Cerebral venous thrombosis at high altitude: A systematic review.

BACKGROUND AND OBJECTIVE: High altitude may be a factor associated with cerebral venous thrombosis (CVT). As our knowledge of CVT at high altitude is limited, it was decided to pool such information from the available case studies to determine whether high altitude can predispose to CVT. METHODS: A systematic review of the literature was performed for cases reporting CVT at high altitude. Searches of the PubMed database (up to July 2016) were performed for publications, using 'cerebral venous thrombosis' and 'high altitude' as keywords. Cross-referencing was also done to complete the search. RESULTS: Ultimately, 13 articles were included in our systematic review. The population consisted of 17 patients, predominately male (14/17), with a mean age of 32 (range: 19-47) years. Altitude range was 3000-8200m. Nine patients stayed at high altitude for>2 weeks; the duration of high altitude stay was unknown for the remainder. A hypercoagulable state was found in nine patients: secondary polycythemia in five; protein C deficiency in one; protein S deficiency in one; and factor V Leiden mutations in two. No comorbidities were found in any of these patients. CONCLUSION: Long-term stays at high altitude in association with a hypercoagulable state - in particular, congenital or acquired thrombophilia - appears to predispose to CVT. The association of CVT with a single exposure to high altitude seems low, but the risk cannot as yet be specifically estimated.

[Contribution of arterial spin labeling to the diagnosis of sudden and transient neurological deficit]. / Apport de la séquence de marquage des spins artériels (ASL) devant un déficit neurologique brutal et transitoire.

MRI is the gold standard exploration for sudden transient neurological events. If diffusion MRI is negative, there may be a diagnostic doubt between transient ischemic attack and other causes of transient neurological deficit. We illustrate how sequence arterial spin labeling (ASL), which evaluates cerebral perfusion, contributes to the exploration of transient neurological events. An ASL sequence was performed in seven patients with a normal diffusion MRI explored for a transient deficit. Cortical hyperperfusion not systematized to an arterial territory was found in three and hypoperfusion systematized to an arterial territory in four. ASL helped guide early management of these patients.

Safety and Efficacy of Cangrelor in Acute Stroke Treated with Mechanical Thrombectomy: Endovascular Treatment of Ischemic Stroke Registry and Meta-analysis.

BACKGROUND AND PURPOSE: Rescue therapies are increasingly used in the setting of endovascular therapy for large-vessel occlusion strokes. Among these, cangrelor, a new P2Y12 inhibitor, offers promising pharmacologic properties to join the reperfusion strategies in acute stroke. We assessed the safety and efficacy profiles of cangrelor combined with endovascular therapy in patients with large-vessel-occlusion stroke. MATERIALS AND METHODS: We performed a retrospective patient data analysis in the ongoing prospective multicenter observational Endovascular Treatment in Ischemic Stroke Registry in France from July 2018 to December 2020 and conducted a systematic review and meta-analysis using several data bases. Indications for cangrelor administration were rescue strategy in case of refractory intracranial occlusion with or without intracranial rescue stent placement, and cervical carotid artery stent placement in case of cervical occlusion (tandem occlusion or isolated cervical carotid occlusion). RESULTS: In the clinical registry, 44 patients were included (median initial NIHSS score, 12; prior intravenous thrombolysis, 29.5%). Intracranial stent placement was performed in 54.5% (n = 24/44), and cervical stent placement, in 27.3% (n = 12/44). Adjunctive aspirin and heparin were administered in 75% (n = 33/44) and 40.9% (n = 18/44), respectively. Rates of symptomatic intracerebral hemorrhage, parenchymal hematoma, and 90-day mortality were 9.5% (n = 4/42), 9.5% (n = 4/42), and 24.4% (n = 10/41). Favorable outcome (90-day mRS, 0-2) was reached in 51.2% (n = 21/41), and successful reperfusion, in 90.9% (n = 40/44). The literature search identified 6 studies involving a total of 171 subjects. In the meta-analysis, including our series data, symptomatic intracerebral hemorrhage occurred in 8.6% of patients (95% CI, 5.0%-14.3%) and favorable outcome was reached in 47.6% of patients (95% CI, 27.4%-68.7%). The 90-day mortality rate was 22.6% (95% CI, 13.6%-35.2%). Day 1 artery patency was observed in 89.7% (95% CI, 81.4%-94.6%). CONCLUSIONS: Cangrelor offers promising safety and efficacy profiles, especially considering the complex endovascular reperfusion procedures in which it is usually applied. Further large prospective data are required to confirm these findings.

Early ADC changes in motor structures predict outcome of acute stroke better than lesion volume.

OBJECTIVES: The lesion volume assessed from diffusion-weighted imaging (DWI) within the first six hours to first week following stroke onset has been proposed as a predictor of functional outcome in clinical studies. However, the prediction accuracy decreases when the DWI lesion volume is measured during the earliest stages of patient evaluation. In this study, our hypothesis was that the combination of lesion location (motor-related regions) and diffusivity measures (such as Apparent Diffusion Coefficient [ADC]) at the acute stage of stroke predict clinical outcome. PATIENTS AND METHODS: Seventy-nine consecutive acute carotid territory stroke patients (median age: 62 years) were included in the study and outcome at three months was assessed using the modified Rankin scale (good outcome: mRS 0-2; poor outcome: mRS 3-5). DWI was acquired within the first six hours of stroke onset (H2) and the following day (D1). Apparent Diffusion Coefficient (ADC) values were measured in the corticospinal tract (CST), the primary motor cortex (M1), the supplementary motor area (SMA), the putamen in the affected hemisphere, and in the contralateral cerebellum to predict stroke outcome. RESULTS: Prediction of poor vs. good outcome at the individual level at H2 (D1, respectively) was achieved with 74% accuracy, 95%CI: 53-89% (75%, 95% CI: 61-89%, respectively) when patients were classified from ADC values measured in the putamen and CST. Prediction accuracy from DWI volumes reached only 62% (95%CI: 42-79%) at H2 and 69% (95%CI: 50-85%) at D1. CONCLUSION: We therefore show that measures of ADC at the acute stage in deeper motor structures (putamen and CST) are better predictors of stroke outcome than DWI lesion volume.

Clot Burden Score and Collateral Status and Their Impact on Functional Outcome in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Collateral status and thrombus length have been independently associated with functional outcome in patients with acute ischemic stroke. It has been suggested that thrombus length would influence functional outcome via interaction with the collateral circulation. We investigated the individual and combined effects of thrombus length assessed by the clot burden score and collateral status assessed by a FLAIR vascular hyperintensity-ASPECTS rating system on functional outcome (mRS). MATERIALS AND METHODS: Patients with anterior circulation acute ischemic stroke due to large-vessel occlusion from the ASTER and THRACE trials treated with endovascular thrombectomy were pooled. The clot burden score and FLAIR vascular hyperintensity score were determined on MR imaging obtained before endovascular thrombectomy. Favorable outcome was defined as an mRS score of 0-2 at 90 days. Association of the clot burden score and the FLAIR vascular hyperintensity score with favorable outcome (individual effect and interaction) was examined using logistic regression models. RESULTS: Of the 326 patients treated by endovascular thrombectomy with both the clot burden score and FLAIR vascular hyperintensity assessment, favorable outcome was observed in 165 (51%). The rate of favorable outcome increased with clot burden score (smaller clots) and FLAIR vascular hyperintensity (better collaterals) values. The association between clot burden score and functional outcome was significantly modified by the FLAIR vascular hyperintensity score, and this association was stronger in patients with good collaterals, with an adjusted OR = 6.15 (95% CI, 1.03-36.81). CONCLUSIONS: The association between the clot burden score and functional outcome varied for different collateral scores. The FLAIR vascular hyperintensity score might be a valuable prognostic factor, especially when contrast-based vascular imaging is not available.

Reliability of the ECASS radiological classification of postthrombolysis brain haemorrhage: a comparison of CT and three MRI sequences.

BACKGROUND: Postthrombolysis brain haemorrhagic transformations (HT) are often categorized with the CT-based classification of the European Cooperative Acute Stroke Study (ECASS). However, little is known about the reliability of this classification and its extension to MRI. Our objective was to compare the inter- and intraobserver reliability of this classification on CT and 3 MRI sequences. METHODS: Forty-three patients with postthrombolysis HT on CT or at least 1 of the 3 MRI sequences: fluid-attenuation inversion recovery (FLAIR), diffusion-weighted imaging (DWI), and T2* gradient recalled echo (T2*GRE) were selected. Twelve control patients without any bleeding were added to avoid a bias based on a pure HT-positive cohort. Each series of images were independently classified with the ECASS method by 6 blinded observers. Inter- and intraobserver reproducibility was categorized from poor to excellent depending on kappa values. RESULTS: The inter- and intraobserver overall concordance of the classification was good for T2*GRE, DWI and CT (kappa > 0.6) and moderate for FLAIR (kappa < 0.6). The interobserver concordance for parenchymal haematomas was excellent for T2*GRE (kappa > 0.8) and moderate for CT, FLAIR and DWI. CONCLUSION: The T2*GRE sequence is the most reproducible method to categorize postthrombolysis HT and has an excellent reliability for the severe parenchymal haematoma category, suggesting that this sequence should be used to assess HT in thrombolytic therapy trials.

Neurological sequelae after cerebral anoxia.

PRIMARY OBJECTIVE: Cardiac arrest can cause neurological impairment. The aim of this study is to confirm the disability and the predominant part of executive and behavioural impairments after cardiac arrest. RESEARCH DESIGN: A retrospective study is proposed. METHODS AND PROCEDURES: All consecutive patients admitted to the Department of Rehabilitation for Neurological Impairments following cerebral anoxia after cardiac arrest between 1995-2007 were included. Clinical and neuropsychological assessment was proposed. MAIN OUTCOMES AND RESULTS: Thirty patients, 19 men, were examined. Ages ranged from 16-58 (mean = 39.5). Fourteen patients presented with severe disability and 16 patients presented with moderate disability. In the first group (severe disability) no patients were autonomous for daily life activities. They presented with dysexecutive syndrome and behavioural disorders associated with amnesia syndrome; 64% of them presented with motor disorders. In the second group, patients with moderate disability were autonomous in daily life but not for the complex activities or functioning. They had no motor impairment but suffered from executive and memory impairments. Behavioural changes were noted. Medical history or demographic data did not differ between the two groups. CONCLUSION: The study confirms the predominant part of executive, memory and behavioural impairments after cardiac arrest. This retrospective study cannot provide prognosis factors and further prognosis studies are needed.

Risk of symptomatic intracerebral hemorrhage in patients treated with intra-arterial thrombolysis.

BACKGROUND: In intra-arterial (IA) thrombolysis trials, higher rates of symptomatic intracerebral haemorrhage (sICH) were found than in trials with intravenous (IV) recombinant tissue plasminogen activator (tPA); this observation could have been due to the inclusion of more severely affected patients in IA thrombolysis trials. In the present study, we investigated the rate of sICH in IA and combined IV + IA thrombolysis versus IV thrombolysis after adjusting for differences in clinical and MRI parameters. METHODS: In this multicenter study, we systematically analyzed data from 645 patients with anterior-circulation strokes treated with either IV or IA thrombolysis within 6 h following symptom onset. Thrombolytic regimens included (1) IV tPA treatment (n = 536) and (2) IA treatment with either tPA or urokinase (n = 74) or (3) combined IV + IA treatment with either tPA or urokinase (n = 35). RESULTS: 44 (6.8%) patients developed sICH. sICH patients had significantly higher scores on the National Institutes of Health Stroke Scale (NIHSS) at admission and pretreatment DWI lesions. The sICH risk was 5.2% (n = 28) in IV thrombolysis, which is significantly lower than in IA (12.5%, n = 9) or IV + IA thrombolysis (20%, n = 7). In a binary logistic regression analysis including age, NIHSS score, time to thrombolysis, initial diffusion weighted imaging lesion size, mode of thrombolytic treatment and thrombolytic agent, the mode of thrombolytic treatment remained an independent predictor for sICH. The odds ratio for IA or IV + IA versus IV treatment was 3.466 (1.19-10.01, 95% CI, p < 0.05). CONCLUSION: In this series, IA and IV + IA thrombolysis is associated with an increased sICH risk as compared to IV thrombolysis, and this risk is independent of differences in baseline parameters such as age, initial NIHSS score or pretreatment lesion size.

[Glass ceiling for women in academic medicine in France]. / Plafond de verre pour les femmes dans les carrières hospitalo-universitaires en France.

OBJECTIVE: To determine whether career development in academic medicine is more difficult for women than for men, and, if any, the nature and level of barriers to this progression. METHODS: Extraction of full-time medical staff in a Parisian hospital group, through the SIGAPS platform; an online questionnaire survey of career choices and barriers experienced by full-time male and female physicians. The study population comprises 181 hospital practitioners and 141 academic physicians (49 associate professors and 92 full professors). RESULTS: Women represent 49% of the medical staff but 15% of full professors. This underrepresentation of women is more important among intensivists/anesthesiologists than technique-based specialists (such as radiologists, biologists…). There is no difference in scientific output, marital status and parenthood between women and men. On the other hand, there is a difference in attitudes highlighted by the EVAR risk-taking scale as well as in the burden of familial involvement and the prejudices felt by women during the academic selection process. CONCLUSION: The glass ceiling exists in one of the largest French hospital group. Career development principles promote merit, but should decrease the benefit of "masculine" attitudes in the competition for academic positions. Academic selection criteria should evolve to limit the disadvantage of women related to deeper familial involvement and less competitive strategies and risk-taking attitudes.

Evaluation of synthetic substituted 1,2-dioxanes as novel agents against human leishmaniasis.

The treatment of human leishmaniasis is currently based on few compounds that are highly toxic, expensive and have a high rate of treatment failure. A number of recent studies on new drugs focuses on natural or semi-synthetic compounds. Among them, the endoperoxide artemisinin, extracted from Artemisia annua, and some of its derivatives have shown leishmanicidal activity. In the present work, a series of structurally simple, fully synthetic 1,2-dioxanes were evaluated for in vitro antileishmanial activity against promastigotes of Leishmania donovani; the cytotoxicity for mammalian cells was also assessed. The six most promising compounds in terms of activity and selectivity were further investigated for their antileishmanial activity on the promastigote forms of L. tropica, L. major and L. infantum and against L. donovani amastigotes. The good performance in terms of potency and selectivity makes these six hits promising candidates for a preliminary lead optimization as antileishmanial agents.

Prevalence and risk factors for Chlamydia trachomatis infection in young women in north-west of Italy.

AIM: The aim of the study was to estimate the prevalence of Chlamydia trachomatis infection, risk factors and best predictors of infection in young sexually active women in north-west of Italy. METHODS: One thousand one hundred and eighty 18-24 years old women of family planning clinics and three STI Clinics over Turin city area underwent vaginal swabs to detect infection and completed a questionnaire. Logistic regression and multivariate analysis identified risk factors and a receiver operating characteristic (ROC) curve was used to assess the model accuracy. RESULTS: Overall prevalence of infection was 10.4% 2.71 times higher (P<0.001) among women afferent to STI clinics than family planning clinics. Higher among women of Eastern European, Asian and South American ethnic origin (P=0.012) compared to Western European or African ethnic origin. Age at first intercourse (P=0.006), absence of a stable partner (P<0.001) partner with urogenital complaints (P<0.001), number of lifetime partners (P<0.001) number of partners in the last 6 months (P<0.001) history of occasional intercourse (P<0.001) and of IST (P<0.007) resulted associated with chlamydial infection. Multivariate analysis showed setting, partner with urogenital complaints and number of lifetime partners as best predictors of infection. ROC curve on variables from multivariate analysis showed an AUC of 0.732. CONCLUSION: The study showed high rates of Chlamydial infection among sexually active women between 18-24 years in north-west area of Italy. Predictors of infection are related to sexual activity and to population sub-groups. Selective screening protocols should be supported by wider and more representative studies in order to increase knowledge and involve public opinion.

Restless legs syndrome is frequently overlooked in patients being evaluated for polyneuropathies.

Restless legs syndrome (RLS) often presents with paresthesias and dysesthesisas. We have investigated the prevalence and clinical features of RLS in a cohort of patients referred for clinical suspicion of peripheral neuropathy (PN). Sixty-four patients with sensory symptoms, and 101 age-matched controls were prospectively evaluated for RLS, PN and causes of both conditions. In the 64 patients (60 +/- 14 years), none were referred with a suspicion of RLS. Forty-one had a sensori-motor PN of which 22 had a definite RLS (54%). When excluding other causes of RLS, 8 of 41 patients had a RLS associated with a neuropathy (20%). The proportion of RLS in the healthy controls was 10%, lower than in the cohort of patients. In patients without PN, 57% had a RLS, and 55% in the whole cohort, a higher proportion than in the healthy controls (P < 0.0001). Patients with PN and RLS had more sleep disorders (P < 0.04), and legs and calves symptoms (P = 0.09) than patients with PN without RLS. Toes symptoms were more frequently observed in patients with PN but without RLS (P < 0.02). We conclude that RLS frequently presents with symptoms suggestive of peripheral neuropathy, and therefore, is often overlooked.

Diffusion-weighted MR imaging characteristics of an acute strokelike form of multiple sclerosis.

The characteristics of multiple sclerosis (MS) lesions on diffusion-weighted sequences and apparent diffusion coefficient (ADC) mapping at the very early phase of symptoms have not been clearly described. We report the case of a young woman who presented with a sudden pseudostroke form of MS resulting in hemiplegia and sudden aphasia. MR imaging showed a lesion of the left internal capsule with reduced ADC, which suggests an ischemic stroke. This case shows that very acute MS lesions may have reduced ADC on MR imaging, reflecting cytotoxic and not vasogenic edema.

Transient cytogenetic relapse in a Ph1-positive chronic myelogenous leukemia patient previously treated with alpha-interferon.

Therapy with alpha-interferon (IFN alpha) can suppress the Ph1-positive hemopoiesis in a percentage of patients with chronic myelogenous leukemia (CML). We used IFN alpha to treat a 30-year-old CML patient, characterized by favourable prognostic signs (such as low leukocytosis, absence of splenomegaly and no increase in bone marrow blasts) at diagnosis, and obtained a complete remission, as evaluated by Southern blot and cytogenetic analysis, after one year of treatment. However, the polymerase chain reaction (PCR) revealed the persistence of a minimal residual disease. The IFN alpha therapy was stopped and the hematological status remained stable until eighteen months later, when a cytogenetic analysis revealed the appearance of a clone characterized by t(9;22) and trisomy 8, accounting for 30% of bone marrow metaphases. This cell population spontaneously regressed in the following months, before any cytotoxic treatment. However, as leukemic cells, detected by PCR, were still present, the patient received a high dose chemotherapy, which induced the complete eradication of the Ph1-positive clone, as demonstrated by the absence of bcr-abl transcript at the PCR reaction. Molecular and cytogenetic remission persist one year later, without any further therapy.

Expression of GATA-1 mRNA in human myeloid leukemic cells.

Expression of the transcription factor GATA-1, which regulates several erythroid specific genes and possibly also some megakaryocytic genes, has been previously detected in normal erythroblasts, megakaryocytes, and basophils, and in some myeloid cell lines. It has been suggested that GATA-1 may be first expressed in a common progenitor and then further activated during erythroid-megakaryocytic and basophilic differentiation and repressed during myeloid maturation. We investigated GATA-1 mRNA expression in highly purified leukemic blasts representing different lineages and stages of myeloid differentiation and in a recently established leukemic cell line, GF-D8, which exhibits morphological, cytochemical and immunophenotypic characteristics of early myeloid progenitor cells. We found GATA-1 expression in five of five myeloid and in one megakaryocytic blast crisis of CML, in four of six cases of myelomonocytic leukemias (M4 according to FAB classification), in one case of erythroleukemia (M6), whereas lymphoid blast crisis of CML and all other FAB groups were completely negative. In addition, a low level of GATA-1 mRNA was also expressed by the GF-D8 cell line. These data further support the hypothesis that GATA-1 expression may occur not only in erythroid and megakaryocytic progenitors, but also in early myeloid progenitors, and then be further regulated during lineage-specific maturation.

Minimal residual disease status in transplanted chronic myelogenous leukemia patients: low incidence of polymerase chain reaction positive cases among 48 long disease-free subjects who received unmanipulated allogeneic bone marrow transplants.

Forty-eight long-term disease-free chronic myelogenous leukemia (CML) patients, who had received unmanipulated allogeneic bone marrow transplants (BMT) for eradication of the Philadelphia (Ph1)-positive clone were studied by polymerase chain reaction (PCR), using a very sensitive PCR procedure and very stringent criteria for preventing and revealing contamination. Nine patients (18%) were positive at the first PCR examination, but only one patient remained PCR positive four years after. However, a second PCR analysis performed on new bone marrow samples obtained at a median interval of 14 months (range 6-16) after the first specimen collection from six of nine originally positive cases, and from 16 of 39 originally negative cases, showed that only one of the six positive cases remained positive, whereas negativity was confirmed in all the originally negative patients. These data are evidence that the Ph1-positive clone is apparently completely eradicated in the majority of CML patients who survive disease-free long-term after an unmanipulated allogeneic BMT and that only sporadic cases remain PCR-positive four years post-BMT. The data also show that at least two sequential bone marrow samples for each patient must be analyzed before drawing conclusions regarding the stable persistence of BCR/ABL transcripts and the minimal residual disease status.

Identical utilization of T-cell receptor gene regions in B-lymphoid blast crisis of chronic myeloid leukemia and B-precursor acute lymphoblastic leukemia.

The configuration of the T-cell receptor (TCR) beta, gamma and delta chain genes was analyzed in 16 cases of B-lymphoid blastic crisis of chronic myeloid leukemia (BC-CML) for a better definition of the biological aspects of this cellular population, in comparison with the molecular features of B-precursor acute lymphoblastic leukemia (ALL). All cases displayed B-phenotypic features, were Ph'-positive and had a rearranged configuration of the breakpoint cluster region (bcr) and of the immunoglobulin heavy chain gene region (JH). The TCR beta chain gene was rearranged in four cases (25%), all of which displayed a monoallelic rearrangement involving the J beta 2 region. The TCR gamma chain gene was rearranged in 13 cases (81%); 13 rearranged alleles utilized the J1/2 regions, while the remaining five utilized JP1. The V regions of the group I were mostly involved. The TCR delta chain gene was rearranged or deleted in 15 cases (94%); the 10 rearranged chromosomes displayed exclusively two patterns referable to partial recombinations, a V2-(D)-D3 and a (D)-D3 type. These two configurations are predominant in B-precursor ALL (75% of rearranged chromosomes) and almost absent in T-ALL. Taken together, these results document the close similarities between the genotypic features of B-lymphoid BC-CML and B-precursor ALL, not only in terms of the incidence of rearrangement but more relevantly with regard to the choice of regions involved in the recombinations. This aspect is particularly evident at the TCR delta locus level.

Hydrocephalus and racemose cysticercosis: surgical alternative by endoscopic third ventriculostomy.

BACKGROUND AND PURPOSE: Hydrocephalus is a frequent and potentially serious complication of neurocysticercosis. Its treatment often requires ventricular shunting. The complication rate is high due to obstruction or material infection, which may justify endoscopic third ventriculostomy (ETV). OBSERVATION: We report a case of obstructive hydrocephalus in a 46-year-old man in the context of racemose cysticercosis, presenting with headaches and transient disorders of consciousness. Imaging showed cystic lesions of the cisterna magna, responsible for hydrocephalus which was treated effectively by ETV. Treatment with albendazole decreased the volume of the cisterna magna cysts. RESULTS: The patient was followed for 6 years after ETV with no recurrence of hydrocephalus despite two more symptomatic episodes of the disease with extension of the cysts into the lumen of the fourth ventricle and into the perispinal subarachnoid spaces, effectively treated by albendazole each time. CONCLUSIONS: Treatment of obstructive hydrocephalus secondary to cerebral racemose cysticercosis by ETV seems to be an effective and safety technique. The role of ETV should be evaluated in this indication.

Endocrine manifestations of chronic HCV infection.

Chronic hepatitis C virus (HCV) infection has been associated with a great number of extra-hepatic manifestations (EHMs), including several endocrine disorders. Currently available epidemiological, clinical and experimental data do not show a link between HCV and all EHMs. Thyroid disorders (TD) and type 2 diabetes, for example, are the most frequent endocrine alterations in patients with chronic HCV infection, but there are only weak evidences that HCV could be involved in hypothalamic-pituitary axis perturbation, bone metabolism alteration and sexual dysfunctions induction. Thus, this issue needs further investigation. Prospective studies have also shown that interferon (IFN)-based therapy for chronic HCV infection can induce or worsen EHMs. In particular, IFN has been associated with development of autoimmunity and/or TD in up to 40% of chronic HCV infected patients. Hence, a careful monitoring of thyroid function should be performed in such patients. The recent approval of direct-acting antiviral agents in IFN-free regimens for chronic hepatitis C treatment will dramatically reduce not only liver-related mortality but also morbidity due to EHMs.