Usefulness of fibrosis-4 (FIB-4) score and metabolic alterations in the prediction of SARS-CoV-2 severity.

Despite vaccination programs, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains a public health problem. Identifying key prognostic determinants of severity of the disease may help better focus health resources. The negative prognostic role for metabolic and hepatic alterations is established; however, the interplay among different metabolic comorbidities and their interconnections with the liver have never been explored.The objective of this study is to evaluate the impact of liver alterations in addition to metabolic comorbidities as a predictor of SARS-CoV-2 severity. 382 SARS-CoV-2 patients were enrolled. Severe SARS-CoV-2 was diagnosed according to international consensus. Transaminases > 2 times the upper limit of normality (2ULN), hepatic steatosis (by ultrasound and/or computed tomography in 133 patients), and FIB-4 defined liver alterations. All data were collected on admission. The results are severe SARS-CoV-2 infection in 156 (41%) patients (mean age 65 ± 17; 60%males). Prevalence of obesity was 25%; diabetes, 17%; hypertension, 44%; dyslipidaemia, 29%; with 13% of the cohort with ≥ 3 metabolic alterations. Seventy patients (18%) had transaminases > 2ULN, 82 (62%) steatosis; 199 (54%) had FIB-4 < 1.45 and 45 (12%) > 3.25. At multivariable analysis, ≥ 3 metabolic comorbidities (OR 4.1, CI 95% 1.8-9.1) and transaminases > 2ULN (OR 2.6, CI 95% 1.3-6.7) were independently associated with severe SARS-CoV-2. FIB-4 < 1.45 was a protective factor (OR 0.42, CI 95% 0.23-0.76). Hepatic steatosis had no impact on disease course. The presence of metabolic alterations is associated with severe SARS-CoV-2 infection, and the higher the number of coexisting comorbidities, the higher the risk of severe disease. Normal FIB-4 values are inversely associated with advanced SARS-CoV-2 regardless of metabolic comorbidities, speculating on use of these values to stratify the risk of severe infection.

Treatment of immune thrombocytopenia (ITP) secondary to malignancy: a systematic review.

Immune thrombocytopenia (ITP) can be associated with lymphoproliferative diseases (LPD) or solid tumors. A systematic review of published literature was conducted to evaluate response to treatment of ITP secondary to malignancy. Primary outcome was overall response (complete response+response) to first-line treatments [steroids alone or in combination with intravenous immunoglobulins (IVIg)]. Among secondary outcomes, overall response to second-line treatments [splenectomy, rituximab or thrombopoietin receptor agonists (TPO-RA)] and death were evaluated. Of the retrieved 238 text articles, 108 were analyzable, for a total of 154 patients: 142 in 105 case reports and 12 in 3 observational studies. Thirty-nine patients had solid tumors, 114 LPD, and 1 both. The median follow up was 19 months (IQR, 9-40). The overall response was 50% (62% in solid tumors, 46% in LPD) after steroids and 47% (67% in solid tumors, 36% in LPD) after steroids+IVIg, which are lower than historical responses observed in primary ITP (≈80%). The overall responses to rituximab (used in LPD only), splenectomy and TPO-RA (70%, 73% and 92%, respectively) were similar to those observed in primary ITP. Seven patients (6%) died due to bleeding events. ITP secondary to malignancy appears to be associated with unsatisfactory response to first-line treatments.

Management of patients with cervical spine trauma in the emergency department: a systematic critical appraisal of guidelines with a view to developing standardized strategies for clinical practice.

Several guidelines on the evaluation of patients with suspected cervical spine trauma in the Emergency Department (ED) exist. High heterogeneity between different guidelines has been reported. Aim of this study was to find areas of agreement and disagreement between guidelines, to identify topics in which further research is needed and to provide an evidence-based cervical spine trauma algorithm for ED physicians. The three most relevant guidelines published on cervical spine trauma in the last 10 years were selected screening websites of the main scientific societies and through the comparison of a normalized Google Scholar and SCOPUS citation index. We compared the selected guidelines through seven a-priori defined questions. In case of disagreement between the guidelines or if the quality of evidence appeared low, evidence from published systematic reviews on the topic was added to build an evidence-based algorithm for approach to spinal trauma in the ED. The three selected guidelines were: NICE 2016, Eastern Association for the Surgery of Trauma 2009 and American Association of Neurological Surgeons and Congress of Neurological Surgeons 2013. We found complete agreement on one question, partial agreement for one questions, no agreement for two questions, while agreement was not assessable for 3 questions. The agreement between different guidelines and the evidence on which recommendations are based is low. An attempt to build an evidence-based algorithm has been made. More studies are needed on many topics.

Incidence of delayed bleeding in patients on antiplatelet therapy after mild traumatic brain injury: a systematic review and meta-analysis.

BACKGROUND: The scientific evidence regarding the risk of delayed intracranial bleeding (DB) after mild traumatic brain injury (MTBI) in patients administered an antiplatelet agent (APA) is scant and incomplete. In addition, no consensus exists on the utility of a routine repeated head computed tomography (CT) scan in these patients. OBJECTIVE: The aim of this study was to evaluate the risk of DB after MTBI in patients administered an APA. METHODS: A systematic review and meta-analysis of prospective and retrospective observational studies enrolling adult patients with MTBI administered an APA and who had a second CT scan performed or a clinical follow-up to detect any DB after a first negative head CT scan were conducted. The primary outcome was the risk of DB in MTBI patients administered an APA. The secondary outcome was the risk of clinically relevant DB (defined as any DB leading to neurosurgical intervention or death). RESULTS: Sixteen studies comprising 2930 patients were included in this meta-analysis. The pooled absolute risk for DB was 0.77% (95% CI 0.23-1.52%), ranging from 0 to 4%, with substantial heterogeneity (I2 = 61%). The pooled incidence of clinically relevant DB was 0.18%. The subgroup of patients on dual antiplatelet therapy (DAPT) had an increased DB risk, compared to the acetylsalicylic acid (ASA)-only patients (2.64% vs. 0.22%; p = 0.04). CONCLUSION: Our systematic review showed a very low risk of DB in MTBI patients on antiplatelet therapy. We believe that such a low rate of DB could not justify routine repeated CT scans in MTBI patients administered a single APA. We speculate that in the case of clinically stable patients, a repeated head CT scan could be useful for select high-risk patients and for patients on DAPT before discharge.

Multicentre external validation of the Canadian Syncope Risk Score to predict adverse events and comparison with clinical judgement.

BACKGROUND: The Canadian Syncope Risk Score (CSRS) has been proposed for syncope risk stratification in the emergency department (ED). The aim of this study is to perform an external multicenter validation of the CSRS and to compare it with clinical judgement. METHODS: Using patients previously included in the SyMoNE database, we enrolled subjects older than 18 years who presented reporting syncope at the ED. For each patient, we estimated the CSRS and recorded the physician judgement on the patients' risk of adverse events. We performed a 30-day follow-up. RESULTS: From 1 September 2015 to 28 February 2017, we enrolled 345 patients; the median age was 71 years (IQR 51-81), 174 (50%) were men and 29% were hospitalised. Serious adverse events occurred in 43 (12%) of the patients within 30 days. The area under the curve of the CSRS and clinical judgement was 0.75 (95% CI 0.68 to 0.81) and 0.68 (95% CI 0.61 to 0.74), respectively. The risk of adverse events of patients at low risk according to the CSRS and clinical judgement was 6.7% and 2%, with a sensitivity of 70% (95% CI 54% to 83%) and 95% (95% CI 84% to 99%), respectively. CONCLUSION: This study represents the first validation analysis of CSRS outside Canada. The overall predictive accuracy of the CSRS is similar to the clinical judgement. However, patients at low risk according to clinical judgement had a lower incidence of adverse events as compared with patients at low risk according to the CSRS. Further studies showing that the adoption of the CSRS improve patients' outcomes is warranted before its widespread implementation.

Obesity and sleep disturbances: The "chicken or the egg" question.

Obesity and sleep disturbances are common conditions in modern societies and accumulating evidence support a close bidirectional causal relationship between these two conditions. Indeed, from one side sleep loss seems to affect energy intake and expenditure through its direct effects on hormone-mediated sensations of satiety and hunger and through the influence on hedonic and psychological aspects of food consumption. Sleep deprived patients have been shown to experiment excessive daytime sleepiness, fatigue, and tiredness that, in a vicious circle, enhances physical inactivity and weight gain. On the other side, obesity is a well-known risk factor for several sleep disorders. This narrative review will discuss the main pathophysiological mechanisms that link sleep loss to obesity and metabolic syndrome with particular attention to the three most common sleep disorders (insomnia, obstructive sleep apnoea syndrome, restless leg syndrome).

Incremental Risk of Intracranial Hemorrhage After Mild Traumatic Brain Injury in Patients on Antiplatelet Therapy: Systematic Review and Meta-Analysis.

BACKGROUND: Mild traumatic brain injury (TBI) is a common event and antiplatelet therapy might represent a risk factor for bleeding. OBJECTIVE: The aim of this study was to evaluate the risk of intracranial hemorrhage (ICH) after mild TBI in patients on antiplatelet therapy through a systematic review and meta-analysis. METHODS: We conducted a systematic review and meta-analysis of prospective and retrospective observational studies on patients with mild TBI on antiplatelet therapy vs. those not on any antithrombotic therapy. The primary outcome was the risk of ICH in patients with mild TBI based on the first computed tomography scan. Secondary outcome was the risk of mortality and neurosurgery. RESULTS: Nine studies and 14,545 patients were included. The incidence of ICH ranged from 3.6% to 29.4% in the antiplatelet group and from 1.6% to 21.1% in the control group. Patients on antiplatelet therapy had a higher risk of ICH after a mild TBI compared with patients that were not on antithrombotic therapy (risk ratio 1.51; 95% confidence interval 1.21-1.88). No difference was found in the composite outcome of mortality and neurosurgery. CONCLUSIONS: Patients on antiplatelet therapy have an increased risk of ICH after mild TBI compared with patients not on antithrombotic therapy. However, the risk is just slightly increased, and the need to perform a computed tomography scan in patients on antiplatelet therapy after a mild TBI should be evaluated case by case, but always considered in patients with other risk factors.

Diagnostic Accuracy of Carotid Doppler Ultrasound for the Detection of Right-to-Left Cardiac Shunt.

BACKGROUND: Right-to-left cardiac shunt is a condition anatomically related to patent foramen ovale (PFO) and potentially related to cryptogenic cerebrovascular events. As recent studies demonstrated a reduction of recurrent stroke in patients undergoing percutaneous PFO closure after a cryptogenic cerebrovascular event, it is now of pivotal importance to screen these patients for Right-to-left shunt(RLS) presence. At this regard, transcranial color Doppler (TCCD) with contrast has a good sensitivity (97%) and specificity (93%) compared to transesophageal echocardiography and became the test of choice to assess RLS presence, thanks to its noninvasive nature. However, temporal bone window is not accessible in 6%-20% patients. Several approaches have been explored to overcome this limitation with encouraging but not definitive results for extracranial internal carotid artery (ICA) approach, proposed in previous pivotal studies. Aims of this study were to further assess the diagnostic accuracy of ICA Doppler ultrasound with contrast for RLS detection compared to TCCD, with the two tests performed simultaneously. MATERIALS AND METHODS: Sixty-four patients underwent simultaneously to TCCD and ICA Doppler ultrasound, both performed at rest and after Valsalva maneuver. Diagnosis of RLS was made, both for TCCD and ICA ultrasound, if=1 microembolic signals (MES) were detected during the examination (either at rest or after Valsalva maneuver). RESULTS: ICA Doppler ultrasound sensitivity and specificity resulted respectively of 97% (confidence interval [CI] 95%) and 100% ([CI] 95%), while negative likelihood ratio was 0.03 (CI 95%). CONCLUSIONS: ICA Doppler ultrasound represents a valid alternative to TCCD for RLS screening in patients without adequate transcranial acoustic window.

Cardiac autonomic dynamics during sleep are lost in patients with TIA and stroke.

Ischaemic stroke is accompanied by important alterations of cardiac autonomic control, which have an impact on stroke outcome. In sleep, cardiac autonomic control oscillates with a predominant sympathetic modulation during REM sleep. We aimed to assess cardiac autonomic control in different sleep stages in patients with ischaemic stroke. Forty-five patients enrolled in the prospective, multicentre SAS-CARE study but without significant sleep-disordered breathing (apnea-hypopnea index < 15/hr) and without atrial fibrillation were included in this analysis. The mean age was 56 years, 68% were male, 76% had a stroke (n = 34, mean National Institutes of Health Stroke Scale [NIHSS] score of 5, 11 involving the insula) and 24% (n = 11) had a transitory ischaemic attack. Cardiac autonomic control was evaluated using three different tools (spectral, symbolic and entropy analysis) according to sleep stages on short segments of 250 beats in all patients. Polysomnographic studies were performed within 7 days and 3 months after the ischaemic event. No significant differences in cardiac autonomic control between sleep stages were observed in the acute phase and after 3 months. Predominant vagal modulation and decreased sympathetic modulation were observed across all sleep stages in ischaemic stroke involving the insula. Patients with ischaemic stroke and transitory ischaemic attack present a loss of cardiac autonomic dynamics during sleep in the first 3 months after the ischaemic event. This change could represent an adaptive phenomenon, protecting the cardiovascular system from the instabilities of autonomic control, or a risk factor for stroke, which precedes the ischaemic event.

Short sleep duration and cardiometabolic risk: from pathophysiology to clinical evidence.

Short sleep duration has a substantial influence on the overall health of an individual. Short sleep time can be a consequence of lifestyle habits, environmental factors, or the presence of a sleep disorder, such as insomnia or sleep-disordered breathing. Short sleep time is associated with increased morbidity and mortality, mainly from cardiovascular disorders (including coronary artery disease, arrhythmias, and hypertension). Several biological mechanisms have been proposed as a possible link between short sleep duration and these diseases, such as involvement of the autonomic nervous system, endothelial function, metabolic regulation, inflammation, and the coagulation system. In this Review, we provide an overview on the effects of short sleep duration on cardiovascular health and diseases and discuss the main pathophysiological mechanisms involved, taking into account both experimental data and clinical evidence.

Secondary prevention of cryptogenic stroke in patients with patent foramen ovale: a systematic review and meta-analysis.

The aim of our study is to compare patent foramen ovale (PFO) closure versus medical treatment and antiplatelet versus anticoagulant therapy in patients with cryptogenic stroke (CS) and PFO. We conducted a systematic review and meta-analysis with trial sequential analysis (TSA) of randomized trials. Primary outcomes are stroke or transient ischemic attack (TIA) and all-cause mortality. Secondary outcomes are peripheral embolism, bleeding, serious adverse events, myocardial infarction and atrial dysrhythmias. We performed an intention to treat meta-analysis with a random-effects model. We include six trials (3677 patients, mean age 47.3 years, 55.8% men). PFO closure is associated with a lower recurrence of stroke or TIA at a mean follow-up of 3.88 years compared to medical therapy [risk ratio (RR) 0.55, 95% CI 0.38-0.81; I2 = 40%]. The TSA confirms this result. No difference is found in mortality (RR 0.74, 95% CI 0.35-1.60; I2 = 0%), while PFO closure is associated with a higher incidence of atrial dysrhythmias (RR 4.55, 95% CI 2.16-9.60; I2 = 25%). The rate of the other outcomes is not different among the two groups. The comparison between anticoagulant and antiplatelet therapy shows no difference in terms of stroke recurrence, mortality and bleeding. There is conclusive evidence that PFO closure reduces the recurrence of stroke or TIA in patients younger than 60 years of age with CS. More data are warranted to assess the consequences of the increase in atrial dysrhythmias and the advantage of PFO closure over anticoagulants.

Diagnostic accuracy of ICD-9 code 780.2 for the identification of patients with syncope in the emergency department.

PURPOSE: Syncope is a common condition that affects individuals of all ages and is responsible for 1-3% of all emergency department (ED) visits. Prospective studies on syncope are often limited by the exiguous number of subjects enrolled. A possible alternative approach would be to use of hospital discharge diagnoses from administrative databases to identify syncope subjects in epidemiological observational studies. We assessed the accuracy of the International Classification of Diseases, Ninth Revision (ICD-9) code 780.2 "syncope and collapse" to identify patients with syncope. METHODS: Patients in two teaching hospitals in Milan, Italy with a triage assessment for ED access that was possibly related to syncope were recruited in this study. We considered the index test to be the attribution of the ICD-9 code 780.2 at ED discharge and the reference standard to be the diagnosis of syncope by the ED physician. RESULTS: The sensitivity, specificity, positive and negative predictive values of the ICD-9 code 780.2 to identify patients with syncope were 0.63 (95% confidence interval [CI] 0.58-0.67), 0.98 (95% CI 0.98-0.99), 0.83 (95% CI 0.79-0.87) and 0.95 (95% CI 0.94-0.95), respectively. CONCLUSIONS: The moderate sensitivity of ICD-9 code 780.2 should be considered when the code is used to identify patients with syncope through administrative databases.

Acute particulate matter affects cardiovascular autonomic modulation and IFN-γ methylation in healthy volunteers.

AIMS: Air particulate matter (PM) is associated with increased cardiovascular morbidity and mortality. Altered autonomic functions play a key role in PM-induced cardiovascular disease. However, previous studies have not address the impact of PM on sympathetic and parasympathetic control of heart function, independently, and using controlled conditions, i.e., increasing titration of PM of known composition, in absence of other potential confounding factors. To fill this gap, here we used symbolic analysis that is capable of detecting non-mutual changes of the two autonomic branches, thus considering them as independent, and concentrations of PM as they could be measured at peak levels in Milan during a polluted winter day. METHODS AND RESULTS: In this randomized, cross-over study, we enrolled 12 healthy subjects who underwent two random sessions: inhalation of filtered air mixture or inhalation of filtered air containing particulate mixture (PM 10, PM 2.5, PM 1.0 and PM 0.5µm). ECG and respiration for autonomic analysis and blood sample for DNA Methylation were collected at baseline (T1), after air exposure (T2) and after 2h (T3). Spectral and symbolic analysis of heart rate variability (HRV) were performed for autonomic control of cardiac function, while alterations in DNA methylation of candidate genes were used to index pro-inflammatory modifications. In the PM expose group, autonomic analysis revealed a significant decrease of 2UV%, index of parasympathetic modulation (14% vs 9%, p = 0.0309), while DNA analysis showed a significant increase of interferon γ (IFN- γ) methylation, from T1 to T3. In a mixed model using T1, T2 and T3, fine and ultrafine PM fractions showed significant associations with IFN- γ methylation and parasympathetic modulation. CONCLUSIONS: Our study shows, for the first time, that in healthy subjects, acute exposure to PM affects parasympathetic control of heart function and it increases methylation of a pro-inflammatory gene (i.e. methylation of interferon γ). Thus, our study suggests that, even in absence of other co-factors and in otherwise healthy individuals, PM per se is sufficient to trigger parasympathetic dysautonomia, independently from changes in sympathetic control, and inflammation, in a dose-dependent manner.