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New-onset atrial fibrillation (AF) during COVID-19 infection is associated with worse cardiovascular outcomes and mortality, with new-onset AF being associated with worse clinical outcomes than recurrent AF. However, it is not known whether a prior history of AF is an independent cardiovascular risk factor predicting worse outcomes in COVID-19 patients. The present investigation sought to determine whether AF should be considered a risk factor for worse outcomes in COVID-19 illness.From March 2020-September 2021 patients testing positive for SARS-CoV-2 with a prior AF diagnosis (n = 3623) were propensity matched to non-AF SARS-CoV-2 positive patients (n = 3610). Multivariable Cox hazard regression was used to determine subsequent MACE (all-cause death, myocardial infarction, HF and stroke) risk among patients with and without AF.COVID-19 patients with a prior history of AF were more likely to be hospitalized, require ICU care, supplemental oxygen, and ventilator support compared COVID-19 patients without a history of AF. There was a 1.40 times higher rate of MACE in the COVID-19 patients with prior AF compared to patients without prior AF (AF history was shown to be an independent risk factor for MACE during a COVID-19 illness. Both recurrent and principally new-onset AF were associated with an increased risk of poor clinical outcomes during COVID-19 illness.

Cardiac implantable electronic devices (CIEDs) provide lifesaving therapy for the treatment of bradyarrhythmias, ventricular tachyarrhythmias, and advanced systolic heart failure. Advances in CIED therapy have expanded the number of patients receiving permanent pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapy devices. These devices improve quality of life and, in many cases, reduce mortality. However, limitations remain in the management of patients who require CIED therapy. This article provides a broad overview of CIED therapy in the management of the cardiac patient.

Background Patients with atrial fibrillation (AF) are at higher risk for developing dementia. Warfarin is a common therapy for the prevention of thromboembolism in AF, valve replacement, and thrombosis patients. The extent to which AF itself increases dementia risk remains unknown. Methods A total 6030 patients with no history of dementia and chronically anticoagulated with warfarin were studied. Warfarin management was provided through a Clinical Pharmacy Anticoagulation Service. Patients were stratified by warfarin indication of AF (n=3015) and non-AF (n=3015) and matched by propensity score (±0.01). Patients were stratified by the congestive heart failure, hypertension, age >75 years, diabetes, stroke (CHADS 2 ) score calculated at the time of warfarin initiation and followed for incident dementia. Results The average age of the AF cohort was 69.3±11.2 years, and 52.7% were male; average age of non-AF cohort was 69.3±10.9 years, and 51.5% were male. Increasing CHADS 2 score was associated with increased dementia incidence, P trend=.004. When stratified by warfarin indication, AF patients had an increased risk of dementia incidence. After multivariable adjustment, AF patients continued to display a significantly increased risk of dementia when compared with non-AF patients across all CHADS 2 scores strata. Conclusions In patients receiving long-term warfarin therapy, dementia risk increased with increasing CHADS 2 scores. However, the presence of AF was associated with higher rates of dementia across all CHADS 2 score strata. These data suggest that AF contributes to the risk of dementia and that this risk is not solely attributable to anticoagulant use. Dementia may be an end manifestation of a systemic disease state, and AF likely contributes to its progression.

Direct oral anticoagulants (DOACs) have been used in clinical practice in the United States for the last 4 to 6 years. Although DOACs may be an attractive alternative to warfarin in many patients, long-term outcomes of use of these medications are unknown. We performed a propensity-matched analysis to report patient important outcomes of death, stroke/transient ischemic attack (TIA), bleeding, major bleeding, and dementia in patients taking a DOAC or warfarin. Patients receiving long-term anticoagulation from June 2010 to December 2014 for thromboembolism prevention with either warfarin or a DOAC were matched 1:1 by index date and propensity score. Multivariable Cox hazard regression was performed to determine the risk of death, stroke/TIA, major bleed, and dementia by the anticoagulant therapy received. A total of 5,254 patients were studied (2,627 per group). Average age was 72.4 ± 10.9 years, and 59.0% were men. Most patients were receiving long-term anticoagulation for AF management (warfarin: 96.5% vs DOAC: 92.7%, p

Risk stratification tools are needed to select the right candidates for catheter ablation of atrial fibrillation (AF). Both the CHADS2 and CHA2DS2-VASc scores have utility in predicting AF-related outcomes and guiding anticoagulation treatment.We sought to determine whether these risk scores predict long-term outcomes after AF ablation and whether one risk score provides comparatively superior performance.CHADS2 and CHA2DS2-VASc scores were calculated in 2179 patients who underwent a first ablation procedure for AF enrolled in the Intermountain Heart Collaborative Study. CHADS2 and CHA2DS2-VASc scores were categorized as 0-1, 2-4, and ≥5. Patient outcomes were analyzed over 5 years for AF/atrial flutter recurrence and major adverse cardiovascular events (MACE: composite of death, stroke, and heart failure hospitalization).The mean age was 65.7 ± 10.5 years, and 61.1% were men. Both scores incrementally predicted risk of AF recurrence, stroke, heart failure, and death at 5 years. Increasing CHADS2 (hazard ratio [HR] 1.19; P.001) and CHA2DS2-VASc (HR 1.15; P.0001) scores were both associated with AF/atrial flutter recurrence. The results were similar for MACE where increasing CHADS2 (HR 1.54; P.0001) and CHA2DS2-VASc (HR 1.32; P.0001) scores were associated with risk. When CHADS2 and CHA2DS2-VASc scores were modeled together, only CHA2DS2-VASc scores significantly predicted AF recurrence (HR 1.13; P = .001), but both were associated with MACE.Both the CHADS2 and CHA2DS2-VASc scores were excellent in stratifying patients for 5-year outcomes after AF ablation. However, the CHA2DS2-VASc score was superior to the CHADS2 score in predicting AF recurrence and AF-related morbidities.

Magnetic resonance imaging (MRI) in patients with left ventricular (LV) leads may cause tissue or lead heating, dislodgment, venous damage, or lead dysfunction.The purpose of this study was to determine the safety of MRI in patients with LV pacing leads.Prospective data on patients with coronary sinus LV leads undergoing clinically indicated MRI at 3 institutions were collected. Patients were not pacemaker-dependent. Scans were performed under pacing nurse, technician, radiologist, and physicist supervision using continuous vital sign, pulse oximetry, and ECG monitoring and a 1.5-T scanner with specific absorption rate1.5 W/kg. Devices were interrogated pre- and post-MRI, programmed to asynchronous or inhibition mode with tachyarrhythmia therapies off (if present), and reprogrammed to their original settings post-MRI.MRI scans (n = 42) were performed in 40 patients with non-MRI conditional LV leads between 2005 and 2013 (mean age 67 ± 9 years, n = 16 [40%] women, median lead implant duration 740 days with interquartile range 125-1173 days). MRIs were performed on the head/neck/spine (n = 35 [83%]), lower extremities (n = 4 [10%]), chest (n = 2 [5%]), and abdomen (n = 1 [2%]). There were no overall differences in pre- and post-MRI interrogation LV lead sensing (12.4 ± 6.2 mV vs 12.9 ± 6.7 mV, P = .38), impedance (724 ± 294 Ω vs 718 ± 312 Ω, P = .67), or threshold (1.4 ± 1.1 V vs 1.4 ± 1.0 V, P = .91). No individual LV lead changes required intervention.MRI scanning was performed safely in non-pacemaker-dependent patients with coronary sinus LV leads who were carefully monitored during imaging without clinically significant adverse effect on LV lead function.

The mechanisms behind the association of atrial fibrillation (AF) and dementia are unknown. One possibility is that exposure to chronic microembolism or microbleeds results in repetitive cerebral injury that is manifest by cognitive decline.The purpose of this study was to test the hypothesis that AF patients with a low percentage of time in the therapeutic range (TTR) are at higher risk for dementia due to under- or overanticoagulation.Patients anticoagulated with warfarin (target international normalized ratio [INR] 2-3), managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service with no history of dementia or stroke/transient ischemic attack, were included in the study. The primary outcome was dementia incidence defined by ICD-9 codes. Percent time in TTR was calculated using the method of linear interpolation and stratified as75%, 51%-75%, 26%-50%, and ≤25%. Multivariable Cox hazard regression was used to determine dementia incidence by percentage categories of TTR.A total of 2605 patients (age 73.7 ± 10.8 years, 1408 [54.0%] male) were studied. The CHADS2 score distribution was 0: 216 (8.3%); 1: 579 (22.2%); 2: 859(33.0%); 3: 708 (27.2%); and ≥4: 243 (9.3%). The percent TTR averaged 63.1 ± 21.3, with percent INR2.0: 25.6% ± 17.9% and percent INR3.0: 16.2% ± 13.6%. Dementia was diagnosed in 109 patients (4.2%) (senile: 37 [1.4%]; vascular: 8 [0.3%]; Alzheimer: 64 (2.5%]). After adjustment, decreasing categories of percent TTR were associated with increased dementia risk (vs75%):25%: hazard ratio (HR) 5.34, P.0001; 26%-50%: HR 4.10, P.0001; and 51%-75%: HR = 2.57, P = .001.Quality of anticoagulation management represented as percent TTR among AF patients without dementia was associated with dementia incidence. These data support the possibility of chronic cerebral injury as a mechanism that underlies the association of AF and dementia.

The Supreme Court has made clear that, absent a clear expression from Congress, U.S. laws do not apply extraterritorially. The Court has noted that the presumption against extraterritoriality has particular force in the context of patent law. The Federal Circuit has given short shrift to this argument. This brief argues that this case presents the opportunity for the Court to strike the appropriate extraterritorial reach for a U.S. patent under 35 U.S.C. § 271(f) and to signal to the Federal Circuit to take the presumption against extraterritoriality seriously.On the merits, the brief offers two approaches to answer this question. The first, following the typical approach to extraterritoriality, argues that the Federal Circuit’s interpretation was unnecessarily broad in light of the presumption against extraterritoriality.Second, the brief offers an alternative approach for patent law, drawing on academic literature, criminal law, and trademark law: courts should consider the potential for conflicts with foreign law in assessing whether liability for patent infringement is appropriate.

Background Survivors of acute myocardial infarction (MI) are at high risk for death from both sudden cardiac death and progressive heart failure. Objective This study sought to determine mortality trends, identify markers of risk, and determine whether outcomes in high-risk patients are altered by revascularization during the implantable cardioverter-defibrillator candidacy observation period. Methods We included 16,793 patients that presented to the catheterization laboratory for acute management of an MI. All patients had 3 years of follow-up to define short- and long-term mortality. Results Across the demographics studied there were no significant differences in baseline characteristics over time, with exception of an observed decline in patients with an ejection fraction (EF) ≤0.35. Nonetheless, at study closure 16.3% of all cases had an EF ≤ 0.35. There was a gradual increase in use of percutaneous coronary intervention and coronary artery bypass graft; however, at the end of the study, the highest level of revascularization use was slightly >50%. For the composite, right and left bundle branch block or QRS > 120, the death rates at 1 and 5 years were 31.8% and 46.8%, respectively. These 1- and 5-year mortality rates were increased with an EF ≤ 0.35 (36.0%, 60.2%). Mortality in those with EF ≤ 0.35 exceeded 20% in all groups with conduction system disease at 90 days and was not significantly impacted by percutaneous coronary intervention. Conclusion The highest risk for death after MI is in patients with an EF ≤ 0.35 and/or conduction system disease. The mortality risk is most pronounced in the early observation period after MI when patients must wait to be considered for an implantable cardioverter-defibrillator.

Laterality defects such as situs inversus are not uncommonly encountered in humans, either in isolation or as part of another syndrome, but can have devastating developmental consequences. The events that break symmetry during early embryogenesis are highly conserved amongst vertebrates and involve the establishment of unidirectional flow by cilia within an organising centre such as the node in mammals or Kupffer's vesicle (KV) in teleosts. Disruption of this flow can lead to the failure to successfully establish left-right asymmetry. The correct apical-posterior cellular position of each node/KV cilium is critical for its optimal radial movement which serves to sweep fluid (and morphogens) in the same direction as its neighbours. Planar cell polarity (PCP) is an important conserved process that governs ciliary position and posterior tilt; however the underlying mechanism by which this occurs remains unclear. Here we show that Bbs8, a ciliary/basal body protein important for intraciliary/flagellar transport and the core PCP protein Vangl2 interact and are required for establishment and maintenance of left-right asymmetry during early embryogenesis in zebrafish. We discovered that loss of bbs8 and vangl2 results in laterality defects due to cilia disruption at the KV. We showed that perturbation of cell polarity following abrogation of vangl2 causes nuclear mislocalisation, implying defective centrosome/basal body migration and apical docking. Moreover, upon loss of bbs8 and vangl2, we observed defective actin organisation. These data suggest that bbs8 and vangl2 act synergistically on cell polarization to establish and maintain the appropriate length and number of cilia in the KV and thereby facilitate correct LR asymmetry.

The aging population has resulted in more patients living with cardiovascular disease, such as atrial fibrillation (AF). Recent focus has been placed on understanding the long-term consequences of chronic cardiovascular disease, such as a potential increased risk of dementia.This study sought to determine whether there is an association between AF and dementia and whether their coexistence is an independent marker of risk.A total of 37,025 consecutive patients from the large ongoing prospective Intermountain Heart Collaborative Study database were evaluated and followed up for a mean of 5 years for the development of AF and dementia. Dementia was sub-typed into vascular (VD), senile (SD), Alzheimer's (AD), and nonspecified (ND).Of the 37,025 patients with a mean age of 60.6 +/- 17.9 years, 10,161 (27%) developed AF and 1,535 (4.1%) developed dementia (179 VD, 321 SD, 347 AD, 688 ND) during the 5-year follow-up. Patients with dementia were older and had higher rates of hypertension, coronary artery disease, renal failure, heart failure, and prior strokes. In age-based analysis, AF independently was significantly associated with all dementia types. The highest risk was in the younger group (70). After dementia diagnosis, the presence of AF was associated with a marked increased risk of mortality (VD: hazard ratio [HR] = 1.38, P = .01; SD: HR = 1.41, P = .001; AD: HR = 1.45; ND: HR = 1.38, P.0001).AF was independently associated with all forms of dementia. Although dementia is strongly associated with aging, the highest risk of AD was in the younger group, in support of the observed association. The presence of AF also identified dementia patients at high risk of death.

The vestigial gene has been shown to control skeletal muscle formation in Drosophila and the related Vestigial-like 2 (Vgl-2) protein plays a similar role in mice. Vgl-family proteins are thought to regulate tissue-specific gene expression by binding to members of the broadly expressed Scalloped/Tef/TEAD transcription factor family. Zebrafish have at least four Vgl genes, including two Vgl-2s, and at least three TEAD genes, including two Tead3s. We describe the cloning and expression of one member from each family in the zebrafish. A novel gene, vgl-2b, with closest homology to mouse and human vgl-2, is expressed transiently in nascent notochord and in muscle fibres as they undergo terminal differentiation during somitogenesis. Muscle cells also express a TEAD-3 homologue, a possible partner of Vgl-2b, during myoblast differentiation and early fibre assembly. Tead-3a is also expressed in rhombomeres, eye and epiphysis regions.

Pax3/7 paired homeodomain transcription factors are important markers of muscle stem cells. Pax3 is required upstream of myod for lateral dermomyotomal cells in the amniote somite to form particular muscle cells. Later Pax3/7-dependent cells generate satellite cells and most body muscle. Here we analyse early myogenesis from, and regulation of, a population of Pax3-expressing dermomyotome-like cells in the zebrafish. Zebrafish pax3 is widely expressed in the lateral somite and, along with pax7, becomes restricted anteriorly and then to the external cells on the lateral somite surface. Midline-derived Hedgehog signals appear to act directly on lateral somite cells to repress Pax3/7. Both Hedgehog and Fgf8, signals that induce muscle formation within the somite, suppress Pax3/7 and promote expression of myogenic regulatory factors (MRFs) myf5 and myod in specific muscle precursor cell populations. Loss of MRF function leads to loss of myogenesis by specific populations of muscle fibres, with parallel up-regulation of Pax3/7. Myod is required for lateral fast muscle differentiation from pax3-expressing cells. In contrast, either Myf5 or Myod is sufficient to promote slow muscle formation from adaxial cells. Thus, myogenic signals act to drive somite cells to a myogenic fate through up-regulation of distinct combinations of MRFs. Our data show that the relationship between Pax3/7 genes and myogenesis is evolutionarily ancient, but that changes in the MRF targets for particular signals contribute to myogenic differences between species.

The digital revolution has now moved beyond music and video files. A person can now translate three-dimensional objects into digital files and, at the press of a button, recreate those items via a 3D printer or similar device. Just as digitization placed pressure on the copyright system, so will these digital computer-aided design (CAD) files stress the patent system. Patents directed to physical objects can now have their value appropriated — not by the transfer of physical embodiments — but by the making, selling, and transferring of CAD files designed to print the invention. We term this phenomenon digital patent infringement. We explore the ways the patent system can respond to protect patent owners against the appropriation of their inventions via these digital files. First, we explore whether indirect infringement doctrines sufficiently protect patent holders against these CAD files. Given the nature of likely accused indirect infringers, we conclude, contrary to earlier literature, that these doctrines likely are not up to the task. Second, we offer novel theories of direct “digital” patent infringement based on the CAD files alone. We consider whether offers to sell and sales of these files should constitute direct patent infringement. Because such commercial activity is an appropriation of the economic value of the patented invention, we believe the law should recognize such an infringement theory. Next, rejecting the prior assumptions of the literature, we provocatively explore whether the CAD files alone should be viewed as infringement for making the patented device, given the de minimis effort it takes to create the item via a 3D printer or related device. As a technological matter, the line between digital and tangible has eroded to the point where one could view these files as infringement. As a legal and policy matter, however, such expansion of patent infringement liability could have significant chilling effects on other actors and incentives, giving us pause in extending liability in this context.

The law’s complexity is such that even apparently minor changes can have numerous “ripple” effects. This Article examines the ripple effects from a change that looks almost certain to occur: broadening patent law’s definition of an infringing “offer to sell.” Currently, courts limit “offers” to formal, contract-law offers, but a policy analysis leads inevitably to the conclusion that “offers” should include advertisements and other promotions, which harm patentees via price erosion. Changing the offer definition to include advertisements and other promotions requires careful considering the effects, including effects on patent litigation, innovation incentives, the extraterritorial reach of United States patent law, third-party liability, and Constitutional concerns. This Article performs that analysis and provides specific recommendations for crafting the definition of an infringing “offer” to sell.

Gone are the days when the term “offer” is confined to first-year contracts courses and the intricacies of contract formation. The offer concept has quietly migrated throughout the law. It now regulates behavior in areas as diverse as criminal law, environmental law, securities law, and intellectual property law. Despite its wide diffusion, the offer concept remains largely unstudied as a legal concept outside of its contract-law environment. This Article begins to fill that gap. The Article begins by deconstructing the meaning of a traditional contract-law “offer” to determine its policy role in contract law, and then compares that role with offer concept’s roles in other areas of the law. Next, the Article compares the offer concept’s policy role in each area of the law to its corresponding definition therein and discusses any inconsistencies between the policy role and the definition. The Article then focuses on patent law’s use of the offer concept to regulate patent infringement and provides two primary analyses: (1) a normative analysis of the offer concept’s optimal definition in patent law and (2) a statutory analysis of the relevant statute. On the basis of the policy and statutory analyses, the Article shows why the current court-generated definition of patent law’s offer concept should be improved. The Article concludes by providing suggestions for improving the use of the offer concept in patent law and the law more generally.

Distal arthrogryposis (DA) is a clinically and genetically heterogeneous condition with mutations in at least five genes encoding for sarcomeric proteins (TNN12, TNNT3, TPM2, MYH3 and MYH8) implicated to date. A significant proportion of cases remain genetically uncharacterised. Here we describe 4 members from a 3 generation consanguineous Irish family that presented with a congenital myopathy resembling King-Denborough syndrome (KDS), characterized by clinical features of ptosis and distal arthrogryposis, and cores on muscle biopsy. Through collaboration with The Sanger Centre as part of the UK10K project, we exome screened these subjects and were able to identify a segregating homozygous misssense mutation in exon 2 of the Endothelin converting enzyme like 1 (ECEL1) gene, recently found to be responsible for DA5D. Population screening enabled us to find two additional DA families that harboured causative variants ECEL1 exons 2 and 15, respectively, reinforcing the notion of a causative link between ecel1 dysfunction and the DA’s. ECEL1 encodes for a type2 transmembrane M13 metallopeptidase with an as yet unidentified substrate, localised to the endoplasmic reticulum and plasma membrane of the central nervous system (CNS). The ecel1 protein is also expressed in skeletal muscle and thought to participate in the formation of the neuromuscular junction (NMJ), but its precise function is currently unknown. We therefore embarked on protein function assays in zebrafish morphants and ECEL1-mutated patient fibroblasts. In particular, we knocked down (KD) ecel1 in zebra fish embryo applying a morpholino approach and found a gross defect in body axis curvature leading to perturbed functional abilities. Microscopic examination revealed disorganised/detached myofibres that have intact sarcolemma. (We have also obtained a zebrafish ecel1 knock out (KO) model achieved by insertion of a null allele by chemical mutagenesis. This model does not exhibit the same trunk curvatur.

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