Cell-type-specific alternative splicing in the Arabidopsis germline.

During sexual reproduction in flowering plants, the two haploid sperm cells (SCs) embedded within the cytoplasm of a growing pollen tube are carried to the embryo sac for double fertilization. Pollen development in flowering plants is a dynamic process that encompasses changes at transcriptome and epigenome levels. While the transcriptome of pollen and SCs in Arabidopsis (Arabidopsis thaliana) is well documented, previous analyses have mostly been based on gene-level expression. In-depth transcriptome analysis, particularly the extent of alternative splicing (AS) at the resolution of SC and vegetative nucleus (VN), is still lacking. Therefore, we performed RNA-seq analysis to generate a spliceome map of Arabidopsis SCs and VN isolated from mature pollen grains. Based on our de novo transcriptome assembly, we identified 58,039 transcripts, including 9,681 novel transcripts, of which 2,091 were expressed in SCs and 3,600 in VN. Four hundred and sixty-eight genes were regulated both at gene and splicing levels, with many having functions in mRNA splicing, chromatin modification, and protein localization. Moreover, a comparison with egg cell RNA-seq data uncovered sex-specific regulation of transcription and splicing factors. Our study provides insights into a gamete-specific AS landscape at unprecedented resolution.

Translational profile of developing phellem cells in Arabidopsis thaliana roots.

The phellem is a specialized boundary tissue providing the first line of defense against abiotic and biotic stresses in organs undergoing secondary growth. Phellem cells undergo several differentiation steps, which include cell wall suberization, cell expansion, and programmed cell death. Yet, the molecular players acting particularly in phellem cell differentiation remain poorly described, particularly in the widely used model plant Arabidopsis thaliana. Using specific marker lines we followed the onset and progression of phellem differentiation in A. thaliana roots and further targeted the translatome of newly developed phellem cells using translating ribosome affinity purification followed by mRNA sequencing (TRAP-SEQ). We showed that phellem suberization is initiated early after phellogen (cork cambium) division. The specific translational landscape was organized in three main domains related to energy production, synthesis and transport of cell wall components, and response to stimulus. Novel players in phellem differentiation related to suberin monomer transport and assembly as well as novel transcription regulators were identified. This strategy provided an unprecedented resolution of the translatome of developing phellem cells, giving a detailed and specific view on the molecular mechanisms acting on cell differentiation in periderm tissues of the model plant Arabidopsis.

Health-related quality of life in seven European countries throughout the course of the COVID-19 pandemic: evidence from the European COvid Survey (ECOS).

PURPOSE: To investigate health-related quality of life (HRQoL) over the course of the COVID-19 pandemic in seven European countries and its association with selected sociodemographic as well as COVID-19-related variables. METHODS: We used longitudinal data from nine quarterly waves collected between April 2020 and January 2022 (sample size per wave ranging from N = 7025 to 7300) of the European COvid Survey (ECOS), a representative survey of adults in Germany, United Kingdom, Denmark, Netherlands, France, Portugal and Italy. HRQoL was measured using the EQ-5D-5L. The association of self-reported COVID-19 infection, perceived health risk from COVID-19, selected sociodemographic variables and the COVID-19 stringency index with HRQoL was analyzed by logistic and linear fixed effects regressions. RESULTS: On average across all nine waves, the proportion of respondents reporting any problems in at least one of the EQ-5D dimensions ranged between 63.8% (Netherlands) and 71.0% (Denmark). Anxiety/depression was the most frequently affected EQ-5D dimension in four countries (Portugal: 52.0%; United Kingdom: 50.2%; Italy: 49.2%; France: 49.0%), whereas pain/discomfort ranked first in three countries (Denmark: 58.3%; Germany: 55.8%; Netherlands: 49.0%). On average across all nine waves, the EQ-VAS score ranged from 70.1 in the United Kingdom to 78.4 in Portugal. Moreover, the EQ-5D-5L index ranged from .82 in Denmark to .94 in France. The occurrence of COVID-19 infection, changes in the perceived risk to one's own health from COVID-19, the occurrence of income difficulties and an increase in the COVID-19 stringency index were associated with increased likelihood of problems in EQ-5D dimensions, reduced EQ-VAS score and reduced EQ-5D-5L index. CONCLUSIONS: Across seven European countries, we found large proportions of respondents reporting problems in HRQoL dimensions throughout the pandemic, especially for anxiety/depression. Various sociodemographic and COVID-19-related variables were associated with HRQoL in longitudinal analysis.

Shorter Reperfusion Time in Stroke is Associated with Better Cognition.

BACKGROUND: Cognitive changes that result from cerebrovascular disease contribute to a poor functional outcome with reduced quality of life. Among patients undergoing endovascular therapy (EVT), we aim to assess cognitive function and evaluate the impact of reperfusion time in cognitive performance. METHODS: Patients with acute right anterior circulation strokes that underwent EVT between January 2018 and August 2020 at Centro Hospitalar de Vila Nova de Gaia/Espinho, participated in the study. Modified treatment in cerebral infarction (mTICI) assessed the level of recanalization. Cognitive evaluation was assessed with Addenbrooke's Cognitive Examination revised (ACE-R). Multiple linear regression analyses were used to determine the association between time for recanalization and ACE-R. The level of significance adopted was 0.05. RESULTS: The mean age of participants was 71.5 (interquartile range [IQR] 62.0-78.2) years, and 50% (22) were women. The median time after stroke was 28.6 months (IQR 18.94-31.55). All patients in our sample had a successful level of recanalization with EVT (mTICI ≥ 2b). Time for recanalization showed an inverse association with the ACE-R (b = -0.0207, P = 0.0203). Also the mRS at 3 months had an inverse association with cognition (b = -5.2803, p = 0.0095). Level of education had a strong and direct relationship with ACE-R results (b = 3.0869, p < 0.0001). CONCLUSIONS: Longer time between stroke symptoms and recanalization with EVT in patients with right hemisphere ischemic stroke lead to lower ACE-R scores. Measures to improve door-to-recanalization time are also important for cognitive performance after ischemic stroke.

Factors associated with non-pharmaceutical interventions compliance during COVID-19 pandemic: a Portuguese cross-sectional survey.

BACKGROUND: The use of non-pharmaceutical interventions (NPI) is one of the main tools used in the coronavirus disease 2019 (COVID-19) pandemic response, including physical distancing, frequent hand washing, face mask use, respiratory hygiene and use of contact tracing apps. Literature on compliance with NPI during the COVID-19 pandemic is limited. METHODS: We studied this compliance and associated factors in Portugal, between 28th October 2020 and 11th January 2021 (Portuguese second and third waves of the pandemic), using logistic regressions. Data were collected through a web-based survey and included questions regarding NPI compliance, COVID-19-related concerns, perception of institutions' performance, agreement with the measures implemented and socio-demographic characteristics. RESULTS: From the 1263 eligible responses, we found high levels of compliance among all COVID-19 related NPI, except for the contact tracing app. Females and older participants showed the highest compliance levels, whereas the opposite was observed for previously infected participants. There was heterogeneity of COVID-19 NPI compliance across Portuguese regions and a clear gradient between concern, government performance's perception or agreement and compliance. CONCLUSIONS: Results suggested areas for further study with important implications for pandemic management and communication, for future preparedness, highlighting other factors to be accounted for when recommending policy measures during public health threats.

Robustness of Wave-Particle Duality under Unruh Effect.

By considering a uniformly accelerated two-level system in an initial superposition state of a qubit, we investigate the loss of coherence induced by the acceleration. In addition, we investigate the impact of acceleration on the complementarity relation in a quantum interferometric circuit or quantum scattering circuit. We present an alternative approach to exploring acceleration effects through examination of quantum coherence decay and degradation in the interference pattern. Our investigations help to provide understanding of the consequences of decoherence induced by the Unruh effect on the wave-particle duality of a uniformly accelerated qubit.

Parental age and the risk of bipolar disorder in the offspring: A systematic review and meta-analysis.

OBJECTIVES: Whether parental age, i.e., paternal or maternal, at childbirth is associated with the risk of bipolar disorder (BD) in offspring remains unclear. We conducted a meta-analysis of observational studies to address this gap. METHODS: PubMed, PsycINFO, Embase, and Web of Science were searched up to June 2021. Studies investigating the associations between parental age at childbirth (exposure) and the risk of BD in offspring (outcome) were eligible for inclusion in our study. Paternal and maternal age were examined separately. Odds ratio (OR) was used as the effect size index. Data were pooled through random-effects meta-analyses. RESULTS: Seven studies involving 3,183,539 participants and 23,253 individuals with BD were included in our meta-analyses. Meta-analyses indicated an increased risk of BD in the offspring of the older paternal age groups (35-44 years old [k = 5; OR = 1.09; 95% CI 1.05, 1.14; p < 0.0001] and ≥45 years old [k = 5; OR = 1.44; 95% CI 1.19, 1.14; p = 0.0001]) in comparison with the reference category (25-34 years old). Meta-analysis also indicated an increased risk of BD in the offspring of the older maternal age group (≥40 years old [k = 3; OR = 1.20; 95% CI 1.10, 1.31; p < 0.0001]) in comparison with the reference category (20-29 years old). CONCLUSIONS: Advanced paternal and maternal age were both associated with an increased risk of BD in offspring. Further studies are needed to investigate the mechanisms behind this association.

Blood donation in times of crisis: Early insight into the impact of COVID-19 on blood donors and their motivation to donate across European countries.

BACKGROUND: In this survey, we aimed to provide early insight into the impact of COVID-19 on blood donors and their motivation to donate during the crisis. STUDY DESIGN AND METHODS: We asked representative samples in 7 European countries (Denmark, France, Germany, Italy, Portugal, the Netherlands and the UK) about their blood donation activity and motivation to donate using an online survey. We analysed donor turnout during the COVID-19 period descriptively and using logistic regression. RESULTS: Of the 7122 people that responded to the survey, 1205 (16·9%) blood donors were identified, with 33·8% donating during the first 4-5 months of the COVID-19 period. We observed that around half of donors donated less than normal. The vast majority of donors that did donate made a special effort to do so in response to COVID-19. The majority of donors were also not aware of their blood being tested for COVID-19 antibodies. Although the perceived risk of infection among all respondents whilst donating blood was relatively low, those who anticipated a high risk of infection were much less likely to donate (OR = 0·540; P-value = 0·006). Furthermore, those that were adherent to COVID guidelines were also less likely to donate (OR = 0·583; P-value = 0·000). DISCUSSION: We suggest that blood collection services consider specialist campaigns that focus on the altruistic motivation of donors during the crisis and that they continue to communicate the additional safety measures in place with the aim of reducing the fear of infection whilst donating blood.

Adult polyglucosan body disease-an atypical compound heterozygous with a novel GBE1 mutation.

INTRODUCTION: Adult polyglucosan body disease (APBD) is an autosomal recessive leukodystrophy characterized by neurogenic bladder starting after 40 years old, spastic paraparesis and peripheral neuropathy. It is mainly resultant from the GBE1 homozygous p.Tyr329Ser (c.986A>C) mutation, especially in Ashkenazi-Jewish patients, although some cases of compound heterozygous have been reported. A genotype-phenotype correlation is not established, but atypical phenotypes have been described mainly in non-p.Tyr329Ser pathogenic variants. CASE REPORT: We describe an atypical case in a 62-year-old Portuguese woman, presenting the typical clinical triad of APBD plus prominent autonomic dysfunction, suggested by orthostatic hypotension and thermoregulatory dysfunction; she has compound heterozygous GBE1 mutations, namely, p.Asn541Asp (c.1621A>G) and p.Arg515Gly (c.1543C>G), the last one not yet reported in literature and whose pathogenicity was suggested by bioinformatics analysis and confirmed by sural nerve biopsy that showed intra-axonal polyglucosan bodies. DISCUSSION: Besides the report of a novel GBE1 mutation, this case also expands the phenotypic spectrum of this disorder, reinforcing autonomic dysfunction as a possible and prominent manifestation of APBD, mimicking autosomal dominant leukodystrophy with autonomic disease in some way. Therefore, we questioned a possible relationship between this genotype and the phenotype marked by dysautonomia. Additionally, we review previously reported cases of APBD in non-homozygous p.Tyr329Ser patients with atypical phenotypes.

Risk factors for obsessive-compulsive symptoms. Follow-up of a community-based youth cohort.

Environmental factors are at least as important as genetic factors for the development of obsessive-compulsive symptoms (OCS), but the identification of such factors remain a research priority. Our study aimed to investigate the association between a broad scope of potential risk factors and OCS in a large community cohort of children and adolescents. We evaluated 1877 participants and their caregivers at baseline and after 3 years to assess various demographic, prenatal, perinatal, childhood adversity, and psychopathological factors. Mean age at baseline was 10.2 years (SD 1.9) and mean age at follow-up was 13.4 years (SD 1.9). Reports of OCS at baseline and follow-up were analyzed using latent variable models. At preliminary regression analysis, 15 parameters were significantly associated with higher OCS scores at follow-up. At subsequent regression analysis, we found that eight of these parameters remained significantly associated with higher follow-up OCS scores while being controlled by each other and by baseline OCS scores. The significant predictors of follow-up OCS were: lower socioeconomic status (p = 0.033); lower intelligence quotient (p = 0.013); lower age (p < 0.001); higher maternal stress level during pregnancy (p = 0.028); absence of breastfeeding (p = 0.017); parental baseline OCS (p = 0.038); youth baseline anxiety disorder (p = 0.023); and youth baseline OCS scores (p < 0.001). These findings may better inform clinicians and policymakers engaged in the mental health assessment and prevention in children and adolescents.

Long-term somatic memory of salinity unveiled from physiological, biochemical and epigenetic responses in two contrasting rice genotypes.

Plants are constantly exposed to environmental fluctuations, that may occur in a single day or over longer periods. In many cases, abiotic stresses are transient and recurrent, impacting how plants respond in subsequent adverse conditions. Adaptation mechanisms may occur at the physiological, biochemical and molecular level, modifying transcriptional response, regulatory proteins, epigenetic marks or metabolites. Here, we aimed to uncover the different strategies that rice uses to respond to recurrent stress. We tested varieties with contrasting behavior towards salinity (tolerance or sensitivity) and imposed salt stress (150 mM NaCl) during 48 h at vegetative and/or reproductive stages. After 48 h of stress in reproductive stage, leaves and roots were harvested separately or otherwise the plants were submitted to a 24 h recovery, prior to sample harvesting. Plants submitted to a recurrent stress responded differently from those suffering a single stress event. In the case of the sensitive genotype, recurrent stress led to lower Na/K ratio in roots and lower hydrogen peroxide accumulation and lipid peroxidation in leaves, but maintenance of global DNA methylation levels. In the tolerant genotype, recurrent stress did neither affect the Na/K ratio nor the stomatal conductance, although the levels of superoxide anion and hydrogen peroxide accumulation were lower, as also observed for global levels of DNA methylation. Our work shows that a short pre-exposure to salt stress may improve rice tolerance to subsequent stress, trough biochemical, physiological and epigenetic processes, with more significant changes visible in the tolerant genotype.

Entry and price competition in the over-the-counter drug market after deregulation: Evidence from Portugal.

In the last two decades, many European countries allowed the sale of over-the-counter (OTC) drugs outside pharmacies. This was expected to lower retail prices through increased competition. Evidence of such price reductions is scarce. We assess the impact of supermarket and outlet entry in the OTC drug market on OTC prices charged by incumbent pharmacies using a difference-in-differences strategy. We use price data on five popular OTC drugs for all retailers located in Lisbon for three distinct points in time (2006, 2010, and 2015). Our results suggest that competitive pressure in the market is mainly exerted by supermarkets, which charge, on average, 20% lower prices than pharmacies. The entry of a supermarket among the main competitors of an incumbent pharmacy is associated with an average 4% to 6% decrease in prices relative to the control group. These price reductions are long-lasting but fairly localized. We find no evidence of price reductions following OTC outlet entry. Additional results from a reduced-form entry model and a propensity score matching difference-in-differences approach support the view that these effects are causal.

Double stenting in T configuration with safety micro-guidewire technique in a complex middle cerebral artery stenosis.

Intracranial arterial stenosis is a frequently misdiagnosed cause of ischemic stroke, associated with high rates of recurrence under medical therapy alone. Endovascular intracranial angioplasty and stenting has increasingly been used worldwide for treatment of symptomatic intracranial stenoses, despite controversial results of the first randomized trials. Lesion morphology and etiology must be considered during endovascular treatment planning. Complex morphologies can lead to serious complications during the endovascular procedure. We present a case of a symptomatic complex middle cerebral artery stenosis that was successfully treated with a double stenting in T configuration, using a safety micro-guidewire technique. During follow-up, intracranial Doppler revealed a non-significant residual stenosis and the patient remained asymptomatic.

Mean platelet volume and mechanical thrombectomy.

BACKGROUND AND PURPOSE: Mean Platelet Volume (MPV) is a marker of platelet activity and it is an independent predictor for long-term outcome in stroke patients. The aim of this study was to evaluate the association between baseline MPV value and clinical outcome at 90-days in anterior circulation stroke and large vessel occlusion (LVO) patients submitted to mechanical thrombectomy (MT). METHODS: We conducted a prospective observational cohort study in acute ischemic stroke (AIS) patients submitted to MT between January 2017 and May 2018. MPV was measured at admission. Patients were initially stratified into two groups according to the mean MPV level. We also compared groups that were stratified according to the MPV cut-off obtained by Peng F et al (10,4 fL) and performed analyses among MPV terciles. RESULTS: A total of 129 patients were included. Mean level of MPV was 10,9 fL. Patients with embolic stroke of undetermined source (ESUS) had significantly higher rates of good outcome at 3 months compared with large-artery atherosclerotic disease and cardioembolism [(82,9%) vs (78,3%) vs (55,2%); p=0,009]. There were no statistically significant differences in the mean MPV value (p=0,222), successful recanalization (p=0,464) and mortality (p=0,343) when evaluated for all TOAST etiologies. There were no statistically significant differences between the two groups according to the MPV level (10,4 and 10,9 fL) or between the terciles (lowest tertile <10,3 fL, median 10,3 - 11,3 fL, highest >11,3fL) concerning functional outcome at 3 months (p=0,357; p=0,24 and p=0,558, respectively), successful recanalization (p=0,108; p=0,582 and p=0,899, respectively) or mortality at 3 months (p=0,465; p=0,061 and p=0,484, respectively). CONCLUSION: Our study did not find an association between elevated MPV and worse outcome at 3 months in patients with acute anterior circulation stroke and LVO treated with MT. Since ischemic strokes have different pathophysiologic mechanisms, MPV may have distinct prognostic value according to each stroke etiology.

Molecular evolution and diversification of the GRF transcription factor family.

- Growth Regulating Factors (GRFs) comprise a transcription factor family with important functions in plant growth and development. They are characterized by the presence of QLQ and WRC domains, responsible for interaction with proteins and DNA, respectively. The QLQ domain is named due to the similarity to a protein interaction domain found in the SWI2/SNF2 chromatin remodeling complex. Despite the occurrence of the QLQ domain in both families, the divergence between them had not been further explored. Here, we show evidence for GRF origin and determined its diversification in angiosperm species. Phylogenetic analysis revealed 11 well-supported groups of GRFs in flowering plants. These groups were supported by gene structure, synteny, and protein domain composition. Synteny and phylogenetic analyses allowed us to propose different sets of probable orthologs in the groups. Besides, our results, together with functional data previously published, allowed us to suggest candidate genes for engineering agronomic traits. In addition, we propose that the QLQ domain of GRF genes evolved from the eukaryotic SNF2 QLQ domain, most likely by a duplication event in the common ancestor of the Charophytes and land plants. Altogether, our results are important for advancing the origin and evolution of the GRF family in Streptophyta.

Synergistic Binding of bHLH Transcription Factors to the Promoter of the Maize NADP-ME Gene Used in C4 Photosynthesis Is Based on an Ancient Code Found in the Ancestral C3 State.

C4 photosynthesis has evolved repeatedly from the ancestral C3 state to generate a carbon concentrating mechanism that increases photosynthetic efficiency. This specialized form of photosynthesis is particularly common in the PACMAD clade of grasses, and is used by many of the world's most productive crops. The C4 cycle is accomplished through cell-type-specific accumulation of enzymes but cis-elements and transcription factors controlling C4 photosynthesis remain largely unknown. Using the NADP-Malic Enzyme (NADP-ME) gene as a model we tested whether mechanisms impacting on transcription in C4 plants evolved from ancestral components found in C3 species. Two basic Helix-Loop-Helix (bHLH) transcription factors, ZmbHLH128 and ZmbHLH129, were shown to bind the C4NADP-ME promoter from maize. These proteins form heterodimers and ZmbHLH129 impairs trans-activation by ZmbHLH128. Electrophoretic mobility shift assays indicate that a pair of cis-elements separated by a seven base pair spacer synergistically bind either ZmbHLH128 or ZmbHLH129. This pair of cis-elements is found in both C3 and C4 Panicoid grass species of the PACMAD clade. Our analysis is consistent with this cis-element pair originating from a single motif present in the ancestral C3 state. We conclude that C4 photosynthesis has co-opted an ancient C3 regulatory code built on G-box recognition by bHLH to regulate the NADP-ME gene. More broadly, our findings also contribute to the understanding of gene regulatory networks controlling C4 photosynthesis.

Rationale and design for a cluster randomized quality-improvement trial to increase the uptake of evidence-based therapies for patients at high cardiovascular risk: The BRIDGE-Cardiovascular Prevention trial.

BACKGROUND: Translating evidence into clinical practice in the management of high cardiovascular risk patients is challenging. Few quality improvement interventions have rigorously evaluated their impact on both patient care and clinical outcomes. OBJECTIVES: The main objectives are to evaluate the impact of a multifaceted educational intervention on adherence to local guidelines for the prescription of statins, antiplatelets and angiotensin converting enzyme inhibitors or angiotensin II receptor blockers for high cardiovascular risk patients, as well as on the incidence of major cardiovascular events. DESIGN: We designed a pragmatic two arm cluster randomized trial involving 40 clusters. Clusters are randomized to receive a multifaceted quality improvement intervention or to routine practice (control). The multifaceted intervention includes: reminders, care algorithms, training of a case manager, audit and feedback reports, and distribution of educational materials to health care providers. The primary endpoint is the adherence to combined evidence-based therapies (statins, antiplatelet therapy and angiotensin converting enzyme inhibitors or angiotensin receptor blockers) at 12 months after the intervention period in patients without contra-indications for these medications. All analyses follow the intention-to-treat principle and take the cluster design into account using linear mixed logistic regression modeling. SUMMARY: If proven effective, this multifaceted intervention would have wide utility as a means of promoting optimal usage of evidence-based interventions for the management of high cardiovascular risk patients.

How to govern the digital transformation of health services.

The impact of digitalization of health services has been profound and is expected to be even more profound in the future. It is important to evaluate whether digital health services contribute to health system goals in an optimal way. This should be done at the level of the service, not the 'digital transformation'. Decisions to adopt new digital health services, at different levels of the health care system, are ideally based on evidence regarding their performance in light of health system goals. In order to evaluate this, a broad perspective should be taken in evaluations of digital health services. Attainment of the broad health system goals, including quality, efficiency and equity, are objectives against which to judge new digital health services. These goals in a broad sense are unaltered by the process of digitalization. Governance should be designed and tailored in such a way to capture all relevant changes in an adequate way. When evaluating digital health services many specific aspects need to be considered. Like for other innovations and (new) technologies, such promises may or may not materialize and potential benefits may also be accompanied by unintended and/or negative (side) effects in the short or long term. Hence, the introduction, implementation, use and funding of digital health technologies should be carefully evaluated and monitored. Governments should play a more active role in the further optimization both of the process of decision making (both at the central and decentral level) and the related outcomes. They need to find a balance between centralized and decentralized activity. Moreover, the broader preparation of the health care system to be able to deal with digitalization, from education, through financial and regulatory preconditions, to implementation of monitoring systems to monitor its effects on health system performance remains important.

Primary Thrombectomy Versus Combined Mechanical Thrombectomy and Intravenous Thrombolysis in Large Vessel Occlusion Acute Ischemic Stroke.

Mechanical thrombectomy (MT) in combination with intravenous thrombolysis (IVT) is the standard of care for patients with acute ischemic stroke with anterior circulation large vessel occlusion. The particular benefit of IVT in these patients is unknown. We performed a retrospective analysis of patients submitted to MT at our center between January 2015 and June 2017. Functional outcome was prospectively assessed using modified Rankin scale (mRS) at 3 months. A total of 234 patients were enrolled, 152 (65%) in the combined treatment group and 82 (35%) in the direct MT group. Patients receiving combined treatment had a higher frequency of intracranial internal carotid artery occlusion (48 [31.6%] versus 16 [19.5%], P = .048) and significantly less strokes of cardioembolic etiology (72 [47.4%] versus 57 [69.5%], P = .01). Other baseline characteristics did not differ between the 2 groups. Good functional outcome at 3 months (mRS 0-2) was trending toward being higher in patients in the combined treatment group (98 [64.9%] versus 42 [52.5%], P = .066). Rates of symptomatic intracranial hemorrhage (5 [3.3%] versus 4 [4.9%], P = .723) and mortality (15 [9.9%] versus 14 [17.5%], P = .099) did not differ between groups. In multivariate logistic regression analysis, we did not find a statistically significant association between the use of IVT and any of the outcomes studied. Our results suggest that combined treatment carries similar effectiveness and safety than direct MT. Randomized controlled trials regarding this subject are warranted.