On p-Values and Statistical Significance.

At the beginning of our research training, we learned about hypothesis testing, p-values, and statistical inference [...].

Simpson's Paradox in Clinical Research: A Cautionary Tale.

The word paradox comes from the Greek paradoxon, meaning something that was contrary to, or contradicted, common sense [...].

SARS-CoV-2 Infection and Outcomes in Children with Inflammatory Bowel Diseases: A Systematic Review.

The impact of COVID-19 on pediatric patients with inflammatory bowel disease (PIBD) is still not clear and the knowledge acquired over the last 2 years is still evolving. This study aims to investigate the risk and clinical outcomes of COVID-19 in patients with PIBD. A systematic search of PubMed and Scopus databases was conducted to identify studies published up until September 2022. Out of the 475 articles screened, 14 studies were included in the review. Of the 4006 children with PIBD included, 390 (9.7%) tested positive for COVID-19. Among those with COVID-19, 5.9% (0-16.7%) needed hospitalization, 0.6% (0-1%) were admitted to the pediatric intensive care unit (PICU), and no deaths were reported. Among the included studies, only four presented details regarding patients' symptoms, with 21% (0-25%) presenting gastrointestinal (GI) symptoms. An association between PIBD activity or specific treatment and COVID-19 outcome could not be established. The prevalence of COVID-19 in patients with PIBD was low; therefore, the initial concerns regarding higher infection risk and worse prognosis in this population are not supported by the currently available data. Further research is needed to determine the natural history of the infection and the optimal treatment for these patients. Much is still unclear and additional studies should be performed in order to optimize prevention and care for this special group of patients.

Non-Communicable Diseases: The Invisible Epidemic.

Historically, communicable diseases, such as HIV/AIDS, viral hepatitis, malaria, poliomyelitis, tuberculosis, influenza and, more recently, the coronavirus disease 2019, have been at the center of global health concerns and initiatives, as they are transmitted from one person to another with a variety of ways, easily spread across national borders, and threaten the lives of millions of people all over the globe [...].

Prognostic Role of Neutrophil-to-Lymphocyte Ratio in Patients with COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a major impact on global health, continuing to put strain on healthcare systems and disrupting socioeconomic life [...].

Clinical Outcomes in the Second versus First Pandemic Wave in Italy: Impact of Hospital Changes and Reorganization

The region of Lombardy was the epicenter of the COVID-19 outbreak in Italy. Emergency Hospital 19 (EH19) was built in the Milan metropolitan area during the pandemic’s second wave as a facility of Humanitas Clinical and Research Center (HCRC). The present study aimed to assess whether the implementation of EH19 was effective in improving the quality of care of COVID-19 patients during the second wave compared with the first one. The demographics, mortality rate, and in-hospital length of stay (LOS) of two groups of patients were compared: the study group involved patients admitted at HCRC and managed in EH19 during the second pandemic wave, while the control group included patients managed exclusively at HCRC throughout the first wave. The study and control group included 903 (56.7%) and 690 (43.3%) patients, respectively. The study group was six years older on average and had more pre-existing comorbidities. EH19 was associated with a decrease in the intensive care unit admission rate (16.9% vs. 8.75%, p <0.001), and an equal decrease in invasive oxygen therapy (3.8% vs. 0.23%, p <0.001). Crude mortality was similar but overlap propensity score weighting revealed a trend toward a potential small decrease. The adjusted difference in LOS was not significant. The implementation of an additional COVID-19 hospital facility was effective in improving the overall quality of care of COVID-19 patients during the first wave of the pandemic when compared with the second. Further studies are necessary to validate the suggested approach.

The Procoagulant Effect of COVID-19 on the Thrombotic Risk of Patients with Hip Fractures Due to Enhanced Clot Strength and Fibrinolysis Shutdown.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) in patients with hip fractures is associated with increased incidence of venous thromboembolism (VTE). The purpose of this study was to evaluate the hemostatic alterations of COVID-19 that are associated with a higher thrombotic risk using rotational thromboelastometry (ROTEM). METHODS: A retrospective observational study was performed including 20 COVID-19 patients with hip fractures. To compare the coagulopathy of patients with mild COVID-19 and hip fractures with the coagulopathy associated with each of these two conditions separately, we used two previously recruited groups of patients; 198 hip fracture patients without COVID-19 and 21 COVID-19 patients without hip fractures. The demographics, clinical parameters, conventional coagulation parameters and ROTEM findings of the three groups were analyzed and compared. RESULTS: COVID-19 hip fracture patients had higher amplitude of clot firmness at 10 min (p < 0.001), higher alpha angle (p < 0.001), higher lysis index at 60 min (p < 0.001), and shorter clot formation time (p < 0.001) than non-COVID-19 hip fracture patients, indicating increased clot strength and impaired fibrinolysis due to COVID-19. The value of lysis index at 60 min (99%) in COVID-19 patients with hip fractures was consistent with fibrinolysis shut down. Multivariable linear regression analysis further confirmed that COVID-19 resulted in increased amplitude of clot firmness at 10 min (p < 0.001), increased maximum clot firmness (p < 0.001), increased lysis index at 60 min (p < 0.001) and increased alpha angle (p < 0.001), but significantly shortened clot formation time (p < 0.001). DISCUSSION: The higher thrombotic risk in COVID-19 patients with hip fractures is characterized by increased clot strength and fibrinolysis shutdown, as shown by ROTEM findings. Further prospective studies are warranted to evaluate the need for modification of thromboprophylaxis to balance the hemostatic derangements of COVID-19 patients with hip fractures.

Pitfalls and perils of survival analysis under incorrect assumptions: the case of COVID-19 data. / Escollos y peligros del análisis de supervivencia bajo supuestos incorrectos: el caso de los datos de COVID-19

Non-parametric survival analysis has become a very popular statistical method in current medical research. However, resorting to survival analysis when its fundamental assumptions are not fulfilled can severely bias the results. Currently, hundreds of clinical studies are using survival methods to investigate factors potentially associated with the prognosis of coronavirus disease 2019 (COVID-19) and test new preventive and therapeutic strategies. In the pandemic era, it is more critical than ever to base decision-making on evidence and rely on solid statistical methods, but this is not always the case. Serious methodological errors have been identified in recent seminal studies about COVID-19: One reporting outcomes of patients treated with remdesivir and another one on the epidemiology, clinical course, and outcomes of critically ill patients. High-quality evidence is essential to inform clinicians about optimal COVID-19 therapies and policymakers about the true effect of preventive measures aiming to tackle the pandemic. Though timely evidence is needed, we should encourage the appropriate application of survival analysis methods and careful peer-review to avoid publishing flawed results, which could affect decision-making. In this paper, we recapitulate the basic assumptions underlying non-parametric survival analysis and frequent errors in its application and discuss how to handle data on COVID-19.

El análisis de supervivencia no paramétrico se ha convertido en un método estadístico muy popular en la investigación médica actual. Sin embargo, recurrir al análisis de supervivencia cuando no se cumplen sus supuestos fundamentales puede sesgar gravemente los resultados. Actualmente, cientos de estudios clínicos están utilizando métodos de supervivencia para investigar factores potencialmente asociados con el pronóstico de la enfermedad por coronavirus 2019 (COVID-19) y probar nuevas estrategias preventivas y terapéuticas. En la era de la pandemia, es más importante que nunca basar la toma de decisiones en pruebas y confiar en métodos estadísticos sólidos, pero no siempre es así. Se han identificado errores metodológicos graves en estudios seminales recientes sobre COVID-19: uno que informa los resultados de los pacientes tratados con remdesivir y otro sobre la epidemiología, el curso clínico y los resultados de los pacientes en estado crítico. La evidencia de alta calidad es esencial para informar a los médicos sobre las terapias COVID-19 óptimas y a los legisladores sobre el verdadero efecto de las medidas preventivas destinadas a abordar la pandemia. Aunque se necesita evidencia oportuna, debemos fomentar la aplicación adecuada de métodos de análisis de supervivencia y una revisión cuidadosa por pares para evitar la publicación de resultados defectuosos, que podrían afectar la toma de decisiones. En este artículo, recapitulamos los supuestos básicos que subyacen al análisis de supervivencia no paramétrico y los errores frecuentes en su aplicación y discutimos cómo manejar los datos sobre COVID-19.

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

Long pentraxin 3 (PTX3) is an essential component of humoral innate immunity, involved in resistance to selected pathogens and in the regulation of inflammation1-3. The present study was designed to assess the presence and significance of PTX3 in Coronavirus Disease 2019 (COVID-19)4-7. 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.

Trends of Online Search of COVID-19 Related Terms in Cyprus.

Knowledge of trends in web searches provides useful information for various purposes, including responses to public health emergencies. This work aims to analyze the popularity of internet search queries for Coronavirus Disease 2019 (COVID-19) and COVID-19 symptoms in Cyprus. Query data for the term Coronavirus were retrieved from Google Trends website between 19 January and 30 June 2020. The study focused on Cyprus and the four most populated cities: Nicosia, Limassol, Larnaca, and Paphos. COVID-19 symptoms including fever, cough, sore throat, shortness of breath, and myalgia were considered in the analysis. Daily and weekly search volumes were described, and their correlation with the evolution of the COVID-19 pandemic and important announcements or events were examined. Three periods of interest peaks were identified in Cyprus. The highest interest in COVID-19-related terms was found in the city of Paphos. The most popular symptoms were fever and cough, and the symptom with the highest increase in popularity was myalgia. At the beginning of the pandemic, the search volume of COVID-19 grew substantially when governments, major organizations, and high-profile figures, globally and locally, made important announcements regarding COVID-19. Health authorities in Cyprus and elsewhere could benefit from constantly monitoring the online interest of the population in order to get timely information that could be used in public health planning and response.

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.

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.

The haemostatic profile in critically ill COVID-19 patients receiving therapeutic anticoagulant therapy: An observational study.

Hypercoagulability and thrombosis remain a challenge in severe coronavirus disease 2019 (COVID-19) infections. Our aim is to investigate the hemostatic profile of critically ill COVID-19 patients on therapeutic anticoagulant treatment.Forty one patients were enrolled into the study. We recruited 11 consecutive, COVID-19, patients who received therapeutic anticoagulant treatment on intensive care unit (ICU) admission. Disease severity indexes, biochemical, hematological and haemostatic parameters, endogenous thrombin potential (ETP), plasminogen activator inhibitor-1 (PAI-1) activity and extrinsically activated rotational thromboelastometry assay (EXTEM) were recorded on days 1, 3, 7. We also enrolled 9 ICU non-COVID-19, 21 non-ICU COVID-19 patients and 20 healthy blood donors as control populations.Critically ill COVID-19 patients demonstrated a more hypercoagulable and hypofibrinolytic profile related to those with COVID-19 mild illness, based on EXTEM amplitude at 10 min (A10), maximum clot firmness (MCF) and lysis index at 60 min (LI60) variables (p = 0.020, 0.046 and 0.001, respectively). Similarly, a more hypercoagulable state was detected in COVID-19 ICU patients related to non-COVID-19 ICU patients based on A10 and MCF parameters (p = 0.03 and 0.04, respectively). On the contrary, ETP and EXTEM (clotting time) CT values were similar between patients with severe and mild form of the COVID-19 infection, probably due to anticoagulant treatment given.Critically ill COVID-19 patients showed a hypercoagulable profile despite the therapeutic anticoagulant doses given. Due to the small sample size and the study design, the prognostic role of the hypercoagulability in this clinical setting remains unknown and further research is required in order to be assessed.

COVID-19 Infection-Related Coagulopathy and Viscoelastic Methods: A Paradigm for Their Clinical Utility in Critical Illness.

Hypercoagulability and thrombosis remain a challenge to diagnose and treat in severe COVID-19 infection. The ability of conventional global coagulation tests to accurately reflect in vivo hypo- or hypercoagulability is questioned. The currently available evidence suggests that markedly increased D-dimers can be used in identifying COVID-19 patients who may need intensive care unit (ICU) admission and close monitoring or not. Viscoelastic methods (VMs), like thromboelastography (TEG) and rotational thromboelastometry (ROTEM), estimate the dynamics of blood coagulation. The evaluation of coagulopathy by VMs in severe COVID-19 infection seems an increasingly attractive option. Available evidence supports that COVID-19 patients with acute respiratory failure suffer from severe hypercoagulability rather than consumptive coagulopathy often associated with fibrinolysis shutdown. However, the variability in definitions of both the procoagulant profile and the clinical outcome assessment, in parallel with the small sample sizes in most of these studies, do not allow the establishment of a clear association between the hypercoagulable state and thrombotic events. VMs can effectively provide insight into the pathophysiology of coagulopathy, detecting the presence of hypercoagulability in critically ill COVID-19 patients. However, it remains unknown whether the degree of coagulopathy can be used in order to predict the outcome, establish a diagnosis or guide anticoagulant therapy.

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

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.

COVID-19 Digestive System Involvement and Clinical Outcomes in a Large Academic Hospital in 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.1 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.2.

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