VTE risk assessment, prevention and diagnosis in pregnancy.

Venous thromboembolism (VTE) is still reported as the leading cause of direct maternal death in pregnancy in serial international reports in developed countries. VTE risk is higher during pregnancy but is further increased by additional well-characterized risk factors. International guidelines recommend that formal VTE risk assessment should be conducted at least in early pregnancy, at delivery and when risk factors change. High quality data supporting optimal VTE prevention strategies are lacking, outside the setting of prevention of VTE recurrence. Moreover, recent high-quality studies have provided much-needed data on diagnostic strategies for pulmonary embolism (PE) in pregnancy. In this review, we summarize knowledge gaps and recently published data in the prevention and diagnosis of VTE in pregnancy. Moreover, we describe ongoing high-quality randomised trials and prospective clinical management studies in this area. High quality clinical studies and trials in pregnancy can be done and must be prioritised, through international network efforts and national funding advocacy. Ultimately, translation of study results to impact upon guidelines and policy will deliver better care to and will protect the lives and health of pregnant people and those contemplating pregnancy throughout the world.

Obstetric anal sphincter injury (OASI) in the presence of an intact perineum.

Obstetric anal sphincter injury (OASI) in the absence of concurrent injury to the perineal skin is not a common diagnosis. A primiparous woman delivered a healthy male infant by spontaneous vertex delivery. At time of delivery, a compound presentation of the fetal hand with the head was noted. Initial examination revealed a presumed second-degree tear; however, a small laceration above the anal verge was noted, which on exploration revealed a perineal injury through the anal sphincter complex. In the operating theatre, the perineal skin was incised to reveal a 3c OASI, which was repaired appropriately. While atypical OASI has been reported previously, this specific injury has never been described in detail in the literature. Awareness of atypical perineal injuries is needed and while careful perineal examination is required in all cases, this is especially important where the perineal skin appears intact to ensure appropriate diagnosis of any concurrent OASI.

Reliability of the modified Frailty Index (mFI) for intervention and continued surveillance in elective infrarenal abdominal aortic aneurysm (AAA).

INTRODUCTION: Frailty has been proven to lead to higher morbidity and mortality rates in surgical patients, independent of age. The modified Frailty Index (mFI) is a validated means of assessing for frailty. AIM OF STUDY: The aim of this study is to ascertain if the mFI correlates with clinician experience in turning down patients for abdominal aortic aneurysm (AAA) surgery and/or AAA surveillance. METHODS: A contemporaneously recorded database of all AAA patients treated during 2017 at a large University Hospital was reviewed. Patients were categorised into the following groups; continued surveillance, turned down for surveillance, patient declined surveillance, patient offered surgery, patient turned down for surgery and patient declined surgery. RESULTS: One hundred and forty two patients were included. Twenty-eight patients <5.5 cm were turned down for surveillance with a mFI of 0.27. Forty-one patients <5.5 cm continued with surveillance, with a mFI of 0.09 (p < 0.0001). Eighteen patients >5.5 cm were turned down for surgical intervention with a median mFI of 0.36. Forty-two patients were offered surgical intervention had a median mFI of 0.09 (p < 0.0001). CONCLUSION: Frailty is associated with higher morbidity and mortality amongst frail patient cohorts. mFI is a valid and easy to use tool to predict perioperative outcomes in AAA intervention. It correlates well with senior, experienced clinicians' decision-making in relation to who should and who should not undergo elective AAA surgery and those patients who should have ongoing aneurysm surveillance.

SVS WIfI score as a predictor of amputation after onset of CLI: Validation in an Irish tertiary vascular unit.

INTRODUCTION: Critical limb ischemia (CLI) in diabetic patients is defined by non-healing foot ulcer or rest pain for more than 2 weeks with ankle pressure of less than 40 mmHg. The SVS WIfI classification system stratifies CLI on the basis of perfusion, extent of wound and superadded infection to provide a composite score which guides further management and predicts final prognosis OBJECTIVE: The aim of the study was to use the SVS WIfI scoring system to predict the need for early revascularization versus early amputation depending on the composite WIfI score at presentation. METHODOLOGY: This was a retrospective observational study. Data was collected on patients admitted with CLI, in the last 2 years, to calculate composite WIfI score. The WIfI categories according to risk of limb loss were identified with endpoint being major or minor amputation. RESULTS: Among the 87 patients reviewed, 35 patients (40%) required major amputation, and 29 of those underwent vascular intervention (83%) as part of their care. Median age of the cohort was 72 and 71% were male patients. Comparative analysis between major amputations and minor amputation showed the median score on initial clinical presentation to be 7 in major amputation and 5 in minor amputations (p < 0.0001). CONCLUSION: The composite WIFi score (a summation of the Wound, Ischaemia, and Infection sub-scores) was a good predictor of need for an amputation WIfI scoring system is a useful tool and should be used early in the management of infected ischaemic limbs.

The effects of substrate composition and topography on the characteristics and growth of cell cultures of cochlear fibrocytes.

Spiral ligament fibrocytes of the cochlea play homoeostatic roles in hearing and their degeneration contributes to hearing loss. Culturing fibrocytes in vitro provides a way to evaluate their functional characteristics and study possible therapies for hearing loss. We investigated whether in vivo characteristics of fibrocytes could be recapitulated in vitro by modifying the culture substrates and carried out proof of concept studies for potential transplantation of culture cells into the inner ear. Fibrocytes cultured from 4 to 5-week old CD/1 mice were grown on 2D substrates coated with collagen I, II, V or IX and, after harvesting, onto or into 3D substrates (hydrogels) of collagen I alone or mixed collagen I and II at a 1:1 ratio. We also assessed magnetic nanoparticle (MNP) uptake. Cell counts, immunohistochemical and ultrastructural studies showed that fibrocytes grown on 2D substrates proliferated, formed both small spindle-shaped and large flat cells that avidly took up MNPs. Of the different collagen coatings, only collagen II had an effect, causing a reduced size of the larger cells. On hydrogels, the cells were plump/rounded with extended processes, resembling native cells. They formed networks over the surface and became incorporated into the gel. In all culture formats, the majority co-expressed caldesmon, aquaporin 1, S-100 and sodium potassium ATPase, indicating a mixed or uncharacterised phenotype. Time-course experiments showed a decrease to ∼50% of the starting population by 4d after seeding on collagen I hydrogels, but better survival (∼60%) was found on collagen I + II gels, whilst TEM revealed the presence of apoptotic cells. Cells grown within gels additionally showed necrosis. These results demonstrate that fibrocytes grown in 3D recapitulate in vivo morphology of native fibrocytes, but have poorer survival, compared with 2D. Therefore hydrogel cultures could be used to study fibrocyte function and might also offer avenues for cell-replacement therapies, but need more optimization for therapeutic use. Fibrocyte function could be modified using MNPs in combination, for example, with gene transfection.

Melatonin as an immunomodulator in children with Down syndrome.

BACKGROUND: Down syndrome (DS) is a disorder characterised by marked immune dysfunction, increased mortality from sepsis, chronic inflammation, increased oxidative stress, sleep disturbance and possibly abnormal endogenous melatonin levels. Melatonin has a myriad of immune functions, and we hypothesised that this therapeutic agent could modulate the innate immune system in this cohort. METHODS: We investigated neutrophil and monocyte function (CD11b, TLR4 expression by flow cytometry), genes involved in TLR signalling (MyD88, IRAK4, TRIF), the inflammasome (NLRP3, IL-1ß), and circadian rhythm (BMAL, CLOCK, CRY) by qPCR, and inflammatory cytokines (IL-2, IL-6, IL-8, IL-18, IL-1ß, TNF-α, IFN-γ, IL-10, IL-1ra, VEGF, Epo, GM-CSF) by enzyme-linked immunosorbent assay (ELISA) following immunomodulation with LPS endotoxin and melatonin. 47 children with DS and 23 age- and sex-matched controls were recruited. RESULTS: We demonstrated that melatonin has several significant effects by reducing CD11b and TLR4 expression, attenuating TLR signalling, genes involved in the inflammasome and has the potential to reduce LPS-induced inflammatory responses. CONCLUSIONS: Immunomodulatory effects of melatonin were found in both paediatric cohorts with more marked effects in the children with DS. Melatonin mediates immune response through a wide array of mechanisms and this immunomodulator may buffer the inflammatory response by regulating pro and anti-inflammatory signalling. IMPACT: We highlight that melatonin mediates its immune response through a wide array of mechanisms, its effects appear to be dose dependant and children with Down syndrome may be more receptive to treatment with it. Immunomodulatory effects of melatonin were demonstrated with marked effects in the children with Down syndrome with a reduction of MyD88, IL-1ß and NLRP3 expression in whole-blood samples. Melatonin is a proposed anti-inflammatory agent with a well-established safety profile, that has the potential for mitigation of pro- and anti-inflammatory cytokines in paediatric Down syndrome cohorts, though further clinical trials are warranted.

Online Search Trends Influencing Anticoagulation in Patients With COVID-19: Observational Study.

BACKGROUND: Early evidence of COVID-19-associated coagulopathy disseminated rapidly online during the first months of 2020, followed by clinical debate about how best to manage thrombotic risks in these patients. The rapid online spread of case reports was followed by online interim guidelines, discussions, and worldwide online searches for further information. The impact of global online search trends and online discussion on local approaches to coagulopathy in patients with COVID-19 has not been studied. OBJECTIVE: The goal of this study was to investigate the relationship between online search trends using Google Trends and the rate of appropriate venous thromboembolism (VTE) prophylaxis and anticoagulation therapy in a cohort of patients with COVID-19 admitted to a tertiary hospital in Ireland. METHODS: A retrospective audit of anticoagulation therapy and VTE prophylaxis among patients with COVID-19 who were admitted to a tertiary hospital was conducted between February 29 and May 31, 2020. Worldwide Google search trends of the term "COVID-19" and anticoagulation synonyms during this time period were determined and correlated against one another using a Spearman correlation. A P value of <.05 was considered significant, and analysis was completed using Prism, version 8 (GraphPad). RESULTS: A statistically significant Spearman correlation (P<.001, r=0.71) was found between the two data sets, showing an increase in VTE prophylaxis in patients with COVID-19 with increasing online searches worldwide. This represents a proxy for online searches and discussion, dissemination of information, and Google search trends relating to COVID-19 and clotting risk, in particular, which correlated with an increasing trend of providing thromboprophylaxis and anticoagulation therapy to patients with COVID-19 in our tertiary center. CONCLUSIONS: We described a correlation of local change in clinical practice with worldwide online dialogue and digital search trends that influenced individual clinicians, prior to the publication of formal guidelines or a local quality-improvement intervention.

The effectiveness of continuous respiratory rate monitoring in predicting hypoxic and pyrexic events: a retrospective cohort study.

Respiratory rate (RR) is routinely used to monitor patients with infectious, cardiac and respiratory diseases and is a component of early warning scores used to predict patient deterioration. However, it is often measured visually with considerable bias and inaccuracy.Objectives. Firstly, to compare distribution and accuracy of electronically measured RR (EMRR) and visually measured RR (VMRR). Secondly, to determine whether, and how far in advance, continuous electronic RR monitoring can predict oncoming hypoxic and pyrexic episodes in infectious respiratory disease.Approach.A retrospective cohort study analysing the difference between EMRR and VMRR was conducted using patient data from a large tertiary hospital. Cox proportional hazards models were used to determine whether continuous, EMRR measurements could predict oncoming hypoxic (SpO2 < 92%) and pyrexic (temperature >38 °C) episodes.Main results.Data were gathered from 34 COVID-19 patients, from which a total of 3445 observations of VMRR (independent of Hawthorne effect), peripheral oxygen saturation and temperature and 729 117 observations of EMRR were collected. VMRR had peaks in distribution at 18 and 20 breaths per minute. 70.9% of patients would have had a change of treatment during their admission based on the UK's National Early Warning System if EMRR was used in place of VMRR. An elevated EMRR was predictive of hypoxic (hazard ratio: 1.8 (1.05-3.07)) and pyrexic (hazard ratio: 9.7 (3.8-25)) episodes over the following 12 h.Significance.Continuous EMRR values are systematically different to VMRR values, and results suggest it is a better indicator of true RR as it has lower kurtosis, higher variance, a lack of peaks at expected values (18 and 20) and it measures a physiological component of breathing directly (abdominal movement). Results suggest EMRR is a strong marker of oncoming hypoxia and is highly predictive of oncoming pyrexic events in the following 12 h. In many diseases, this could provide an early window to escalate care prior to deterioration, potentially preventing morbidity and mortality.

Health-related quality of life and quality of care in pregnant and postnatal women during the coronavirus disease 2019 pandemic: A cohort study.

OBJECTIVE: Health-related quality of life (HRQoL) and the delivery of high-quality care are ongoing concerns when caring for pregnant women during the coronavirus disease 2019 (COVID-19) pandemic. We compared self-reported HRQoL and hospital quality of care among perinatal women with and without COVID-19. METHODS: This is a prospective cohort study of perinatal women attending a tertiary maternity unit during the pandemic. Eighteen women who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and 20 SARS-CoV-2-negative women were recruited. Participants completed the Short Form Health Survey (SF-12), Clinical Outcomes in Routine Evaluation-Outcome Measure, and Quality from the Patient's Perspective questionnaires. Mean scores were compared. RESULTS: Of the Non-COVID-19 cohort, 95% (n = 19) were Caucasian, whereas 67% (n = 12) of the COVID-19 cohort were not Caucasian (χ2  = 16.01, P < 0.001). The mean SF-12 for physical health in the COVID-19 cohort had significantly lower scores (P < 0.002). There was no difference in mental health and well-being between cohorts. The quality of care experienced was notably similar and very positive. CONCLUSION: There was a significantly greater burden on physical health among pregnant women with COVID-19. Mental health and psychological status were similar in both groups. High quality of care during a pandemic is possible to deliver in a maternity setting, irrespective of COVID-19 status.

Von Willebrand factor propeptide in severe coronavirus disease 2019 (COVID-19): evidence of acute and sustained endothelial cell activation.

Endothelial cell (EC) activation plays a key role in the pathogenesis of pulmonary microvascular occlusion, which is a hallmark of severe coronavirus disease 2019 (COVID-19). Consistent with EC activation, increased plasma von Willebrand factor antigen (VWF:Ag) levels have been reported in COVID-19. Importantly however, studies in other microangiopathies have shown that plasma VWF propeptide (VWFpp) is a more sensitive and specific measure of acute EC activation. In the present study, we further investigated the nature of EC activation in severe COVID-19. Markedly increased plasma VWF:Ag [median (interquatile range, IQR) 608·8 (531-830)iu/dl] and pro-coagulant factor VIII (FVIII) levels [median (IQR) 261·9 (170-315) iu/dl] were seen in patients with severe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Sequential testing showed that these elevated VWF-FVIII complex levels remained high for up to 3 weeks. Similarly, plasma VWFpp levels were also markedly elevated [median (IQR) 324·6 (267-524) iu/dl]. Interestingly however, the VWFpp/VWF:Ag ratio was reduced, demonstrating that decreased VWF clearance contributes to the elevated plasma VWF:Ag levels in severe COVID-19. Importantly, plasma VWFpp levels also correlated with clinical severity indices including the Sequential Organ Failure Assessment (SOFA) score, Sepsis-Induced Coagulopathy (SIC) score and the ratio of arterial oxygen partial pressure to fractional inspired oxygen (P/F ratio). Collectively, these findings support the hypothesis that sustained fulminant EC activation is occurring in severe COVID-19, and further suggest that VWFpp may have a role as a biomarker in this setting.

Readability of online COVID-19 health information: a comparison between four English speaking countries.

BACKGROUND: The internet is now the first line source of health information for many people worldwide. In the current Coronavirus Disease 2019 (COVID-19) global pandemic, health information is being produced, revised, updated and disseminated at an increasingly rapid rate. The general public are faced with a plethora of misinformation regarding COVID-19 and the readability of online information has an impact on their understanding of the disease. The accessibility of online healthcare information relating to COVID-19 is unknown. We sought to evaluate the readability of online information relating to COVID-19 in four English speaking regions: Ireland, the United Kingdom, Canada and the United States, and compare readability of website source provenance and regional origin. METHODS: The Google® search engine was used to collate the first 20 webpage URLs for three individual searches for 'COVID', 'COVID-19', and 'coronavirus' from Ireland, the United Kingdom, Canada and the United States. The Gunning Fog Index (GFI), Flesch-Kincaid Grade (FKG) Score, Flesch Reading Ease Score (FRES), Simple Measure of Gobbledygook (SMOG) score were calculated to assess the readability. RESULTS: There were poor levels of readability webpages reviewed, with only 17.2% of webpages at a universally readable level. There was a significant difference in readability between the different webpages based on their information source (p < 0.01). Public Health organisations and Government organisations provided the most readable COVID-19 material, while digital media sources were significantly less readable. There were no significant differences in readability between regions. CONCLUSION: Much of the general public have relied on online information during the pandemic. Information on COVID-19 should be made more readable, and those writing webpages and information tools should ensure universal accessibility is considered in their production. Governments and healthcare practitioners should have an awareness of the online sources of information available, and ensure that readability of our own productions is at a universally readable level which will increase understanding and adherence to health guidelines.