| 1. |
- Lawrenson, Kate, et al.
(författare)
-
Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus
- 2016
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
Tidskriftsartikel (refereegranskat)abstract
- A locus at 19p13 is associated with breast cancer (BC) and ovarian cancer (OC) risk. Here we analyse 438 SNPs in this region in 46,451 BC and 15,438 OC cases, 15,252 BRCA1 mutation carriers and 73,444 controls and identify 13 candidate causal SNPs associated with serous OC (P=9.2 × 10-20), ER-negative BC (P=1.1 × 10-13), BRCA1-associated BC (P=7.7 × 10-16) and triple negative BC (P-diff=2 × 10-5). Genotype-gene expression associations are identified for candidate target genes ANKLE1 (P=2 × 10-3) and ABHD8 (P<2 × 10-3). Chromosome conformation capture identifies interactions between four candidate SNPs and ABHD8, and luciferase assays indicate six risk alleles increased transactivation of the ADHD8 promoter. Targeted deletion of a region containing risk SNP rs56069439 in a putative enhancer induces ANKLE1 downregulation; and mRNA stability assays indicate functional effects for an ANKLE1 3′-UTR SNP. Altogether, these data suggest that multiple SNPs at 19p13 regulate ABHD8 and perhaps ANKLE1 expression, and indicate common mechanisms underlying breast and ovarian cancer risk.
|
|
| 2. |
- Couch, Fergus J., et al.
(författare)
-
Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer
- 2016
-
Ingår i: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 7:11375, s. 1-13
-
Tidskriftsartikel (refereegranskat)abstract
- Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 x 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for similar to 11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
|
|
| 3. |
- Brill, Jason B., et al.
(författare)
-
The Role of TEG and ROTEM in Damage Control Resuscitation
- 2021
-
Ingår i: Shock. - : LIPPINCOTT WILLIAMS & WILKINS. - 1073-2322 .- 1540-0514. ; 56:1S, s. 52-61
-
Tidskriftsartikel (refereegranskat)abstract
- Trauma-induced coagulopathy is associated with very high mortality, and hemorrhage remains the leading preventable cause of death after injury. Directed methods to combat coagulopathy and attain hemostasis are needed. The available literature regarding viscoelastic testing, including thrombelastography (TEG) and rotational thromboelastometry (ROTEM), was reviewed to provide clinically relevant guidance for emergency resuscitation. These tests predict massive transfusion and developing coagulopathy earlier than conventional coagulation testing, within 15 min using rapid testing. They can guide resuscitation after trauma, as well. TEG and ROTEM direct early transfusion of fresh frozen plasma when clinical gestalt has not activated a massive transfusion protocol. Reaction time and clotting time via these tests can also detect clinically significant levels of direct oral anticoagulants. Slowed clot kinetics suggest the need for transfusion of fibrinogen via concentrates or cryoprecipitate. Lowered clot strength can be corrected with platelets and fibrinogen. Finally, viscoelastic tests identify fibrinolysis, a finding associated with significantly increased mortality yet one that no conventional coagulation test can reliably detect. Using these parameters, guided resuscitation begins within minutes of a patients arrival. A growing body of evidence suggests this approach may improve survival while reducing volumes of blood products transfused.
|
|
| 4. |
- Holmes, Michael V., et al.
(författare)
-
Secretory Phospholipase A(2)-IIA and Cardiovascular Disease
- 2013
-
Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 62:21, s. 1966-1976
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives This study sought to investigate the role of secretory phospholipase A(2) (sPLA(2))-IIA in cardiovascular disease. less thanbrgreater than less thanbrgreater thanBackground Higher circulating levels of sPLA(2)-IIA mass or sPLA(2) enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA(2) inhibitor (varespladib) was stopped prematurely for lack of efficacy. less thanbrgreater than less thanbrgreater thanMethods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA(2)-IIA isoenzyme, as an instrumental variable. less thanbrgreater than less thanbrgreater thanResults PLA2G2A rs11573156 C allele associated with lower circulating sPLA(2)-IIA mass (38% to 44%) and sPLA(2) enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA(2)-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. less thanbrgreater than less thanbrgreater thanConclusions Reducing sPLA(2)-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
|
|
| 5. |
- Hörer, Tal M., 1971-, et al.
(författare)
-
Endovascular Resuscitation and Trauma Management (EVTM) : Practical Aspects and Implementation
- 2021
-
Ingår i: Shock. - : Lippincott Williams & Wilkins. - 1073-2322 .- 1540-0514. ; 56:1S, s. 37-41
-
Tidskriftsartikel (refereegranskat)abstract
- In recent years there has been a tremendous increase in hemorrhage control by endovascular methods. Traumatic and non-traumatic hemorrhage is being more frequently managed with endografts, embolization agents and minimal invasive methods. These methods initially were used in hemodynamically stable patients only, whereas now are being implemented in acute settings and hemodynamically unstable patients. The strategy of using endovascular and combined open-endo methods approach for hemodynamic instability in trauma and non-trauma patients has been named EVTM- EndoVascular resuscitation and Trauma Management. The EVTM concept will be presented in this article, describing how it is developed and used, as well as its limitations and future aspects.
|
|
| 6. |
- Kauvar, David, et al.
(författare)
-
Circulatory Trauma: A Paradigm for Understanding the Role of Endovascular Therapy in Hemorrhage Control
- 2021
-
Ingår i: Shock. - : LIPPINCOTT WILLIAMS & WILKINS. - 1073-2322 .- 1540-0514. ; 56:1S, s. 22-29
-
Tidskriftsartikel (refereegranskat)abstract
- The pathophysiology of traumatic hemorrhage is a phenomenon of vascular disruption and the symptom of bleeding represents one or more vascular injuries. In the Circulatory Trauma paradigm traumatic hemorrhage is viewed as injury to the circulatory system and suggests the underlying basis for endovascular hemorrhage control techniques. The question "Where is the patient bleeding?" is replaced by "Which blood vessels are disrupted?" and stopping bleeding becomes a matter of selective vessel access and vascular flow control. Control of traumatic hemorrhage has traditionally been performed via external access to the end organ that is bleeding followed by the application of direct pressure, packing, or clamping and repair of directly affected blood vessels. In the circulatory trauma paradigm, bleeding is seen as disruption to vessels which may be accessed internally, from within the vascular system. A variety of endovascular treatments such as balloon occlusion, embolization, or stent grafting can be used to control hemorrhage throughout the body. This narrative review presents a brief overview of the current role of endovascular therapy in the management of circulatory trauma. The authors draw on their personal experience combined with the last decade of published experiences with the use of endovascular techniques in trauma and present general recommendations for their evolving use. The focus of the review is on the use of endovascular techniques as specific vascular treatments using the circulatory trauma paradigm.
|
|
| 7. |
- McCoy, Christopher Cameron, et al.
(författare)
-
Back to the Future: Whole Blood Resuscitation of the Severely Injured Trauma Patient
- 2021
-
Ingår i: Shock. - : LIPPINCOTT WILLIAMS & WILKINS. - 1073-2322 .- 1540-0514. ; 56:1S
-
Tidskriftsartikel (refereegranskat)abstract
- Following advances in blood typing and storage, whole blood transfusion became available for the treatment of casualties during World War I. While substantially utilized during World War II and the Korean War, whole blood transfusion declined during the Vietnam War as civilian centers transitioned to blood component therapies. Little evidence supported this shift, and recent conflicts in Iraq and Afghanistan have renewed interest in military and civilian applications of whole blood transfusion. Within the past two decades, civilian trauma centers have begun to study transfusion protocols based upon cold-stored, low anti-A/B titer type O whole blood for the treatment of severely injured civilian trauma patients. Early data suggests equivalent or improved resuscitation and hemostatic markers with whole blood transfusion when compared to balanced blood component therapy. Additional studies are taking place to define the optimal way to utilize low-titer type O whole blood in both prehospital and trauma center resuscitation of bleeding patients.
|
|
| 8. |
- Ordonez, Carlos A., et al.
(författare)
-
The Colombian Experience in Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) : The Progression From a Large Caliber to a Low-Profile Device at a Level I Trauma Center
- 2021
-
Ingår i: Shock. - : Lippincott Williams & Wilkins. - 1073-2322 .- 1540-0514. ; 56:1S, s. 42-45
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Resuscitative Endovascular Balloon Occlusion of the Aorta (REBOA) is now performed in many trauma centers, it is used at more than 250 hospitals in the United States and there is an increase rate of publications with the experience in these centers, but there is a gap of knowledge regarding the use of REBOA in Latin-America. This paper endeavors to describe the utilization of REBOA at a high level Latin-American Trauma Center and the transition from a large caliber to a low-profile device with the concomitant reduction in the groin access complications.Methods: A prospective, observational, single-center study was conducted. We included all trauma patients who underwent REBOA. We recorded data from admission parameters, complications, and clinical outcomes.Results: Fifty patients were included. Most of the REBOA catheters were inserted in the operating room [47 (94%)], and the arterial access was done by surgical cutdown [40 (80%)]. All the complications were associated with the catheter of 11 Fr Sheath used in 36 patients [n = 8/36 (22%) vs. n = 0/14 (0%); P = 0.05].Conclusion: REBOA can be used safely in blunt or penetrating thoracic, abdominal, and pelvic trauma. The insertion of a 7 Fr Sheath was associated with lower complications, so its use should be preferred over larger calibers.
|
|
| 9. |
- Roberts, Derek J., et al.
(författare)
-
Endovascular Versus Open: Emergency Department Resuscitative Endovascular Balloon Occlusion of the Aorta or Thoracotomy for Management of Post-Injury Non-compressible Torso Hemorrhage
- 2020
-
Ingår i: JOURNAL OF ENDOVASCULAR RESUSCITATION AND TRAUMA MANAGEMENT. - : OREBRO UNIV HOSPITAL. - 2002-7567. ; 4:2, s. 109-119
-
Forskningsöversikt (refereegranskat)abstract
- Non-compressible torso hemorrhage (NCTH) (i.e. bleeding from anatomical locations not amenable to control by direct pressure or tourniquet application) is a leading cause of potentially preventable death after injury. In select trauma patients with infra-diaphragmatic NCTH-related hemorrhagic shock or traumatic circulatory arrest, occlusion of the aorta proximal to the site of hemorrhage may sustain or restore spontaneous circulation. While the traditional method of achieving proximal aortic occlusion included Emergency Department thoracotomy (EDT) with descending thoracic aortic cross-clamping, resuscitative endovascular balloon occlusion of the aorta (REBOA) affords a less invasive option when thoracotomy is not required for other indications. In this article, we review the innovation, pathophysiologic effects, indications for, and technique of EDT and partial, intermittent, and complete REBOA in injured patients, including recommended methods for reversing aortic occlusion. We also discuss advantages and disadvantages of each of these methods of proximal aortic occlusion and review studies comparing their effectiveness and safety for managing post-injury NCTH. We conclude by providing recommendations as to when each of these methods may be best, when indicated, to manage injured patients with NCTH.
|
|
| 10. |
- Tatum, Danielle, et al.
(författare)
-
Time to Hemorrhage Control in a Hybrid ER System : Is It Time to Change?
- 2021
-
Ingår i: Shock. - : Lippincott Williams & Wilkins. - 1073-2322 .- 1540-0514. ; 56:1S, s. 16-21
-
Tidskriftsartikel (refereegranskat)abstract
- Time to hemorrhage control is critical, as mortality in patients with severe hemorrhage that arrive to trauma centers with sign of life remains over 40%. Prompt identification and management of severe hemorrhage is paramount to reducing mortality. In traditional US trauma systems, the early hospital course of a severely hemorrhaging patient typically proceeds from the trauma resuscitation bay to the operating room or angiography suite with a potential stop for radiological imaging. This protracted journey can prove fatal as it consumes valuable minutes. In contrast to the current US system is a newly developed and increasingly adopted system in Japan called the hybrid emergency room system (HERS). The hybrid ER is equipped to allow resuscitation, imaging, and damage control intervention to occur in the ER without the need to transport the patient to a subsequent destination. The HERS is relatively new and remains restricted to a small number of institutions, limiting the ability to robustly examine impact(s) on patient outcomes. Even if proven to yield superior outcomes, there are significant obstacles to adopting the HERS in the US. Challenges such as the high cost of building and implementing a HER system, return on investment, and the significant differences between the US and Japan in terms of physician training, trauma center, and reimbursement schemes may render the hybrid ER system to be unfeasible in most current trauma centers. Barriers aside, the Japanese hybrid ER system remains the most novel recent advancement in the quest to reduce potentially preventable mortality from hemorrhage.
|
|
