Oculomotor nerve guidance and terminal branching requires interactions with differentiating extraocular muscles.

Muscle function is dependent on innervation by the correct motor nerves. Motor nerves are composed of motor axons which extend through peripheral tissues as a compact bundle, then diverge to create terminal nerve branches to specific muscle targets. As motor nerves approach their targets, they undergo a transition where the fasciculated nerve halts further growth then after a pause, the nerve later initiates branching to muscles. This transition point is potentially an intermediate target or guidepost to present specific cellular and molecular signals for navigation. Here we describe the navigation of the oculomotor nerve and its association with developing muscles in mouse embryos. We found that the oculomotor nerve initially grew to the eye three days prior to the appearance of any extraocular muscles. The oculomotor axons spread to form a plexus within a mass of cells, which included precursors of extraocular muscles and other orbital tissues and expressed the transcription factor Pitx2. The nerve growth paused in the plexus for more than two days, persisting during primary extraocular myogenesis, with a subsequent phase in which the nerve branched out to specific muscles. To test the functional significance of the nerve contact with Pitx2+ cells in the plexus, we used two strategies to genetically ablate Pitx2+ cells or muscle precursors early in nerve development. The first strategy used Myf5-Cre-mediated expression of diphtheria toxin A to ablate muscle precursors, leading to loss of extraocular muscles. The oculomotor axons navigated to the eye to form the main nerve, but subsequently largely failed to initiate terminal branches. The second strategy studied Pitx2 homozygous mutants, which have early apoptosis of Pitx2-expressing precursor cells, including precursors for extraocular muscles and other orbital tissues. Oculomotor nerve fibers also grew to the eye, but failed to stop to form the plexus, instead grew long ectopic projections. These results show that neither Pitx2 function nor Myf5-expressing cells are required for oculomotor nerve navigation to the eye. However, Pitx2 function is required for oculomotor axons to pause growth in the plexus, while Myf5-expressing cells are required for terminal branch initiation.

The long-term effect of the Earned Income Tax Credit on women's physical and mental health.

Using a novel method, and data from the National Longitudinal Survey of Youth 1979 (NLSY79), we estimate the cumulative, long-term, causal effect of Earned Income Tax Credit (EITC) eligibility on women's physical and mental health at age 50. We find that an increase in lifetime eligible EITC benefits is associated with long-term improvements in physical health, such as reduced occurrence of activity-limiting health problems and reduced reported diagnoses of mild and severe diseases. We explore intermediate health behaviors and outcomes, and find that an increase in lifetime eligible EITC benefits increases the number of hours worked and access to employer-sponsored health insurance, and decreases body mass index in the short-term. We find no significant effects of the EITC on mental health at age 50. Finally, we find that White women benefit disproportionately from the EITC in terms of mobility-related health issues, while Black and Hispanic women benefit in terms of lung-related illnesses like asthma, as well as cancer and stroke.

Preliminary Results of the Outpatient Endovascular and Interventional Society National Registry.

PURPOSE: To present a new outcomes-based registry to collect data on outpatient endovascular interventions, a relatively new site of service without adequate historical data to assess best clinical practices. Quality data collection with subsequent outcomes analysis, benchmarking, and direct feedback is necessary to achieve optimal care. MATERIALS AND METHODS: The Outpatient Endovascular and Interventional Society (OEIS) established the OEIS National Registry in 2017 to collect data on safety, efficacy, and quality of care for outpatient endovascular interventions. Since then, it has grown to include a peripheral artery disease (PAD) module with plans to expand to include cardiac, venous, dialysis access, and other procedures in future modules. As a Qualified Clinical Data Registry approved by the Centers for Medicare and Medicaid Services, this application also supports new quality measure development under the Quality Payment Program. All physicians operating in an office-based laboratory or ambulatory surgery center can use the Registry to analyze de-identified data and benchmark performance against national averages. Major adverse events were defined as death, stroke, myocardial infarction, acute onset of limb ischemia, index bypass graft or treated segment thrombosis, and/or need for urgent/emergent vascular surgery. RESULTS: Since Registry inception in 2017, 251 participating physicians from 64 centers located in 18 states have participated. The current database includes 18,134 peripheral endovascular interventions performed in 12,403 PAD patients (mean age 72.3±10.2 years; 60.1% men) between January 2017 and January 2020. Cases were performed primarily in an office-based laboratory (85.1%) or ambulatory surgery center setting (10.4%). Most frequently observed procedure indications from 16,086 preprocedure form submissions included claudication (59%), minor tissue loss (16%), rest pain (9%), acute limb ischemia (5%), and maintenance of patency (3%). Planned diagnostic procedures made up 12.2% of cases entered, with the remainder indicated as interventional procedures (87.6%). The hospital transfer rate was 0.62%, with 88 urgent/emergent transfers and 24 elective transfers. The overall complication rate for the Registry was 1.87% (n=338), and the rate of major adverse events was 0.51% (n=92). Thirty-day mortality was 0.03% (n=6). CONCLUSION: This report describes the current structure, methodology, and preliminary results of OEIS National Registry, an outcomes-based registry designed to collect quality performance data with subsequent outcome analysis, benchmarking, and direct feedback to aid clinicians in providing optimal care.

Safety and Efficacy of Arterial Closure Devices in an Office-Based Angiosuite.

INTRODUCTION: We aimed to compare the safety and efficacy of 5 arterial closure devices in an outpatient endovascular surgery center. METHODS: We retrospectively reviewed all cases using femoral arterial access performed between January 2012 and December 2013. Five different arterial closure devices (AngioSeal, Perclose, StarClose, ExoSeal, and Mynx) were used by 7 endovascular surgeons. All femoral arteries were accessed with 6F sheaths under ultrasound guidance. All patients received systemic anticoagulation with sodium heparin (70 IU/kg). Sheath-shot angiograms of all arterial punctures were taken before deploying closure devices. Device failure was defined as any partial or complete failure requiring additional closure assistance. Minor complication was defined as any event that occurred because of incomplete hemostasis but did not result in hospitalization, including hematoma, hypotension, bleeding, arterial dissection, or extended recovery. Major complication was defined as any event that occurred because of incomplete hemostasis requiring inpatient management. Any device failure was identified per device and per surgeon. Device safety, efficacy, and relationships between other variables were analyzed using a binomial logistic regression. Results with P values < 0.05 were considered to be statistically significant. RESULTS: During the study period, there were a total of 3142 endovascular procedures, including 1976 arterial cases (62.9%). Out of 1898 femoral artery punctures, closure devices were used in 1810 (95.4%), which forms the basis of this report. Device failure occurred in 151 cases (8.34%), and minor complications occurred in 53 cases (2.93%). There were 11 hospitalizations (0.61%). AngioSeal had both the lowest device failure rate (3.5%) and minor complication rate (1.3%). Our data showed a significant difference between the respective arterial closure devices for device failure rate (P = 0.007) and minor complication rate (P = 0.049), but not for major complication rate (P = 0.199). No significant difference was observed between surgeons for device failure (P = 0.798), minor complication (P = 0.218), or major complication rate (P = 0.899). CONCLUSIONS: With the lowest device failure and minor complication rate, AngioSeal is a consistently well-performing arterial closure device in the office surgical suite setting.

Wage and Employment Growth in America's Drug Epidemic: Is All Growth Created Equal?

The rise in drug overdose deaths in the United States since the turn of the millennium has been extraordinary. A popular narrative paints a picture whereby opioid overdoses among white, male, less-educated, rural workers have been caused by reduced economic opportunities borne by such people. In this article, we causally test the validity of this theory by using Bartik-type variables to explore the relationship between local economic conditions and county opioid overdose death rates. We add to the literature by exploring how both employment and wage growth in different types of industries are related to opioid overdose deaths for the population as a whole, as well as for rural (vs. urban), male (vs. female) and white (vs. black) populations. We find mixed evidence. Our results confirm that wage and employment growth in industries more likely to employ low-skill workers are important protective factors for rural, white males. However, we also find evidence that economic improvements in low-skill industries are just as important in protecting blacks and women against opioid overdoses, and for workers in metro counties. We also find evidence that employment growth in high-paying industries has led to increases in opioid overdoes rates.

Increasing the GluN2A/GluN2B Ratio in Neurons of the Mouse Basal and Lateral Amygdala Inhibits the Modification of an Existing Fear Memory Trace.

UNLABELLED: Reconsolidation updating is a form of memory modification in which an existing memory can become destabilized upon retrieval and subsequently be modified via protein-synthesis-dependent reconsolidation. However, not all memories appear to destabilize upon retrieval and thus are not modifiable via reconsolidation updating approaches and the neurobiological basis for this remains poorly understood. Here, we report that auditory fear memories created with 10 tone-shock pairings are resistant to retrieval-dependent memory destabilization and are associated with an increase in the synaptic GluN2A/GluN2B ratio in neurons of the basal and lateral amygdala (BLA) compared with weaker fear memories created via one or three tone-shock pairings. To increase the GluN2A/GluN2B ratio after learning, we generated a line of mice that expresses an inducible and doxycycline-dependent GFP-GluN2A transgene specifically in α-CaMKII-positive neurons. Our findings indicate that increasing the GluN2A/GluN2B ratio in BLA α-CaMKII-positive neurons after a weak fear memory has consolidated inhibits retrieval-dependent memory destabilization and modification of the fear memory trace. This was associated with a reduction in retrieval-dependent AMPA receptor trafficking, as evidenced by a reduction in retrieval-dependent phosphorylation of GluR1 at serine-845. In addition, we determined that increasing the GluN2A/GluN2B ratio before fear learning significantly impaired long term memory consolidation, whereas short-term memory remained unaltered. An increase in the GluN2A/GluN2B ratio after fear learning had no influence on fear extinction or expression. Our results underscore the importance of NMDAR subunit composition for memory destabilization and suggest a mechanism for why some memories are resistant to modification. SIGNIFICANCE STATEMENT: Memory modification using reconsolidation updating is being examined as one of the potential treatment approaches for attenuating maladaptive memories associated with emotional disorders. However, studies have shown that, whereas weak memories can be modified using reconsolidation updating, strong memories can be resistant to this approach. Therefore, treatments targeting the reconsolidation process are unlikely to be clinically effective unless methods are devised to enhance retrieval-dependent memory destabilization. Currently, little is known about the cellular and molecular events that influence the induction of reconsolidation updating. Here, we determined that an increase in the GluN2A/GluN2B ratio interferes with retrieval-dependent memory destabilization and inhibits the initiation of reconsolidation updating.

Radial artery access for peripheral endovascular procedures.

OBJECTIVE: The radial artery is often used for coronary angiography, with a demonstrated decrease in local complications and an increase in postoperative mobility of the patient. Data on radial artery access for peripheral endovascular procedures, however, are limited. We describe our experience with radial artery access for diagnostic and endovascular interventions. METHODS: Between February 2012 and March 2015, there were 95 endovascular procedures performed using radial artery access in 80 unique patients. Demographic and clinical data were recorded. Perioperative, postoperative, and 30-day follow-up data were evaluated retrospectively for major and minor complications. Major adverse events included any immediate hospitalization admission, stroke, hand amputation, bleeding requiring transfusion, hematoma requiring surgery, and death. Minor complications included superficial bleeding and hematoma. RESULTS: The patients (52.6% male, 47.4% female) had a mean age of 72.1 ± 9.4 years. Radial artery access was used for diagnostic purposes in 15.8% of all procedures and for therapeutic intervention, including angioplasty and stenting, in 84.2%. The radial artery was the only access point in 80% of patients and was accessed in conjunction with other sites in 20%. Percutaneous access was achieved in 100% of patients with a 100% technical success rate. Hemostasis after catheterization was achieved by manual compression (22.1%) and TR band (Terumo Medical, Tokyo, Japan; 77.9%). Major adverse events occurred in three cases (3.2%) and were unrelated to radial artery access. Radial artery access site-related complications occurred in three cases (3.2%), all of which were minor hematomas that required no treatment. The risk of radial artery complication was not associated with procedure type, vessels treated, or use of heparin. The incidence of stroke, hand ischemia, and upper extremity limb or finger loss was 0%. CONCLUSIONS: Radial artery access for peripheral endovascular procedures appears to be safe and effective and should be considered more often. Complication rates are lower than those reported for femoral artery access.

Fixed dose subcutaneous low molecular weight heparins versus adjusted dose unfractionated heparin for the initial treatment of venous thromboembolism.

BACKGROUND: Low molecular weight heparins (LMWHs) have been shown to be effective and safe in preventing venous thromboembolism (VTE). They may also be effective for the initial treatment of VTE. This is the third update of the Cochrane Review first published in 1999. OBJECTIVES: To evaluate the efficacy and safety of fixed dose subcutaneous low molecular weight heparin compared to adjusted dose unfractionated heparin (intravenous or subcutaneous) for the initial treatment of people with venous thromboembolism (acute deep venous thrombosis or pulmonary embolism). SEARCH METHODS: For this update the Cochrane Vascular Information Specialist (CIS) searched the Cochrane Vascular Specialised Register (15 September 2016). In addition the CIS searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8) in the Cochrane Library (searched 15 September 2016) and trials' registries. SELECTION CRITERIA: Randomised controlled trials comparing fixed dose subcutaneous LMWH with adjusted dose intravenous or subcutaneous unfractionated heparin (UFH) in people with VTE. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed for quality and extracted data. MAIN RESULTS: Six studies were added to this update resulting in a total of 29 included studies (n = 10,390). The quality of the studies was downgraded as there was a risk of bias in some individual studies relating to risk of attrition and reporting bias; in addition several studies did not adequately report on the randomisation methods used nor on how the treatment allocation was concealed.During the initial treatment period, the incidence of recurrent venous thromboembolic events was lower in participants treated with LMWH than in participants treated with UFH (Peto odds ratio (OR) 0.69, 95% confidence intervals (CI) 0.49 to 0.98; 6238 participants; 18 studies; P = 0.04; moderate-quality evidence). After a follow-up of three months, the period in most of the studies for which oral anticoagulant therapy was given, the incidence of recurrent VTE was lower in participants treated with LMWH than in participants with UFH (Peto OR 0.71, 95% CI 0.56 to 0.90; 6661 participants; 16 studies; P = 0.005; moderate-quality evidence). Furthermore, at the end of follow-up, LMWH was associated with a lower rate of recurrent VTE than UFH (Peto OR 0.72, 95% CI 0.59 to 0.88; 9489 participants; 22 studies; P = 0.001; moderate-quality evidence). LMWH was also associated with a reduction in thrombus size compared to UFH (Peto OR 0.71, 95% CI 0.61 to 0.82; 2909 participants; 16 studies; P < 0.00001; low-quality evidence), but there was moderate heterogeneity (I² = 56%). Major haemorrhages occurred less frequently in participants treated with LMWH than in those treated with UFH (Peto OR 0.69, 95% CI 0.50 to 0.95; 8780 participants; 25 studies; P = 0.02; moderate-quality evidence). There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (Peto OR 0.84, 95% CI 0.70 to 1.01; 9663 participants; 24 studies; P = 0.07; moderate-quality evidence). AUTHORS' CONCLUSIONS: This review presents moderate-quality evidence that fixed dose LMWH reduced the incidence of recurrent thrombotic complications and occurrence of major haemorrhage during initial treatment; and low-quality evidence that fixed dose LMWH reduced thrombus size when compared to UFH for the initial treatment of VTE. There was no difference in overall mortality between participants treated with LMWH and those treated with UFH (moderate-quality evidence). The quality of the evidence was assessed using GRADE criteria and downgraded due to concerns over risk of bias in individual trials together with a lack of reporting on the randomisation and concealment of treatment allocation methods used. The quality of the evidence for reduction of thrombus size was further downgraded because of heterogeneity between studies.

New Vein Compression Entities in Patients with Unexplained Leg Swelling.

BACKGROUND: This retrospective study identifies often overlooked anatomical sites for nonthrombotic venous outflow obstruction (NTVO) in patients with unexplained lower extremity edema and pain. METHODS: We reviewed the charts of 75 consecutive patients experiencing symptoms of unexplained lower extremity edema with pain that were unexplained by ultrasound, computed tomography angiography (CTA), and magnetic resonance imaging (MRI), who subsequently underwent venography in an outpatient medical office from 2010 to 2014. We categorized venograms based on the presence or absence of NTVO lesions and calculated prevalence of each at specific sites. The patients with NTVO lesions showing >50% stenosis on venography were then treated with angioplasty and/or stenting. After intervention, we documented subjective levels of pain and edema. RESULTS: Of the 75 venograms reviewed, physicians classified 52 as normal and 23 as showing evidence of compression, including 9 with May-Thurner syndrome and 14 with anatomical compressions at previously underreported sites. These 14 compression sites occurred at the following: iliofemoral vein at the inguinal ligament region (n = 7, 50%), external iliac vein at the iliac artery bifurcation (n = 1, 7.1%), both inguinal ligament region and iliac artery bifurcation (n = 4, 28.6%), and popliteal vein at the popliteal fossa (n = 2, 14.3%). Nine of the 14 patients (64.3%) reported total or near total resolution of lower extremity pain and edema at follow-up between 1 and 7 months (mean = 5.3 ± 2 months, median = 6 months) after balloon angioplasty and/or stent. Five with failed primary interventions underwent subsequent stenting and/or angioplasty and reported total or near total resolution of pain and clinical resolution of edema. CONCLUSIONS: This study provides evidence to broaden the disease profile of venous compression syndromes to other sites such as the hypogastric artery, inguinal ligament, and popliteal fossa. The results support previous research that suggests increased incidence of NTVO exists among patients with unexplained lower extremity edema and pain. In an effort to encourage further exploration, we developed a diagnostic algorithm to support a critical and systematic review of patients with lower extremity edema and pain that may go unexplained using traditional diagnostic measures, including ultrasound, CTA, and MRI alone.

U.S. Child Safety Seat Laws: Are they Effective, and Who Complies?

This paper assesses the effectiveness of child safety seat laws in the United States. Over the past 35 years, these laws have steadily increased mandatory child safety seat restraint ages. We exploit state-year level variation in the age until which children are required to ride in child safety seats to estimate triple difference models using Fatality Analysis Reporting System (FARS) data from 1975 to 2011. Our findings show that increasing the age thresholds is effective in increasing the actual age of children in safety seats. Across the child-age distribution, restraint rates increase by between 10 and 30 percentage points or by between 50 and 170 percent, in the long run. We also estimate the impact of the child safety seat laws on the likelihood that a child dies in a fatal accident. We find that the laws saved up to 39 children per year. Finally, we find that the laws primarily induce compliant parents to switch from traditional seatbelt use to child safety seat use, with only small effects among parents who do not restrain their children.