Snakebite envenomation is a major public health issue which causes severe morbidity and mortality, affecting millions of people annually. Of a diverse range of clinical manifestations, local and systemic haemorrhage are of particular relevance, as this may result in ischemia, organ failure and even cardiovascular shock. Thus far, in vitro studies have failed to recapitulate the haemorrhagic effects observed in vivo. Here, we present an organ-on-a-chip approach to investigate the effects of four different snake venoms on a perfused microfluidic blood vessel model. We assess the effect of the venoms of four snake species on epithelial barrier function, cell viability, and contraction/delamination. Our findings reveal two different mechanisms by which the microvasculature is being affected, either by disruption of the endothelial cell membrane or by delamination of the endothelial cell monolayer from its matrix. The use of our blood vessel model may shed light on the key mechanisms by which tissue-damaging venoms exert their effects on the capillary vessels, which could be helpful for the development of effective treatments against snakebites.

UNASSIGNED: Hyperkalaemia is a common electrolyte abnormality seen in critically ill patients. In haemorrhagic shock, it may contribute to cardiac arrest and has been identified as a potential marker for tissue hypoxia. However, the significance of its role in haemorrhagic shock and its contribution to mortality remains unclear. This study aimed to examine the potential underlying pathophysiology and evaluate the incidence and characteristics of patients with hyperkalaemia on hospital arrival in bleeding trauma patients before transfusions and its mortality.
UNASSIGNED: A retrospective cohort study was conducted on adult patients with traumatic bleeding admitted to a European Major Trauma Centre between January 2016 and December 2021. Patients were classified according to their serum potassium levels on arrival, and relevant clinical parameters between non-hyperkalaemic and hyperkalaemic patients were compared.
UNASSIGNED: Among the 83 patients in this study, 8 (9.6 %) presented with hyperkalaemia on arrival. The median shock index showed a higher tendency in the hyperkalaemic group. Hyperkalaemia was found to be more common among younger patients who sustained penetrating trauma. Mortality rates were higher in the hyperkalaemic group, but the difference was not statistically significant.
UNASSIGNED: Our results suggest that hyperkalaemia occurs frequently in bleeding trauma patients on hospital arrival pre-transfusions, indicating a more severe illness. Our findings provide insights into the pathophysiology and characteristics of hyperkalaemia in bleeding trauma patients. Further studies are required to investigate the mechanisms by which hyperkalaemia contributes to mortality in haemorrhagic shock patients.

Therapeutic anticoagulation showed inconsistent results in hospitalized patients with COVID-19 and selection of the best patients to use this strategy still a challenge balancing the risk of thrombotic and hemorrhagic outcomes. The present post-hoc analysis of the ACTION trial evaluated the variables independently associated with both bleeding events (major bleeding or clinically relevant non-major bleeding) and the composite outcomes thrombotic events (venous thromboembolism, myocardial infarction, stroke, systemic embolism, or major adverse limb events). Variables were assessed one by one with independent logistic regressions and final models were chosen based on Akaike information criteria. The model for bleeding events showed an area under the curve of 0.63 (95% confidence interval [CI] 0.53 to 0.73), while the model for thrombotic events had an area under the curve of 0.72 (95% CI 0.65 to 0.79). Non-invasive respiratory support was associated with thrombotic but not bleeding events, while invasive ventilation was associated with both outcomes (Odds Ratio of 7.03 [95 CI% 1.95 to 25.18] for thrombotic and 3.14 [95% CI 1.11 to 8.84] for bleeding events). Beyond respiratory support, creatinine level (Odds Ratio [OR] 1.01 95% CI 1.00 to 1.02 for every 1.0 mg/dL) and history of coronary disease (OR 3.67; 95% CI 1.32 to 10.29) were also independently associated to the risk of thrombotic events. Non-invasive respiratory support, history of coronary disease, and creatinine level may help to identify hospitalized COVID-19 patients at higher risk of thrombotic complications.ClinicalTrials.gov: NCT04394377.

UNASSIGNED: The placenta accreta spectrum is a complex disorder characterized by abnormal invasion of the placenta into the uterine wall, posing a significant risk of life-threatening haemorrhage for patients. Its incidence is on the rise, largely attributed to the increasing rates of caesarean sections. Management of this spectrum involves a multidisciplinary approach, although standardized protocols are not yet established. While caesarean hysterectomy remains the standard Gold, several adjunctive treatments have emerged in recent years to mitigate bleeding risk and associated morbidity. Among these, prophylactic occlusion balloons placed in the internal iliac arteries have shown promise. The aim of our study is to demonstrate the effect of prophylactic occlusion balloons in both uterine iliac arteries in the management of placental accreta spectrum disorders.
UNASSIGNED: A retrospective monocentric cohort study was conducted in the Department \"C\" of Gynaecology and Obstetrics at the Maternity Center of Tunis. The study spanned three years, from January 2nd, 2020, to December 31st, 2022. The study population consisted of two groups: Control Group (CG) comprised patients who underwent caesarean hysterectomy without internal-iliac prophylactic occlusion balloons, and Occlusion balloons of both internal iliac arteries Group (OBIIAG) included patients who underwent caesarean hysterectomy with internal-iliac prophylactic occlusion balloons.
UNASSIGNED: A total of 38 patients were included in the study, all of whom exhibited similar epidemiological characteristics and comparable personal and obstetric histories. The most prevalent risk factor among the patients was a history of caesarean section (92%). On average, patients were diagnosed at 30 weeks of gestation, with third-trimester bleeding being the most common presentation (71% of cases). The median gestational age at delivery was between 36 and 37 weeks. We observed a significant difference in blood loss between the two groups (2888 ml in the control group and 1828 ml in the group with internal-iliac prophylactic occlusion balloons, p < 0.05). Implementation of this technique resulted in a reduced need for massive transfusions (p < 0.01) and shorter operating times (126 min for the control group and 92 min for the group with internal-iliac prophylactic occlusion balloons; p = 0.04). There were no significant differences in morbidity between the two groups.
UNASSIGNED: The intra-iliac prophylactic occlusion balloons can help reduce the risk of hemorrhage and the morbidities that come with the placenta accreta spectrum disorder.

OBJECTIVE: Incidence of bleeding amongst warfarin and direct oral anticoagulant (DOAC) users is greater following a respiratory tract infection (RTI). It is unclear whether immediate antibiotics modify this association. We estimated the risk of bleeding amongst warfarin and DOAC users with RTI by antibiotic treatment.
METHODS: This retrospective cohort study used data from the Clinical Practice Research Datalink (CPRD) GOLD for adults in England prescribed warfarin or a DOAC, who sought primary care for an RTI between 1st January 2011 and 31st December 2019. Outcomes were major bleeding (hospital admission for intracranial or gastrointestinal bleeding), and non-major bleeding (hospital admission or General Practice consult for epistaxis, haemoptysis, or haematuria). Cox models derived hazard ratios (HRs) and 95% confidence intervals (CIs) for each outcome, adjusting for confounders using inverse probability of treatment weighting.
RESULTS: Of 14 817 warfarin and DOAC users consulting for an RTI, 8768 (59%) were prescribed immediate antibiotics and 6049 (41%) were not. Approximately 49% were female, and median age was 76 years. Antibiotics were associated with reduced risk of major bleeding (adjusted HR 0.38, 95% CI 0.25 to 0.58). This was consistent across several sensitivity analyses. Antibiotics were also associated with a reduced risk of non-major bleeding (adjusted HR 0.78, 95% CI 0.61 to 0.99).
CONCLUSIONS: Immediate antibiotics were associated with reduced risk of bleeding amongst warfarin and DOAC users with an RTI. Further work is needed to understand mechanisms and confirm whether a lower threshold for antibiotic use for RTI in this population may be beneficial.

BACKGROUND: Tonsillectomy is a frequently performed otolaryngological procedure and is associated with significant postoperative pain and bleeding. A number of studies have investigated methods to reduce pain and bleeding. Coblation and BiZact devices have both been claimed to have favourable pain outcomes following tonsillectomy. This study was designed to investigate these two techniques in a direct comparison of postoperative pain and bleeding.
METHODS: In this single blinded, randomized control trial, 61 patients were randomly assigned to undergo tonsillectomy with either the BiZact or Coblation device. Pain scores were collected for 14 days postoperatively using a Visual Analogue Score scale. Secondary outcome data was collected for duration of surgery, intra-operative bleeding, return to normal, and secondary bleeding rates.
RESULTS: Coblation was found to have lower postoperative pain on day 1 (P < 0.05). BiZact was found to have lower postoperative pain on day 7 (P < 0.05) and day 11 (P < 0.05). Pain scores for other days were not significant. There was no significant difference in set-up time, procedural time and return to normal activities. The BiZact group had a longer time to achieve haemostasis (P < 0.001) and greater intraoperative blood loss (P < 0.01). There was a trend towards more significant secondary bleeding in the BiZact arm, however, this study was not adequately powered to assess this finding.
CONCLUSIONS: Both Coblation and BiZact devices appear to provide a safe and effective method for tonsillectomy in adults. Reduced pain on day 1 may make Coblation more suitable for day-case surgery.

BACKGROUND: Matrix metalloproteinases (MMPs) are implied in blood-brain barrier degradation and haemorrhagic transformation following ischaemic stroke, but their local relevance in the hyperacute disease phase is unknown. We aimed to examine ultra-early MMP-9 and MMP-2 release into collateral blood vessels, and to assess its prognostic value before therapeutic recanalisation by endovascular thrombectomy (EVT).
METHODS: We report a cross-sectional proof-of-concept study including patients undergoing EVT for large-vessel ischaemic stroke at the University Hospital Würzburg, Germany. We obtained liquid biopsies from the collateral circulation before recanalisation, and systemic control samples. Laboratory workup included quantification of MMP-9 and MMP-2 plasma concentrations by cytometric bead array, immunohistochemical analyses of cellular MMP-9 and MMP-2 expression, and detection of proteolytic activity by gelatine zymography. The clinical impact of MMP concentrations was assessed by stratification according to intracranial haemorrhagic lesions on postinterventional computed tomography (Heidelberg Bleeding Classification, HBC) and early functional outcome (modified Rankin Scale, mRS). We used multivariable logistic regression, receiver-operating-characteristic (ROC) curves, and fixed-level estimates of test accuracy measures to study the prognostic value of MMP-9 concentrations.
RESULTS: Between August 3, 2018, and September 16, 2021, 264 matched samples from 132 patients (86 [65.2%] women, 46 [34.8%] men, aged 40-94 years) were obtained. Median (interquartile range, IQR) MMP-9 (279.7 [IQR 126.4-569.6] vs 441 [IQR 223.4-731.5] ng/ml, p < 0.0001) but not MMP-2 concentrations were increased within collateral blood vessels. The median MMP-9 expression level of invading neutrophils was elevated (fluorescence intensity, arbitrary unit: 2276 [IQR 1007-5086] vs 3078 [IQR 1108-7963], p = 0.0018). Gelatine zymography experiments indicated the locally confined proteolytic activity of MMP-9 but not of MMP-2. Pretherapeutic MMP-9 release into stroke-affected brain regions predicted the degree of intracerebral haemorrhages and clinical stroke severity after recanalisation, and independently increased the odds of space-occupying parenchymal haematomas (HBC1c-3a) by 1.54 times, and the odds of severe disability or death (mRS ≥5 at hospital discharge) by 2.33 times per 1000 ng/ml increase. Excessive concentrations of MMP-9 indicated impending parenchymal haematomas and severe disability or death with high specificity.
CONCLUSIONS: Measurement of MMP-9 within collateral blood vessels is feasible and identifies patients with stroke at risk of major intracerebral haemorrhages and poor outcome before therapeutic recanalisation by EVT, thereby providing evidence of the concept validity of ultra-early local stroke biomarkers.
BACKGROUND: This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) and the Interdisciplinary Centre for Clinical Research (IZKF) at the University of Würzburg.

BACKGROUND: Guidelines advise 50 % and 25 % dose reduction of the therapeutic nadroparin dose (86 IU/kg) in patients with eGFR 15-29 and 30-60 ml/min respectively. For monitoring, peak anti-Xa levels are suggested. Data lack whether this results in therapeutic anti-Xa levels or in anti-Xa levels that are comparable to those of patients without renal impairment.
OBJECTIVE: To determine dose ranges in patients with renal impairment that result in therapeutic anti-Xa levels and to determine the percentage of the 86 IU/kg dose that results in anti-Xa levels normally occurring in patients without renal impairment.
METHODS: A retrospective cohort study was conducted in five hospitals. Patients ≥18 years of age, with an eGFR ≥ 15 ml/min were included. The first correctly sampled peak (i.e. 3-5 h after ≥ third administration, regardless of dose per patient) was included. Simulated prediction models were developed using multiple linear regression.
RESULTS: 770 patients were included. eGFR and hospital affected the association between dose and anti-Xa level. The doses for peak anti-Xa levels of 0.75 IU/ml differed substantially between hospitals and ranged from 55 to 91, 65-359 and 68-168 IU/kg in eGFR 15-29, 30-60 and > 60 ml/min/1.73m2, respectively. In eGFR 15-29 and 30-60 ml/min/1.73m2, doses of 75 % and 91 % of 86 IU/kg respectively, were needed for anti-Xa levels normally occurring in patients with eGFR > 60 ml/min.
CONCLUSIONS: We advise against anti-Xa based dose-adjustments as long as anti-Xa assays between laboratories are not harmonized and an anti-Xa target range is not validated. A better approach might be to target levels similar to eGFR > 60 ml/min/1.73m2, which are achieved by smaller dose reductions.

OBJECTIVE: To explore the feasibility of using marking and fusion image-guided technique with cone-beam CT (CBCT) in cases of kidney ruptured haemorrhage without extravascular leakage in digital subtraction angiography (DSA) images.
METHODS: This is a retrospective case-control study that included 43 patients who underwent transcatheter arterial embolization for kidney ruptured haemorrhage and difficult haemostasis. The patients were divided into two groups: the CBCT group (cases without extravascular leakage observed in angiography) and the control group (cases with clearly identifiable target vessels in angiography). The baseline characteristics and clinical outcomes were collected and analysed.
RESULTS: The results showed no statistically significant differences in the duration of the procedure and intraoperative blood transfusion between the control and CBCT groups (P > .05). The study clarified that the CBCT group had a significantly higher rate of improvement of gross haematuria compared to the control group (P < .05). The CBCT group showed a greater increase in haemoglobin and a lesser increase in creatinine. The clinical success rates were 87.5% in the control group and 90.9% in the CBCT group (P > .05).
CONCLUSIONS: The marking and fusion image-guided technique is useful in cases of kidney ruptured haemorrhage without extravascular leakage of contrast agent. The technique is safe, feasible, and effective, and we believe it is superior to purely DSA-guidance.
CONCLUSIONS: The use of the marking and fusion image-guided technique is recommended to overcome the challenge of undetectable target vessels during interventional procedures. This technique is considered as non-inferior to purely DSA-guided interventional procedures where the target vessels are clearly identifiable.

OBJECTIVE: To describe the relationships between different methods of measuring functional fibrinogen levels in severely injured, bleeding trauma patients across multiple timepoints during hospitalisation.
METHODS: In 100 adult trauma patients enrolled in the FEISTY pilot randomised clinical trial at four tertiary trauma centres in Australia, blood samples were collected prospectively. Consistency of agreement was calculated, comparing functional fibrinogen levels measured by four methods - ROTEM® Delta and Sigma FIBTEM A5, TEG® 6s CFF MA, and gold-standard Clauss Fibrinogen.
RESULTS: Comparing the ROTEM® Delta and new-generation ROTEM® Sigma machine, consistency of agreement for FIBTEM A5, measured by calculating intraclass correlation coefficients (ICCs), was ≥0.73 across all analysed timepoints, with mean differences (Sigma minus Delta) of 0.10-3.57 mm. Corresponding values comparing the ROTEM® Sigma FIBTEM A5 and TEG® 6s CFF MA were ICC = 0.55-0.82 and ICC = 4.69-7.97 (CFF MA minus A5). Comparing ROTEM® Sigma FIBTEM A5 and Clauss Fibrinogen Analysis (CFA), among statistically significant simple linear regression models, R2 was 0.25-0.67, and comparing TEG® 6s CFF MA and CFA (CFA) 0.65-0.82, although not all differences were significant with the latter comparison. Relationships across all timepoints combined were Clauss Fibrinogen (CF) (g/L) = 0.21𝑥 + 0.004 (where 𝑥 = ROTEM® Sigma FIBTEM A5 in mm) and (g/L) = 0.16𝑥 - 0.06 (where 𝑥 = TEG® 6s CFF MA in mm).
CONCLUSIONS: The present study revealed acceptable agreement between four different assays measuring functional fibrinogen, with current- and previous-generation ROTEM® machines (Sigma, Delta) performing similarly measuring functional fibrinogen via FIBTEM assay. This suggests that haemostatic resuscitation algorithms designed for the ROTEM® Delta can be applied to the ROTEM® Sigma to guide fibrinogen replacement.