Prenatal Exposure to Methamphetamine Causes Vascular Dysfunction in Adult Male Offspring

Methamphetamine use during pregnancy can have negative consequences on the offspring. However, most studies investigating the impact of prenatal exposure to methamphetamine have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine on the adult cardiovascular system. This study investigated the impact of chronic fetal exposure to methamphetamine on vascular function in adult offspring. Pregnant female rats received daily saline or methamphetamine (5 mg/kg) injections starting on gestational day 1 and continuing until the pups were born. Vascular function was assessed in 5 month old offspring. Prenatal methamphetamine significantly decreased both the efficacy and potency of acetylcholine-induced relaxation in isolated male (but not female) aortas when perivascular adipose tissue (PVAT) remained intact. However, prenatal methamphetamine had no impact on acetylcholine-induced relaxation when PVAT was removed. Nitroprusside-induced relaxation of the aorta was unaffected by prenatal methamphetamine. Angiotensin II-induced contractile responses were significantly potentiated in male (but not female) aortas regardless of the presence of PVAT. This effect was reversed by L-nitro arginine methyl ester (L-NAME). Serotonin- and phenylephrine-induced contraction were unaffected by prenatal methamphetamine. Prenatal methamphetamine had no impact on acetylcholine-induced relaxation of third order mesenteric arteries and no effect on basal blood pressure. These data provide evidence that prenatal exposure to methamphetamine sex-dependently alters vasomotor function in the vasculature and may increase the risk of developing vascular disorders later in adult life

Fossil evidence for a pharyngeal origin of the vertebrate pectoral girdle

The origin of vertebrate paired appendages is one of the most investigated and debated examples of evolutionary novelty. Paired appendages are widely considered key innovations that allowed new opportunities for controlled swimming and gill ventilation and were prerequisites for the eventual transition from water to land. The last 150 years of debate has been shaped by two contentious theories: the ventrolateral fin-fold hypothesis and the archipterygium hypothesis. The latter proposes that fins and girdles evolved from an ancestral gill arch. Although tantalizing developmental evidence has revived interest in this idea, it is apparently unsupported by fossil evidence. Here we present fossil evidence of a pharyngeal basis for the vertebrate shoulder girdle. We use CT scanning to reveal details of the braincase of Kolymaspis sibirica, a placoderm fish from the Early Devonian of Siberia that suggests a pharyngeal component of the shoulder. We combine these findings with refreshed comparative anatomy of placoderms and jawless outgroups to place the origin of the shoulder girdle on the sixth branchial arch. These findings provide a novel framework for understanding the origin of the pectoral girdle. Our new evidence clarifies the location of the presumptive head-trunk interface in jawless fishes and explains the constraint on branchial arch number in gnathostomes. The results revive a key aspect of the archipterygium hypothesis, but also reconciles it with the ventrolateral fin fold model

Environmental Symbiont Acquisition May Not Be the Solution to Warming Seas for Reef-Building Corals

BACKGROUND: Coral reefs worldwide are in decline. Much of the mortality can be attributed to coral bleaching (loss of the coral's intracellular photosynthetic algal symbiont) associated with global warming. How corals will respond to increasing oceanic temperatures has been an area of extensive study and debate. Recovery after a bleaching event is dependent on regaining symbionts, but the source of repopulating symbionts is poorly understood. Possibilities include recovery from the proliferation of endogenous symbionts or recovery by uptake of exogenous stress-tolerant symbionts. METHODOLOGY/PRINCIPAL FINDINGS: To test one of these possibilities, the ability of corals to acquire exogenous symbionts, bleached colonies of Porites divaricata were exposed to symbiont types not normally found within this coral and symbiont acquisition was monitored. After three weeks exposure to exogenous symbionts, these novel symbionts were detected in some of the recovering corals, providing the first experimental evidence that scleractinian corals are capable of temporarily acquiring symbionts from the water column after bleaching. However, the acquisition was transient, indicating that the new symbioses were unstable. Only those symbiont types present before bleaching were stable upon recovery, demonstrating that recovery was from the resident in situ symbiont populations. CONCLUSIONS/SIGNIFICANCE: These findings suggest that some corals do not have the ability to adjust to climate warming by acquiring and maintaining exogenous, more stress-tolerant symbionts. This has serious ramifications for the success of coral reefs and surrounding ecosystems and suggests that unless actions are taken to reverse it, climate change will lead to decreases in biodiversity and a loss of coral reefs

Longitudinal Pooled Deep Sequencing of the Plasmodium vivax K12 Kelch Gene in Cambodia Reveals a Lack of Selection by Artemisinin

The emergence of artemisinin resistance among Plasmodium falciparum in the Greater Mekong subregion threatens malaria control interventions and is associated with multiple unique mutations in K13 (PF3D7_1343700). The aim of this study was to survey Cambodian Plasmodium vivax for mutations in the K13 ortholog (K12, PVX_083080) that might similarly confer artemisinin resistance. Extracted DNA from Cambodian isolates collected between 2009 and 2012 was pooled by province and year and submitted for next-generation sequencing. Single-nucleotide polymorphisms (SNPs) were identified using a pile-up approach that detected minority SNPs. Among the 14 pools, we found six unique SNPs, including three nonsynonymous SNPs, across six codons in K12. However, none of the SNPs were orthologous to artemisinin resistance–conferring mutations in PF3D7_1343700, and nonsynonymous changes did not persist through time within populations. These results suggest a lack of selection in the P. vivax population in Cambodia due to artemisinin drug pressure

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients

Study Objective: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients. Design and Setting: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC0–12), AUC0–4, 12-h troughs (C12 h), maximum concentrations (Cmax), oral clearance (Cl), with dose-normalized AUC0–12, troughs, and Cmax with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms. Patients: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated. Measurements and Main Results: Black recipients exhibited higher tacrolimus AUC0–12 (Race: p = 0.005), lower AUC* (Race: p \u3c 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p \u3c 0.001; Sex: p = 0.066). Greater cumulative (Sex: p \u3c 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0–12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0–12 was \u3c100 \u3eng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%–19% of tacrolimus variability in dose (p = 0.002); AUC0–12 h* (p \u3c 0.001), and Cl (p \u3c 0.001). Conclusions: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0–12 h

Beyond Single Nucleotide Polymorphisms: CYP3A5∗3 ∗6 ∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗3(rs776746), ∗6(10264272), and ∗7(41303343), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C \u3e T (rs1128503), 2677G \u3e T/A(rs2032582), and 3435C \u3e T(rs1045642). Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P \u3c 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (P \u3c 0.001) with 50% lower AUC∗ (P \u3c 0.001) than Poor metabolizers. No differences in C12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose (P = 0.03), CL (P = 0.023), CL/LBW (P = 0.022), and AUC∗ (P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5∗3∗4∗5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks

Continuity Culture: A Key Factor for Building Resilience and Sound Recovery Capabilities

This article investigates the extent to which Jordanian service organizations seek to establish continuity culture through testing, training, and updating of their business continuity plans. A survey strategy was adopted in this research. Primary and secondary data were used. Semistructured interviews were conducted with five senior managers from five large Jordanian service organizations registered with the Amman Stock Exchange. The selection of organizations was made on the basis of simple random sampling. Interviews targeted the headquarters only in order to obtain a homogenous sample. Three out of five organizations could be regarded as crisis prepared and have better chances for recovery. The other two organizations exhibited characteristics of standard practice that only emphasizes the recovery aspect of business continuity management (BCM), while paying less attention to establishing resilient cultures and embedding BCM. The findings reveal that the ability to recover following major incidents can be improved by embedding BCM in the culture of the organization and by making BCM an enterprise-wide process. This is one of few meticulous studies that have been undertaken in the Middle East and the first in Jordan to investigate the extent to which service organizations focus on embedding BCM in the organizational culture

Can standardized patients replace physicians as OSCE examiners?

BACKGROUND: To reduce inter-rater variability in evaluations and the demand on physician time, standardized patients (SP) are being used as examiners in OSCEs. There is concern that SP have insufficient training to provide valid evaluation of student competence and/or provide feedback on clinical skills. It is also unknown if SP ratings predict student competence in other areas. The objectives of this study were: to examine student attitudes towards SP examiners; to compare SP and physician evaluations of competence; and to compare predictive validity of these scores, using performance on the multiple choice questions examination (MCQE) as the outcome variable. METHODS: This was a cross-sectional study of third-year medical students undergoing an OSCE during the Internal Medicine clerkship rotation. Fifty-two students rotated through 8 stations (6 physician, 2 SP examiners). Statistical tests used were Pearson's correlation coefficient, two-sample t-test, effect size calculation, and multiple linear regression. RESULTS: Most students reported that SP stations were less stressful, that SP were as good as physicians in giving feedback, and that SP were sufficiently trained to judge clinical skills. SP scored students higher than physicians (mean 90.4% +/- 8.9 vs. 82.2% +/- 3.7, d = 1.5, p < 0.001) and there was a weak correlation between the SP and physician scores (coefficient 0.4, p = 0.003). Physician scores were predictive of summative MCQE scores (regression coefficient = 0.88 [0.15, 1.61], P = 0.019) but there was no relationship between SP scores and summative MCQE scores (regression coefficient = -0.23, P = 0.133). CONCLUSION: These results suggest that SP examiners are acceptable to medical students, SP rate students higher than physicians and, unlike physician scores, SP scores are not related to other measures of competence

The burden of Malaria in the democratic Republic of the Congo

Despite evidence that older children and adolescents bear the highest burden of malaria, large malaria surveys focus on younger children. We used polymerase chain reaction data from the 2013-2014 Demographic and Health Survey in the Democratic Republic of Congo (including children aged <5 years and adults aged ≥15 years) and a longitudinal study in Kinshasa Province (participants aged 6 months to 98 years) to estimate malaria prevalence across age strata. We fit linear models and estimated prevalences for each age category; adolescents aged 10-14 years had the highest prevalence. We estimate approximately 26 million polymerase chain reaction-detectable infections nationally. Adolescents and older children should be included in surveillance studies

Pooled Amplicon Deep Sequencing of Candidate Plasmodium falciparum Transmission-Blocking Vaccine Antigens

Polymorphisms within Plasmodium falciparum vaccine candidate antigens have the potential to compromise vaccine efficacy. Understanding the allele frequencies of polymorphisms in critical binding regions of antigens can help in the designing of strain-transcendent vaccines. Here, we adopt a pooled deep-sequencing approach, originally designed to study P. falciparum drug resistance mutations, to study the diversity of two leading transmission-blocking vaccine candidates, Pfs25 and Pfs48/45. We sequenced 329 P. falciparum field isolates from six different geographic regions. Pfs25 showed little diversity, with only one known polymorphism identified in the region associated with binding of transmission-blocking antibodies among our isolates. However, we identified four new mutations among eight non-synonymous mutations within the presumed antibody-binding region of Pfs48/45. Pooled deep sequencing provides a scalable and cost-effective approach for the targeted study of allele frequencies of P. falciparum candidate vaccine antigens