Publications by authors named "Daniele Piovani"

48 Publications

The use of thromboelastography (TEG) and rotational thromboelastometry (ROTEM) in neonates: a systematic review.

Eur J Pediatr 2021 Jun 16. Epub 2021 Jun 16.

Laboratory of Haematology and Blood Bank Unit, School of Medicine, Attikon University Hospital, National and Kapodistrian University of Athens, Athens, Greece.

"Developmental hemostasis" refers to the dynamic process of gradual hemostatic maturation. Conventional coagulation tests seem to fail to accurately depict the in vivo hemostasis, while viscoelastic tests, thromboelastography (TEG), and rotational thromboelastometry (ROTEM) appear very promising as they provide insight more rapidly and accurately into the hemostatic potential. We systematically reviewed the literature in PubMed to examine the use of TEG and ROTEM in neonates. Our search yielded 34 studies, of which 18 concerned healthy neonates and 16 sick neonates. These viscoelastic tests have shown accelerated initiation of coagulation, increased clot strength, and increased fibrinolysis in healthy neonates compared to children and adults. Cord blood leads to a hypercoagulable state as compared to whole blood when testing is performed with TEG. Pre-term neonates have a more hypocoagulable profile, but balanced hemostasis, related to term neonates, that evolves to a more procoagulant phenotype over the first month of life. Critically ill neonates exhibit a more hypocoagulable profile as compared to healthy neonates. TEG and ROTEM have shown predictive value for bleeding events in critically ill neonates and neonates undergoing cardiopulmonary bypass or therapeutic hypothermia.Conclusion: TEG and ROTEM need to become part of the standard coagulation assessment in clinical settings in which hemostatic abnormalities are involved, as they seem to provide more rapid and accurate information regarding the hemostatic profile of the neonates. Their predictive value for bleeding events in critically ill neonates could lead to a more targeted therapy optimizing utilization of blood products. What is Known: • Conventional coagulation tests seem to fail to accurately depict the in vivo hemostasis. • TEG and ROTEM delineate more rapidly and accurately the hemostatic potential. What is New: • TEG and ROTEM have shown predictive value for bleeding events. • TEG and ROTEM may lead to a more targeted transfusion therapy optimizing utilization of blood products.
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http://dx.doi.org/10.1007/s00431-021-04154-4DOI Listing
June 2021

Rotational Thromboelastometry in Neonates Admitted to a Neonatal Intensive Care Unit: A Large Cross-sectional Study.

Semin Thromb Hemost 2021 Jun 15. Epub 2021 Jun 15.

Laboratory of Haematology and Blood Bank Unit, "Attikon" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

The aim of the present study was to assess the coagulation profile in neonatal critical illness using rotational thromboelastometry (ROTEM), and to investigate its association with disease severity and its potential prognostic role in this clinical setting. Over a period of 67 months (July 2014-February 2020) 423 critically ill neonates with confirmed or suspected sepsis, perinatal hypoxia, or respiratory distress syndrome, hospitalized in our neonatal intensive care unit were included in the study. Demographic, clinical, and laboratory data were recorded on admission day and arterial blood was analyzed on ROTEM analyzer using the standard extrinsically activated rotational thromboelastometry assay (EXTEM). Neonatal illness severity scores (Modified NEOMOD [Neonatal Multiple Organ Dysfunction] and SNAPPE [Score for Neonatal Acute Physiology with Perinatal Extension]) were calculated at the same time as ROTEM analysis. Mortality during in-hospital stay was the main outcome measure. Multivariable analyses showed that a 10 mm decrease in EXTEM clot amplitude recorded at 10 minutes (A10) is significantly associated with a higher mortality (odds ratio [OR] = 1.69, 95% confidence interval [CI]: 1.33-2.08). Higher modified NEOMOD (OR = 1.36, 95% CI: 1.26-1.47) and higher SNAPPE scores (OR = 1.06, 95% CI: 1.04-1.08) were also associated with increased mortality. The CT and A10 variables demonstrated the best prognostic performance among the EXTEM parameters for mortality (area under the curve [AUC] = 0.78; 95% CI: 0.69-0.86 and AUC = 0.76; 95% CI: 0.66-0.85, respectively), showing an optimal cut-off CT ≥63 seconds and A10 ≤37 mm. Using optimal cut-off values of the EXTEM parameters for prediction of mortality, neonates with CT ≥63 seconds were 7.4 times more likely to die (OR = 7.40, 95% CI: 3.50-15.65), while neonates with A10 ≤37 mm were 5.8 times more likely to die (OR = 5.88, 95% CI: 2.94-12.50). An EXTEM hypocoagulable profile on disease onset was shown to be an independent risk factor for in-hospital mortality in neonatal critical illness.
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http://dx.doi.org/10.1055/s-0041-1729964DOI Listing
June 2021

Rotational Thromboelastometry Findings Are Associated with Symptomatic Venous Thromboembolic Complications after Hip Fracture Surgery.

Clin Orthop Relat Res 2021 06 2. Epub 2021 Jun 2.

A. G. Tsantes, A. Gialeraki, A. E. Tsantes, Laboratory of Haematology and Blood Bank Unit, Attiko Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Venous thromboembolism is a common complication after hip fractures. However, there are no reliable laboratory assays to identify patients at risk for venous thromboembolic (VTE) events after major orthopaedic surgery.

Question/purposes: (1) Are rotational thromboelastometry (ROTEM) findings associated with the presence or development of symptomatic VTE after hip fracture surgery? (2) Were any other patient factors associated with the presence or development of symptomatic VTE after hip fracture surgery? (3) Which ROTEM parameters were the most accurate in terms of detecting the association of hypercoagulability with symptomatic VTE?

Methods: This retrospective study was conducted over a 13-month period. In all, 354 patients with femoral neck and peritrochanteric fractures who underwent hip hemiarthoplasty or cephallomedullary nailing were assessed for eligibility. Of those, 99% (349 of 354) were considered eligible for the study, 1% (3 of 354) of patients were excluded due to coagulation disorders, and another 1% (2 of 354) were excluded because they died before the postoperative ROTEM analysis. An additional 4% (13 of 354) of patients were lost before the minimum study follow-up of 3 months, leaving 95% (336 of 354) for analysis. A ROTEM analysis was performed in all patients at the time of their hospital admission, within hours of the injury, and on the second postoperative day. The patients were monitored for the development of symptoms indicative of VTE, and the gold standard tests for diagnosing VTE, such as CT pulmonary angiography or vascular ultrasound, were selectively performed only in symptomatic patients and not routinely in all patients. Therefore, this study evaluates the association of ROTEM with only clinically evident VTE events and not with all VTE events. ROTEM results did not affect the clinical surveillance of the study group and the decision for further work up. To determine whether ROTEM findings were associated with the presence or development of symptomatic VTE, ROTEM parameters were compared between patients with and without symptomatic VTE. To establish whether any other patient factors were associated with the presence or development of symptomatic VTE after hip fracture surgery, clinical parameters and conventional laboratory values were also compared between patients with and without symptomatic VTE. Finally, to determine which ROTEM parameters were the most accurate in terms of detecting the association of hypercoagulability with symptomatic VTE, the area under the curve (AUC) for certain cut off values of ROTEM parameters was calculated.

Results: We found several abnormal ROTEM values to be associated with the presence or development of symptomatic VTE. The preoperative maximum clot firmness was higher in patients with clinically evident VTE than in patients without these complications (median [interquartile range] 70 mm [68 to 71] versus 65 mm [61 to 68]; p < 0.001). The preoperative clot formation time was lower in patients with clinically evident VTE than those without clinically evident VTE (median 61 seconds [58 to 65] versus 70 seconds [67 to 74]; p < 0.001), and also the postoperative clot formation time was lower in patients with clinically evident VTE than those without these complications (median 52 seconds [49 to 59] versus 62 seconds [57 to 68]; p < 0.001). Increased BMI was also associated with clinically evident VTE (odds ratio 1.26 [95% confidence interval 1.07 to 1.53]; p < 0.001). We found no differences between patients with and without clinically evident VTE in terms of age, sex, smoking status, comorbidities, and preoperative use of anticoagulants. Lastly, preoperative clot formation time demonstrated the best performance for detecting the association of hypercoagulability with symptomatic VTE (AUC 0.89 [95% CI 0.81 to 0.97]), with 81% (95% CI 48% to 97%) sensitivity and 86% (95% CI 81% to 89%) specificity for clot formation time ≤ 65 seconds.

Conclusion: ROTEM's performance in this preliminary study was promising in terms of its association with symptomatic VTE. This study extended our earlier work by demonstrating that ROTEM has a high accuracy in detecting the level of hypercoagulability that is associated with symptomatic VTE. However, until its performance is validated in a study that applies a diagnostic gold standard (such as venography, duplex/Doppler, or chest CT) in all patients having ROTEM to confirm its performance, ROTEM should not be used as a regular part of clinical practice.

Level Of Evidence: Level IV, diagnostic study.
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http://dx.doi.org/10.1097/CORR.0000000000001832DOI Listing
June 2021

Seeking Strategies to Optimize Blood Utilization: The Preliminary Experience with Implementing a Patient Blood Management Program in a Greek Tertiary Hospital.

J Clin Med 2021 May 15;10(10). Epub 2021 May 15.

Laboratory of Haematology and Blood Bank Unit, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, 12462 Athens, Greece.

Objectives: Our aim was to assess blood utilization after implementation of a patient blood management (PBM) program in a Greek tertiary hospital.

Methods: An electronic transfusion request form and a prospective audit of transfusion practice were implemented. After the one-year implementation period, a retrospective review was performed to assess transfusion practice in medical patients.

Results: Pre-PBM, a total of 9478 RBC units were transfused (mean: 1.75 units per patient) compared with 9289 transfused units (mean: 1.57 units per patient) post-PBM. Regarding the post-PBM period, the mean hemoglobin (Hb) level of the 3099 medical patients without comorbidities transfused was 7.19 ± 0.79 gr/dL. Among them, 2065 (66.6%) had Hb levels >7.0 gr/dL, while 167 (5.3%) had Hb levels >8.0 gr/dL. In addition, 331 (25.3%) of the transfused patients with comorbidities had Hb >8.0 gr/dL. The Hb transfusion thresholds significantly differed across the clinics ( < 0.001), while 21.8% of all medical non-bleeding patients received more than one RBC unit transfusion.

Conclusion: A poor adherence with the restrictive transfusion threshold of 7.0 gr/dL was observed. The adoption of a less strict threshold might be a temporary step to allow physicians to become familiar with the program and be informed on the safety and advantages of the restrictive transfusion strategy.
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http://dx.doi.org/10.3390/jcm10102141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157216PMC
May 2021

Mental Health and Perceived Access to Care among People Who Inject Drugs in Athens, Greece.

J Clin Med 2021 Mar 12;10(6). Epub 2021 Mar 12.

Medical School, University of Cyprus, Nicosia 2029, Cyprus.

Poor mental health among human immunodeficiency virus (HIV)-positive people who inject drugs (PWID) may contribute to stigma, and together they act as barriers to medical care. This analysis aims to examine factors associated with the mental health of PWID and their network contacts, and the association of poor mental health with the experience of HIV-related stigmatizing events, with HIV-related social support, and with perceived access to care. Data were collected during the Transmission Reduction Intervention Project (TRIP) conducted in Athens, Greece (2013-2015). PWID ( = 292; = 122 HIV-positive) were interviewed both at baseline and follow-up. Items of depression, anxiety, and general positive affect subscales of the Mental Health Inventory were used to explore the psychological distress and well-being of participants at follow-up. Items of the Access to Care Scale were used to evaluate perceived access to medical care at baseline and follow-up. Linear regression showed that unemployment was positively related to depression (β = 1.49, = 0.019), while injecting drug use was a risk factor for a low general positive affect score (β = -3.21, = 0.015). Poor mental health was not linked to HIV-related stigma or social support. Positive perception of access to care was associated in multivariable analyses with low depression (β = -0.22, = 0.049). The perceived access to care score improved from baseline to follow-up ( = 0.019) and HIV-positive participants had a higher score than HIV-negative participants. Future interventions should include targets to improve the mental well-being of participants, reduce psychosocial distress, and minimize perceived barriers to accessing medical care.
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http://dx.doi.org/10.3390/jcm10061181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002050PMC
March 2021

Drug Injection-Related and Sexual Behavior Changes in Drug Injecting Networks after the Transmission Reduction Intervention Project (TRIP): A Social Network-Based Study in Athens, Greece.

Int J Environ Res Public Health 2021 03 1;18(5). Epub 2021 Mar 1.

Medical School, University of Cyprus, Nicosia 2029, Cyprus.

The Transmission Reduction Intervention Project (TRIP) was a network-based, enhanced contact tracing approach, targeting recently HIV-infected people who inject drugs (PWID) in Athens, Greece (2013-2015). This analysis examines behavioral changes of participants in TRIP and their determinants between baseline and follow-up visits to the program. All participants of TRIP were tested for HIV and interviewed using a questionnaire with items on drug injection-related and sexual behaviors. Multivariable logistic regression models were used to examine potential relationships between participants' behaviors and sociodemographic or other characteristics. The analysis included 292 participants. At follow-up, the percentage of participants who injected drugs decreased [92.5%, = 270 versus 72.3%, = 211 ( < 0.001)], and more participants adopted safer behaviors. Employment, age, and gender were significantly associated with some behavioral changes. For instance, unemployed participants were half as likely as the employed to stop drug injection [adjusted odds ratio (aOR): 0.475, 95% confidence interval (CI): 0.228, 0.988]. Increasing age was associated with lower probability of sharing syringes at follow-up (aOR: 0.936, 95%CI: 0.887, 0.988). Finally, females were less likely than males to improve their behavior related to sharing cookers, filters, or rinse water (aOR: 0.273, 95% CI: 0.100, 0.745). In conclusion, adoption of safer behaviors was observed following TRIP implementation. Future prevention programs should focus on younger PWID and especially females. Social efforts to support employment of PWID are also important.
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http://dx.doi.org/10.3390/ijerph18052388DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967732PMC
March 2021

Ethnic Differences in the Smoking-Related Risk of Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis.

J Crohns Colitis 2021 Mar 15. Epub 2021 Mar 15.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.

Background And Aims: The association between smoking and inflammatory bowel disease (IBD) relies on old meta-analyses including exclusively non-Jewish White populations. Uncertainty persists regarding the role of smoking in other ethnicities.

Methods: We systematically searched Medline/PubMed, Embase and Scopus for studies examining tobacco smoking and the risk of developing IBD, i.e., Crohn's disease (CD) or ulcerative colitis (UC). Two authors independently extracted study data and assessed each study's risk-of-bias. We examined heterogeneity and small-study effect, and calculated summary estimates using random-effects models. Stratified analyses and meta-regression were employed to study the association between study-level characteristics and effect estimates. The strength of epidemiological evidence was assessed through prespecified criteria.

Results: We synthesized 57 studies examining the smoking-related risk of developing CD and UC. Non-Jewish White smokers were at increased risk of CD (29 studies; RR: 1.95, 95% CI: 1.69‒2.24; moderate evidence). No association was observed in Asian, Jewish and Latin-American populations (11 studies; RR: 0.97; 95% CI: 0.83-1.13), with no evidence of heterogeneity across these ethnicities. Smokers were at reduced risk of UC (51 studies; RR: 0.55, 95% CI: 0.48-0.64; weak evidence) irrespectively of ethnicity; however, cohort studies, large studies and those recently published showed attenuated associations.

Conclusions: This meta-analysis did not identify any increased risk of CD in smokers in ethnicities other than non-Jewish Whites, and confirmed the protective effect of smoking on UC occurrence. Future research should characterize the genetic background of CD patients across different ethnicities to improve our understanding on the role of smoking in CD pathogenesis.
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http://dx.doi.org/10.1093/ecco-jcc/jjab047DOI Listing
March 2021

The Brain-Gut Axis: Psychological Functioning and Inflammatory Bowel Diseases.

J Clin Med 2021 Jan 20;10(3). Epub 2021 Jan 20.

Department of Biomedical Sciences, Humanitas University, 20090 Milan, Italy.

The brain-gut axis represents a complex bi-directional system comprising multiple interconnections between the neuroendocrine pathways, the autonomous nervous system and the gastrointestinal tract. Inflammatory bowel disease (IBD), comprising Crohn's disease and ulcerative colitis, is a chronic, relapsing-remitting inflammatory disorder of the gastrointestinal tract with a multifactorial etiology. Depression and anxiety are prevalent among patients with chronic disorders characterized by a strong immune component, such as diabetes mellitus, cancer, multiple sclerosis, rheumatoid arthritis and IBD. Although psychological problems are an important aspect of morbidity and of impaired quality of life in patients with IBD, depression and anxiety continue to be under-diagnosed. There is lack of evidence regarding the exact mechanisms by which depression, anxiety and cognitive dysfunction may occur in these patients, and whether psychological disorders are the result of disease activity or determinants of the IBD occurrence. In this comprehensive review, we summarize the role of the brain-gut axis in the psychological functioning of patients with IBD, and discuss current preclinical and clinical data on the topic and therapeutic strategies potentially useful for the clinical management of these patients. Personalized pathways of psychological supports are needed to improve the quality of life in patients with IBD.
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http://dx.doi.org/10.3390/jcm10030377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863941PMC
January 2021

Prospective Temporal Validation of the Neonatal Bleeding Risk (NeoBRis) Index.

Thromb Haemost 2020 Dec 24. Epub 2020 Dec 24.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1055/a-1343-3342DOI Listing
December 2020

Reply to Ghirardello et al Letter to the Editor.

Thromb Haemost 2020 Dec 9. Epub 2020 Dec 9.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

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http://dx.doi.org/10.1055/a-1333-7387DOI Listing
December 2020

Confounding and bias in observational studies in inflammatory bowel disease: a meta-epidemiological study.

Aliment Pharmacol Ther 2021 03 9;53(6):712-721. Epub 2020 Dec 9.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Background: Observational research concerning inflammatory bowel disease (IBD) is highly susceptible to spurious findings because of confounding and bias.

Aim: To investigate how these issues were reported in this research field.

Methods: We identified and appraised a random sample of 160 observational studies concerning IBD published in high-impact gastroenterology journals and the most respected specialty journals of the condition. We applied a standardised methodology to assess how confounding and bias were reported and discussed, and investigated the association between yearly citations and study characteristics using mixed-effect multivariable regression analysis.

Results: The authors of 67 out of 160 articles (41.9%) mentioned confounding, and in 89 cases (55.6%) reported any bias. Although most authors applied strategies to minimise confounding or bias (n = 139; 86.9%) and acknowledged at least one unadjusted confounder (n = 116; 72.5%), a minority commented about whether the main findings could have been affected (n = 60; 37.5%). Very few authors (n = 7; 4.4%) called for caution in interpreting the results in the discussion. Reporting of confounding and bias was particularly lacking for case-control studies, those not using routinely collected data, those employing laboratory analyses as the primary method of assessment and studies investigating non-modifiable exposures. In adjusted analyses, mentioning or alluding to confounding was positively associated with yearly citations (P = 0.010), whereas calling for a cautious interpretation of the findings was not.

Conclusions: Reporting of confounding is inadequate and its acknowledgement is often neglected in interpreting high-impact observational research in IBD. These results encourage a more careful evaluation of the consequences of confounding and bias.
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http://dx.doi.org/10.1111/apt.16222DOI Listing
March 2021

Effect of early application of social distancing interventions on COVID-19 mortality over the first pandemic wave: An analysis of longitudinal data from 37 countries.

J Infect 2021 Jan 1;82(1):133-142. Epub 2020 Dec 1.

Medical School, University of Cyprus, Nicosia, Cyprus.

Objectives: To estimate the effect of early application of social distancing interventions on Covid-19 cumulative mortality during the first pandemic wave.

Methods: Ecological longitudinal study using multivariable negative binomial regression for panel data. Daily numbers of Covid-19 cases and deaths, and data on social distancing interventions, for the 37 member countries of the Organization for Economic Cooperation and Development (OECD) were analysed.

Results: Covid-19 cumulative mortality over the first pandemic wave varied widely across countries (range, 4.16 to 855 deaths per million population). On average, one-day delay in application of mass gatherings ban was associated with an adjusted increase in Covid-19 cumulative mortality by 6.97% (95% CI, 3.45 to 10.5), whilst a one-day delay in school closures was associated with an increase of 4.37% (95% CI, 1.58 to 7.17) over the study period. We estimated that if each country had enacted both interventions one week earlier, Covid-19 cumulative mortality could have been reduced by an average of 44.1% (95% CI, 20.2 to 67.9).

Conclusions: Early application of mass gatherings ban and school closures in outbreak epicentres was associated with an important reduction in Covid-19 cumulative mortality during the first pandemic wave. These findings may support policy decision making.
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http://dx.doi.org/10.1016/j.jinf.2020.11.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706420PMC
January 2021

Higher coagulation activity in hip fracture patients: A case-control study using rotational thromboelastometry.

Int J Lab Hematol 2021 Jun 24;43(3):477-484. Epub 2020 Nov 24.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Introduction: Trauma-induced coagulopathy has been extensively investigated in the multitrauma setting, but only sparsely following moderate orthopedic trauma. The purpose of this study was to evaluate changes in the hemostatic profile of patients with hip fractures, using rotational thromboelastometry (ROTEM).

Methods: 198 patients with hip fractures who underwent surgery were included in the study. A matched group of 52 healthy individuals was also enrolled. Demographics, conventional laboratory assays, and ROTEM parameters were recorded and compared between patients and healthy adults. The preoperative and postoperative ROTEM values of fractured patients were also compared.

Results: The conventional coagulation assays were similar for the 2 groups. However, several ROTEM parameters including EXTEM MCF (P < .001), EXTEM alpha angle (P < .001), INTEM MCF (P < .001), INTEM A10 (P < .001), and INTEM alpha angle (P < .001) significantly differed between the 2 groups indicating a higher coagulation potential following hip fractures. Also, fractured patients had significantly lower INTEM and EXTEM CT values (P = .008 and P = .012, respectively) and significantly lower INTEM and EXTEM CFT values (P < .001). Adjusted analysis for confounders further confirmed the direct relationship between hip fracture and higher coagulation activity. Last, INTEM CT and CFT significantly decreased (P = .008 and P < .001, respectively), while INTEM MCF, A10, and alpha angle significantly increased (P < .001) postoperatively, indicating that surgery further increases the coagulation potential.

Conclusion: A higher coagulation activity following hip fractures and surgical treatment can be detected by ROTEM shortly after the injury, even when this is undetectable by conventional coagulation assays.
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http://dx.doi.org/10.1111/ijlh.13409DOI Listing
June 2021

Macrophage expression and prognostic significance of the long pentraxin PTX3 in COVID-19.

Nat Immunol 2021 01 18;22(1):19-24. Epub 2020 Nov 18.

Humanitas Clinical and Research Center-IRCCS, Milan, Italy.

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19). RNA-sequencing analysis of peripheral blood mononuclear cells, single-cell bioinformatics analysis and immunohistochemistry of lung autopsy samples revealed that myelomonocytic cells and endothelial cells express high levels of PTX3 in patients with COVID-19. Increased plasma concentrations of PTX3 were detected in 96 patients with COVID-19. PTX3 emerged as a strong independent predictor of 28-d mortality in multivariable analysis, better than conventional markers of inflammation, in hospitalized patients with COVID-19. The prognostic significance of PTX3 abundance for mortality was confirmed in a second independent cohort (54 patients). Thus, circulating and lung myelomonocytic cells and endothelial cells are a major source of PTX3, and PTX3 plasma concentration can serve as an independent strong prognostic indicator of short-term mortality in COVID-19.
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http://dx.doi.org/10.1038/s41590-020-00832-xDOI Listing
January 2021

Evaluating Non-Statistically Significant Results From Trials in Practice.

JAMA 2020 10;324(16):1679

Humanitas University: Humanitas Clinical and Research Center, IRCCS, Milan, Italy.

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http://dx.doi.org/10.1001/jama.2020.15645DOI Listing
October 2020

The role of ROTEM variables based on clot elasticity and platelet component in predicting bleeding risk in thrombocytopenic critically ill neonates.

Eur J Haematol 2021 Feb 27;106(2):175-183. Epub 2020 Oct 27.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

Background: Our aim was to investigate the role of thromboelastometry (ROTEM) parameters, including maximum clot elasticity (MCE) and platelet component (PLTEM MCE and PLTEM MCF), in early prediction of bleeding events in thrombocytopenic critically ill neonates.

Material And Methods: This single-center, prospective cohort study included 110 consecutive thrombocytopenic neonates with sepsis, suspected sepsis, or hypoxia. On the first day of disease onset, ROTEM EXTEM and FIBTEM assays were performed and the neonatal bleeding assessment tool was used for the evaluation of bleeding events.

Results: Most EXTEM and FIBTEM ROTEM parameters significantly differed between neonates with (n = 77) and without bleeding events (n = 33). Neonates with bleeding events had significantly lower PLTEM MCE and PLTEM MCF values compared to those without bleeding events (P < .001). Platelet count was found to be strongly positively correlated with EXTEM A5 (Spearman's rho = 0.61, P < .001) and A10 (rho = 0.64, P < .001). EXTEM A10 demonstrated the best prognostic performance (AUC = 0.853) with an optimal cutoff value (≤37 mm) (sensitivity = 91%, specificity = 76%) for prediction of bleeding events in thrombocytopenic neonates.

Conclusions: EXTEM A5 and EXTEM A10 were found to be strong predictors of hemorrhage, compared to most ROTEM variables quantifying clot elasticity and platelet component in thrombocytopenic critically ill neonates.
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http://dx.doi.org/10.1111/ejh.13534DOI Listing
February 2021

Study of critically ill patients with COVID-19 in New York City.

Lancet 2020 10;396(10257):1064

Humanitas Clinical and Research Center, IRCCS, Rozzano, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(20)32072-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7544488PMC
October 2020

Patients' perspectives on smoking and inflammatory bowel disease: An online survey in collaboration with European Federation of Crohn's and Ulcerative Colitis Associations.

World J Gastroenterol 2020 Aug;26(29):4343-4355

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele MI, Milan 20090, Italy.

Background: Smoking has detrimental effects on Crohn's disease (CD) activity while data on ulcerative colitis (UC) are conflicting. Little is known about the use and impact of alternative smoking products in inflammatory bowel diseases (IBD).

Aim: To understand the patients' perceptions of the impact of smoking on their IBD and to assess differences between CD and UC patients.

Methods: The questionnaire was developed by Philip Morris Products SA in cooperation with European Federation of Crohn's and Ulcerative Colitis Associations. The final survey questionnaire consisted of 41 questions divided in 8 categories: (1) Subject screener; (2) Smoking history; (3) Background information; (4) IBD disease background; (5) Current disease status; (6) Current therapeutics and medications; and (7) Current nicotine/cigarettes use and awareness of the impacts of smoking on IBD. The questionnaire was submitted online from 4 November 2019 to 11th March 2020 through the European Federation of Crohn's and Ulcerative Colitis Associations website to IBD patients who were current smokers or had a history of smoking.

Results: In total 1050 IBD patients speaking nine languages participated to the survey. Among them, 807 (76.9%) patients declared to have ever smoked or consumed an alternative smoking product, with a higher proportion of current cigarette smokers among CD patients (CD: 63.1% UC: 54.1%, = 0.012). About two-thirds of the participants declared to have ever stopped cigarette smoking and restarted (67.0%), with a significantly higher proportion among UC patients compared to CD patients (73.1% 62.0%, = 0.001). We also found significant differences between CD and UC patients in the awareness of the health consequences of smoking in their disease and in the perceived impact of smoking on disease activity, for both cigarettes and alternative smoking products.

Conclusion: This survey found significant differences between CD and UC patients in both awareness and perception of the impact of smoking on their disease. Further efforts should be done to encourage smoking cessation for all IBD patients, including UC patients.
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http://dx.doi.org/10.3748/wjg.v26.i29.4343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7422536PMC
August 2020

A Risk Score for Predicting the Incidence of Hemorrhage in Critically Ill Neonates: Development and Validation Study.

Thromb Haemost 2021 Feb 24;121(2):131-139. Epub 2020 Aug 24.

Laboratory of Haematology and Blood Bank Unit, "Attiko" Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.

The aim of the study was to develop and validate a prediction model for hemorrhage in critically ill neonates which combines rotational thromboelastometry (ROTEM) parameters and clinical variables. This cohort study included 332 consecutive full-term and preterm critically ill neonates. We performed ROTEM and used the neonatal bleeding assessment tool (NeoBAT) to record bleeding events. We fitted double selection least absolute shrinkage and selection operator logit regression to build our prediction model. Bleeding within 24 hours of the ROTEM testing was the outcome variable, while patient characteristics, biochemical, hematological, and thromboelastometry parameters were the candidate predictors of bleeding. We used both cross-validation and bootstrap as internal validation techniques. Then, we built a prognostic index of bleeding by converting the coefficients from the final multivariable model of relevant prognostic variables into a risk score. A receiver operating characteristic analysis was used to calculate the area under curve (AUC) of our prediction index. EXTEM A10 and LI60, platelet counts, and creatinine levels were identified as the most robust predictors of bleeding and included them into a Neonatal Bleeding Risk (NeoBRis) index. The NeoBRis index demonstrated excellent model performance with an AUC of 0.908 (95% confidence interval [CI]: 0.870-0.946). Calibration plot displayed optimal calibration and discrimination of the index, while bootstrap resampling ensured internal validity by showing an AUC of 0.907 (95% CI: 0.868-0.947). We developed and internally validated an easy-to-apply prediction model of hemorrhage in critically ill neonates. After external validation, this model will enable clinicians to quantify the 24-hour bleeding risk.
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http://dx.doi.org/10.1055/s-0040-1715832DOI Listing
February 2021

A snapshot of the ongoing clinical research on COVID-19.

F1000Res 2020 18;9:373. Epub 2020 May 18.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milano, 20090, Italy.

The pandemic of coronavirus disease 2019 (COVID-19) presents an unprecedented challenge to rapidly develop new diagnostic, preventive and therapeutic strategies. Currently, thousands of new COVID-19 patients are quickly enrolled in clinical studies. We aimed to investigate the characteristics of the COVID-19 studies registered in ClinicalTrials.gov and report the extent to which they have incorporated features that are desirable for generating high-quality evidence. On April 28, 2020, a total of 945 studies on COVID-19 have been registered in ClinicalTrials.gov; 586 studies are interventional (62.0%), the most frequent allocation scheme is the parallel group assignment (437; 74.6%), they are open-label and the most common primary purpose is the research on treatment. Too many of the ongoing interventional studies have a small expected sample size and may not generate credible evidence at completion. This might lead to a delayed recognition of effective therapies that are urgently needed, and a waste of time and resources. In the COVID-19 pandemic era, it is crucial that the adoption of new diagnostic, preventive and therapeutic strategies is based upon evidence coming from well-designed, adequately powered and carefully conducted clinical trials.
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http://dx.doi.org/10.12688/f1000research.23843.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7256468PMC
June 2020

Liver tests abnormalities in COVID-19: trick or treat?

J Hepatol 2020 11 27;73(5):1275-1276. Epub 2020 May 27.

Division of Internal Medicine and Hepatology, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy; Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.jhep.2020.05.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251403PMC
November 2020

Early Predictors of Clinical Deterioration in a Cohort of 239 Patients Hospitalized for Covid-19 Infection in Lombardy, Italy.

J Clin Med 2020 May 20;9(5). Epub 2020 May 20.

Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Milan, Italy.

We described features of hospitalized Covid-19 patients and identified predictors of clinical deterioration. We included patients consecutively admitted at Humanitas Research Hospital (Rozzano, Milan, Italy); retrospectively extracted demographic; clinical; laboratory and imaging findings at admission; used survival methods to identify factors associated with clinical deterioration (defined as intensive care unit (ICU) transfer or death), and developed a prognostic index. Overall; we analyzed 239 patients (29.3% females) with a mean age of 63.9 (standard deviation [SD]; 14.0) years. Clinical deterioration occurred in 70 patients (29.3%), including 41 (17.2%) ICU transfers and 36 (15.1%) deaths. The most common symptoms and signs at admission were cough (77.8%) and elevated respiratory rate (34.1%), while 66.5% of patients had at least one coexisting medical condition. Imaging frequently revealed ground-glass opacity (68.9%) and consolidation (23.8%). Age; increased respiratory rate; abnormal blood gas parameters and imaging findings; coexisting coronary heart disease; leukocytosis; lymphocytopenia; and several laboratory parameters (elevated procalcitonin; interleukin-6; serum ferritin; C-reactive protein; aspartate aminotransferase; lactate dehydrogenase; creatinine; fibrinogen; troponin-I; and D-dimer) were significant predictors of clinical deterioration. We suggested a prognostic index to assist risk-stratification (C-statistic; 0.845; 95% CI; 0.802‒0.887). These results could aid early identification and management of patients at risk, who should therefore receive additional monitoring and aggressive supportive care.
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http://dx.doi.org/10.3390/jcm9051548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7290833PMC
May 2020

COVID-19 Digestive System Involvement and Clinical Outcomes in a Large Academic Hospital in Milan, Italy.

Clin Gastroenterol Hepatol 2020 09 11;18(10):2366-2368.e3. Epub 2020 May 11.

Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy; IBD Center, Department of Gastroenterology, Humanitas Clinical and Research Center IRCCS, Rozzano, Milan, Italy.

Since February 2020, the COVID-19 pandemic has spread to Italy affecting more than 100,000 people. Several studies have reported a high prevalence of gastrointestinal (GI) symptoms, and investigated their potential association with clinical outcomes. The timing, clinical significance, and possible impact on viral spread of GI symptoms presentation have not been fully elucidated. Elevation of liver function tests and other laboratory values has also been reported; however, their prognostic significance has not been clearly established..
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http://dx.doi.org/10.1016/j.cgh.2020.05.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7211605PMC
September 2020

Compassionate Use of Remdesivir in Covid-19.

N Engl J Med 2020 06 15;382(25):e101. Epub 2020 May 15.

Humanitas University, Milan, Italy

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http://dx.doi.org/10.1056/NEJMc2015312DOI Listing
June 2020

Methods for multiple outcome meta-analysis of gene-expression data.

MethodsX 2020 21;7:100834. Epub 2020 Feb 21.

Department of Computer Science and Biomedical Informatics, University of Thessaly, Lamia 35131, Greece.

Meta-analysis is a valuable tool for the synthesis of evidence across a wide range study types including high-throughput experiments such as genome-wide association studies (GWAS) and gene expression studies. There are situations though, in which we have multiple outcomes or multiple treatments, in which the multivariate meta-analysis framework which performs a joint modeling of the different quantities of interest may offer important advantages, such as increasing statistical power and allowing performing global tests. In this work we adapted the multivariate meta-analysis method and applied it in gene expression data. With this method we can test for pleiotropic effects, that is, for genes that influence both outcomes or discover genes that have a change in expression not detectable in the univariate method. We tested this method on data regarding inflammatory bowel disease (IBD), with its two main forms, Crohn's disease (CD) and Ulcerative colitis (UC), sharing many clinical manifestations, but differing in the location and extent of inflammation and in complications. The Stata code is given in the Appendix and it is available at: www.compgen.org/tools/multivariate-microarrays.•Multivariate meta-analysis method for gene expression data.•Discover genes with pleiotropic effects.•Differentially Expressed Genes (DEGs) identification in complex traits.
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http://dx.doi.org/10.1016/j.mex.2020.100834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7078352PMC
February 2020

Systematic review with meta-analysis: biologics and risk of infection or cancer in elderly patients with inflammatory bowel disease.

Aliment Pharmacol Ther 2020 05 13;51(9):820-830. Epub 2020 Mar 13.

Department of Biomedical Sciences, Humanitas University, Milan, Italy.

Background: Uncertainty exists concerning the risk of infection and cancer associated with biologic therapies in elderly patients with inflammatory bowel disease (IBD).

Aims: To identify, synthesise and critically appraise the available evidence on the topic.

Methods: We systematically searched Medline/PubMed, Embase and Scopus, through October 2019, and recent conference proceedings, to identify studies investigating the risk of serious infections, opportunistic infections, any infection and cancer in elderly IBD patients (>60 years) exposed to biologics as compared to those unexposed to biologics. Two reviewers independently extracted study data and assessed each study's risk of bias. We examined heterogeneity, and calculated summary effect estimates using fixed- and random effects models. Quality of evidence was determined with GRADE.

Results: We included 15 studies (one post hoc analysis of a randomised trial, nine cohort and five case-control studies). Elderly IBD patients treated with biologics were at increased risk of developing serious infections (random effects summary relative risk: 2.70, 95% CI: 1.56-4.66; seven studies; I  = 57%) and opportunistic infections (3.16, 1.09-9.20; four studies; I  = 73%). The occurrence of any infection (1.67, 0.51-5.43; five studies; I  = 75%) and cancer (0.90, 0.64-1.26; nine studies; I  = 0%) was not significantly affected. Nevertheless, our confidence in the effect estimates is rather limited; the quality of evidence is low to very low.

Conclusions: Biologics are likely to increase the risk of serious and opportunistic infections in old IBD patients. Large prospective studies are needed to further assess the biologic treatments' long-term safety profile in this population.
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http://dx.doi.org/10.1111/apt.15692DOI Listing
May 2020

Statins and inflammatory bowel disease: Where do we stand?

Eur J Intern Med 2020 05 6;75:10-14. Epub 2020 Mar 6.

Department of Biomedical Sciences, Humanitas University, Milan, Italy; IBD Center, Humanitas Clinical and Research Center - IRCCS, Milan, Italy.

Inflammatory bowel disease is a chronic autoimmune disorder of the western world that is rapidly expanding in newly industrialized countries. Novel strategies are urgently needed to prevent and improve the treatment of this costly and disabling disease. Statins are the most commonly prescribed drugs worldwide. Besides their lipid-lowering effects, statins may exert complex immunomodulatory properties and multiple pleiotropic effects including the inhibition of T-cell activation, antigen-presenting function and leukocyte infiltration of target organs which might render statins as beneficial agents for inflammatory and autoimmune conditions. In this review, we summarize the experimental findings on the topic, and critically appraise the epidemiological evidence regarding the value of statins as a potential strategy for preventing and treating inflammatory bowel disease. Several experimental studies have shown that statins reduce inflammation in animal models of colitis; however, clinical studies investigating their disease-modifying and preventive potential in IBD have demonstrated some limitations and conflicting results. The available epidemiological evidence is not yet sufficient to support the use of statin for preventing or treating inflammatory bowel disease. Additional high-quality research is warranted.
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http://dx.doi.org/10.1016/j.ejim.2020.02.017DOI Listing
May 2020

Antibiotic prescription in the outpatient paediatric population attending emergency departments in Lombardy, Italy: a retrospective database review.

BMJ Paediatr Open 2019 11;3(1):e000546. Epub 2019 Dec 11.

Laboratory for Mother and Child Health, Department of Public Health, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milano, Italy.

Objectives: This study aimed to assess the appropriateness of antibiotic prescription in children seen in emergency departments (EDs) and to compare prescription profiles in ED and primary care.

Design: This is a retrospective analysis of healthcare administrative databases.

Setting: The study analysed data collected in emergency departments (EDs) and primary care practices (PCPs) in Lombardy, Italy.

Participants: Children and adolescents between 1 and 13 years old with an ED access and/or an antibiotic prescription in the first semester of 2012 participated in the study. Only those with an index event (ie, without ED access, hospital admissions or antibiotic prescriptions in the previous 60 days) were included.

Main Outcome Measures: The main outcomes are percentage of subjects receiving amoxicillin (first-choice antibiotic) and percentages receiving macrolides/cephalosporins (second-choice therapies).

Results: During the observation period, 133 275 children had one ED access, and 26 087 (19.6%) received an antibiotic prescription. In all, 56.1% of children seen for upper respiratory tract infections (URTIs) received an antibiotic, with a prevalence of 67.8% for otitis media and 56.4% for pharyngotonsillitis; 22.3% of children were given amoxicillin after a visit for URTIs, with no differences among infections, and 19.6% received macrolides and cephalosporins. Few differences were found when comparing the index antibiotic prescriptions in ED and PCP settings. A higher prescription of second-choice antibiotics was observed among children cared for by PCPs compared with children attending EDs (31.3% vs 23.4%, χ =720, p<0.001). The place of residence was the main determinant of the qualitative profile of prescriptions.

Conclusions: More must be done to improve rational use of antibiotics in the ED and PCP setting, and educational interventions including physicians in both setting are strongly needed.
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http://dx.doi.org/10.1136/bmjpo-2019-000546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937000PMC
December 2019

TEMPO-Nanocellulose/Ca Hydrogels: Ibuprofen Drug Diffusion and In Vitro Cytocompatibility.

Materials (Basel) 2020 Jan 2;13(1). Epub 2020 Jan 2.

Department of Chemistry, Materials, and Chemical Engineering "G. Natta"-Politecnico di Milano, Piazza Leonardo da Vinci 32, I-20133 Milano, Italy.

Stable hydrogels with tunable rheological properties were prepared by adding Ca ions to aqueous dispersions of 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO)-oxidized and ultra-sonicated cellulose nanofibers (TOUS-CNFs). The gelation occurred by interaction among polyvalent cations and the carboxylic units introduced on TOUS-CNFs during the oxidation process. Both dynamic viscosity values and pseudoplastic rheological behaviour increased by increasing the Ca concentration, confirming the cross-linking action of the bivalent cation. The hydrogels were proved to be suitable controlled release systems by measuring the diffusion coefficient of a drug model (ibuprofen, IB) by high-resolution magic angle spinning (HR-MAS) nuclear magnetic resonance (NMR) spectroscopy. IB was used both as free molecule and as a 1:1 pre-formed complex with β-cyclodextrin (IB/β-CD), showing in this latter case a lower diffusion coefficient. Finally, the cytocompatibility of the TOUS-CNFs/Ca hydrogels was demonstrated in vitro by indirect and direct tests conducted on a L929 murine fibroblast cell line, achieving a percentage number of viable cells after 7 days higher than 70%.
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http://dx.doi.org/10.3390/ma13010183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981511PMC
January 2020

Efficacy and safety of biologic agents and tofacitinib in moderate-to-severe ulcerative colitis: A systematic overview of meta-analyses.

United European Gastroenterol J 2019 12 17;7(10):1285-1303. Epub 2019 Oct 17.

Medical School, University of Cyprus, Nicosia, Cyprus.

Background: Ulcerative colitis (UC) is an inflammatory disease of the colon and rectum. Treatment options include biologics and tofacitinib.

Objectives: We aim to summarize the evidence on efficacy and safety of biologics and tofacitinib in moderate-to-severe UC.

Methods: PubMed, Embase, Scopus, and the Cochrane Library were systematically searched to identify meta-analyses of randomized controlled trials assessing adalimumab, golimumab, infliximab, vedolizumab, and tofacitinib in UC. Efficacy outcomes included induction and maintenance of clinical response, clinical remission and mucosal healing. Safety outcomes included adverse events and serious adverse events.

Results: The overview involved 31 meta-analyses. All four biologics and tofacitinib were superior to placebo regarding efficacy. Indirect comparisons suggested that infliximab may be better than adalimumab and golimumab to induce clinical response and mucosal healing. Safety analyses indicated no increased rates of adverse events, except for infliximab.

Conclusions: Biologics and tofacitinib are efficacious and safe for treating UC. These findings can support clinical decision-making.
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http://dx.doi.org/10.1177/2050640619883566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6894001PMC
December 2019
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