Influences of Intermittent Preventive Treatment and Persistent Multiclonal Plasmodium falciparum Infections on Clinical Malaria Risk

BACKGROUND: Intermittent preventive treatment (IPT) of malaria involves administration of curative doses of antimalarials at specified time points to vulnerable populations in endemic areas, regardless whether a subject is known to be infected. The effect of this new intervention on the development and maintenance of protective immunity needs further understanding. We have investigated how seasonal IPT affects the genetic diversity of Plasmodium falciparum infections and the risk of subsequent clinical malaria. MATERIAL AND METHODS: The study included 2227 Ghanaian children (3-59 months) who were given sulphadoxine-pyrimethamine (SP) bimonthly, artesunate plus amodiaquine (AS+AQ) monthly or bimonthly, or placebo monthly for six months spanning the malaria transmission season. Blood samples collected at three post-interventional surveys were analysed by genotyping of the polymorphic merozoite surface protein 2 gene. Malaria morbidity and anaemia was monitored during 12 months follow-up. RESULTS: Monthly IPT with AS+AQ resulted in a marked reduction in number of concurrent clones and only children parasite negative just after the intervention period developed clinical malaria during follow-up. In the placebo group, children without parasites as well as those infected with ≥2 clones had a reduced risk of subsequent malaria. The bimonthly SP or AS+AQ groups had similar number of clones as placebo after intervention; however, diversity and parasite negativity did not predict the risk of malaria. An interaction effect showed that multiclonal infections were only associated with protection in children without intermittent treatment. CONCLUSION: Molecular typing revealed effects of the intervention not detected by ordinary microscopy. Effective seasonal IPT temporarily reduced the prevalence and genetic diversity of P. falciparum infections. The reduced risk of malaria in children with multiclonal infections only seen in untreated children suggests that persistence of antigenically diverse P. falciparum infections is important for the maintenance of protective malaria immunity in high transmission settings

Facilitation of lethal ventricular arrhythmias by therapeutic digoxin in conscious post infarction dogs

The proarrhythmic potential of digoxin, administered in a therapeutic dosage regimen, was evaluated in conscious dogs in the subacute phase of myocardial infarction. In this evaluation, digoxin (0.0125 mg/kg/day intravenously) or vehicle were administered to conscious dogs for periods of 5 to 7 days, commencing 4 to 5 days after anterior myocardial infarction. Before treatment, programmed ventricular stimulation failed to initiate ventricular tachycardia in 26 post infarction dogs. After treatment, programmed stimulation initiated ventricular tachyarrhythmias in only 1 of 13 digoxin-treated dogs (1.36 +/- 0.17 ng/ml serum digoxin) and in 0 of 13 vehicle-treated dogs. However, the incidences of early ventricular fibrilation (4 of 10 digoxin vs 0 of 12 vehicle; p p < 0.05) occurring in response to the development of posterolateral ischemia in the presence of previous anterior myocardial infarction was significantly greater in digoxin-treated (1.47 +/- 0.19 ng/ml serum digoxin) than in vehicle-treated animals. These findings suggest an enhanced susceptibility toward the development of ischemia-related lethal arrhythmias in the presence of therapeutic digoxin serum concentrations early after myocardial infarction, which is not predicted by programmed ventricular stimulation testing.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26443/1/0000531.pd

Datathons and Software to Promote Reproducible Research

Background: Datathons facilitate collaboration between clinicians, statisticians, and data scientists in order to answer important clinical questions. Previous datathons have resulted in numerous publications of interest to the critical care community and serve as a viable model for interdisciplinary collaboration. Objective: We report on an open-source software called Chatto that was created by members of our group, in the context of the second international Critical Care Datathon, held in September 2015. Methods: Datathon participants formed teams to discuss potential research questions and the methods required to address them. They were provided with the Chatto suite of tools to facilitate their teamwork. Each multidisciplinary team spent the next 2 days with clinicians working alongside data scientists to write code, extract and analyze data, and reformulate their queries in real time as needed. All projects were then presented on the last day of the datathon to a panel of judges that consisted of clinicians and scientists. Results: Use of Chatto was particularly effective in the datathon setting, enabling teams to reduce the time spent configuring their research environments to just a few minutes—a process that would normally take hours to days. Chatto continued to serve as a useful research tool after the conclusion of the datathon. Conclusions: This suite of tools fulfills two purposes: (1) facilitation of interdisciplinary teamwork through archiving and version control of datasets, analytical code, and team discussions, and (2) advancement of research reproducibility by functioning postpublication as an online environment in which independent investigators can rerun or modify analyses with relative ease. With the introduction of Chatto, we hope to solve a variety of challenges presented by collaborative data mining projects while improving research reproducibility

Precision asteroseismology of the pulsating white dwarf GD 1212 using a two-wheel-controlled Kepler spacecraft

We present a preliminary analysis of the cool pulsating white dwarf GD 1212, enabled by more than 11.5 days of space-based photometry obtained during an engineering test of the two-reaction-wheel-controlled Kepler spacecraft. We detect at least 19 independent pulsation modes, ranging from 828.2-1220.8 s, and at least 17 nonlinear combination frequencies of those independent pulsations. Our longest uninterrupted light curve, 9.0 days in length, evidences coherent difference frequencies at periods inaccessible from the ground, up to 14.5 hr, the longest-period signals ever detected in a pulsating white dwarf. These results mark some of the first science to come from a two-wheel-controlled Kepler spacecraft, proving the capability for unprecedented discoveries afforded by extending Kepler observations to the ecliptic.Comment: 8 pages, 4 figures, accepted for publication in The Astrophysical Journa

Postinfarction sudden death: Significance of inducible ventricular tachycardia and infarct size in a conscious canine model

The relationship between inducible ventricular tachycardia in the convalescent phase of myocardial infarction and subsequent spontaneous ventricular fibrillation is uncertain. Thirty conscious instrumented dogs underwent programmed ventricular stimulation 5 days after anterior infarction; 15 had inducible ventricular tachycardia and 15 were noninducible. Following programmed ventricular stimulation, the application of a 150 uA current to the intima of the proximal circumflex artery initiated intimal damage, thrombosis, and acute ischemia of the posterolateral wall. After 20 minutes of ischemia, 73% inducible and 15% noninducible anlmals developed ventricular fibrillation (p p p < 0.001) animals. Inducible ventricular tachycardia following infarction was highly predictive of spontaneous ventricular fibrillation during a later ischemic episode in this model. The mass of previously injured myocardium was a critical determinant of both.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25787/1/0000349.pd

Prevention of ventricular fibrillation by dextrorotatory sotalol in a conscious canine model of sudden coronary death

The antiarrhythmic and antifibrillatory actions of the dextrorotatory isomer of sotalol, administered in a multiple-dose regimen, were evaluated in conscious dogs 3 to 5 days after anterior myocardial infarction. The intravenous administration of d-sotalol, four 8 mg/kg doses over a 24-hour treatment period, suppressed the induction of ventricular tachycardia by programmed electrical stimulation in six of nine dogs tested, slowed the rate of the induced tachyarrhythmia in two of the remaining three dogs, and provided significant protection (5 of 8 d-sotalol vs 0 of 8 vehicle control) against the development of ventricular fibrillation in response to ischemia at a site distant to a previous myocardial infarction. Increases in ventricular myocardial refractoriness and in QTc and paced QT intervals suggest that class III electrophysiologic actions contribute to the antiarrhythmic properties of dextrorotatory sotalol in this animal model. The degree of beta-adrenergic receptor blockade produced by d-sotalol in this dose regimen was negligible. These findings suggest the potential utility of d-sotalol in the prevention of ventricular tachycardia and ventricular fibrillation in the setting of myocardial infarction, particularly when beta-adrenergic receptor blockade is undesirable or contraindicated.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/25694/1/0000248.pd

Evaluation of left ventricular ejection fraction as a measure of pump performance in patients with chronic mitral regurgitation

Left ventricular (LV) ejection fraction may not adequately detect a reduction in LV systolic performance resulting from chronic mitral regurgitation (MR), due to ventricular unloading into the low-impedance left atrium. To determine whether LV ejection fraction sufficiently gauges myocardial function in MR, nine patients were studied using micromanometer-measured LV pressures and biplane cineventriculography before and 1 year after mitral valve surgery. Six control patients were also studied. LV ejection fraction was normal in MR patients, despite an increase in LV end-systolic volume index. LV end-systolic pressure-volume and stress-volume ratios in MR patients were lower than in controls ( P < 0.05 and P < 0.01), suggesting that LV systolic performance fell. One year after mitral valve surgery, LV ejection fraction decreased ( P < 0.05) even though LV end-systolic volume index ( P < 0.05), pressure-volume ( P < 0.05), and stress-volume ratios ( P < 0.01) all improved. Thus, LV ejection fraction inadequately reflected LV systolic function in MR patients before and after mitral valve surgery. Cathet. Cardiovasc. Intervent. 49:290–296, 2000. © 2000 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/35248/1/14_ftp.pd

Electrophysiologic actions of pirmenol in dogs with recent myocardial infarction

The electrophysiologic actions of pirmenol, an investigational class I antiarrhythmic agent, were evaluated in eight anesthetized dogs, 5 to 10 days after anterior myocardial infarction. Before administration of the drug, programmed ventricular stimulation failed to initiate nonsustained or sustained ventricular tachyarrhythmias (VT) in any of the postinfarction dogs. After the cumulative administration of 2.5, 5.0, and 10.0 mg/kg pirmenol, programmed stimulation initiated sustained VT in six of the eight postinfarction dogs tested, with one additional dog responding with reproducible nonsustained VT (15 to 20 monomorphic complexes) after pirmenol adminstration. Only one of eight postinfarction dogs tested remained noninducible throughout the primenol dosing schedule. Administration of pirmenol tended to increase ventricular excitation thresholds, relative (p p p &lt; 0.01 after 2.5, 5, and 10, mg/kg) refractory periods between ischemically injured and normal noninjured ventricular myocardium. These findings suggest a potential for the provocation or aggravation of ventricular arrhythmias by pirmenol in the setting of recent myocardial infarction.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/26034/1/0000107.pd

Electrophysiologic actions and antifibrillatory efficacy of subacute left stellectomy in a conscious, post-infarction canine model of ischemic ventricular fibrillation

The autonomic nervous system appears to modulate ventricular arrhythmias associated with acute myocardial ischemia. This study investigated the electrophysiologic effects and antifibrillatory actions of subacute left stellectomy in a conscious, post-infarction canine model of sudden cardiac death.Twenty-two dogs with a previous anterior wall myocardial infarction and inducible ventricular arrhythmias were randomized to undergo either left stellectomy (n = 12) or remain as sham-denervated controls (n = 10). Five to 7 days post left stellectomy, there were no significant changes in heart rate, electrocardiographic intervals or ventricular refractoriness compared to sham-denervated controls. Acute posterolateral ischemia was produced in left stellectomy and sham-denervated dogs by anodal current-induced thrombosis via a previously positioned electrode in the left circumflex coronary artery. Ventricular fibrillation developed within 1 hour of the onset of ischemia (early ventricular fibrillation) in 3/12 (25%) left stellectomy dogs versus 8/10 (80%) sham-denervated controls (P P = 0.072). Small differences in regional myocardial norepinephrine content, which is a marker for neuronal integrity, occurred in the mid-posterolateral and mid-anteroseptal regions of the left ventricle after left stellectomy. Overall norepinephrine concentration after left stellectomy was 409.70 +/- 9.90 ng/g vs 428.07 +/- 10.84 ng/g in sham controls (P = NS).In summary, subacute left stellectomy significantly reduces the incidence of ventricular fibrillation occurring within 1 hour of the onset of acute posterolateral ischemia at a distance to a previous myocardial infarction in conscious dogs, and tends to reduce the ischemic post-infarction mortality at 24 hours after the onset of ischemia. This protective effect of left stellectomy is not due to any alteration in cardiac electrophysiologic parameters measured prior to the development of acute posterolateral ischemia, nor is it related to regional denervation as determined by myocardial tissue concentration of residual norepinephrine.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/28039/1/0000478.pd

Allelic Expression of Deleterious Protein-Coding Variants across Human Tissues

Personal exome and genome sequencing provides access to loss-of-function and rare deleterious alleles whose interpretation is expected to provide insight into individual disease burden. However, for each allele, accurate interpretation of its effect will depend on both its penetrance and the trait's expressivity. In this regard, an important factor that can modify the effect of a pathogenic coding allele is its level of expression; a factor which itself characteristically changes across tissues. To better inform the degree to which pathogenic alleles can be modified by expression level across multiple tissues, we have conducted exome, RNA and deep, targeted allele-specific expression (ASE) sequencing in ten tissues obtained from a single individual. By combining such data, we report the impact of rare and common loss-of-function variants on allelic expression exposing stronger allelic bias for rare stop-gain variants and informing the extent to which rare deleterious coding alleles are consistently expressed across tissues. This study demonstrates the potential importance of transcriptome data to the interpretation of pathogenic protein-coding variants