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Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG®) five- and ten-min amplitudes (A5 and A10), and maximum amplitude (MA), using TEG® 5000 technology. We aimed to investigate the performance of A5 and A10 in predicting low MA in severely injured trauma patients and identify optimal cut-off values for hemostatic intervention based on early amplitudes, using the cartridge-based TEG® 6s technology. Adult trauma patients with hemorrhagic shock were included in the iTACTIC randomized controlled trial at six European Level I trauma centers between 2016 and 2018. After admission, patients were randomized to hemostatic therapy guided by conventional coagulation tests (CCT) or viscoelastic hemostatic assays (VHA). Patients with available admission-TEG® 6s data were included in the analysis, regardless of treatment allocation. Low MA was defined as

Purpose: We investigated whether hepcidin and erythroferrone (ERFE) could complement the Athlete Biological Passport (ABP) in indirectly detecting a 130 mL packed red blood cells (RBCs) autologous blood transfusion. Endurance performance was evaluated.Methods: Forty-eight healthy men (n = 24) and women (n = 24) participated. Baseline samples were collected weekly followed by randomization to a blood transfusion (BT, n = 24) or control group (CON, n = 24). Only the BT group donated 450 mL whole blood from which 130 mL RBCs was reinfused four weeks later. Blood samples were collected 3, 7, 14, 21 and 28 days after donation, and 3, 6, and 24 hours and 2, 3, and 6 days following reinfusion. In the CON group samples were collected with the same frequency. Endurance performance was evaluated by a 650-kCal time trial (n = 13) before and one and six days after reinfusion.Results: A time×treatment effect existed (P < 0.05) for hepcidin and ERFE. Hepcidin was increased (P < 0.01) ~110 and 89% six and 24 hours after reinfusion. Using an individual approach (99% specificity, e.g. allowing 1:100 false-positive), sensitivities, i.e. true positives, of 30% and 61% was found for hepcidin and ERFE, respectively. For the ABP, the most sensitive marker was Off-hr score ([Hb] (g·L-1) - 60 × √RET%) (P < 0.05) with a maximal sensitivity of ~58% and ~ 9% following donation and reinfusion, respectively. Combining the findings for hepcidin, ERFE and the ABP yielded a sensitivity across all time-points of 83% following reinfusion in BT. Endurance performance increased 24 hours (+6.4%, P < 0.01) and six days following reinfusion (+5.8%, P < 0.01).Conclusions: Hepcidin and ERFE may serve as biomarkers in an anti-doping context following an ergogenic, small-volume blood transfusion.

Cancer cells fuel their increased need for nucleotide supply by upregulating one-carbon (1C) metabolism, including the enzymes methylenetetrahydrofolate dehydrogenase-cyclohydrolase 1 and 2 (MTHFD1 and MTHFD2). TH9619 is a potent inhibitor of dehydrogenase and cyclohydrolase activities in both MTHFD1 and MTHFD2, and selectively kills cancer cells. Here, we reveal that, in cells, TH9619 targets nuclear MTHFD2 but does not inhibit mitochondrial MTHFD2. Hence, overflow of formate from mitochondria continues in the presence of TH9619. TH9619 inhibits the activity of MTHFD1 occurring downstream of mitochondrial formate release, leading to the accumulation of 10-formyl-tetrahydrofolate, which we term a 'folate trap'. This results in thymidylate depletion and death of MTHFD2-expressing cancer cells. This previously uncharacterized folate trapping mechanism is exacerbated by physiological hypoxanthine levels that block the de novo purine synthesis pathway, and additionally prevent 10-formyl-tetrahydrofolate consumption for purine synthesis. The folate trapping mechanism described here for TH9619 differs from other MTHFD1/2 inhibitors and antifolates. Thus, our findings uncover an approach to attack cancer and reveal a regulatory mechanism in 1C metabolism.In this study, Green, Marttila, Kiweler et al. characterize one-carbon metabolism rewiring in response to a dual MTHFD1 and MTHFD2 inhibitor. This work provides insight into one-carbon fluxes, and reveals a previously uncharacterized vulnerability in cancer cells created by folate trapping.

The number of individuals with diabetes and pre-diabetes is constantly increasing. These conditions are overrepresented in patients undergoing percutaneous coronary intervention and are associated with adverse prognosis. Optimal glycaemic control during an acute coronary syndrome is a relevant factor for the improvement of longer-term outcomes. In addition, the implementation of newer glucose-lowering drugs with proven cardiovascular benefits has a remarkable impact on recurrence of events, hospitalisations for heart failure and mortality. In this narrative review, we outline the current state-of-the art recommendations for glucose-lowering therapy in patients with diabetes undergoing coronary intervention. In addition, we discuss the most recent evidence-based indications for revascularisation in patients with diabetes as well as the targets for glycaemic control post revascularisation. Current treatment goals for concomitant risk factor control are also addressed. Lastly, we acknowledge the presence of knowledge gaps in need of future research.

Background Poor health-related quality of life (HRQL) is common in heart failure (HF) and strongly predicts death and HF hospitalization in all regions of the world. Understanding facors associated with HRQL could therefore lead to improved prognosis in HF patients. Despite that the majority of HF occurs in low- and middle-income countries, there are limited data characterizing self-perceived health HRQL and its correlates in these settings. Purpose To examine clinical and social correlates of HRQL in patients with HF from high- (HIC), upper middle- (UMIC), lower middle-(LMIC) and low-income (LIC) countries. Methods Between 2017 and 2020, we enrolled 23,292 patients with HF (32% inpatients, 61% men) from 40 countries in the Global Congestive Heart Failure Study. We recorded HRQL at baseline using Kansas City Cardiomyopathy Questionnaire (KCCQ)-12. In a cross-sectional analysis, we compared age- and sex-adjusted mean KCCQ-12 summary scores (SS: 0–100, higher=better) between patients from different country income levels. We used multivariable linear regression examining correlations (estimates expressed as β-coefficients) of KCCQ-12-SS with sociodemographic-, comorbidity-, treatment- and symptom-covariates. The adjusted model (37 covariates) was informed by univariable findings, clinical importance and backward selection. We used partial R2-estimates to understand the contribution to the variability in KCCQ-12-SS of 4 different groups of covariates. (sociodemographic, comorbidities, treatments and signs and symptoms of congestion). Results Mean age was 63 years and 40% were in NYHA class III–IV. Average HRQL was 55± SD 0.5. It was 62.5 (95% CI 62.0–63.1) in HIC, 56.8 (56.1–57.4) in UMIC, 48.6 (48.0–49.3) in LMIC, and 38.5 (37.3–39.7) in LICs (p Conclusion The most important correlates of HRQL in HF patients relate to HF symptom severity, irrespective of country-income level. Improved symptom control may have a big impact on HRQL, especially in LICs. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Bayer AG

Genetic risk factors play important roles in the etiology of oral, dental, and craniofacial diseases. Identifying the relevant risk loci and understanding their molecular biology could highlight new prevention and management avenues. Our current understanding of oral health genomics suggests that dental caries and periodontitis are polygenic diseases, and very large sample sizes and informative phenotypic measures are required to discover signals and adequately map associations across the human genome. In this article, we introduce the second wave of the Gene-Lifestyle Interactions and Dental Endpoints consortium (GLIDE2) and discuss relevant data analytics challenges, opportunities, and applications. In this phase, the consortium comprises a diverse, multiethnic sample of over 700,000 participants from 21 studies contributing clinical data on dental caries experience and periodontitis. We outline the methodological challenges of combining data from heterogeneous populations, as well as the data reduction problem in resolving detailed clinical examination records into tractable phenotypes, and describe a strategy that addresses this. Specifically, we propose a 3-tiered phenotyping approach aimed at leveraging both the large sample size in the consortium and the detailed clinical information available in some studies, wherein binary, severity-encompassing, and “precision,” data-driven clinical traits are employed. As an illustration of the use of data-driven traits across multiple cohorts, we present an application of dental caries experience data harmonization in 8 participating studies ( N = 55,143) using previously developed permanent dentition tooth surface–level dental caries pattern traits. We demonstrate that these clinical patterns are transferable across multiple cohorts, have similar relative contributions within each study, and thus are prime targets for genetic interrogation in the expanded and diverse multiethnic sample of GLIDE2. We anticipate that results from GLIDE2 will decisively advance the knowledge base of mechanisms at play in oral, dental, and craniofacial health and disease and further catalyze international collaboration and data and resource sharing in genomics research.

Severely injured trauma patients are often coagulopathic and early hemostatic resuscitation is essential. Previous studies have revealed linear relationships between thrombelastography (TEG

The clinical state of shock constitutes a relative or absolute deficiency of circulating volume for adequate oxygen delivery to meet the metabolic demands.1 Although shock states differ in epidemiology, etiology, and pathophysiologic pathways, a common denominator of shock is endothelial barrier dysfunction.2, 3 Different kinds of shock states, such as occurring after major surgery, trauma, and in sepsis, can result in strong pro‐inflammatory host responses with ensuing endothelial hyperpermeability.4, 5, 6 Loss of endothelial barrier results in leakage of fluid into surrounding tissue, contributing to edema, tissue hypoxia, and organ failure.6 This loss of fluids further aggravates the intravascular circulatory volume deficiency during shock. Obviously, septic and traumatic shock are different entities, with different etiologies and differences in initiation of host response and coagulation response. However, endothelial activation with loss of endothelial barrier integrity is a common finding in both shock states. In trauma‐induced shock, current resuscitation strategies consist of the early transfusion of whole blood or a balanced ratio of plasma, platelets, and red blood cells.7, 8 The aim of resuscitation is to ensure adequate oxygen delivery and to correct coagulopathy. Plasma transfusion may play a key role, as trials point toward improved survival with high dose or early use of plasma transfusion compared to standard care.9, 10, 11 Upon reaching surgical hemostasis, it is general practice to stop transfusion. However, as a result of ongoing inflammation and endothelial activation, patients can continue to be fluid dependent, which is often responded to with crystalloids. However, liberal use of crystalloids in traumatic hemorrhagic shock is associated with increased mortality and increased endothelial permeability, inflammation, and reduced perfusion of vital organs.12, 13, 14 In septic shock, the primary treatment of shock is volume resuscitation with crystalloid or colloids, as advocated in guidelines.15 However, comparable to traumatic hemorrhagic shock, use of a restrictive fluid balance reduces the occurrence of organ failure as well as mortality in sepsis.16, 17, 18 most likely, the association between the amount of infused volume and adverse outcome in shock states is related to increased shedding of the glycocalix, breakdown of adherent junctions, and tight junctions resulting in an increased gradient of leakage over the hyper permeable endothelium.19 Taken together, due to a relative or absolute deficiency of intravascular volume, patients with shock are likely to need volume expansion to maintain perfusion pressure. This poses a challenge to the treatment of shock, as fluid therapy is both a cornerstone of therapy as well as a foe. Different fluids may have differential effects on endothelial integrity. Low‐protein‐content fluids seem to aggravate shedding of glycocalix,20 whereas protein‐rich fluids such as plasma may be superior to normal saline in protecting the glycocalix and endothelial barrier function.21 Transfusion with plasma as a volume expander in shock may seem controversial at first, but one needs to consider that despite the fact that plasma is transfused in millions of patients annually, there currently is limited understanding of its mechanisms of action. In traumatic blood loss, transfusion of plasma may improve survival by decreasing exsanguination.7, 10 The common perception is that plasma is a pro‐coagulant blood product, by replenishing coagulation factors. However, as plasma contains coagulation factors but also anticoagulant proteins, the net effect of plasma on coagulation may be neutral. In line with this, plasma transfusion increases the amount of coagulation factors as well as levels of anti‐coagulant proteins,22 resulting in unchanged thrombin generation, at least in non‐bleeding critically ill patients with an inflammatory‐driven consumption coagulopathy. In patients with traumatic hemorrhagic shock, it is not apparent whether the mechanism of effect of plasma is directly related to the correction of coagulopathy.23 In rats with hemorrhagic shock, deranged thrombin formation was somewhat restored with resuscitation with plasma but not with crystalloids, but whether this relates to prevention of dilutional coagulopathy or to a specific pro‐coagulant effect of plasma is not clear.24, 25 Other mechanisms of the protective effect of plasma may be at hand. These may include preservation of the glycocalix, decreasing inflammation and decreasing endothelial leak. This review aims to discuss the potential of plasma as a resuscitation fluid in shock, with an emphasis on possible mechanisms of benefit on the activated endothelium. Studies comparing plasma with other fluids on (markers of) endothelial integrity have found effects both in (models of) trauma‐induced shock and in septic shock. As loss of endothelial integrity may be a common denominator of shock, we will discuss both these shock states.

Early diagnosis and compression treatment are important to prevent progression in breast cancer-related arm lymphedema (BCRAL). However, some mild BCRAL can be reversible, and therefore, compression treatment may not be needed. The aim of this study was to investigate the proportion of women with mild BCRAL showing progression/no progression of lymphedema after treatment with or without compression garments, differences in changes of lymphedema relative volume (LRV), local tissue water and subjective symptoms during 6 months. Also, adherence to self-care was examined.Seventy-five women diagnosed with mild BCRAL were randomized to a compression group (CG) or noncompression group (NCG). Both groups received self-care instructions, and the CG were treated with a standard compression garment (ccl 1). Women in the NCG who progressed in LRV ≥2%, or exceeded 10% dropped out, and received appropriate treatment. The proportion showing progression/no progression of LRV, and changes in LRV was measured by Water Displacement Method. Changes in local tissue water were measured by Tissue Dielectric Constant (TDC), subjective symptoms by Visual Analogue Scale, and self-care by a questionnaire.A smaller proportion of LRV progression was found in the CG compared to the NCG at 1, 2 and 6 months follow-up (Early treatment with compression garment can prevent progression in mild BCRAL.

Diabetes is a hypercoagulable state predisposing to cardiovascular disease. Physical exercise can improve cardiovascular health but may also cause hypoglycemia in insulin-treated patients. We compared hemostatic profiles of patients with type 1 diabetes (T1D) with healthy controls and delineated hemostatic changes of hypoglycemia, induced with or without exercise, in patients with T1D. Thromboelastography (TEG®6s) was used to compare hemostatic profiles of patients with T1D (N=15, (mean±SD) age 29.4±8.1 years, HbA1c 6.8±0.5%, diabetes duration 13.1±6.2 years, BMI 23.7±2.0 kg/m2) with individually matched healthy controls (N=15) . In addition, the patients with T1D underwent (randomized, crossover design) two separate hyperinsulinemic euglycemic-hypoglycemic clamp days. During decline in plasma glucose and the initial 15 min of hypoglycemia, the subjects were either resting or performing moderate-intensity exercise. TEG was performed at baseline euglycemia and after 15 min and 60 min of hypoglycemia. Compared with healthy controls, patients with T1D were more hypercoagulable with shorter R-time (P In conclusion, patients with T1D have a more hypercoagulable profile than healthy controls, and exercise-related hypoglycemia induces coagulation without a compensatory fibrinolytic activity, which may increase susceptibility for thrombosis. Disclosure P.G.Hagelqvist: None. A.Andersen: n/a. K.Maytham: None. S.Engberg: Employee; Novo Nordisk A/S. U.Pedersen-bjergaard: Advisory Panel; Novo Nordisk A/S, Sanofi. P.I.Johansson: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd. Funding Independent research fund Denmark (1030-00256B) Grosserer L.F. Foghts Fund (21.761)

Background: After resuscitation from out-of-hospital cardiac arrest, mean arterial pressure below 65 mm Hg is avoided with vasopressors. A higher blood-pressure target could potentially improve outcome. The aim of this pilot trial was to investigate the effect of a higher mean arterial pressure target on biomarkers of organ injury. Methods: This was a single-centre, double-blind trial of 50 consecutive, comatose out-of-hospital cardiac arrest patients randomly assigned in a 1:1 ratio to a mean arterial pressure target of 65 mm Hg (MAP65) or 72 mm Hg (MAP72). Modified blood pressure modules with a –10% offset were used, enabling a double-blind study design. End-points were biomarkers of organ injury including markers of endothelial integrity (soluble trombomodulin) brain damage (neuron-specific enolase) and renal function (estimated glomerular filtration rate). Results: Mean arterial pressure was significantly higher in MAP72 with a mean difference of 5 mm Hg (pgroup=0.03). After 48 h, soluble trombomodulin (median (interquartile range)) was 8.2 (6.7–12.9) ng/ml and 8.3 (6.0–10.8) ng/ml (p=0.29), neuron-specific enolase was 20 (13–31 μg/l) and 18 (13–44 μg/l) p=0.79) and estimated glomerular filtration rate (mean (±standard deviation)) was 61±19 ml/min/1.73m2 and 48±22 ml/min/1.73 m2 (p=0.08) for the MAP72 and MAP65 groups, respectively. Renal replacement therapy was needed in eight patients (31%) in MAP65 and three patients (13%) in MAP72 (p=0.14). Conclusions: Double-blind allocation to different mean arterial pressure targets is feasible in comatose out-of-hospital cardiac arrest patients. A mean arterial pressure target of 72 mm Hg compared to 65 mm Hg did not result in improved biomarkers of organ injury. We observed a trend towards preserved renal function in the MAP72 group.

Background: Out-of-hospital cardiac arrest (OHCA) is a leading cause of death. Even if successfully resuscitated, mortality remains high due to ischemic and reperfusion injury (I/R). The oxygen deprivation leads to a metabolic derangement amplified upon reperfusion resulting in an uncontrolled generation of reactive oxygen species in the mitochondria triggering cell death mechanisms. The understanding of I/R injury in humans following OHCA remains sparse, with no existing treatment to attenuate the reperfusion injury. Aim: To describe metabolic derangement in patients following resuscitated OHCA. Methods: Plasma from consecutive resuscitated unconscious OHCA patients drawn at hospital admission were analyzed using ultra-performance-liquid-mass-spectrometry. Sixty-one metabolites were prespecified for quantification and studied. Results: In total, 163 patients were included, of which 143 (88%) were men, and the median age was 62 years (53–68). All measured metabolites from the tricarboxylic acid (TCA) cycle were significantly higher in non-survivors vs. survivors (180-days survival). Hierarchical clustering identified four clusters (A-D) of patients with distinct metabolic profiles. Cluster A and B had higher levels of TCA metabolites, amino acids and acylcarnitine species compared to C and D. The mortality was significantly higher in cluster A and B (A:62% and B:59% vs. C:21 % and D:24%, p < 0.001). Cluster A and B had longer time to return of spontaneous circulation (A:33 min (21–43), B:27 min (24–35), C:18 min (13–28), and D:18 min (12–25), p < 0.001). Conclusion: Circulating levels of metabolites from the TCA cycle best described the variance between survivors and non-survivors. Four different metabolic phenotypes with significantly different mortality were identified.

The Danish Capital Region Blood Bank operates a 24/7 on-call service staffed with physicians specialized in hemostatic management to guide clinicians in hemostatic resuscitation, including administration of prohemostatic therapy (PHT). The outcome of patients who receive PHT as part of hemostatic resuscitation remains unanswered. The objective of this study was therefore to investigate clinical outcome of patients receiving PHT managed by the on-call service. We identified 287 patients who received PHT during 2015-16, of which 161 (59%) received fibrinogen concentrate (FC), 111 (39%) received prothrombin complex concentrate (PCC), and 15 (5%) received recombinant factor VIIa (rFVIIa) as the first product. Patients were critically ill with a 30-day mortality of 31%. Among FC recipients, cardiothoracic admission, non-trauma, and antithrombotics predicted survival. FC recipients had lower platelet count and thrombelastography clot strengths than the other PHT groups and within the group, these factors predicted mortality. The symptomatic thromboembolic event (TE) rate at 30 days was 5%. For PCC recipients, vitamin K antagonists predicted survival, while rivaroxaban predicted mortality. TE rate was 2%. We did not identify factors associated with survival in the small group of rFVIIa recipients. TE rate was 13%. In summary, trauma and coagulopathy predicted mortality in patients who received FC and our data suggest that optimization of PHT algorithms may be possible. Outcome of patients who received PCC was comparable to results reported elsewhere and its use may be safe in a setting as reported here. Recombinant FVIIa was rarely used but had the highest incidence of arterial thromboembolism.

Endothelial dysfunction has not previously been investigated as a thrombogenic risk factor among patients with acute lymphoblastic leukemia (ALL), known to be at high risk of thromboembolism. We retrospectively explored the association between three circulating biomarkers of endothelial dysfunction (thrombomodulin, syndecan-1, VEGFR-1) measured in prospectively collected blood samples and risk of thromboembolism in 55 cases and 165 time-matched controls, treated according to the NOPHO ALL2008 protocol. In age-, sex-, and risk group-adjusted analysis, increasing levels of thrombomodulin and VEGFR-1 were independently associated with increased odds of developing thromboembolism (OR 1.37 per 1 ng/mL [95% CI 1.20‒1.56, P 30 days before thromboembolic diagnosis. Thrombomodulin levels were on average 3.2 ng/mL (95% CI 2.6-8.2 ng/mL) higher in samples with measurable asparaginase activity (P

Fulfilling customer orders in engineer-to-order (ETO) settings entails customization and, thus, greater complexity: detail and uncertainty. Tactical planning aims at demand–supply (DS) balancing by ensuring cross-functional integration (CFI), which incorporates coordination as one dimension. This study uses a case study approach to identify the key coordination mechanisms applied in the customer order fulfilment processes (COFPs) to mitigate the negative impact of complexity on DS balancing in four ETO-oriented settings. Within-case analyses identify the applied mechanisms, and a cross-case analysis elaborates on how they influence the detail and uncertainty in decision-making and problem-solving activities. Findings suggest a positive effect of formalized activity sequences, balanced team compositions, effective task designs and supportive information systems (ISs); and a positive (but contingent) effect of the other mechanisms. Future research may address other CFI dimensions (collaboration), statistically test the findings, or qualitatively deepen the understanding of the forms and impacts of individual mechanisms.

The challenging demand-supply balancing in engineer-to-order (ETO) environments is often attributed to complexity. This study expands the understanding of managing complexity to obtain demand-suppl...

Purpose: Contemporary trauma resuscitation prioritizes control of bleeding and uses major haemorrhage protocols (MHPs) to prevent and treat coagulopathy. We aimed to determine whether augmenting MHPs with Viscoelastic Haemostatic Assays (VHA) would improve outcomes compared to Conventional Coagulation Tests (CCTs). Methods: This was a multi-centre, randomized controlled trial comparing outcomes in trauma patients who received empiric MHPs, augmented by either VHA or CCT-guided interventions. Primary outcome was the proportion of subjects who, at 24 h after injury, were alive and free of massive transfusion (10 or more red cell transfusions). Secondary outcomes included 28-day mortality. Pre-specified subgroups included patients with severe traumatic brain injury (TBI). Results: Of 396 patients in the intention to treat analysis, 201 were allocated to VHA and 195 to CCT-guided therapy. At 24 h, there was no difference in the proportion of patients who were alive and free of massive transfusion (VHA: 67%, CCT: 64%, OR 1.15, 95% CI 0.76–1.73). 28-day mortality was not different overall (VHA: 25%, CCT: 28%, OR 0.84, 95% CI 0.54–1.31), nor were there differences in other secondary outcomes or serious adverse events. In pre-specified subgroups, there were no differences in primary outcomes. In the pre-specified subgroup of 74 patients with TBI, 64% were alive and free of massive transfusion at 24 h compared to 46% in the CCT arm (OR 2.12, 95% CI 0.84–5.34). Conclusion: There was no difference in overall outcomes between VHA- and CCT-augmented-major haemorrhage protocols.

With new market developments and e-commerce, there is an increased use of and interest in automation for order picking. This paper presents a systematic review and content analysis of the literatur...

Kitting is a materials-feeding principle commonly used with mixed-model assembly, but literature is lacking with respect to how kit quality can be supported. The purpose of this paper is to create an understanding of the links between kit preparation design aspects and kit preparation error types, that can be useful to support kit quality. The paper draws on empirical data from a multiple case study in the automotive industry to study how typical kit errors are linked to eight kit preparation design aspects: location, work organisation, storage policy, batching policy, storage packaging, kit carrier and container, picking information system, and error communication. The findings suggest several opportunities related to kit preparation design aspects for preventing kit errors and facilitating kit error corrections. The paper extends earlier knowledge and can support kit quality of industrial kit preparation.

An increasingly recognized prognostic factor for out-of-hospital-cardiac-arrest (OHCA) patients is the ischemia-reperfusion injury after restored blood circulation. Endothelial injury is common in patients resuscitated from cardiac arrest and is associated with poor outcome. This study was designed to investigate if iloprost infusion, a prostacyclin analogue, reduces endothelial damage in OHCA patients.50 patients were randomized in a placebo controlled double-blinded trial and allocated 1:2 to 48-hours iloprost infusion, (1 ng/kg/min) or placebo (saline infusion). Endothelial biomarkers (soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), vascular endothelial cadherine (VEcad), nucleosomes) and sympathoadrenal activation (epinephrine/norepinephrine) from baseline to 48 and 96-hours were evaluated.Iloprost infusion did not influence endothelial biomarkers by the 48-hour endpoint. A rebound effect was observed with higher biomarker plasma values in the iloprost group (sTM p=0.02; Syndecan p=0.004; nucleosomes p0.001; VEcad p0.03) after 96-hours. There was a significant difference in 180-day mortality in favor of placebo. There was no difference regarding total adverse events between groups (p=0.73). Two patients were withdrawn in the iloprost group due to hypotension.The administration of low-dose iloprost (1ng/kg/min) to OHCA patients did not significantly influence endothelial biomarkers as measured by the 48- hour endpoint. A rebound effect was however observed in the 96-hour statistical model, with increasing endothelial biomarker levels after cessation of the iloprost-infusion.

Purpose: Endotheliopathy of trauma (EoT), as defined by circulating levels of syndecan-1 ≥ 40 ng/mL, has been reported to be associated with significantly increased transfusion requirements and a doubled 30-day mortality. Increased shedding of the glycocalyx points toward the endothelial cell membrane composition as important for the clinical outcome being the rationale for this study. Results: The plasma metabolome of 95 severely injured trauma patients was investigated by mass spectrometry, and patients with EoT vs. non-EoT were compared by partial least square-discriminant analysis, identifying succinic acid as the top metabolite to differentiate EoT and non-EoT patients (VIP score = 3). EoT and non-EoT patients’ metabolic flux profile was inferred by integrating the corresponding plasma metabolome data into a genome-scale metabolic network reconstruction analysis and performing a functional study of the metabolic capabilities of each group. Model predictions showed a decrease in cholesterol metabolism secondary to impaired mevalonate synthesis in EoT compared to non-EoT patients. Intracellular task analysis indicated decreased synthesis of thromboxanA2 and leukotrienes, as well as a lower carnitine palmitoyltransferase I activity in EoT compared to non-EoT patients. Sensitivity analysis also showed a significantly high dependence of eicosanoid-associated metabolic tasks on alpha-linolenic acid as unique to EoT patients. Conclusions: Model-driven analysis of the endothelial cells’ metabolism identified potential novel targets as impaired thromboxane A2 and leukotriene synthesis in EoT patients when compared to non-EoT patients. Reduced thromboxane A2 and leukotriene availability in the microvasculature impairs vasoconstriction ability and may thus contribute to shock in EoT patients. These findings are supported by extensive scientific literature; however, further investigations are required on these findings.

International audience; Heart failure (HF) is one of the major challenges in the management of diabetes patients. Among subjects with diabetes, up to 20% could have HF. Conversely, diabetes prevalence in HF patients varies greatly from more than 10% up to 50%. When it is present, the risk of mortality and rehospitalization increases substantially. In addition, current evidence points to an increased risk of atrial fibrillation and sudden cardiac death in patients with diabetes. The inter-relation between diabetes cardiomyopathy, left ventricular hypertrophy, coronary artery disease and renal dysfunction indicates complex and intricate pathways. Despite the great value of clinical assessment and echocardiography, there is insufficient data to suggest systematic screening for HF in asymptomatic patients with diabetes. There is little evidence to indicate that improved glycaemic control improves HF outcome in this population. In the case of established HF, the general guidelines apply in diabetes patients. However, recent advances concerning glucose-lowering treatment in patients with cardiovascular disease suggest that the choice of glucose-lowering agent is of crucial interest and should be based on the patient’s phenotype. New drug classes, such as SGLT2 inhibitors, seem to be of particular benefit in these patients. In the future, new personalized strategies should aim at not only good control of the glycaemic level but also the reduction and possibly the prevention of HF onset.

In a pilot study, we found a significant reduction in mean daily sequential organ failure assessment score in mechanically ventilated patients with COVID-19 who received prostacyclin, compared to placebo. We here investigate the effect on biomarkers of endothelial activation and damage.Post-hoc study of a randomized controlled trial in adult patients with confirmed SARS-CoV-2 infection, mechanically ventilated, with soluble thrombomodulin (sTM) plasma levels4 ng/mL. Patients received prostacyclin infusion (1 ng/kg/min) or placebo. Blood samples were collected at baseline and 24 h.Eighty patients were randomized (41 prostacyclin, 39 placebo). The median changes in syndecan-1 plasma levels at 24 h were -3.95 (IQR: -21.1 to 2.71) ng/mL in the prostacyclin group vs. 3.06 (IQR: -8.73 to 20.5) ng/mL in the placebo group (difference of the medians: -7.01 [95% CI: -22.3 to -0.231] ng/mL, corresponding to -3% [95% CI: -11% to 0%], p = 0.04). Changes in plasma levels of sTM, PECAM-1, p-selectin, and CD40L did not differ significantly between groups.Prostacyclin infusion, compared to placebo, resulted in a measurable decrease in endothelial glycocalyx shedding (syndecan-1) at 24 h, suggesting a protective effect on the endothelium, which may be related to the observed reduction in organ failure.

Rationale The mortality in SARS-CoV-2 infected patients requiring mechanical ventilation remains high and endotheliopathy has been implicated. Objective To determine the effect of prostacyclin infusion in mechanically ventilated SARS-CoV-2 infected patients with severe endotheliopathy. Methods We conducted a multicenter, randomized, clinical trial in COVID-19 infected adults requiring mechanical ventilation having a plasma level of thrombomodulin >4ng/ml who were randomized to 72-hours infusion of prostacyclin 1 ng/kg/min or placebo. Measurements The main outcome was the number of days alive and without mechanical ventilation within 28-days. Key secondary outcomes were 28-day mortality and serious adverse events within 7 days. Main Results Eighty patients were randomized (41 prostacyclin, 39 placebo). The number of days alive without mechanical ventilation at 28-days was 16.0 days (SD 12) versus 5.0 days (SD 10), [95% CI -21.0 to 5.0], P=0.07) in the prostacyclin and the placebo groups, respectively. The 28-day mortality was 21.9% versus 43.6% in the prostacyclin and the placebo groups, respectively (risk ratio 0.50 [95% CI 0.24 to 0.96] P=0.056). The incidence of serious adverse events within 7 days were 2.4% vs. 12,8% (risk ratio 0.19 [95% CI 0.001 to 1.11], P=0.10) in the prostacyclin and the placebo groups, respectively. Conclusions and relevance Prostacyclin were not associated with a significant reduction in the number of days alive and without mechanical ventilation within 28-days. The point estimates, however, favored the prostacyclin group in all analyses, including 28-day mortality, warranting further investigation in larger trials. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT04420741. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).