Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke ...compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.
NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.
Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio HR 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.
Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.
Bayer and Janssen.
Abstract
Background
Anaplasmosis presents with fever, headache, and laboratory abnormalities including leukopenia and thrombocytopenia. Polymerase chain reaction (PCR) is the preferred diagnostic but ...is overutilized. We determined if routine laboratory tests could exclude anaplasmosis, improving PCR utilization.
Methods
Anaplasma PCR results from a 3-year period, with associated complete blood count (CBC) and liver function test results, were retrospectively reviewed. PCR rejection criteria, based on white blood cell (WBC) and platelet (PLT) counts, were developed and prospectively applied in a mock stewardship program. If rejection criteria were met, a committee mock-refused PCR unless the patient was clinically unstable or immunocompromised.
Results
WBC and PLT counts were the most actionable routine tests for excluding anaplasmosis. Retrospective review demonstrated that rejection criteria of WBC ≥11 000 cells/µL or PLT ≥300 000 cells/µL would have led to PCR refusal in 428 of 1685 true-negative cases (25%) and 3 of 66 true-positive cases (5%) involving clinically unstable or immunocompromised patients. In the prospective phase, 155 of 663 PCR requests (23%) met rejection criteria and were reviewed by committee, which endorsed refusal in 110 of 155 cases (71%) and approval in 45 (29%), based on clinical criteria. PCR was negative in all 45 committee-approved cases. Only 1 of 110 mock-refused requests yielded a positive PCR result; this patient was already receiving doxycycline at the time of testing.
Conclusions
A CBC-based stewardship algorithm would reduce unnecessary Anaplasma PCR testing, without missing active cases. Although the prospectively evaluated screening approach involved medical record review, this was unnecessary to prevent errors and could be replaced by a rejection comment specifying clinical situations that might warrant overriding the algorithm.
A laboratory screening algorithm using total white blood cell and platelet count cutoff values can be used to rule out anaplasmosis and reduce overutilization of Anaplasma polymerase chain reaction testing, even when disease incidence is relatively high.
Individuals with cystic fibrosis (CF) develop complications of the gastrointestinal tract influenced by genetic variants outside of CFTR. Cystic fibrosis-related diabetes (CFRD) is a distinct form of ...diabetes with a variable age of onset that occurs frequently in individuals with CF, while meconium ileus (MI) is a severe neonatal intestinal obstruction affecting ∼20% of newborns with CF. CFRD and MI are slightly correlated traits with previous evidence of overlap in their genetic architectures. To better understand the genetic commonality between CFRD and MI, we used whole-genome-sequencing data from the CF Genome Project to perform genome-wide association. These analyses revealed variants at 11 loci (6 not previously identified) that associated with MI and at 12 loci (5 not previously identified) that associated with CFRD. Of these, variants at SLC26A9, CEBPB, and PRSS1 associated with both traits; variants at SLC26A9 and CEBPB increased risk for both traits, while variants at PRSS1, the higher-risk alleles for CFRD, conferred lower risk for MI. Furthermore, common and rare variants within the SLC26A9 locus associated with MI only or CFRD only. As expected, different loci modify risk of CFRD and MI; however, a subset exhibit pleiotropic effects indicating etiologic and mechanistic overlap between these two otherwise distinct complications of CF.
Genetic modifiers play a significant role in two independent complications of cystic fibrosis (CF): neonatal intestinal obstruction and diabetes. Whole-genome sequencing followed by common and rare variant association identified pleiotropic loci displaying concordant and/or discordant modification of each trait, revealing unexpected mechanistic overlap between distinct complications of CF.
Abstract
Background
Both COVID-19 and the measures taken to control the pandemic may significantly affect cardiovascular health. The effects of a lockdown on physical activity and its potential ...consequences for arrhythmia burden remain largely unknown.
Purpose
In this study, we investigated the effect of the lockdown during the first COVID-19 wave on patients' physical activity and arrhythmia burden.
Methods
All patients with an ICD connected to a Carelink home-monitoring system from two Dutch hospitals were included. Anonymized data on physical activity, heart rate, and occurrence of ventricular tachycardia/fibrillation (VT/VF), and atrial fibrillation/tachycardia (AF/AT) were obtained and were compared between March-April 2020 (lockdown) and March-April 2019 (reference) within each patient. The study was approved by the local ethics committee.
Results
The ICDs of 531 patients registered significantly less activity during de lockdown period compared to the reference period (210±104 min vs 182±103 min, p<0.0001, Figure 1, panels A and B), while weather conditions improved (1A). Daytime and nighttime heart rates were significantly lower during lockdown compared to the reference period (71.3±9 bpm vs 72.6±9 bpm, p<0.0001 and 63.4±9 vs 63.8±9, p=0.02, respectively). AF/AT burden increased (Figure 2A) while number of VT/VF episodes decreased (2B). There was no significant difference in number of NSVT episodes.
Conclusion
During the lockdown in the first COVID-19 wave, the Carelink system revealed significantly less activity, increase in AF/AT burden and decrease in VT/VF episodes. Further investigation is needed to understand the relationship between physical activity and the occurrence of arrhythmias in ICD patients.
Funding Acknowledgement
Type of funding sources: None.
We sought to identify factors that are predictive of liver transplantation or death in patients with primary sclerosing cholangitis (PSC), and to develop and validate a contemporaneous risk score for ...use in a real‐world clinical setting. Analyzing data from 1,001 patients recruited to the UK‐PSC research cohort, we evaluated clinical variables for their association with 2‐year and 10‐year outcome through Cox‐proportional hazards and C‐statistic analyses. We generated risk scores for short‐term and long‐term outcome prediction, validating their use in two independent cohorts totaling 451 patients. Thirty‐six percent of the derivation cohort were transplanted or died over a cumulative follow‐up of 7,904 years. Serum alkaline phosphatase of at least 2.4 × upper limit of normal at 1 year after diagnosis was predictive of 10‐year outcome (hazard ratio HR = 3.05; C = 0.63; median transplant‐free survival 63 versus 108 months; P < 0.0001), as was the presence of extrahepatic biliary disease (HR = 1.45; P = 0.01). We developed two risk scoring systems based on age, values of bilirubin, alkaline phosphatase, albumin, platelets, presence of extrahepatic biliary disease, and variceal hemorrhage, which predicted 2‐year and 10‐year outcomes with good discrimination (C statistic = 0.81 and 0.80, respectively). Both UK‐PSC risk scores were well‐validated in our external cohort and outperformed the Mayo Clinic and aspartate aminotransferase‐to‐platelet ratio index (APRI) scores (C statistic = 0.75 and 0.63, respectively). Although heterozygosity for the previously validated human leukocyte antigen (HLA)‐DR*03:01 risk allele predicted increased risk of adverse outcome (HR = 1.33; P = 0.001), its addition did not improve the predictive accuracy of the UK‐PSC risk scores. Conclusion: Our analyses, based on a detailed clinical evaluation of a large representative cohort of participants with PSC, furthers our understanding of clinical risk markers and reports the development and validation of a real‐world scoring system to identify those patients most likely to die or require liver transplantation.
SKS splitting parameters are measured in the Aegean region using events recorded at a dense temporary network in the south Aegean and the operating permanent networks, especially focusing in the ...back‐arc and the near‐trench areas of the Hellenic arc. In general, fast anisotropy directions are trench perpendicular in the back‐arc area and trench parallel near the trench. Anisotropy measurements near the volcanic arc mark the transition between these two regions. In the back arc, a gradual increase is observed in delay times from south to north, with a prevailing NE‐SW direction. In Cyclades, this pattern is correlated with GPS velocities and stretching lineations of metamorphic core complexes. Our preferred source of anisotropy in the back‐arc region is the mantle wedge flow, induced by the retreating descending slab. The westernmost termination of the trench reveals directions parallel with the Kefalonia Transform Fault and perpendicular to the convergence boundary. Beneath Peloponnese, the trench‐parallel flow is probably located beneath the shallow‐dipping slab, although scattered measurements may also reflect fossil anisotropy from a past NW‐SE strike of the trench. In western Crete, which may be entering a stage of continental collision, the anisotropy pattern changes to trench perpendicular, with a possible subslab source. Good nulls in central east Crete indicate a change in the anisotropy origin toward the east. At the easternmost side of the trench, fast directions are trench parallel. This reflects a similar subslab flow that may become toroidal around the slab edge beneath western Turkey. This may also produce a trench‐parallel flow within the mantle wedge.
Key Points
Trench‐perpendicular anisotropy in the back‐arc area of the Aegean
Trench‐parallel anisotropy near the Hellenic trench
Trench‐perpendicular anisotropy in W. Crete: change of pattern towards the east
The recognition of dementia as a multifactorial disorder encourages the exploration of new pathways to understand its origins. Social health might play a role in cognitive decline and dementia, but ...conceptual clarity is lacking and this hinders investigation of associations and mechanisms. The objective is to develop a conceptual framework for social health to advance conceptual clarity in future studies.
We use the following steps: underpinning for concept advancement, concept advancement by the development of a conceptual model, and exploration of its potential feasibility. An iterative consensus-based process was used within the international multidisciplinary SHARED project.
Underpinning of the concept drew from a synthesis of theoretical, conceptual and epidemiological work, and resulted in a definition of social health as wellbeing that relies on capacities both of the individual and the social environment. Consequently, domains in the conceptual framework are on both the individual (e.g., social participation) and the social environmental levels (e.g., social network). We hypothesize that social health acts as a driver for use of cognitive reserve which can then slow cognitive impairment or maintain cognitive functioning. The feasibility of the conceptual framework is demonstrated in its practical use in identifying and structuring of social health markers within the SHARED project.
The conceptual framework provides guidance for future research and facilitates identification of modifiable risk and protective factors, which may in turn shape new avenues for preventive interventions. We highlight the paradigm of social health in dementia as a priority for dementia research.
We present the discovery and validation of two TESS exoplanets orbiting nearby M dwarfs: TOI-2084 b, and TOI-4184b. We characterized the host stars by combining spectra from
Shane
/Kast and
Magellan
.../FIRE, spectral energy distribution analysis, and stellar evolutionary models. In addition, we used Gemini-South/Zorro & -North/Alopeke high-resolution imaging, archival science images, and statistical validation packages to support the planetary interpretation. We performed a global analysis of multi-colour photometric data from TESS and ground-based facilities in order to derive the stellar and planetary physical parameters for each system. We find that TOI-2084 band TOI-4184 bare sub-Neptune-sized planets with radii of
R
p
= 2.47 ± 0.13
R
⊕
and
R
p
= 2.43 ± 0.21
R
⊕
, respectively. TOI-2084 b completes an orbit around its host star every 6.08 days, has an equilibrium temperature of
T
eq
= 527 ± 8 K and an irradiation of
S
p
= 12.8 ± 0.8
S
⊕
. Its host star is a dwarf of spectral M2.0 ± 0.5 at a distance of 114 pc with an effective temperature of
T
eff
= 3550 ± 50 K, and has a wide, co-moving M8 companion at a projected separation of 1400 au. TOI-4184 b orbits around an M5.0 ± 0.5 type dwarf star (
K
mag
= 11.87) each 4.9 days, and has an equilibrium temperature of
T
eq
= 412 ± 8 K and an irradiation of
S
p
= 4.8 ± 0.4
S
⊕
. TOI-4184 is a metal poor star (Fe/H = −0.27 ± 0.09 dex) at a distance of 69 pc with an effective temperature of
T
eff
= 3225 ± 75 K. Both planets are located at the edge of the sub-Jovian desert in the radius-period plane. The combination of the small size and the large infrared brightness of their host stars make these new planets promising targets for future atmospheric exploration with JWST.
ABSTRACT We present continuum and molecular line observations at 230 and 345 GHz from the Submillimeter Array (SMA) toward three protostars in the Perseus L1448N region. The data are from the large ...project "Mass Assembly of Stellar Systems and their Evolution with the SMA." Three dust continuum sources, Source B, Source NW, and Source A, are detected at both frequencies. These sources have corresponding emission peaks in C18O ( ), 13CO ( ), and HCO+ ( ), and have offsets with N2D+ ( ) peaks. High angular resolution data from a complementary continuum survey with the Karl G. Jansky Very Large Array show that Source B is associated with three 8 mm continuum objects, Source NW with two, and Source A remains single. These results suggest that multiplicity in L1448N exists at different spatial scales from a few thousand AU to <100 AU. Velocity gradients in each source obtained from two-dimensional fits to the SMA C18O emission are found to be perpendicular to within 20° of the outflow directions as revealed by 12CO ( ). We have observed that Sources B and NW with multiplicity have higher densities than Source A without multiplicity. This suggests that thermal Jeans fragmentation can be relevant in the fragmentation process. However, we have not observed a difference in the ratio between rotational and gravitational energy between sources with and without multiplicity. We also have not observed a trend between non-thermal velocity dispersions and the level of fragmentation. Our study has provided the first direct and comprehensive comparison between multiplicity and core properties in low-mass protostars, although based on small number statistics.
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