Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4·5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial.

BACKGROUND: The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy). METHODS: DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0-2 or return to baseline at 90 days, with a non-inferiority margin of -0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants. FINDINGS: Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference -0·051, two-sided 95% CI -0·160 to 0·059; per-protocol risk difference -0·062, two-sided 95% CI -0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22-13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46-1·84). INTERPRETATION: We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment. FUNDING: Australian National Health and Medical Research Council and Stryker USA.

Urgent computed tomography angiography in paediatric stroke.

AIM: To improve delivery of acute therapies for acute ischaemic stroke (AIS). METHOD: We identified factors influencing the speed of diagnosis and delivery of acute therapies in a prospective cohort of 21 children with suspected AIS (eight with AIS, 13 stroke mimics) and explored them in a retrospective cohort with confirmed AIS. RESULTS: Approximately half of the prospective and total AIS cohorts presented with acute, sustained hemiparesis, and were diagnosed relatively quickly. AIS was suspected and diagnosed more slowly in the half presenting with symptoms other than sustained hemiparesis. Thirty-one out of 51 patients with AIS (19 females, 32 males, mean age 8 years 6 months, SD 5 years 4 months) had arterial abnormalities identified by computed tomography angiography (CTA) or magnetic resonance angiography (MRA): 11 with large vessel occlusion, six with dissection, five with moyamoya disease, nine with other arteriopathies. Among these patients, those initially imaged with CTA were diagnosed more quickly than those with initial magnetic resonance imaging/angiography, which facilitated thrombectomy and thrombolytic therapy. Twenty out of 51 had AIS without arterial abnormalities on CTA or MRA: eight with lenticulostriate vasculopathy and 12 with other small-vessel AIS. Among these patients, 80% were ineligible for thrombolysis for reasons beyond delay to diagnosis, and all showed good outcomes with supportive treatments alone. INTERPRETATION: Clinical features at presentation influence rapidity with which childhood AIS is suspected and diagnosed. Readily available CTA can direct thrombectomy in patients with large vessel occlusion and thrombolysis in most, but not all, eligible patients. WHAT THIS PAPER ADDS: Children with acute ischaemic stroke (AIS) commonly present with symptoms other than sustained hemiparesis. Stroke is more slowly recognized in these patients, which limits potential therapies. Computed tomography angiography (CTA) accurately identifies AIS with large vessel occlusion, enabling timely endovascular thrombectomy. CTA is sufficient to direct thrombolytic therapy in most eligible children. Most childhood AIS without arterial abnormalities identified by CTA had good outcomes.

Identification of several clades of novel single-stranded circular DNA viruses with conserved stem-loop structures in pig feces.

Metagenomic analysis of fecal samples collected from diarrheal swine detected sequences encoding a replication initiator protein (Rep). The genomes of ten novel single-stranded DNA viruses were determined, and they exhibited a similar genome organization. The two putative open reading frames (ORFs) encoding Rep and the capsid protein are bidirectionally transcribed and separated by two intergenic regions. Stem-loop structure(s) typical of genomes that undergo the rolling-circle DNA replication mechanism were observed. Phylogenetically, these ten genomes are in a monophyletic clade with the previously described porcine stool-associated virus (PoSCV) but are divergent enough to be further classified into to six distinct virus clades.

A divergent clade of circular single-stranded DNA viruses from pig feces.

Using metagenomics and molecular cloning methods, we characterized five novel small, circular viral genomes from pig feces that are distantly related to chimpanzee and porcine stool-associated circular viruses, (ChiSCV and PoSCV1). Phylogenetic analysis placed these viruses into a highly divergent clade of this rapidly growing new viral family. This new clade of viruses, provisionally named porcine stool-associated circular virus 2 and 3 (PoSCV2 and PoSCV3), encodes a stem-loop structure (presumably the origin of DNA replication) in the small intergenic region and a replication initiator protein commonly found in other biological systems that replicate their genomes via the rolling-circle mechanism. Furthermore, these viruses also exhibit three additional overlapping open reading frames in the large intergenic region between the capsid and replication initiator protein genes.

Balloon assisted Woven endobridge deployment (BAWD): A safety and efficacy study.

BACKGROUND: Balloon-assisted deployment/remodelling is a proven adjunctive technique for coil embolization of intracranial aneurysms, and it may be a helpful adjunct in delivering the Woven EndoBridge (WEB) device. OBJECTIVE: To evaluate the safety, efficacy and feasibility of balloon-assisted WEB deployment in both ruptured and unruptured intracranial aneurysms in both typical and atypical locations. METHODS: Patients who underwent treatment of ruptured and unruptured intracranial aneurysms with the BAWD technique were retrospectively identified from a prospectively maintained database at two neurointerventional centres. Patient demographics, aneurysm characteristics, technical procedure details, clinical and imaging outcomes were reviewed. RESULTS: Thirty-three aneurysms (23 women) were identified with a median age of 58 years. There were 15 (45.5%) ruptured aneurysms, 25 (64.3%) in the anterior circulation and 12 (36.4%) aneurysms having an atypical location for WEB treatment. The average aneurysm size was 6.8 mm (greatest dimension), 4.6 mm (height) and 4.5 mm (width), and 25 (75.8%) aneurysms had a wide neck morphology. One patient died (3.0%) secondary to a procedure-related complication, and there was no procedure-related permanent morbidity. Complete and adequate aneurysm occlusion on mid-term follow-up DSA was 85.2% and 92%, respectively. CONCLUSION: Balloon-assisted WEB deployment appears to be a safe and effective technique that may increase the utility of the WEB device. Further prospective studies on BAWD should be considered.

A Corpus-Based Investigation of Extra-Textual, Connective, and Emphasizing Additions in English-Chinese Conference Interpreting.

Findings from conference interpreting research in the Chinese context have suggested that interpreters barely produce extra-textual additions in rigidly structured press conferences, and that adding connectives and intensifiers is only required to help the English-speaking audience capture the logic embedded in implicit Chinese interclausal relations. Previous research in the Chinese context has tended to draw data almost exclusively from the Chinese Premier's Press Conference interpreting, which features interpreting from Chinese into English. In order to enrich conference interpreting corpora in Asia and to examine additions in the opposite interpreting direction for the same language pair, this study drew on authentic materials of six interpreted press conferences held at the American Institute in Taiwan (AIT). Contrary to previous research, our results showed that conference interpreters exhibited a certain degree of "visibility" through producing extra-textual additions, which is typical of interpreting in various community-based settings. Moreover, the addition of extra connectives and intensifiers that are common in Chinese-to-English interpreting was also identified. It is proposed that the interpreters' production of extra-textual additions is connected with the specific context of the AIT, whereas the connective and emphasizing additions are to a large extent caused by the grammaticalization process wherein particular linguistic devices change into discourse markers to fulfill the communicative needs in both English and Chinese.

A corpus-based study of modal verbs in Chinese-English governmental press conference interpreting.

This study investigates the use of modal verbs in Chinese-English government press conference (GPC) interpretation. Modal verbs mark the speaker's opinion of or attitude toward the event described in a sentence. Interpreters also use modal verbs to indicate the stances of the source language speakers. The use of modal verbs has been examined in such contexts as research papers, textbooks, and second language learners' output; however, studies that compare differences in modal verbs between source and target languages in the context of interpreting are sparse. The investigation being reported is based on a comparable corpus-an original Chinese GPC and its English-translated version-and a parallel corpus-a translated English GPC and the original English version from the US. The results of the comparable corpus analysis indicate that the frequency of modal verbs in translated English is significantly higher than in original Chinese, in which only 40% of the modal verbs in translated English are consistent with their Chinese counterparts, while others are employed through amplification and value variation. The results of the parallel corpus analysis suggest that the increase of modal verbs in the target texts may help to achieve certain types of pragmatic functions in English.

The RNA profile of porcine parvovirus 4, a boca-like virus, is unique among the parvoviruses.

PPV4 transcribes its genome from a single promoter, and the RNAs are generated via alternate splicing coupled with alternate polyadenylation, a strategy similar to that of the bocaviruses; however, several differences were detected. The PPV4 ORF1 codes for four NS proteins, while the bocavirus ORF1 codes for 1-3 NS proteins. Whereas the VP1/VP2 capsid proteins of bocavirus are encoded by a single RNA, VP1 and VP2 of PPV4 are encoded by two separate RNAs. While ORF3 of PPV4 encodes two NP proteins, ORF3 of bocavirus codes for only one NP polypeptide. Taken together, PPV4 is unique among the parvoviruses.

Detection of a novel porcine parvovirus, PPV4, in Chinese swine herds.

To determine whether the novel porcine parvovirus type 4 (PPV4) recently reported in America is prevalent in China, a set of specific primers was designed and used for molecular survey of PPV4 among the clinical samples collected from various provinces of China between 2006 and 2010. The results showed that PPV4 is present in Chinese swine herds at a rate of 2.09% (12/573) among the clinical samples examined and 0.76% (1/132) among the samples taken from healthy animals. We also noted that PPV4 was not detected in samples taken prior to 2009. Analysis of the coding sequences showed that the Chinese and American PPV4 genome sequences are closely related with greater than 99% nucleotide sequence identity. Similar to a previous study, viral genomes in head-to-tail configuration of various lengths of the non-coding region were detected. Our findings confirmed that PPV4 is a unique recently discovered virus in pigs. Phylogenetically, PPV4 is most closely related to bovine parvovirus 2 (BPV2, which is not a Bocavirus and is not assigned to any Parvovirinae genus) and shares limited ORF1 (33.6%) and ORF2 (24.5%) amino acid identity. With respect to genome structure and organization, PPV4 encodes an ORF3 in the middle of the viral genome that resembles the Bocavirus genus. However, the PPV4 ORF3 encoded protein shares minimal amino acid identity with the ORF3 encoded proteins of the Bocavirus genus.

Identification and molecular cloning of a novel porcine parvovirus.

A novel porcine parvovirus, PPV4, was identified in the lung lavage of a diseased pig coinfected with porcine circovirus type 2. This virus exhibits limited similarity to its closest relative, bovine parvovirus 2, but resembles viruses of the genus Bocavirus (bovine parvovirus, canine minute virus and human bocavirus) that encode an additional ORF3. The ORF3 of PPV4 is predicted to encode a protein of 204 amino acid residues, which is similar in size to the ORF3-encoded proteins of the bocaviruses. Whereas the ORF3-encoded proteins of bocaviruses share significant similarity with each other, the PPV4 ORF3 encoded protein does not exhibit homology with any protein in the GenBank non-redundant database.

Homologous recombination within the capsid gene of porcine circovirus type 2 subgroup viruses via natural co-infection.

Several studies had reported homologous recombination between two porcine circovirus (PCV) type 2 subgroup viruses, PCV2a and PCV2b. The recombination events described thus far mapped either within the Rep gene sequences or the sequences flanking the Rep gene region. Previously, the presence of both PCV2a and PCV2b DNA sequences in tissues of the same infected swine from the 2005 United States PCV-associated disease outbreak was reported, which indicates that the animal was co-infected with both PCV2 subgroup viruses. Here, two naturally occurring chimeric genomes were identified that exhibited homologous recombination within the capsid gene sequences, and infectious viruses were recovered from both chimeric genomes after transfection into tissue culture cells.

Thrombectomy in stroke of unknown onset, wake up stroke and late presentations: Australian experience from 2 comprehensive stroke centres.

Two recent randomized controlled trials (RCTs) showed selected patients treated with endovascular thrombectomy (EVT) more than 6 h from acute ischemic stroke (AIS) onset had significant improvement in functional outcome at 90 days compared with standard care alone. Our aim is to determine the outcome and predictors of good outcome in AIS patients undergoing EVT with unknown-onset, or late presentation, stroke after 6 h from time last seen well, or witnessed stroke onset, at two Australian comprehensive stroke centres. A retrospective analysis of functional outcome and mortality at 90-days from a prospective cohort of 56 consecutive patients with unknown-onset, or late presentation, stroke with large vessel occlusion (LVO) in the anterior cerebral circulation undergoing EVT over a 15-month period (2016-2017). We evaluated factors which correlated with good functional outcome defined as a 90-day modified Rankin scale (mRS) 0-2. Recanalization times and symptomatic intracranial haemorrhage (sICH) rates were also examined. A good functional outcome was achieved in 35 patients (62%). Eight patients died (14%). Median time-to-recanalization was 7.6 h. SICH occurred in four patients (7%). Factors which predicted good 90-day functional outcome included baseline National Institutes of Health Stroke Scale (NIHSS) < 16, 24 h NIHSS < 10, baseline Alberta Stroke Program Early CT Score (ASPECTS) ≥ 8, pre-procedural CT perfusion imaging and LVO lesion location. This study shows good 'real world' outcomes, comparable to published RCTs, in patients with unknown-onset, or late presentation, stroke treated with EVT more than 6 h from stroke onset.

Long-term follow-up of aneurysms treated electively with woven stent-assisted coiling.

BACKGROUND: Preliminary short-term results for stent-assisted coil embolization (SACE) using woven/braided stents have been promising. However, evidence supporting mid- to long-term efficacy and durability is lacking. OBJECTIVE: To report the long-term results for the durability of elective intracranial aneurysms treated with woven stents. MATERIALS AND METHODS: Between May 2012 and May 2015, 98 consecutive patients with 103 aneurysms underwent elective woven SACE across three Australian neurovascular centres. All patients had immediate, 6- and 18-month clinical and radiological follow-up. Radiological assessment was performed with modified Raymond-Roy occlusion scores based on angiography results, while clinical assessment was based on the modified Rankin Scale. RESULTS: Six-month follow-up was available in 100 aneurysms, and an 18-month follow-up in 97 aneurysms. Total occlusion rates of 82% were achieved at inception, 82% at 6 months, and 90% at 18 months. Satisfactory occlusion with small neck remnants was present in 17% at inception, 16% at 6 months, and 9% at 18 months. Good neurological outcomes were achieved in 95% at 18 months. Intraprocedural thromboembolic events were recorded in 3% and delayed events in 1% (all in patients taking clopidogrel). Aneurysm recurrence occurred in one patient (1%). Technical complications occurred in 5%. The total complication rate was 10%. CONCLUSIONS: Woven SACE is safe, efficacious, and durable at long-term 18-month follow-up, with very low recurrence and re-treatment rates. Preliminary results appear better than those for traditional laser-cut stents.

Specific functions of the Rep and Rep׳ proteins of porcine circovirus during copy-release and rolling-circle DNA replication.

The roles of two porcine circovirus replication initiator proteins, Rep and Rep׳, in generating copy-release and rolling-circle DNA replication intermediates were determined. Rep uses the supercoiled closed-circular genome (ccc) to initiate leading-strand synthesis (identical to copy-release replication) and generates the single-stranded circular (ssc) genome from the displaced DNA strand. In the process, a minus-genome primer (MGP) necessary for complementary-strand synthesis, from ssc to ccc, is synthesized. Rep׳ cleaves the growing nascent-strand to regenerate the parent ccc molecule. In the process, a Rep׳-DNA hybrid containing the right palindromic sequence (at the origin of DNA replication) is generated. Analysis of the virus particle showed that it is composed of four components: ssc, MGP, capsid protein and a novel Rep-related protein (designated Protein-3).

Unique circovirus-like genome detected in pig feces.

Using a metagenomic approach and molecular cloning methods, we identified, cloned, and sequenced the complete genome of a novel circular DNA virus, porcine stool-associated virus (PoSCV4), from pig feces. Phylogenetic analysis of the deduced replication initiator protein showed that PoSCV4 is most related to a fur seal feces-associated circular DNA virus.

Identification of a novel single-stranded circular DNA virus in pig feces.

Porcine stool-associated circular virus 5 (PoSCV5) was detected in the feces of a pig with diarrhea. The complete 3,062-nucleotide genome contains two bidirectionally transcribed open reading frames (ORFs). Phylogenetic analysis of the deduced replication initiator protein (Rep) places PoSCV5 alone on a deep branch among the small circular Rep-encoding single-stranded DNA viruses.

Divergent picornavirus from a Turkey with gastrointestinal disease.

A novel picornavirus, turkey avisivirus (TuASV), was identified from the feces of turkeys (Meleagris gallopavo) with gastrointestinal disease from a farm in Indiana. Its genome organization is as follows: 5' untranslated region (UTR)(IRES-II) [VP0, VP3, VP1, 2A, 2B, 2C, 3A, 3B, 3C(pro), 3D(pol)] 3' UTR-poly(A). TuASV shares only 34% (P1), 36% (P2), and 35% (P3) amino acid identities with avihepatoviruses, indicating that it potentially represents a novel picornavirus genus.

Porcine circovirus: transcription and DNA replication.

This review summarizes the molecular studies pertaining to porcine circovirus (PCV) transcription and DNA replication. The genome of PCV is circular, single-stranded DNA and contains 1759-1768 nucleotides. Both the genome-strand (packaged in the virus particle) and the complementary-strand (synthesized in the new host) encode viral proteins. Among a multitude of RNAs synthesized by alternate splicing, only rep and rep' are essential for virus DNA replication via the rolling-circle replication (RCR) mechanism. In contrast to other RCR biological systems which utilize only one multi-functional protein, Rep, to replicate their respective genomes, PCV requires two proteins, Rep and Rep'. During DNA synthesis, the PCV origin of DNA replication (Ori), which contains a pair of inverted repeats (palindrome), exists in a destabilized four-stranded configuration (the melting-pot model) and permits both the palindromic-strand and the complementary-strand to serve as templates simultaneously for initiation and termination. Inherent in the "melting-pot" model is the template-strand-switching mechanism. This mechanism is the basis for the "correction or conversion" of any mutated nucleotide sequences engineered into either arm of the palindrome and the incorporation of "illegitimate recombination" (addition or deletion of nucleotides) events that are commonly observed at the Ori of other RCR biological systems during DNA replication.