Palaeogenomics of Upper Palaeolithic to Neolithic European hunter-gatherers.

Modern humans have populated Europe for more than 45,000 years1,2. Our knowledge of the genetic relatedness and structure of ancient hunter-gatherers is however limited, owing to the scarceness and poor molecular preservation of human remains from that period3. Here we analyse 356 ancient hunter-gatherer genomes, including new genomic data for 116 individuals from 14 countries in western and central Eurasia, spanning between 35,000 and 5,000 years ago. We identify a genetic ancestry profile in individuals associated with Upper Palaeolithic Gravettian assemblages from western Europe that is distinct from contemporaneous groups related to this archaeological culture in central and southern Europe4, but resembles that of preceding individuals associated with the Aurignacian culture. This ancestry profile survived during the Last Glacial Maximum (25,000 to 19,000 years ago) in human populations from southwestern Europe associated with the Solutrean culture, and with the following Magdalenian culture that re-expanded northeastward after the Last Glacial Maximum. Conversely, we reveal a genetic turnover in southern Europe suggesting a local replacement of human groups around the time of the Last Glacial Maximum, accompanied by a north-to-south dispersal of populations associated with the Epigravettian culture. From at least 14,000 years ago, an ancestry related to this culture spread from the south across the rest of Europe, largely replacing the Magdalenian-associated gene pool. After a period of limited admixture that spanned the beginning of the Mesolithic, we find genetic interactions between western and eastern European hunter-gatherers, who were also characterized by marked differences in phenotypically relevant variants.

An assessment of puberty status in adolescents from the European Upper Paleolithic.

Childhood and adolescence are two life-history stages that are either unique to humans, or significantly expanded in the human life course relative to other primates. While recent studies have deepened our knowledge of childhood in the Upper Paleolithic, adolescence in this period remains understudied. Here, we use bioarchaeological maturational markers to estimate puberty status of 13 Upper Paleolithic adolescents from sites in Russia, Czechia, and Italy to 1) evaluate the feasibility of the application of bioarchaeological puberty assessment methods to Upper Paleolithic (Homo sapiens) skeletal individuals, 2) estimate the timing and tempo of puberty in Upper Paleolithic adolescents compared to other archaeological populations analyzed using the same method, and 3) characterize adolescence in the Upper Paleolithic by contextualizing the results of this puberty assessment with data on individual and population-level health, morbidity and burial practices. Our results revealed that while puberty had begun by 13.5 years of age for the majority of individuals, there was a lot of variability, with the adolescents from Arene Candide (AC1 and AC16), both aged around 16 years when they died, taking several years longer to progress through puberty than their peers. Assessing the age of menarche was challenging due to the paucity of female adolescents, but based on the available evidence, it appears to have occurred between 16 and 17 years of age. For some, full adulthood had been achieved by 17-22 years, similar to the patterns seen in modern wealthy countries and in advance of historic populations living in urbanized environments. The bioarchaeological analysis of puberty among Upper Paleolithic adolescents has important implications for the study of the emergence of adolescence within human-life histories, as well as for understanding the developmental plasticity of sexual maturation across past and present human populations.

Programmed Death Ligand 1 (PD-L1) Expression in Lymphomas: State of the Art.

The interaction of programmed death-1 (PD-1) on T lymphocytes with its ligands Programmed Death Ligand 1 (PD-L1) and Programmed Death Ligand 2 (PD-L2) on tumor cells and/or tumor-associated macrophages results in inhibitory signals to the T-cell receptor pathway, consequently causing tumor immune escape. PD-L1/PD-L2 are currently used as predictive tissue biomarkers in clinical practice. Virtually PD-L1 levels expressed by tumor cells are associated with a good response to immune checkpoint blockade therapies targeting the PD-1/PD-L1 axis. These therapies restore T-cell antitumor immune response by releasing T-lymphocytes from the inhibitory effects of tumor cells. Immune checkpoint therapies have completely changed the management of patients with solid cancers. This therapeutic strategy is less used in hematological malignancies, although good results have been achieved in some settings, such as refractory/relapsed classic Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Variable results have been obtained in diffuse large B-cell lymphoma and T-cell lymphomas. Immunohistochemistry represents the main technique for assessing PD-L1 expression on tumor cells. This review aims to describe the current knowledge of PD-L1 expression in various types of lymphomas, focusing on the principal mechanisms underlying PD-L1 overexpression, its prognostic significance and practical issues concerning the evaluation of PD-L1 immunohistochemical results in lymphomas.

Associations of Early Systolic Blood Pressure Control and Outcome After Thrombolysis-Eligible Acute Ischemic Stroke: Results From the ENCHANTED Study.

BACKGROUND AND PURPOSE: In thrombolysis-eligible patients with acute ischemic stroke, there is uncertainty over the most appropriate systolic blood pressure (SBP) lowering profile that provides an optimal balance of potential benefit (functional recovery) and harm (intracranial hemorrhage). We aimed to determine relationships of SBP parameters and outcomes in thrombolyzed acute ischemic stroke patients. METHODS: Post hoc analyzes of the ENCHANTED (Enhanced Control of Hypertension and Thrombolysis Stroke Study), a partial-factorial trial of thrombolysis-eligible and treated acute ischemic stroke patients with high SBP (150-180 mm Hg) assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) alteplase and intensive (target SBP, 130-140 mm Hg) or guideline-recommended (target SBP <180 mm Hg) treatment. All patients were followed up for functional status and serious adverse events to 90 days. Logistic regression models were used to analyze 3 SBP summary measures postrandomization: attained (mean), variability (SD) in 1-24 hours, and magnitude of reduction in 1 hour. The primary outcome was a favorable shift on the modified Rankin Scale. The key safety outcome was any intracranial hemorrhage. RESULTS: Among 4511 included participants (mean age 67 years, 38% female, 65% Asian) lower attained SBP and smaller SBP variability were associated with favorable shift on the modified Rankin Scale (per 10 mm Hg increase: odds ratio, 0.76 [95% CI, 0.71-0.82]; P<0.001 and 0.86 [95% CI, 0.76-0.98]; P=0.025) respectively, but not for magnitude of SBP reduction (0.98, [0.93-1.04]; P=0.564). Odds of intracranial hemorrhage was associated with higher attained SBP and greater SBP variability (1.18 [1.06-1.31]; P=0.002 and 1.34 [1.11-1.62]; P=0.002) but not with magnitude of SBP reduction (1.05 [0.98-1.14]; P=0.184). CONCLUSIONS: Attaining early and consistent low levels in SBP <140 mm Hg, even as low as 110 to 120 mm Hg, over 24 hours is associated with better outcomes in thrombolyzed acute ischemic stroke patients. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01422616.

The genetic history of Ice Age Europe.

Modern humans arrived in Europe ~45,000 years ago, but little is known about their genetic composition before the start of farming ~8,500 years ago. Here we analyse genome-wide data from 51 Eurasians from ~45,000-7,000 years ago. Over this time, the proportion of Neanderthal DNA decreased from 3-6% to around 2%, consistent with natural selection against Neanderthal variants in modern humans. Whereas there is no evidence of the earliest modern humans in Europe contributing to the genetic composition of present-day Europeans, all individuals between ~37,000 and ~14,000 years ago descended from a single founder population which forms part of the ancestry of present-day Europeans. An ~35,000-year-old individual from northwest Europe represents an early branch of this founder population which was then displaced across a broad region, before reappearing in southwest Europe at the height of the last Ice Age ~19,000 years ago. During the major warming period after ~14,000 years ago, a genetic component related to present-day Near Easterners became widespread in Europe. These results document how population turnover and migration have been recurring themes of European prehistory.

Fabry-Stroke Italian Registry (FSIR): a nationwide, prospective, observational study about incidence and characteristics of Fabry-related stroke in young-adults. Presentation of the study protocol.

BACKGROUND: TIA and stroke, both ischemic and hemorrhagic, may complicate Fabry disease at young-adult age and be the first manifestation that comes to the clinician's attention. No definite indications have yet been elaborated to guide neurologists in Fabry disease diagnostics. In current practice, it is usually sought in case of cryptogenic strokes (while Fabry-related strokes can also occur by classical pathogenic mechanisms) or through screening programs in young cerebrovascular populations. Data on recurrence and secondary prevention of Fabry's stroke are scanty. METHODS: The study had a prospective observational design involving 33 Italian neurological Stroke Units. Considering the incidence of TIA/stroke in the European population aged < 60 years and the frequency of Fabry disease in this category (as foreseen by a pilot study held at the Careggi University-Hospital, Florence), we planned to screen for Fabry disease a total of 1740 < 60-year-old individuals hospitalized for TIA, ischemic, or hemorrhagic stroke. We investigated TIA and stroke pathogenesis through internationally validated scales and we gathered information on possible early signs of Fabry disease among all cerebrovascular patients. Every patient was tested for Fabry disease through dried blood spot analysis. Patients who received Fabry disease diagnosis underwent a 12-month follow-up to monitor stroke recurrence and multi-system progression after the cerebrovascular event. DISCUSSION: The potential implications of this study are as follows: (i) to add information about the yield of systematic screening for Fabry disease in a prospective large cohort of acute cerebrovascular patients; (ii) to deepen knowledge of clinical, pathophysiological, and prognostic characteristics of Fabry-related stroke.

Primary effusion lymphoma occurring in the setting of transplanted patients: a systematic review of a rare, life-threatening post-transplantation occurrence.

BACKGROUND: Primary effusion lymphoma is a rare, aggressive large B-cell lymphoma strictly linked to infection by Human Herpes virus 8/Kaposi sarcoma-associated herpes virus. In its classic form, it is characterized by body cavities neoplastic effusions without detectable tumor masses. It often occurs in immunocompromised patients, such as HIV-positive individuals. Primary effusion lymphoma may affect HIV-negative elderly patients from Human Herpes virus 8 endemic regions. So far, rare cases have been reported in transplanted patients. The purpose of our systematic review is to improve our understanding of this type of aggressive lymphoma in the setting of transplantation, focusing on epidemiology, clinical presentation, pathological features, differential diagnosis, treatment and outcome. The role of assessing the viral serological status in donors and recipients is also discussed. METHODS: We performed a systematic review adhering to the PRISMA guidelines. The literature search was conducted on PubMed/MEDLINE, Web of Science, Scopus, EMBASE and Cochrane Library, using the search terms "primary effusion lymphoma" and "post-transplant". RESULTS: Our search identified 13 cases of post-transplant primary effusion lymphoma, predominantly in solid organ transplant recipients (6 kidney, 3 heart, 2 liver and 1 intestine), with only one case after allogenic bone marrow transplantation. Long-term immunosuppression is important in post-transplant primary effusion lymphoma commonly developing several years after transplantation. Kaposi Sarcoma occurred in association with lymphoma in 4 cases of solid organ recipients. The lymphoma showed the classical presentation with body cavity effusions in absence of tumor masses in 10 cases; 2 cases presented as solid masses, lacking effusions and one case as effusions associated with multiple organ involvement. Primary effusion lymphoma occurring in the setting of transplantation was more often Epstein Barr-virus negative. The prognosis was poor. In addition to chemotherapy, reduction of immunosuppressive treatment, was generally attempted. CONCLUSIONS: Primary effusion lymphoma is a rare, but often fatal post-transplant complication. Its rarity and the difficulty in achieving the diagnosis may lead to miss this complication. Clinicians should suspect primary effusion lymphoma in transplanted patients, presenting generally with unexplained body cavity effusions, although rare cases with solid masses are described.

Unique foot posture in Neanderthals reflects their body mass and high mechanical stress.

Neanderthal foot bone proportions and morphology are mostly indistinguishable from those of Homo sapiens, with the exception of several distinct Neanderthal features in the talus. The biomechanical implications of these distinct talar features remain contentious, fueling debate around the adaptive meaning of this distinctiveness. With the aim of clarifying this controversy, we test phylogenetic and behavioral factors as possible contributors, comparing tali of 10 Neanderthals and 81 H. sapiens (Upper Paleolithic and Holocene hunter-gatherers, agriculturalists, and postindustrial group) along with the Clark Howell talus (Omo, Ethiopia). Variation in external talar structures was assessed through geometric morphometric methods, while bone volume fraction and degree of anisotropy were quantified in a subsample (n = 45). Finally, covariation between point clouds of site-specific trabecular variables and surface landmark coordinates was assessed. Our results show that although Neanderthal talar external and internal morphologies were distinct from those of H. sapiens groups, shape did not significantly covary with either bone volume fraction or degree of anisotropy, suggesting limited covariation between external and internal talar structures. Neanderthal external talar morphology reflects ancestral retentions, along with various adaptations to high levels of mobility correlated to their presumably unshod hunter-gatherer lifestyle. This pairs with their high site-specific trabecular bone volume fraction and anisotropy, suggesting intense and consistently oriented locomotor loading, respectively. Relative to H.sapiens, Neanderthals exhibit differences in the talocrural joint that are potentially attributable to cultural and locomotor behavior dissimilarity, a talonavicular joint that mixes ancestral and functional traits, and a derived subtalar joint that suggests a predisposition for a pronated foot during stance phase. Overall, Neanderthal talar variation is attributable to mobility strategy and phylogenesis, while H. sapiens talar variation results from the same factors plus footwear. Our results suggest that greater Neanderthal body mass and/or higher mechanical stress uniquely led to their habitually pronated foot posture.

More data on ancient human mitogenome variability in Italy: new mitochondrial genome sequences from three Upper Palaeolithic burials.

BACKGROUND: Recently, the study of mitochondrial variability in ancient humans has allowed the definition of population dynamics that characterised Europe in the Late Pleistocene and Early Holocene. Despite the abundance of sites and skeletal remains few data are available for Italy. AIM: We reconstructed the mitochondrial genomes of three Upper Palaeolithic individuals for some of the most important Italian archaeological contexts: Paglicci (South-Eastern Italy), San Teodoro (South-Western Italy) and Arene Candide (North-Western Italy) caves. SUBJECTS AND METHODS: We explored the phylogenetic relationships of the three mitogenomes in the context of Western Eurasian ancient and modern variability. RESULTS: Paglicci 12 belongs to sub-haplogroup U8c, described in only two other Gravettian individuals; San Teodoro 2 harbours a U2'3'4'7'8'9 sequence, the only lineage found in Sicily during the Late Pleistocene and Early Holocene; Arene Candide 16 displays an ancestral U5b1 haplotype already detected in other Late Pleistocene hunter-gatherers from Central Europe. CONCLUSION: Regional genetic continuity is highlighted in the Gravettian groups that succeeded in Paglicci. Data from one of the oldest human remains from Sicily reinforce the hypothesis that Epigravettian groups carrying U2'3'4'7'8'9 could be the first inhabitants of the island. The first pre-Neolithic mitogenome from North-Western Italy, sequenced here, shows more affinity with continental Europe than with the Italian peninsula.

Automatic Measurement of the Carotid Blood Flow for Wearable Sensors: A Pilot Study.

The assessment of the velocity of blood flowing in the carotid, in modern clinical practice, represents an important exam performed both in emergency situations and as part of scheduled screenings. It is typically performed by an expert sonographer who operates a complex and costly clinical echograph. Unfortunately, in developing countries, in rural areas, and even in crowded modern cities, the access to this exam can be limited by the lack of suitable personnel and ultrasound equipment. The recent availability of low-cost, handheld devices has contributed to solving part of the problem, but a wide access to the exam is still hampered by the lack of expert sonographers. In this work, an automated procedure is presented with the hope that, in the near future, it can be integrated into a low-cost, handheld instrument that is also suitable for self-measurement, for example, as can be done today with the finger oximeter. The operator should only place the probe on the neck, transversally with respect to the common tract of the carotid. The system, in real-time, automatically locates the vessel lumen, places the sample volume, and performs an angle-corrected velocity measurement of the common carotid artery peak velocity. In this study, the method was implemented for testing on the ULA-OP 256 scanner. Experiments on flow phantoms and volunteers show a performance in sample volume placement similar to that achieved by expert operators, and an accuracy and repeatability of 3.2% and 4.5%, respectively.

Visual Measurement System for Wheel-Rail Lateral Position Evaluation.

Railway infrastructure must meet safety requirements concerning its construction and operation. Track geometry monitoring is one of the most important activities in maintaining the steady technical conditions of rail infrastructure. Commonly, it is performed using complex measurement equipment installed on track-recording coaches. Existing low-cost inertial sensor-based measurement systems provide reliable measurements of track geometry in vertical directions. However, solutions are needed for track geometry parameter measurement in the lateral direction. In this research, the authors developed a visual measurement system for track gauge evaluation. It involves the detection of measurement points and the visual measurement of the distance between them. The accuracy of the visual measurement system was evaluated in the laboratory and showed promising results. The initial field test was performed in the Vilnius railway station yard, driving at low velocity on the straight track section. The results show that the image point selection method developed for selecting the wheel and rail points to measure distance is stable enough for TG measurement. Recommendations for the further improvement of the developed system are presented.

Reduced Admissions for Cerebrovascular Events During COVID-19 Outbreak in Italy.

BACKGROUND AND PURPOSE: We aimed to investigate the rate of hospital admissions for cerebrovascular events and of revascularization treatments for acute ischemic stroke in Italy during the coronavirus disease 2019 (COVID-19) outbreak. METHODS: The Italian Stroke Organization performed a multicenter study involving 93 Italian Stroke Units. We collected information on hospital admissions for cerebrovascular events from March 1 to March 31, 2020 (study period), and from March 1 to March 31, 2019 (control period). RESULTS: Ischemic strokes decreased from 2399 in 2019 to 1810 in 2020, with a corresponding hospitalization rate ratio (RR) of 0.75 ([95% CI, 0.71-0.80] P<0.001); intracerebral hemorrhages decreased from 400 to 322 (hospitalization RR, 0.81 [95% CI, 0.69-0.93]; P=0.004), and transient ischemic attacks decreased from 322 to 196 (hospitalization RR, 0.61 [95% CI, 0.51-0.73]; P<0.001). Hospitalizations decreased in Northern, Central, and Southern Italy. Intravenous thrombolyses decreased from 531 (22.1%) in 2019 to 345 in 2020 (19.1%; RR, 0.86 [95% CI, 0.75-0.99]; P=0.032), while primary endovascular procedures increased in Northern Italy (RR, 1.61 [95% CI, 1.13-2.32]; P=0.008). We found no correlation (P=0.517) between the hospitalization RRs for all strokes or transient ischemic attack and COVID-19 incidence in the different areas. CONCLUSIONS: Hospitalizations for stroke or transient ischemic attacks across Italy were reduced during the worst period of the COVID-19 outbreak. Intravenous thrombolytic treatments also decreased, while endovascular treatments remained unchanged and even increased in the area of maximum expression of the outbreak. Limited hospitalization of the less severe patients and delays in hospital admission, due to overcharge of the emergency system by COVID-19 patients, may explain these data.

Intensive blood pressure reduction with intravenous thrombolysis therapy for acute ischaemic stroke (ENCHANTED): an international, randomised, open-label, blinded-endpoint, phase 3 trial.

BACKGROUND: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. METHODS: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age ≥18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130-140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. FINDINGS: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6-4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87-1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60-0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70-1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. INTERPRETATION: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. FUNDING: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract: a tricky diagnosis of a gastric case.

BACKGROUND: Indolent T-cell lymphoproliferative disorder of the gastrointestinal tract is a rare low-grade clonal lymphoid proliferation, included as a provisional entity in the current World Health Organization classification. The disease is generally localized to the gastrointestinal tract, mainly small bowel and colon. Involvement of other organs is infrequently reported. The majority of patients show a protracted clinical course with persistent disease. A prolonged survival, even without treatment, is common. CASE PRESENTATION: A 28-year-old woman had a 2-year history of dyspepsia and lactose intolerance. Autoimmune diseases and celiac disease were excluded. No gross lesions were identified by endoscopy. Multiple gastric biopsies showed a small-sized lymphoid infiltrate, expanding the lamina propria, with a non-destructive appearance. The lymphoid cells were positive for CD3, CD4, CD5, CD7 and negative for CD20, CD8, CD56, CD103, PD1, CD30, ALK1, CD10, BCL6, perforin, TIA-1, Granzyme B and Epstein-Barr virus-encoded RNA. KI-67 index was low (5%). Molecular analysis revealed a clonal T-cell receptor γ rearrangement. Bone marrow was microscopically free of disease, but molecular testing identified the same T-cell receptor γ rearrangement present in the gastric biopsies. After the diagnosis of indolent T-cell lymphoproliferative disorder of the gastrointestinal tract, the patient received steroid therapy, only for 2 months. She is alive, with a stable disease restricted to the stomach, at 12 months from diagnosis. CONCLUSIONS: Indolent T-cell lymphoproliferative disorder is usually a disease of adulthood (median age: 51 yrs). The small bowel and colon are the sites most commonly involved. Our case occurred in a young woman and affected the stomach, sparing small intestine and colon. Clonality testing identified involvement of bone marrow, a site infrequently affected in this disease. Our aim is focusing on the main diagnostic issues. If appropriate immunostainings and molecular analysis are not performed, the subtle infiltrate may be easily overlooked. The risk of misdiagnosis as more aggressive lymphomas, causing patient overtreatment, needs also to be considered.

Transcranial Doppler sonography for detecting stenosis or occlusion of intracranial arteries in people with acute ischaemic stroke.

BACKGROUND: An occlusion or stenosis of intracranial large arteries can be detected in the acute phase of ischaemic stroke in about 42% of patients. The approved therapies for acute ischaemic stroke are thrombolysis with intravenous recombinant tissue plasminogen activator (rt-PA), and mechanical thrombectomy; both aim to recanalise an occluded intracranial artery. The reference standard for the diagnosis of intracranial stenosis and occlusion is intra-arterial angiography (IA) and, recently, computed tomography angiography (CTA) and magnetic resonance angiography (MRA), or contrast-enhanced MRA. Transcranial Doppler (TCD) and transcranial colour Doppler (TCCD) are useful, rapid, noninvasive tools for the assessment of intracranial large arteries pathology. Due to the current lack of consensus regarding the use of TCD and TCCD in clinical practice, we systematically reviewed the literature for studies assessing the diagnostic accuracy of these techniques compared with intra-arterial IA, CTA, and MRA for the detection of intracranial stenosis and occlusion in people presenting with symptoms of ischaemic stroke. OBJECTIVES: To assess the diagnostic accuracy of TCD and TCCD for detecting stenosis and occlusion of intracranial large arteries in people with acute ischaemic stroke. SEARCH METHODS: We limited our searches from January 1982 onwards as the transcranial Doppler technique was only introduced into clinical practice in the 1980s. We searched MEDLINE (Ovid) (from 1982 to 2018); Embase (Ovid) (from 1982 to 2018); Database of Abstracts of Reviews of Effects (DARE); and Health Technology Assessment Database (HTA) (from 1982 to 2018). Moreover, we perused the reference lists of all retrieved articles and of previously published relevant review articles, handsearched relevant conference proceedings, searched relevant websites, and contacted experts in the field. SELECTION CRITERIA: We included all studies comparing TCD or TCCD (index tests) with IA, CTA, MRA, or contrast-enhanced MRA (reference standards) in people with acute ischaemic stroke, where all participants underwent both the index test and the reference standard within 24 hours of symptom onset. We included prospective cohort studies and randomised studies of test comparisons. We also considered retrospective studies eligible for inclusion where the original population sample was recruited prospectively but the results were analysed retrospectively. DATA COLLECTION AND ANALYSIS: At least two review authors independently screened the titles and abstracts identified by the search strategies, applied the inclusion criteria, extracted data, assessed methodological quality (using QUADAS-2), and investigated heterogeneity. We contacted study authors for missing data. MAIN RESULTS: A comprehensive search of major relevant electronic databases (MEDLINE and Embase) from 1982 to 13 March 2018 yielded 13,534 articles, of which nine were deemed eligible for inclusion. The studies included a total of 493 participants. The mean age of included participants was 64.2 years (range 55.8 to 69.9 years). The proportion of men and women was similar across studies. Six studies recruited participants in Europe, one in south America, one in China, and one in Egypt. Risk of bias was high for participant selection but low for flow, timing, index and reference standard. The summary sensitivity and specificity estimates for TCD and TCCD were 95% (95% CI = 0.83 to 0.99) and 95% (95% CI = 0.90 to 0.98), respectively. Considering a prevalence of stenosis or occlusion of 42% (as reported in the literature), for every 1000 people who receive a TCD or TCCD test, stenosis or occlusion will be missed in 21 people (95% CI = 4 to 71) and 29 (95% CI = 12 to 58) will be wrongly diagnosed as harbouring an intracranial occlusion. However, there was substantial heterogeneity between studies, which was no longer evident when only occlusion of the MCA was considered, or when the analysis was limited to participants investigated within six hours. The performance of either TCD or TCCD in ruling in and ruling out a MCA occlusion was good. Limitations of this review were the small number of identified studies and the lack of data on the use of ultrasound contrast medium. AUTHORS' CONCLUSIONS: This review provides evidence that TCD or TCCD, administered by professionals with adequate experience and skills, can provide useful diagnostic information for detecting stenosis or occlusion of intracranial vessels in people with acute ischaemic stroke, or guide the request for more invasive vascular neuroimaging, especially where CT or MR-based vascular imaging are not immediately available. More studies are needed to confirm or refute the results of this review in a larger sample of stroke patients, to verify the role of contrast medium and to evaluate the clinical advantage of the use of ultrasound.

Aspirin or anticoagulation after cryptogenic stroke with patent foramen ovale: systematic review and meta-analysis of randomized controlled trials.

INTRODUCTION: Since closure has restrictive eligibility criteria, the vast majority of patients with cryptogenic stroke and patent foramen ovale (PFO) receive medical treatment. However, the optimal antithrombotic strategy is still unclear. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to define risk/benefit profile of anticoagulation compared with antiplatelet treatment in PFO-related stroke. METHODS: Systematic review protocol was registered in PROSPERO (CRD42019117559). Following PRISMA guidelines, we searched MEDLINE, EMBASE, and Cochrane CENTRAL database (2000-2019) for RCTs randomly allocating patients with cryptogenic stroke and PFO to medical treatment. Risk of bias was assessed with Cochrane RoB tool. Main outcomes were stroke recurrence and major bleeding. RoPE score-dependent analysis was implemented to define a possible role for patient selection. RESULTS: Five RCTs met inclusion criteria (3 high-, 1 fair-, 1 poor-quality RCTs). Overall, meta-analysis included 1565 patients (mean age 55.5 years), 753 (48.1%) receiving anticoagulation. Compared with antiplatelet treatment, anticoagulation conveyed no net benefit in prevention of recurrent stroke (OR = 0.66, 95% CI 0.41-1.07, pheterogeneity = 0.46), and associated with a non-significant higher risk of major bleeding (OR = 1.64, 95% CI 0.79-3.43, pheterogeneity = 0.57). In patients with high RoPE score, anticoagulation significantly reduced the risk of recurrent stroke (OR = 0.22, 95% CI 0.06-0.8, pheterogeneity = 0.88). CONCLUSION: Our meta-analysis shows that anticoagulation confers no net benefit in recurrent stroke prevention over antiplatelets in patients with PFO-related stroke. RoPE score might help in selecting patients benefiting from anticoagulation, but further trials are needed to delineate risk/benefit profile of anticoagulation.

Clinical RoPE (cRoPE) score predicts patent foramen ovale detection among stroke patients: a multicenter observational study.

BACKGROUD: The role of patent foramen ovale (PFO) in cryptogenic stroke (CS) is debated. Tools to predict PFO occurrence and attributable fraction are needed to guide cost-effective diagnostics and treatment. Risk of Paradoxical Embolism (RoPE) score relies on neuroimaging findings, which might be inconclusive in up to 30% of cases. METHODS: We developed a clinical-based easy tool to predict the presence and attributable fraction of PFO in CS patients, without using neuroimaging. The clinical RoPE (cRoPE) score, ranging 1-10, was elaborated through Delphi method from the original RoPE score, replacing cortical infarction with the Oxfordshire Community Stroke Project (OCSP) classification (lacunar stroke = 0 points, other subtypes = 1 point). Then, from the SISIFO (Studio Italiano di prevalenza nello Stroke Ischemico di pervietà del Forame Ovale, or Prevalence of Patent Foramen Ovale in Ischemic Stroke in Italy) study, a multicenter, prospective study on consecutive acute ischemic stroke patients (n = 1130) classified by Trial of Org 10172 in Acute Stroke Treatment (TOAST) and OCSP criteria and undergoing PFO testing, we selected the VV-CDC cohort (Vibo Valentia, Città di Castello, n = 323) to test the accuracy of cRoPE in predicting PFO detection. We compared cRoPE with RoPE to verify cRoPE reliability. Finally, we tested, through ROC analysis, the performance of cRoPE depending on TOAST classification. RESULTS: Overall, PFO was detected in 21% in VV-CDC and in 23.4% in remaining SISIFO cohort (n = 807). cRoPEAUC and RoPEAUC were similar in VV-CDC. cRoPE performance was comparable with RoPE among CS (cRoPEAUC 0.76, 95%CI 0.67-0.85, RoPEAUC 0.75, 95%CI 0.66-0.84). Moving to the remaining SISIFO cohort, cRoPE confirmed satisfactory accuracy in predicting PFO detection in CS patients (cRoPEAUC 0.71, 95%CI 0.66-0.78, p = 0.032). CONCLUSIONS: Conclusions: cRoPE might help in stratification of patients with CS, allowing accurate esteem of the likelihood of PFO to be found, especially in cases when neuroimaging is inconclusive.

Long-Term Risk of Stroke After Transient Global Amnesia in Two Prospective Cohorts.

Background and Purpose- Transient global amnesia (TGA) is known as a benign syndrome, but recent data from neuroradiological studies support an ischemic cause in some cases, which might suggest an increased susceptibility to cerebrovascular events. We determined the long-term risk of stroke after a first TGA in 2 independent prospective cohorts. Methods- In 2 independent prospective cohorts of patients with TGA (OXVASC [Oxford Vascular Study], population-based; NU (Northern Umbria) cohort, TGA registry), cardiovascular risk factors and long-term outcomes, including stroke and major cardiovascular events, were identified on follow-up. Cardiovascular risk factors were treated according to primary prevention guidelines. In OXVASC, the age-/sex-adjusted risk of stroke during follow-up was compared with that expected from the rate in the underlying study population. Results- Among 525 patients with TGA (425 NU and 100 OXVASC), mean (SD) age was 65.1 (9.5) years and 42.5% male. Hypertension (58.1%), dyslipidemia (40.4%), and smoking (36.4%) were the most frequent cardiovascular risk factors. The risk of stroke was similar in the 2 cohorts, with a pooled annual risk of 0.6% (95% CI, 0.4-0.9) and a 5-year cumulative risk of 2.7% (1.1-4.3). Moreover, the stroke risk in OXVASC cases was no greater than that expected in the underlying study population (adjusted relative risk=0.73; 0.12-4.54; P=0.74). Conclusions- TGA does not carry an increased risk of stroke, at least when cardiovascular risk factors are treated according to primary prevention guidelines.

Low-Dose versus Standard-Dose Intravenous Alteplase in Acute Ischemic Stroke.

BACKGROUND: Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS: Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS: The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS: This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).