Research affiliated to staff at the Mater Misericordiae University Hospital

Recent Submissions

  • Cohort profile: BIOVASC-late, a prospective multicentred study of imaging and blood biomarkers of carotid plaque inflammation and risk of late vascular recurrence after non-severe stroke in Ireland.

    McCabe, John Joseph; Giannotti, Nicola; McNulty, Jonathan; Collins, Sean; Coveney, Sarah; Murphy, Sean; Barry, Mary; Harbison, Joseph; Cronin, Simon; Williams, David; et al. (2020-07-19)
    Purpose: Inflammation is important in stroke. Anti-inflammatory therapy reduces vascular events in coronary patients. 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) identifies plaque inflammation-related metabolism. However, long-term prospective cohort studies investigating the association between carotid plaque inflammation, identified on 18F-FDG PET and the risk of recurrent vascular events, have not yet been undertaken in patients with stroke. Participants: The Biomarkers Imaging Vulnerable Atherosclerosis in Symptomatic Carotid disease (BIOVASC) study and Dublin Carotid Atherosclerosis Study (DUCASS) are two prospective multicentred observational cohort studies, employing near-identical methodologies, which recruited 285 patients between 2008 and 2016 with non-severe stroke/transient ischaemic attack and ipsilateral carotid stenosis (50%-99%). Patients underwent coregistered carotid 18F-FDG PET/CT angiography and phlebotomy for measurement of inflammatory cytokines. Plaque 18F-FDG-uptake is expressed as maximum standardised uptake value (SUVmax) and tissue-to-background ratio. The BIOVASC-Late study is a follow-up study (median 7 years) of patients recruited to the DUCASS/BIOVASC cohorts. Findings to date: We have reported that 18F-FDG-uptake in atherosclerotic plaques of patients with symptomatic carotid stenosis predicts early recurrent stroke, independent of luminal narrowing. The incorporation of 18F-FDG plaque uptake into a clinical prediction model also improves discrimination of early recurrent stroke, when compared with risk stratification by luminal stenosis alone. However, the relationship between 18F-FDG-uptake and late vascular events has not been investigated to date. Future plans: The primary aim of BIOVASC-Late is to investigate the association between SUVmax in symptomatic 'culprit' carotid plaque (as a marker of systemic inflammatory atherosclerosis) and the composite outcome of any late major vascular event (recurrent ischaemic stroke, coronary event or vascular death). Secondary aims are to investigate associations between: (1) SUVmax in symptomatic plaque, and individual vascular endpoints (2) SUVmax in asymptomatic contralateral carotid plaque and SUVmax in ipsilateral symptomatic plaque (3) SUVmax in asymptomatic carotid plaque and major vascular events (4) inflammatory cytokines and vascular events. Keywords: adult neurology; cardiovascular imaging; preventive medicine; stroke.
  • Competing mortality risks: predicted cardiovascular disease risk versus predicted risk of breast cancer mortality in patients receiving adjuvant chemotherapy in a single Irish center.

    Prior, Lisa; Featherstone, Hannah; O'Reilly, David; Nugent, Killian; Lim, Marvin; McCaffrey, John; Higgins, Michaela J; Kelly, Catherine M (2021-02-23)
    Background: Due to advances in care, most women diagnosed with breast cancer do not die from the disease itself. Instead, cardiovascular disease (CVD) remains the most frequent cause of death. Many breast cancer patients are older and have established CVD risk factors. They are at further risk due to exposure to anthracyclines, HER2 targeted agents, endocrine therapy and radiotherapy. In this study, we compared the 10-year predicted risk of breast cancer mortality versus that of cardiovascular (CV) morbidity/mortality in breast cancer patients receiving adjuvant chemotherapy using online predictive risk calculators. Furthermore, we evaluated the predicted outcome of CV risk factor optimisation on their overall CV risk. Methods: This was a cross sectional study. All patients with resected Stage I-III breast cancer who received adjuvant chemotherapy at our centre from September 2015 to November 2016 were identified. Data recorded included demographics, tumor characteristics, treatments and CV risk factors. To calculate predicted 10-year risk of CVD and impact of lifestyle changes, we used the JBS3 (Joint British Society) online risk calculator. To calculate the predicted 10-year risk of breast cancer mortality, we used the PREDICT calculator. Biostatistical methods included Wilcoxon signed rank test for predicted CVD risk pre and post cardiovascular risk optimization. Results: We identified 102 patients. Of this cohort, 76 patients were ≥ 50 years & 26 were < 50 years of age. The group had significant baseline cardiovascular risk factors: increased BMI (68 %, n = 70), ex-smoking (34 %, n = 35), current smoking (13 %, n = 13), hypertension (47 %, n = 47) and dyslipidemia (57 %). Of the total group, 48 % had a high (> 20 %) and 37 % had a moderate (10-20 %) 10-year predicted breast cancer mortality risk. Regarding 10-year predicted risk of CVD, 11 % and 22 % fell into the high (> 20 %) and moderate (10-20 %) risk categories, respectively. Assuming CV risk factor optimisation, there was a predicted improvement in median 10-year CV risk from 26.5 to 9.9 % (p = .005) in the high CVD risk group and from 14.0 to 6.6 % (p < .001) in the moderate CVD risk group. Conclusions: Benefits predicted with a CVD risk intervention model indicates that this should be incorporated into routine breast oncology care.
  • Incidence and risk factors of delirium in surgical intensive care unit.

    Ali, Muhammad Asghar; Hashmi, Madiha; Ahmed, Waqas; Raza, Syed Amir; Khan, Muhammad Faisal; Salim, Bushra (2021-03-03)
    Background: To evaluate the incidence and modifiable risk factors of delirium in surgical intensive care unit (SICU) of tertiary care hospital in a low-income and middle-income country. Methods: We conducted a single cohort observational study in patients over 18 years of age who were admitted to the SICU for >24 hours in Aga Khan University Hospital from January to December 2016. Patients who had pre-existing cognitive dysfunction were excluded. Intensive Care Delirium Screening Checklist was used to assess delirium. Incidence of delirium was computed, and univariate and multivariable analyses were performed to observe the relationship between outcome and associated factors. Results: The average patient age was 43.29±17.38 and body mass index was 26.25±3.57 kg/m2. Delirium was observed in 19 of 87 patients with an incidence rate of 21.8%. Multivariable analysis showed chronic obstructive pulmonary disease, pain score >4 and hypernatremia were strong predictors of delirium. Midazolam (adjusted OR (aOR)=7.37; 95% CI 2.04 to 26.61) and propofol exposure (aOR=7.02; 95% CI 1.92 to 25.76) were the strongest independent predictors of delirium while analgesic exposures were not statistically significant to predict delirium in multivariable analysis. Conclusion: Delirium is a significant risk factor of poor outcome in SICU. There was an independent association between pain, sedation, COPD, hypernatremia and fever in developing delirium.
  • Impact of COVID-19 on the pain and disability of patients with adult spinal deformity.

    Kieser, D C; Bourghli, A; Larrieu, D; Cawley, D T; Hayashi, K; Jakinapally, S; Pizones, J; Boissiere, L; Obeid, I (2021-03-02)
    Purpose: To evaluate the pain and functional effect of the COVID-19 pandemic on patients with ASD reflected by their response to SRS-22, ODI, and SF-36 questionnaires. Methods: Patients who had stable pain and functional outcome scores over the preceding 2 years were enrolled in a local prospectively collected adult spinal deformity (ASD) database. A reanalysis of their SRS22, ODI and SF-36 data 14 days into confinement were compared to their last pre-confinement scores. Results: 89 patients were included in this study (average age 60.7 years, 91% female) with an average time from last FU until confinement of 9.6 months. The ODI total score worsened by 5 points post-confinement with no difference seen in personal care, walking and social life. In contrast, the SRS-22 score showed small improvements in function/activity and satisfaction, but no significant differences for the other domains. Similarly, the SF-36 showed small improvements in physical function, physical and emotional role, vitality and PCS. Conclusion: The global COVID-19 pandemic and ensuing confinement had variable overall effects on ASD patients, without the expected marked worsening. In addition, this study illustrates that the SRS-22 questionnaire is less influenced by environmental and psychological factors than the ODI supporting its objectivity and accuracy in the evaluation of the QoL of ASD patients.
  • Dynamic left ventricular outflow tract gradient resulting from Takotsubo cardiomyopathy ameliorated by intra-aortic balloon pump counterpulsation: a case report.

    O'Brien, Jim; Mahony, Stephen; Byrne, Roger J; Byrne, Robert A (2021-03-03)
    Background: Takotsubo cardiomyopathy is a variant of acute coronary syndrome with characteristic acute left ventricular apical ballooning. Uncommonly, there can be associated left ventricular outflow tract (LVOT) obstruction causing cardiogenic shock refractory to inotropic support. The use of afterload-reducing mechanical support such as intra-aortic balloon pump (IABP) counterpulsation is not routinely employed in instances of this kind. Case summary: In our case report, we describe a 66-year-old female with acute Takotsubo cardiomyopathy and associated LVOT obstruction which failed to respond to high-dose dobutamine and whose clinical trajectory was worsened by fast atrial fibrillation with rapid ventricular response. Within 24 h of admission, the patient had an IABP placed which rapidly improved her haemodynamics. Two days later, IABP was removed and within 6 days of admission, apical ballooning and LVOT obstruction had fully recovered. Conclusion: We recommend early use of mechanical support with IABP counterpulsation to expedite recovery in patients with acute Takotsubo cardiomyopathy with associated LVOT obstruction.
  • Preoperative C-reactive protein and other inflammatory markers as predictors of postoperative complications in patients with colorectal neoplasia.

    Alsaif, Sufana H; Rogers, Ailín C; Pua, Priscilla; Casey, Paul T; Aherne, Geoff G; Brannigan, Ann E; Mulsow, Jurgen J; Shields, Conor J; Cahill, Ronan A (2021-03-13)
    Background: Inflammatory markers are measured following colorectal surgery to detect postoperative complications. However, the association of these markers preoperatively with subsequent postoperative course has not yet been usefully studied. Aim: The aim of this study is to assess the ability of preoperative C-reactive protein (CRP) and other inflammatory marker measurements in the prediction of postoperative morbidity after elective colorectal surgery. Methods: This is a retrospective study which catalogs 218 patients undergoing elective, potentially curative surgery for colorectal neoplasia. Preoperative laboratory results of the full blood count (FBC), C-reactive protein (CRP) and carcinoembryonic antigen (CEA) were recorded. Multivariable analysis was performed to examine preoperative variables against 30-day postoperative complications by type and grade (Clavien-Dindo (CD)), adjusting for age, sex, BMI, smoking status, medical history, open versus laparoscopic operation, and tumor characteristics. Results: Elevated preoperative CRP (≥ 5 mg/L) was significantly predictive of all-cause mortality, with an OR of 17.0 (p < 0.001) and was the strongest factor to predict a CD morbidity grade ≥ 3 (OR 41.9, p < 0.001). Other factors predictive of CD morbidity grade ≥ 3 included smoking, elevated preoperative platelet count and elevated preoperative neutrophil-lymphocyte ratio (OR 15.6, 8.6, and 6.3 respectively, all p < 0.05). CRP values above 5.5 mg/L were indicative of all-cause morbidity (AUC = 0.871), and values above 17.5 mg/L predicted severe complications (AUC = 0.934). Conclusions: Elevated preoperative CRP predicts increased postoperative morbidity in this patient cohort. The results herein aid risk and resource stratification and encourage preoperative assessment of inflammatory propensity besides simple sepsis exclusion.
  • Letter in response to "COVID-19, Virchow's triad and thromboembolic risk in obese pregnant women".

    Calcaterra, Giuseppe; Bassareo, Pier Paolo; Mehta, Jawahar L (2021-03-24)
  • Overview of recent advances in metastatic triple negative breast cancer.

    O'Reilly, David; Sendi, Maha Al; Kelly, Catherine M (2021-03)
    Metastatic triple negative breast cancer (TNBC) has an aggressive phenotype with a predilection for visceral organs and brain. Best responses to chemotherapy are predominately in the first line. Recent studies have demonstrated improved progression free survival with the combination of atezolizumab/pembrolizumab and chemotherapy in programmed death-ligand 1 positive metastatic TNBC. However, a recent trial in a similar population showed no benefit for atezoli-zumab and paclitaxel which led to a Food and Drug Administration alert. Two phase III trials (OLYMPIAD and BROCADE3) demonstrated a benefit in progression free survival (PFS) but not overall survival in patients with BRCA-associated metastatic TNBC treated with Olaparib or Talazoparib respectively. For those treated with Talazoparib, the time to deterioration in health related-quality of life was also longer compared to chemotherapy. The BROCADE3 trial demonstrated that the combination of a platinum and veliparib increased PFS in first-line metastatic TNBC but at the cost of increased toxicity. There are no head-to-head comparisons of a poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and platinums. There are unanswered questions regarding the role of PARPi maintenance after platinum therapy as is standard of care in BRCA-associated ovarian cancer. Other areas of therapeutic interest include targeting aberrations in the phosphoinositide 3-kinase pathway, protein kinase B, mammalian target of rapamycin or utilising antibody drug conjugates. This review focusses on recent and emerging therapeutic options in metastatic TNBC. We searched PubMed, and recent international meetings from American Society of Clinical Oncology, San Antonio Breast Cancer Conference and the European Society of Medical Oncology.
  • Successful transition from insulin to sulfonylurea, on second attempt, in a 24-year-old female with neonatal diabetes secondary to KCNJ11 gene mutation.

    Hajji, Sulaiman; Aljenaee, Khaled; Garrahy, Aoife; Byrne, Maria (2021-04-09)
    Neonatal diabetes (NDM) is defined as diabetes that occurs in the first 6 months of life, the majority of cases are due to sporadic mutations. ATP-sensitive potassium channels located in the beta cells of the pancreas play a major role in insulin secretion and blood glucose homeostasis. Mutations that alter the function of these channels may lead to NDM. We report a case of a 26-year-old Irish woman who was diagnosed with NDM at the age of 4 weeks and treated as type 1 diabetes mellitus, with multiple daily injections of insulin with suboptimal glycaemic control and frequent episodes of hypoglycaemic. She underwent genetic testing for NDM and was diagnosed with a KCNJ11 gene mutation. She was transitioned to high dose glibenclamide at the age of 16 years, but the trial failed due to poor glycaemic control and patient preference, and she was restarted on insulin. At 24 years of age, she was successfully transitioned from insulin (total daily dose 50 units) to high dose sulfonylurea (SU) (glibenclamide 15 mg twice daily). This resulted in optimal control of blood glucose (HbA1C fell from 63 to 44 mmol/mol), lower rates of hypoglycaemic and better quality of life. This case demonstrates that a second trial of SU in later life may be successful.
  • The impact of frailty on survival in elderly intensive care patients with COVID-19: the COVIP study.

    Jung, Christian; Flaatten, Hans; Fjølner, Jesper; Bruno, Raphael Romano; Wernly, Bernhard; Artigas, Antonio; Bollen Pinto, Bernardo; Schefold, Joerg C; Wolff, Georg; Kelm, Malte; et al. (2021-04-19)
    Background: The COVID-19 pandemic has led highly developed healthcare systems to the brink of collapse due to the large numbers of patients being admitted into hospitals. One of the potential prognostic indicators in patients with COVID-19 is frailty. The degree of frailty could be used to assist both the triage into intensive care, and decisions regarding treatment limitations. Our study sought to determine the interaction of frailty and age in elderly COVID-19 ICU patients. Methods: A prospective multicentre study of COVID-19 patients ≥ 70 years admitted to intensive care in 138 ICUs from 28 countries was conducted. The primary endpoint was 30-day mortality. Frailty was assessed using the clinical frailty scale. Additionally, comorbidities, management strategies and treatment limitations were recorded. Results: The study included 1346 patients (28% female) with a median age of 75 years (IQR 72-78, range 70-96), 16.3% were older than 80 years, and 21% of the patients were frail. The overall survival at 30 days was 59% (95% CI 56-62), with 66% (63-69) in fit, 53% (47-61) in vulnerable and 41% (35-47) in frail patients (p < 0.001). In frail patients, there was no difference in 30-day survival between different age categories. Frailty was linked to an increased use of treatment limitations and less use of mechanical ventilation. In a model controlling for age, disease severity, sex, treatment limitations and comorbidities, frailty was independently associated with lower survival. Conclusion: Frailty provides relevant prognostic information in elderly COVID-19 patients in addition to age and comorbidities. Trial registration NCT04321265 , registered 19 March 2020.
  • Powered air-purifying respirators do not compromise air quality in the operating theatre.

    Brady, Deirdre; Boran, Nicola; O'Malley, Dara Ann; Joy, Jessy; O'Neill, Aoife; Dalli, Jeffrey; Cahill, Ronan; Jerry, Jincy (2021-04-15)
  • Systolic and Diastolic Functions After a Brief Acute Bout of Mild Exercise in Normobaric Hypoxia.

    Magnani, Sara; Mulliri, Gabriele; Roberto, Silvana; Sechi, Fabio; Ghiani, Giovanna; Sainas, Gianmarco; Nughedu, Giorgio; Vargiu, Romina; Bassareo, Pier Paolo; Crisafulli, Antonio (2021-04-23)
    Acute hypoxia (AH) is a challenge to the homeostasis of the cardiovascular system, especially during exercise. Research in this area is scarce. We aimed to ascertain whether echocardiographic, Doppler, and tissue Doppler measures were able to detect changes in systolic and diastolic functions during the recovery after mild exercise in AH. Twelve healthy males (age 33.5 ± 4.8 years) completed a cardiopulmonary test on an electromagnetically braked cycle-ergometer to determine their maximum workload (Wmax). On separate days, participants performed randomly assigned two exercise sessions consisting in 3 min pedalling at 30% of Wmax: (1) one test was conducted in normoxia (NORMO) and (2) one in normobaric hypoxia with FiO2 set to 13.5% (HYPO). Hemodynamics were assessed with an echocardiographic system. The main result was that the HYPO session increased parameters related to myocardial contractility such as pre-ejection period and systolic myocardial velocity with respect to the NORMO test. Moreover, the HYPO test enhanced early transmitral filling peak velocities. No effects were detected for left ventricular volumes, as end-diastolic, end-systolic, and stroke volume were similar between the NORMO and the HYPO test. Results of the present investigation support the hypothesis that a brief, mild exercise bout in acute normobaric hypoxia does not impair systolic or diastolic functions. Rather, it appears that stroke volume is well preserved and that systolic and early diastolic functions are enhanced by exercise in hypoxia.
  • Barriers to and facilitators of HIV serostatus disclosure to sexual partners among postpartum women living with HIV in South Africa.

    Adeniyi, Oladele Vincent; Nwogwugwu, Charlotte; Ajayi, Anthony Idowu; Lambert, John (2021-05-13)
    Background: Disclosure of HIV serostatus to a sexual partner can facilitate partner's support and testing and better treatment outcomes. Studies examining changes in disclosure rates of serostatus from delivery and postpartum periods are scarce. Our study fills this gap by using a follow-up survey of postpartum women with HIV to examine if disclosure prevalence has improved compared to the proportion recorded at childbirth. We further assessed the reasons for non-disclosure and correlates of serostatus disclosure to sexual partners. Methods: We conducted a cross-sectional analytical study (exit interview) with a final sample of 485 postpartum women with HIV drawn from the East London Prospective Cohort study database between January and May 2018. Disclosure of HIV status to partner was based on self-reporting. We fitted adjusted and unadjusted logistic regression models and also conducted descriptive statistical analyses. Sampling weights were used to correct for sampling errors. Results: Overall, 81.8% of women in the study cohort had disclosed their status to their partners, representing a 7.4 percentage point increase since child delivery. After adjusting for important covariates, women were more likely to disclose their status if they were married [adjusted odds ratio (AOR): 3.10; 95% confidence interval (CI):1.39-6.91] but were less likely to disclose if they used alcohol [AOR: 0.61; 95% CI:0.37-0.99] or had reported adherence to ART [AOR: 0.59; 95% CI:0.36-0.96]. Fear of rejection, stigma or being judged, new or casual relationships, and having a violent partner were the main reasons for not disclosing HIV status to sexual partners. Conclusion: We found a relatively higher rate of HIV status disclosure in the cohort compared to the rate recorded at childbirth, suggesting an improvement over time. Also, complicated relationship dynamics and fear of social exclusion still constitute barriers to HIV status disclosure to sexual partners despite patients' counselling.
  • Next generation proteomics with drug sensitivity screening identifies sub-clones informing therapeutic and drug development strategies for multiple myeloma patients.

    Tierney, Ciara; Bazou, Despina; Majumder, Muntasir M; Anttila, Pekka; Silvennoinen, Raija; Heckman, Caroline A; Dowling, Paul; O'Gorman, Peter (2021-06-18)
    With the introduction of novel therapeutic agents, survival in Multiple Myeloma (MM) has increased in recent years. However, drug-resistant clones inevitably arise and lead to disease progression and death. The current International Myeloma Working Group response criteria are broad and make it difficult to clearly designate resistant and responsive patients thereby hampering proteo-genomic analysis for informative biomarkers for sensitivity. In this proof-of-concept study we addressed these challenges by combining an ex-vivo drug sensitivity testing platform with state-of-the-art proteomics analysis. 35 CD138-purified MM samples were taken from patients with newly diagnosed or relapsed MM and exposed to therapeutic agents from five therapeutic drug classes including Bortezomib, Quizinostat, Lenalidomide, Navitoclax and PF-04691502. Comparative proteomic analysis using liquid chromatography-mass spectrometry objectively determined the most and least sensitive patient groups. Using this approach several proteins of biological significance were identified in each drug class. In three of the five classes focal adhesion-related proteins predicted low sensitivity, suggesting that targeting this pathway could modulate cell adhesion mediated drug resistance. Using Receiver Operating Characteristic curve analysis, strong predictive power for the specificity and sensitivity of these potential biomarkers was identified. This approach has the potential to yield predictive theranostic protein panels that can inform therapeutic decision making.
  • Platelets, extracellular vesicles and coagulation in pulmonary arterial hypertension.

    Cullivan, Sarah; Murphy, Claire A; Weiss, Luisa; Comer, Shane P; Kevane, Barry; McCullagh, Brian; Maguire, Patricia B; Ní Ainle, Fionnuala; Gaine, Sean P (2021-06-04)
    Pulmonary arterial hypertension is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in pulmonary arterial hypertension which may provide insights into the pathobiology of the disease and opportunities to explore new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle autocrine and paracrine signalling in pulmonary arterial hypertension, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, extracellular vesicles and coagulation pathways in the pathobiology of pulmonary arterial hypertension. We highlight important unanswered clinical questions and the implications of these observations for future research and pulmonary arterial hypertension-directed therapies.
  • Steroid use in elderly critically ill COVID-19 patients.

    Jung, Christian; Wernly, Bernhard; Fjølner, Jesper; Bruno, Raphael Romano; Dudzinski, David; Artigas, Antonio; Bollen Pinto, Bernardo; Schefold, Joerg C; Wolff, Georg; Kelm, Malte; et al. (2021-10-07)
    This secondary analysis of the COVIP study shows a higher 30-day mortality in critically ill elderly COVID-19 patients who received steroids as part of their treatment @cjungMD
  • SKAP2-BRAF fusion and response to an MEK inhibitor in a patient with metastatic melanoma resistant to immunotherapy.

    Chew, Sonya Minmin; Lucas, Mairi; Brady, Michelle; Kelly, Catherine Margaret (2021-06-24)
    A woman in her 40s presented to the emergency department with headache and unintentional weight loss in September 2018. Investigations revealed a widely metastatic pan-negative melanoma of unknown primary. She had multiple lines of treatment including combination immunotherapy and chemotherapy. Next-generation sequencing identified an SKAP2-BRAF fusion protein, and she was commenced on an MEK inhibitor in September 2019 with a partial response seen on restaging scans after 6 weeks and a dramatic fall in her lactate dehydrogenase from 2248 IU/L to 576 IU/L. Unfortunately, the response was not maintained and she died from progression of her cancer in January 2020. SKAP2-BRAF fusions have a dimerisation domain that paradoxically activates the mitogen-activated protein kinase pathway, resulting in hyperproliferation if first-generation or second-generation BRAF inhibitors are used. Our knowledge is limited regarding the complex effects of targeted therapy in rare BRAF fusion proteins.
  • Global reporting of pulmonary embolism-related deaths in the World Health Organization mortality database: Vital registration data from 123 countries.

    Barco, Stefano; Valerio, Luca; Gallo, Andrea; Turatti, Giacomo; Mahmoudpour, Seyed Hamidreza; Ageno, Walter; Castellucci, Lana A; Cesarman-Maus, Gabriela; Ddungu, Henry; De Paula, Erich Vinicius; et al. (2021-06-15)
    Introduction: Pulmonary embolism (PE) has not been accounted for as a cause of death contributing to cause-specific mortality in global reports. Methods: We analyzed global PE-related mortality by focusing on the latest year available for each member state in the World Health Organization (WHO) mortality database, which provides age-sex-specific aggregated mortality data transmitted by national authorities for each underlying cause of death. PE-related deaths were defined by International Classification of Diseases, Tenth Revision codes for acute PE or nonfatal manifestations of venous thromboembolism (VTE). The 2001 WHO standard population served for standardization. Results: We obtained data from 123 countries covering a total population of 2 602 561 422. Overall, 50 (40.6%) were European, 39 (31.7%) American, 13 (10.6%) Eastern Mediterranean, 13 (10.6%) Western Pacific, 3 (2.4%) Southeast Asian, and 2 (1.6%) African. Of 116 countries classifiable according to population income, 57 (49.1%) were high income, 42 (36.2%) upper-middle income, 14 (12.1%) lower-middle income, and 3 (2.6%) low income. A total of 18 726 382 deaths were recorded, of which 86 930 (0.46%) were attributed to PE. PE-related mortality rate increased with age in most countries. The reporting of PE-related deaths was heterogeneous, with an age-standardized mortality rate ranging from 0 to 24 deaths per 100 000 population-years. Income status only partially explained this heterogeneity. Conclusions: Reporting of PE-related mortality in official national vital registration was characterized by extreme heterogeneity across countries. These findings mandate enhanced efforts toward systematic and uniform coverage of PE-related mortality and provides a case for full recognition of PE and VTE as a primary cause of death.
  • Coagulopathy of hospitalised COVID-19: A Pragmatic Randomised Controlled Trial of Therapeutic Anticoagulation versus Standard Care as a Rapid Response to the COVID-19 Pandemic (RAPID COVID COAG - RAPID Trial): A structured summary of a study protocol for a randomised controlled trial.

    Sholzberg, Michelle; Tang, Grace H; Negri, Elnara; Rahhal, Hassan; Kreuziger, Lisa Baumann; Pompilio, Carlos E; James, Paula; Fralick, Michael; AlHamzah, Musaad; Alomran, Faris; et al. (2021-03-10)
    Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial PARTICIPANTS: The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: 1) Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; 2) Admitted to hospital for COVID-19; 3) One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: a. D-Dimer ≥2 times ULN OR b. D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; 4) > 18 years of age; 5) Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: 1) pregnancy; 2) hemoglobin <80 g/L in the last 72 hours; 3) platelet count <50 x 109/L in the last 72 hours; 4) known fibrinogen <1.5 g/L (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 5) known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); 6) patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); 7) patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; 8) patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; 9) known bleeding within the last 30 days requiring emergency room presentation or hospitalization; 10) known history of a bleeding disorder of an inherited or active acquired bleeding disorder; 11) known history of heparin-induced thrombocytopenia; 12) known allergy to UFH or LMWH; 13) admitted to the intensive care unit at the time of screening; 14) treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; 15) Imminent death according to the judgement of the most responsible physician; 16) enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients.

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