Complete Atrioventricular Heart Block From an Epilepsy Treatment

Atrioventricular (AV) heart block without adequate escape rhythm can result in sudden cardiac arrest and death. We report complete (third degree) AV block in a 16 year-old boy as a late effect of vagus nerve stimulation (VNS). He experienced brief, daily, complex partial seizures, treated with lamotrigine, levetiracetam, and the placement of Model 102 VNS at age 4. Electroencephalography (EEG) showed generalized slow spike-and-wave discharges consistent with Lennox-Gastaut syndrome. At age 12, his VNS was changed to Model 303 PereniaDURA/Model 103 Demipulse generator, set at an output current of 2.25 mA on a standard 30 seconds on, 5 minutes off paradigm. At age 16, he experienced episodes of sudden collapse followed by unconsciousness. Holter monitor showed 15 second symptomatic complete AV block without escape (Figure 1). The patient was taking psychotropic medication with potential cardiac side effects: methylphenidate (tachycardia), guanfacine (first degree AV block), and haloperidol (prolonged QT interval, Torsades de Pointes). Haloperidol, methylphenidate, and VNS were stopped without further symptoms. Off these medications, the VNS was resumed at reduced current (1.25 mA), with re-occurrence of symptomatic AV block. Again, the VNS was stopped and symptoms/heart block ceased. Psychotropic medication was resumed without any side effects

Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3–synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3+CD147+), but not single antigen (GPC3-CD147+) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients

Dosing and safety profile of aficamten in symptomatic obstructive hypertrophic cardiomyopathy: results from from SEQUOIA‐HCM

Background: Aficamten, a novel cardiac myosin inhibitor, reversibly reduces cardiac hypercontractility in obstructive hypertrophic cardiomyopathy. We present a prespecified analysis of the pharmacokinetics, pharmacodynamics, and safety of aficamten in SEQUOIA‐HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). Methods and Results: A total of 282 patients with obstructive hypertrophic cardiomyopathy were randomized 1:1 to daily aficamten (5–20 mg) or placebo between February 1, 2022, and May 15, 2023. Aficamten dosing targeted the lowest effective dose for achieving site‐interpreted Valsalva left ventricular outflow tract gradient <30 mm Hg with left ventricular ejection fraction (LVEF) ≥50%. End points were evaluated during titration (day 1 to week 8), maintenance (weeks 8–24), and washout (weeks 24–28), and included major adverse cardiac events, new‐onset atrial fibrillation, implantable cardioverter‐defibrillator discharges, LVEF <50%, and treatment‐emergent adverse events. At week 8, 3.6%, 12.9%, 35%, and 48.6% of patients achieved 5‐, 10‐, 15‐, and 20‐mg doses, respectively. Baseline characteristics were similar across groups. Aficamten concentration increased by dose and remained stable during maintenance. During the treatment period, LVEF decreased by −0.9% (95% CI, −1.3 to −0.6) per 100 ng/mL aficamten exposure. Seven (4.9%) patients taking aficamten underwent per‐protocol dose reduction for site‐interpreted LVEF <50%. There were no treatment interruptions or heart failure worsening for LVEF <50%. No major adverse cardiovascular events were associated with aficamten, and treatment‐emergent adverse events were similar between treatment groups, including atrial fibrillation. Conclusions: A site‐based dosing algorithm targeting the lowest effective aficamten dose reduced left ventricular outflow tract gradient with a favorable safety profile throughout SEQUOIA‐HCM

Complete Atrioventricular Heart Block From an Epilepsy Treatment

Atrioventricular (AV) heart block without adequate escape rhythm can result in sudden cardiac arrest and death. We report complete (third degree) AV block in a 16 year-old boy as a late effect of vagus nerve stimulation (VNS). He experienced brief, daily, complex partial seizures, treated with lamotrigine, levetiracetam, and the placement of Model 102 VNS at age 4. Electroencephalography (EEG) showed generalized slow spike-and-wave discharges consistent with Lennox-Gastaut syndrome. At age 12, his VNS was changed to Model 303 PereniaDURA/Model 103 Demipulse generator, set at an output current of 2.25 mA on a standard 30 seconds on, 5 minutes off paradigm. At age 16, he experienced episodes of sudden collapse followed by unconsciousness. Holter monitor showed 15 second symptomatic complete AV block without escape (Figure 1). The patient was taking psychotropic medication with potential cardiac side effects: methylphenidate (tachycardia), guanfacine (first degree AV block), and haloperidol (prolonged QT interval, Torsades de Pointes). Haloperidol, methylphenidate, and VNS were stopped without further symptoms. Off these medications, the VNS was resumed at reduced current (1.25 mA), with re-occurrence of symptomatic AV block. Again, the VNS was stopped and symptoms/heart block ceased. Psychotropic medication was resumed without any side effects

Op18 reveals the contribution of nonkinetochore microtubules to the dynamic organization of the vertebrate meiotic spindle

Accuracy in chromosome segregation depends on the assembly of a bipolar spindle. Unlike mitotic spindles, which have roughly equal amounts of kinetochore microtubules (kMTs) and nonkinetochore microtubules (non-kMTs), vertebrate meiotic spindles are predominantly comprised of non-kMTs, a large subset of which forms an antiparallel “barrel” array at the spindle equator. Though kMTs are needed to drive chromosome segregation, the contributions of non-kMTs are more mysterious. Here, we show that increasing the concentration of Op18/stathmin, a component of the chromosome-mediated microtubule formation pathway that directly controls microtubule dynamics, can be used to deplete non-kMTs in the vertebrate meiotic spindle assembled in Xenopus egg extracts. Under these conditions, kMTs and the spindle pole-associated non-kMT arrays persist in smaller spindles. In excess Op18, distances between sister kinetochores, an indicator of tension across centromeres, remain unchanged, even though kMTs flux poleward with a ≈30% slower velocity, and chromosomes oscillate more than in control metaphase spindles. Remarkably, kinesin-5, a conserved motor protein that can push microtubules apart and is required for the assembly and maintenance of bipolar meiotic spindles, is not needed to maintain spindle bipolarity in the presence of excess Op18. Our data suggest that non-kMTs in meiotic spindles contribute to normal kMT dynamics, stable chromosome positioning, and the establishment of proper spindle size. We propose that without non-kMTs, metaphase meiotic spindles are similar to mammalian mitotic spindles, which balance forces to maintain metaphase spindle organization in the absence of extensive antiparallel microtubule overlap at the spindle equator or a key mitotic kinesin

Balancing Curriculum Freedom and Regulation in the Netherlands

The extent to which the goals and contents of (compulsory) education should to be regulated has been a complicated balancing act in the Netherlands. Against a background of a longstanding statutory tradition of freedom of education, governmental decisions about ‘what knowledge is of most worth’ have been delicate. The purpose of the analysis described in this article is to disentangle, interpret and discuss this complicated balancing act between curriculum regulation and curriculum freedom during the past 40 years and to learn from other countries by putting the results into a wider European curriculum policy perspective. The contribution will end with discussing issues that need to be carefully considered with respect to the recent Dutch policy shift towards output regulation by means of mandatory achievement tests for mathematics, mother tongue and English at the end of lower secondary education