G. Akpede, S. Okhobgenin, and O. Omoniwa; the staff of the Institute of Lassa Fever Research and Control (ILFRC), Irrua Specialist Teaching Hospital, Irrua, Edo State, Nigeria; A. Schlattl and T. Zichner; S. Lewis, E. Appelbaum, and L. Fulton; A. Yurovsky and I. Padioleau; N. Kaelin and F. Laplace; E. Drury and H. Arbery; A. Naranjo, M. Victoria Parra, and C. Duque; S. Däkel, B. Lenz, and S. Schrinner; S. Bumpstead; and C. Fletcher-Hoppe. Funding for this work was from the Wellcome Trust Core Award 090532/Z/09/Z and Senior Investigator Award 095552/Z/11/Z (P.D.), and grants WT098051 (R.D.), WT095908 and WT109497 (P.F.), WT086084/Z/08/Z and WT100956/Z/13/Z (G.M.), WT097307 (W.K.), WT0855322/Z/08/Z (R.L.), WT090770/Z/09/Z (D.K.), the Wellcome Trust Major Overseas program in Vietnam grant 089276/Z.09/Z (S.D.), the Medical Research Council UK grant G0801823 (J.L.M.), the UK Biotechnology and Biological Sciences Research Council grants BB/I02593X/1 (G.M.) and BB/I021213/1 (A.R.L.), the British Heart Foundation (C.A.A.), the Monument Trust (J.H.), the European Molecular Biology Laboratory (P.F.), the European Research Council grant 617306 (J.L.M.), the Chinese 863 Program 2012AA02A201, the National Basic Research program of China 973 program no. 2011CB809201, 2011CB809202 and 2011CB809203, Natural Science Foundation of China 31161130357, the Shenzhen Municipal Government of China grant ZYC201105170397A (J.W.), the Canadian Institutes of Health Research Operating grant 136855 and Canada Research Chair (S.G.), Banting Postdoctoral Fellowship from the Canadian Institutes of Health Research (M.K.D.), a Le Fonds de Recherche duQuébec-Santé (FRQS) research fellowship (A.H.), Genome Quebec (P.A.), the Ontario Ministry of Research and Innovation – Ontario Institute for Cancer Research Investigator Award (P.A., J.S.), the Quebec Ministry of Economic Development, Innovation, and Exports grant PSR-SIIRI-195 (P.A.), the German Federal Ministry of Education and Research (BMBF) grants 0315428A and 01GS08201 (R.H.), the Max Planck Society (H.L., G.M., R.S.), BMBF-EPITREAT grant 0316190A (R.H., M.L.), the German Research Foundation (Deutsche Forschungsgemeinschaft) Emmy Noether Grant KO4037/1-1 (J.O.K.), the Beatriu de Pinos Program grants 2006 BP-A 10144 and 2009 BP-B 00274 (M.V.), the Spanish National Institute for Health Research grant PRB2 IPT13/0001-ISCIII-SGEFI/FEDER (A.O.), Ewha Womans University (C.L.), the Japan Society for the Promotion of Science Fellowship number PE13075 (N.P.), the Louis Jeantet Foundation (E.T.D.), the Marie Curie Actions Career Integration grant 303772 (C.A.), the Swiss National Science Foundation 31003A_130342 and NCCR “Frontiers in Genetics” (E.T.D.), the University of Geneva (E.T.D., T.L., G.M.), the US National Institutes of Health National Center for Biotechnology Information (S.S.) and grants U54HG3067 (E.S.L.), U54HG3273 and U01HG5211 (R.A.G.), U54HG3079 (R.K.W., E.R.M.), R01HG2898 (S.E.D.), R01HG2385 (E.E.E.), RC2HG5552 and U01HG6513 (G.T.M., G.R.A.), U01HG5214 (A.C.), U01HG5715 (C.D.B.), U01HG5718 (M.G.), U01HG5728 (Y.X.F.), U41HG7635 (R.K.W., E.E.E., P.H.S.), U41HG7497 (C.L., M.A.B., K.C., L.D., E.E.E., M.G., J.O.K., G.T.M., S.A.M., R.E.M., J.L.S., K.Y.), R01HG4960 and R01HG5701 (B.L.B.), R01HG5214 (G.A.), R01HG6855 (S.M.), R01HG7068 (R.E.M.), R01HG7644 (R.D.H.), DP2OD6514 (P.S.), DP5OD9154 (J.K.), R01CA166661 (S.E.D.), R01CA172652 (K.C.), P01GM99568 (S.R.B.), R01GM59290 (L.B.J., M.A.B.), R01GM104390 (L.B.J., M.Y.Y.), T32GM7790 (C.D.B., A.R.M.), P01GM99568 (S.R.B.), R01HL87699 and R01HL104608 (K.C.B.), T32HL94284 (J.L.R.F.), and contracts HHSN268201100040C (A.M.R.) and HHSN272201000025C (P.S.), Harvard Medical School Eleanor and Miles Shore Fellowship (K.L.), Lundbeck Foundation Grant R170-2014-1039 (K.L.), NIJ Grant 2014-DN-BX-K089 (Y.E.), the Mary Beryl Patch Turnbull Scholar Program (K.C.B.), NSF Graduate Research Fellowship DGE-1147470 (G.D.P.), the Simons Foundation SFARI award SF51 (M.W.), and a Sloan Foundation Fellowship (R.D.H.). E.E.E. is an investigator of the Howard Hughes Medical Institute

Bedrock controls on subglacial landform distribution and geomorphological processes : evidence from the Late Devensian Irish Sea Ice Stream

Ice streams play an important role as regulators of the behaviour of modern ice sheets, taking the form of corridors of fast flowing ice. Similar zones of fast moving ice have also been recognised draining the margins of the Late Devensian British and Irish Ice Sheet. Although the geomorphological and sedimentary signatures of palaeo ice streams have received significant attention, allowing the identification of these former ice streams, the influence of bedrock geology on the processes occurring beneath these palaeo ice streams is less well understood, even though subglacial geology has been shown to control the location ice streams within the West Antarctic Ice Steam. This paper highlights the role played by bedrock geology on landform distribution beneath a much older ice stream, the Late Devensian Irish Sea Ice Stream. The spatial relationships displayed between subglacial landforms and bedrock geology are described from Anglesey, northwest Wales, and the Rhins of Galloway, southwest Scotland; both sites occur close to the eastern margin of this Irish Sea Ice Stream. A link has been established between landform morphology and distribution, and the disposition of the main tectonostratigraphical units within the bedrock. Changes in landform morphology are shown to have been locally controlled by large-scale faults and/or major lithological boundaries, with less durable bedrock lithologies controlling the location and lateral extent of relatively faster flowing portions of the ice stream

Early Immunologic Response in Multiply Injured Patients With Orthopaedic Injuries Is Associated With Organ Dysfunction.

OBJECTIVES: To quantify the acute immunologic biomarker response in multiply injured patients with axial and lower extremity fractures and to explore associations with adverse short-term outcomes including organ dysfunction and nosocomial infection (NI). DESIGN: Prospective cohort study. SETTING: Level 1 academic trauma center. PATIENTS: Consecutive multiply injured patients, 18-55 years of age, with major pelvic and lower extremity orthopaedic injuries (all pelvic/acetabular fractures, operative femur and tibia fractures) that presented as a trauma activation and admitted to the intensive care unit from April 2015 through October 2016. Sixty-one patients met inclusion criteria. INTERVENTION: Blood was collected upon presentation to the hospital and at the following time points: 8, 24, 48 hours, and daily during intensive care unit admission. Blood was processed by centrifugation, separation into 1.0-mL plasma aliquots, and cryopreserved within 2 hours of collection. MAIN OUTCOME MEASUREMENTS: Plasma analyses of protein levels of cytokines/chemokines were performed using a Luminex panel Bioassay of 20 immunologic mediators. Organ dysfunction was measured by the Marshall Multiple Organ Dysfunction score (MODScore) and nosocomial infection (NI) was recorded. Patients were stratified into low (MODS ≤ 4; n = 34) and high (MODS \u3e 4; n = 27) organ dysfunction groups. RESULTS: The MODS \u3e4 group had higher circulating levels of interleukin (IL)-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), IL-1 receptor antagonist (IL-1RA), and monokine induced by interferon gamma (MIG) compared with the MODS ≤4 group at nearly all time points. MODS \u3e4 exhibited lower levels of IL-21 and IL-22 compared with MODS ≤4. Patients who developed NI (n = 24) had higher circulating concentrations of IL-10, MIG, and high mobility group box 1 (HMGB1) compared with patients who did not develop NI (n = 37). CONCLUSIONS: Temporal quantification of immune mediators identified 8 biomarkers associated with greater levels of organ dysfunction in polytrauma patients with major orthopaedic injuries. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence

Insights into the association between coagulopathy and inflammation: abnormal clot mechanics are a warning of immunologic dysregulation following major injury.

BackgroundSevere injury initiates a complex physiologic response encompassing multiple systems and varies phenotypically between patients. Trauma-induced coagulopathy may be an early warning of a poorly coordinated response at the molecular level, including a deleterious immunologic response and worsening of shock states. The onset of trauma-induced coagulopathy (TIC) may be subtle however. In previous work, we identified an early warning sign of coagulopathy from the admission thromboelastogram, called the MAR ratio. We hypothesized that a low MAR ratio would be associated with specific derangements in the inflammatory response.MethodsIn this prospective, observational study, 88 blunt trauma patients admitted to the intensive care unit (ICU) were identified. Concentrations of inflammatory mediators were recorded serially over the course of a week and the MAR ratio was calculated from the admission thromboelastogram. Correlation analysis was used to assess the relationship between MAR and inflammatory mediators. Dynamic network analysis was used to assess coordination of immunologic response.ResultsSeventy-nine percent of patients were male and mean age was 37 years (SD 12). The mean ISS was 30.2 (SD 12) and mortality was 7.2%. CRITICAL patients (MAR ratio ≤14.2) had statistically higher shock volumes at three time points in the first day compared to NORMAL patients (MAR ratio >14.2). CRITICAL patients had significant differences in IL-6 (P=0.0065), IL-8 (P=0.0115), IL-10 (P=0.0316) and MCP-1 (P=0.0039) concentrations compared to NORMAL. Differences in degree of expression and discoordination of immune response continued in CRITICAL patients throughout the first day.ConclusionsThe admission MAR ratio may be the earliest warning signal of a pathologic inflammatory response associated with hypoperfusion and TIC. A low MAR ratio is an early indication of complicated dysfunction of multiple molecular processes following trauma