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Insertable cardiac monitors are minimally invasive devices designed for implantation in the chest wall of patients to record heart rhythms and relate them to symptoms over prolonged periods. The Jot Dx™ (Abbott Laboratories, Abbott Park, IL, USA) is the latest Food and Drug Administration-cleared insertable cardiac monitor that is Bluetooth™ enabled allowing for near-immediate transmission of data from patients to physicians. We report on the first paediatric patient, in a patient weighing 11.7 kg, to undergo a modified, vertical, parasternal implantation of a Jot Dx™.

Implantable cardiac monitors (ICM) allow for symptom-rhythm correlation. Current manufacturer recommendations call for implantation of ICMs diagonally in the left anterior chest. Complications such as skin tenting and device erosion have occurred using this technique in pediatric patients. The purpose of this study was to assess the safety and efficacy of implanting ICMs via new vertical-parasternal technique (VP) compared to manufacturer-recommended diagonal technique (D) in pediatric patients. Single-center, IRB-approved retrospective study of pediatric patients that underwent ICM implantation from 01/01/2017 to 12/01/2021. All implants were performed after informed consent, under sterile conditions in the electrophysiology laboratory. Data collected included demographics, implant orientation (VP or D), complications, device type, presence of P-wave, and measurement of R-wave amplitude at implantation and follow-up. ICMs were implanted in 34 patients without congenital heart disease. Initial R-wave amplitude average for VP 1.00, D 0.99 (p = NS). Follow-up R-wave amplitude was 0.97 VP and 0.93 for D (p = NS). Median follow-up period for VP was 11 and for D was 20 months (p = NS). D cohort had only post-procedural complication due to skin tenting of the ICM in child 2.5 years of age. No skin tenting, erosions, or complications occurred in the vertical-parasternal implant technique. Vertical-Parasternal ICM implantation is as safe and effective as the manufacturer-recommended diagonal implant. Short- and long-term data demonstrate an equivalent R-wave detection and no significant signal deterioration, even in very young children. No skin tenting, erosions, or complications occurred in the vertical parasternal implant technique.

To manage ocular redness effectively, health-care practitioners require an understanding of the pathophysiology, clinical features and differential diagnosis of ocular redness, as well as comprehensive knowledge of medical therapies available and their pharmacologic properties. This review aims to provide a clinically relevant summary of the current literature on the mechanism of action, efficacy, and safety of current over-the-counter (OTC) decongestants available for reduction of ocular redness due to minor irritations. Currently marketed OTC products indicated for such use in the United States include topical solutions of tetrahydrozoline 0.05%, naphazoline 0.012% to 0.03%, and brimonidine 0.025%. All 3 agents are adrenergic receptor agonists but vary in their receptor-binding profiles: tetrahydrozoline is a selective α1 receptor agonist; naphazoline is a mixed α1/α2 receptor agonist; and brimonidine is a selective α2 receptor agonist. These OTC decongestants produce vasoconstriction of conjunctival blood vessels, which results in a rapid reduction in ocular redness. In general, ocular adverse events reported in published studies of these OTC decongestants were minimal, mild, and transient, with no significant adverse systemic effects. However, ocular decongestants with α1-adrenergic receptor agonist activity can be associated with loss of effectiveness with continued use (ie, tachyphylaxis) and rebound redness upon treatment discontinuation. In clinical trials of the selective α2-adrenergic receptor agonist brimonidine 0.025%, tachyphylaxis was not observed, and rebound redness was rarely reported.

Phrenic nerve injury can lead to a disruption of the autonomic nervous system (ANS) resulting in episodes of bradycardic arrest. Implanted diaphragmatic pacing has been used to overcome phrenic nerve paralysis, but these do not change the ANS. Therefore, patients with phrenic nerve paralysis may require the implantation of a permanent cardiac pacemaker to overcome bradycardic episodes. Having two electronic devices in the same patient may lead to device-device interaction (DDI). This can result in over-sensing leading to lack of pacing of either device. We present the case of a 17-year-old pediatric male with phrenic nerve injury who required implantation of both diaphragm and cardiac pacemaker. Intra-procedural interrogation of the cardiac pacemaker demonstrated DDI in unipolar mode, but not in bipolar. Thus, we demonstrated the safe utilization of multiple implantable electronic devices in the pediatric patient without device-device interaction.

Transseptal puncture (TSP) is commonly conducted under the guidance of fluoroscopy and/or intracardiac echocardiography (ICE) at the fossa ovalis (FO) to gain percutaneous access to the left atrium for intracardiac procedures. Issues with traditional TSP include: additional vascular access through a sheath, and fluoroscopy exposes patients to ionizing radiation. TSP, if not done appropriately can result in serious complications. We studied the feasibility of optical coherence tomography (OCT) guidance of TSP with ex vivo and in vivo experiments. Results show that OCT can provide detailed structure information to identify FO allowing for safe TSP.

Large-scale human genetics studies are ascertaining increasing proportions of populations as they continue growing in both number and scale. As a result, the amount of cryptic relatedness within these study cohorts is growing rapidly and has significant implications on downstream analyses. We demonstrate this growth empirically among the first 92,455 exomes from the DiscovEHR cohort and, via a custom simulation framework we developed called SimProgeny, show that these measures are in-line with expectations given the underlying population and ascertainment approach. For example, we identified ∼66,000 close (first- and second-degree) relationships within DiscovEHR involving 55.6% of study participants. Our simulation results project that >70% of the cohort will be involved in these close relationships as DiscovEHR scales to 250,000 recruited individuals. We reconstructed 12,574 pedigrees using these relationships (including 2,192 nuclear families) and leveraged them for multiple applications. The pedigrees substantially improved the phasing accuracy of 20,947 rare, deleterious compound heterozygous mutations. Reconstructed nuclear families were critical for identifying 3,415 de novo mutations in ∼1,783 genes. Finally, we demonstrate the segregation of known and suspected disease-causing mutations through reconstructed pedigrees, including a tandem duplication in LDLR causing familial hypercholesterolemia. In summary, this work highlights the prevalence of cryptic relatedness expected among large healthcare population genomic studies and demonstrates several analyses that are uniquely enabled by large amounts of cryptic relatedness.

The increasing demand for rigor in empirical economics has led to the growing use of auxiliary tests (balance, specification, over-identification, placebo, etc.) supporting the credibility of a paper’s main results. We dub these “sniff tests” because standards for passing are subjective and rejection is bad news for the author. Sniff tests offer a new window into publication bias since authors prefer them to be insignificant, the reverse of standard statistical tests. Collecting a sample of nearly 30,000 sniff tests across 60 economics journals, we provide the first estimate of their aggregate probability-value (p-value) distribution. For the subsample of balance tests in randomized controlled trials (for which the distribution of p-values is known to be uniform absent publication bias, allowing reduced-form methods to be employed) estimates suggest that 45% of failed tests remain in the “file drawer” rather than being published. For the remaining sample with an unknown distribution of p-values, structural estimates suggest an even larger file-drawer problem, as high as 91%. Fewer significant sniff tests show up in top-tier journals, smaller tables, and more recent articles. We find no evidence of author manipulation other than a tendency to overly attribute significant sniff tests to bad luck.

The springtime sublimation process of Mars' southern seasonal polar CO$_2$ ice cap features dark fan-shaped deposits appearing on the top of the thawing ice sheet. The fan material likely originates from the surface below the ice sheet, brought up via CO$_2$ jets breaking through the seasonal ice cap. Once the dust and dirt is released into the atmosphere, the material may be blown by the surface winds into the dark streaks visible from orbit. The location, size and direction of these fans record a number of parameters important to quantifying seasonal winds and sublimation activity, the most important agent of geological change extant on Mars. We present results of a systematic mapping of these south polar seasonal fans with the Planet Four online citizen science project. Planet Four enlists the general public to map the shapes, directions, and sizes of the seasonal fans visible in orbital images. Over 80,000 volunteers have contributed to the Planet Four project, reviewing 221 images, from Mars Reconnaissance Orbiter's HiRISE (High Resolution Imaging Science Experiment) camera, taken in southern spring during Mars Years 29 and 30. We provide an overview of Planet Four and detail the processes of combining multiple volunteer assessments together to generate a high fidelity catalog of $\sim$ 400,000 south polar seasonal fans. We present the results from analyzing the wind directions at several locations monitored by HiRISE over two Mars years, providing new insights into polar surface winds., Comment: 75 pages, 46 figures, minor revisions discovered in proof, accepted and in press at Icarus

To ascertain the structure–activity relationship of the core 1,2,4-trioxolane substructure of dispiro ozonides OZ277 and OZ439, we compared the antimalarial activities and ADME profiles of the 1,2-dioxolane, 1,2,4-trioxane, and 1,2,4,5-tetraoxane isosteres. Consistent with previous data, both dioxolanes had very weak antimalarial properties. For the OZ277 series, the trioxane isostere had the best ADME profile, but its overall antimalarial efficacy was not superior to that of the trioxolane or tetraoxane isosteres. For the OZ439 series, there was a good correlation between the antimalarial efficacy and ADME profiles in the rank order trioxolane > trioxane > tetraoxane. As we have previously observed for OZ439 versus OZ277, the OZ439 series peroxides had superior exposure and efficacy in mice compared to the corresponding OZ277 series peroxides.

Background Artemisinin resistance observed in Southeast Asia threatens the continued use of artemisinin-based combination therapy in endemic countries. Additionally, the diversity of chemical mode of action in the global portfolio of marketed antimalarials is extremely limited. Addressing the urgent need for the development of new antimalarials, a chemical class of potent antimalarial compounds with a novel mode of action was recently identified. Herein, the preclinical characterization of one of these compounds, ACT-451840, conducted in partnership with academic and industrial groups is presented. Method and Findings The properties of ACT-451840 are described, including its spectrum of activities against multiple life cycle stages of the human malaria parasite Plasmodium falciparum (asexual and sexual) and Plasmodium vivax (asexual) as well as oral in vivo efficacies in two murine malaria models that permit infection with the human and the rodent parasites P. falciparum and Plasmodium berghei, respectively. In vitro, ACT-451840 showed a 50% inhibition concentration of 0.4 nM (standard deviation [SD]: ± 0.0 nM) against the drug-sensitive P. falciparum NF54 strain. The 90% effective doses in the in vivo efficacy models were 3.7 mg/kg against P. falciparum (95% confidence interval: 3.3–4.9 mg/kg) and 13 mg/kg against P. berghei (95% confidence interval: 11–16 mg/kg). ACT-451840 potently prevented male gamete formation from the gametocyte stage with a 50% inhibition concentration of 5.89 nM (SD: ± 1.80 nM) and dose-dependently blocked oocyst development in the mosquito with a 50% inhibitory concentration of 30 nM (range: 23–39). The compound’s preclinical safety profile is presented and is in line with the published results of the first-in-man study in healthy male participants, in whom ACT-451840 was well tolerated. Pharmacokinetic/pharmacodynamic (PK/PD) modeling was applied using efficacy in the murine models (defined either as antimalarial activity or as survival) in relation to area under the concentration versus time curve (AUC), maximum observed plasma concentration (Cmax), and time above a threshold concentration. The determination of the dose–efficacy relationship of ACT-451840 under curative conditions in rodent malaria models allowed prediction of the human efficacious exposure. Conclusion The dual activity of ACT-451840 against asexual and sexual stages of P. falciparum and the activity on P. vivax have the potential to meet the specific profile of a target compound that could replace the fast-acting artemisinin component and harbor additional gametocytocidal activity and, thereby, transmission-blocking properties. The fast parasite reduction ratio (PRR) and gametocytocidal effect of ACT-451840 were recently also confirmed in a clinical proof-of-concept (POC) study., Sergio Wittlin and colleagues report in vivo and in vitro modelling of antimalarial activity and dose-efficacy of a new drug candidate., Author Summary Why Was This Study Done? The limited diversity of chemical mode of action in the global portfolio of marketed antimalarials along with recently observed artemisinin resistance that threatens the current first-line treatment highlights the urgent need for development of new antimalarials. In accordance with target product profiles defined by the Medicines for Malaria Venture ([MMV]; www.mmv.org), a new model of not-for-profit public–private partnership providing guidance to the development of new drugs, ACT-451840, a new chemical class of potent compounds with a novel mode of action, was selected for early development. This manuscript integrates a number of studies performed to characterize preclinically ACT-451840 and illustrates the new antimalarial drug development paradigm. What Did the Researchers Do and Find? This study used in vitro models to investigate compound activity on sexual and asexual blood stages and a mouse model to study the human parasite P. falciparum in vivo. While being fully active against artemisinin-resistant strains, ACT-451840 shares many of the favorable properties of artemisinins like its fast onset of action, activity against all asexual blood stage forms, and a PRR of >4 log per parasite cycle. Pharmacodynamic properties of ACT-451840 were interpreted in two mouse models of malaria with respect to the pharmacokinetic properties, with the objective to establish the portable PK/PD parameters to estimate efficacious exposure. What Do These Findings Mean? Modeling the dose–efficacy relationship of ACT-451840 supported prediction of the human efficacious exposure and therefore laid the groundwork for the new clinical development phases. Confirmed in an experimental human malaria infection model, the properties of ACT-451840, including its fast action observed in in vitro and in vivo models and its transmission-blocking activity, suggest this compound may be able to replace the artemisinin component in artemisinin-based combination therapy.

This article describes the development of a research-based assessment tool, the Central Dogma Concept Inventory. The instrument consists of 23 multiple-select questions about information flow in molecular biology and gauges conceptual understanding in depth across the undergraduate curriculum., Scientific teaching requires scientifically constructed, field-tested instruments to accurately evaluate student thinking and gauge teacher effectiveness. We have developed a 23-question, multiple select–format assessment of student understanding of the essential concepts of the central dogma of molecular biology that is appropriate for all levels of undergraduate biology. Questions for the Central Dogma Concept Inventory (CDCI) tool were developed and iteratively revised based on student language and review by experts. The ability of the CDCI to discriminate between levels of understanding of the central dogma is supported by field testing (N = 54), and large-scale beta testing (N = 1733). Performance on the assessment increased with experience in biology; scores covered a broad range and showed no ceiling effect, even with senior biology majors, and pre/posttesting of a single class focused on the central dogma showed significant improvement. The multiple-select format reduces the chances of correct answers by random guessing, allows students at different levels to exhibit the extent of their knowledge, and provides deeper insight into the complexity of student thinking on each theme. To date, the CDCI is the first tool dedicated to measuring student thinking about the central dogma of molecular biology, and version 5 is ready to use.