Epidemiological and associative research from humans and animals identifies correlations between the environment and health impacts. The environment-health inter-relationship is effected through an ...individual's underlying genetic variation and mediated by mechanisms that include the changes to gene regulation that are associated with the diversity of phenotypes we exhibit. However, the causal relationships have yet to be established, in part because the associations are reduced to individual interactions and the combinatorial effects are rarely studied. This problem is exacerbated by the fact that our genomes are highly dynamic; they integrate information across multiple levels (from linear sequence, to structural organisation, to temporal variation) each of which is open to and responds to environmental influence. To unravel the complexities of the genomic basis of human disease, and in particular non-communicable diseases that are also influenced by the environment (e.g., obesity, type II diabetes, cancer, multiple sclerosis, some neurodegenerative diseases, inflammatory bowel disease, rheumatoid arthritis) it is imperative that we fully integrate multiple layers of genomic data. Here we review current progress in integrated genomic data analysis, and discuss cases where data integration would lead to significant advances in our ability to predict how the environment may impact on our health. We also outline limitations which should form the basis of future research questions. In so doing, this review will lay the foundations for future research into the impact of the environment on our health.
Abstract
Background
Isavuconazole is a triazole antifungal available in IV and capsule formulation. Prescribing information states that capsules should not be chewed, crushed, dissolved or opened ...because the drug was not studied in this manner. However, considering the pharmacokinetics of the capsules, we theorized opening and sprinkling the contents into an enteral feeding tube (EFT) would result in adequate absorption and systemic concentrations of isavuconazole.
Objectives
To determine whether patients receiving isavuconazonium sulphate capsules via EFT would achieve clinical blood concentrations of isavuconazole.
Methods
Nineteen solid organ and HCT recipients receiving isavuconazole via EFT for prevention or treatment of invasive fungal infection (IFI) were prospectively identified at four academic medical centres in the USA. Patients were included in this evaluation if they received isavuconazole via EFT for at least 5 days and therapeutic drug monitoring (TDM) was performed.
Results
TDM was performed after a median of 7 days (range 6–17) following EFT administration and 15 days (range 7–174) of isavuconazole therapy overall. Median isavuconazole concentration was 1.8 μg/mL (range 0.3–5.2). Median isavuconazole concentrations in patients with or without prior IV administration were 1.8 μg/mL (range 0.3–5.2) and 2.2 μg/mL (range 0.8–3.6; P = 0.896), respectively. Concentrations achieved with the EFT route were similar to or greater than the corresponding concentrations via the IV route in six patients who had TDM performed during both routes of administration.
Conclusions
It is reasonable to consider opening isavuconazonium sulphate capsules and administering the contents enterally for prevention and treatment of IFI.
Although climate change models predict relatively modest increases in temperature in the tropics by the end of the century, recent analyses identify tropical ectotherms as the organisms most at risk ...from climate warming. Because metabolic rate in ectotherms increases exponentially with temperature, even a small rise in temperature poses a physiological threat to tropical ectotherms inhabiting an already hot environment. If correct, the metabolic theory of climate warming has profound implications for global biodiversity, since tropical insects and arachnids constitute the vast majority of animal species. Predicting how climate change will translate into fitness consequences for tropical arthropods requires an understanding of the effects of temperature increase on the entire life history of the species. Here, in a comprehensive case study of the fitness consequences of the projected temperature increase for the tropics, we conducted a split‐brood experiment on the neotropical pseudoscorpion, Cordylochernes scorpioides, in which 792 offspring from 33 females were randomly assigned at birth to control‐ and high‐temperature treatments for rearing through the adult stage. The diurnally varying, control treatment temperature was determined from long‐term, average daily temperature minima and maxima in the pseudoscorpion's native habitat. In the high temperature treatment, increasing temperature by the 3.5 °C predicted for the tropics significantly reduced survival and accelerated development at the cost of reduced adult size and a dramatic decrease in level of sexual dimorphism. The most striking effects, however, involved reproductive traits. Reared at high temperature, males produced 45% as many sperm as control males, and females failed to reproduce. Sequencing of the mitochondrial ND2 gene revealed two highly divergent haplogroups that differed substantially in developmental rate and survivorship but not in reproductive response to high temperature. Our findings suggest that reproduction may be the Achilles’ heel of tropical ectotherms, as climate warming subjects them to an increasingly adverse thermal environment.
Recent theory suggests that global warming may be catastrophic for tropical ectotherms. Although most studies addressing temperature effects in ectotherms utilize constant temperatures, Jensen's ...inequality and thermal stress considerations predict that this approach will underestimate warming effects on species experiencing daily temperature fluctuations in nature. Here, we tested this prediction in a neotropical pseudoscorpion. Nymphs were reared in control and high-temperature treatments under a constant daily temperature regime, and results compared to a companion fluctuating-temperature study. At constant temperature, pseudoscorpions outperformed their fluctuating-temperature counterparts. Individuals were larger, developed faster, and males produced more sperm, and females more embryos. The greatest impact of temperature regime involved short-term, adult exposure, with constant temperature mitigating high-temperature effects on reproductive traits. Our findings demonstrate the importance of realistic temperature regimes in climate warming studies, and suggest that exploitation of microhabitats that dampen temperature oscillations may be critical in avoiding extinction as tropical climates warm.
Abstract
Every year, the Student Debates Subcommittee (SDS) of the Student Affairs Committee (SAC) for the annual Entomological Society of America (ESA) meeting organizes the Student Debates. This ...year, the SAC selected topics based on their synergistic effect or ability to ignite exponential positive change when addressed as a whole. For the 2019 Student Debates, the SAC SDS identified these topic areas for teams to debate and unbiased introduction speakers to address: 1) how to better communicate science to engage the public, particularly in the area of integrated pest management (IPM), 2) the influential impacts of climate change on agriculturally and medically relevant insect pests, and 3) sustainable agriculture techniques that promote the use of IPM to promote food security. Three unbiased introduction speakers gave a foundation for our audience to understand each debate topic, while each of six debate teams provided a strong case to support their stance or perspective on a topic. Debate teams submitted for a competitive spot for the annual ESA Student Debates and trained for the better part of a year to showcase their talents in presenting logical arguments for a particular topic. Both the debate teams and unbiased introduction speakers provided their insight toward a better understanding of the complexities of each topic and established a foundation to delve further into the topics of science advocacy and communication, climate change, and the many facets of integrated pest management.
The aims of this study were to optimize the experimental conditions for labeling extracellularly oriented, solvent-exposed cysteine residues of γ-aminobutyric acid transporter 1 (GAT1) with the ...membrane-impermeant sulfhydryl reagent 2-(trimethylammonium)ethylmethanethiosulfonate (MTSET) and to characterize the functional and pharmacological consequences of labeling on transporter steady-state and presteady-state kinetic properties. We expressed human GAT1 in
Xenopus laevis
oocytes and used radiotracer and electrophysiological methods to assay transporter function before and after sulfhydryl modification with MTSET. In the presence of NaCl, transporter exposure to MTSET (1–2.5 mM for 5–20 min) led to partial inhibition of GAT1-mediated transport, and this loss of function was completely reversed by the reducing reagent dithiothreitol. MTSET treatment had no functional effect on the mutant GAT1 C74A, whereas the membrane-permeant reagents
N
-ethylmaleimide and tetramethylrhodamine-6-maleimide inhibited GABA transport mediated by GAT1 C74A. Ion replacement experiments indicated that MTSET labeling of GAT1 could be driven to completion when valproate replaced chloride in the labeling buffer, suggesting that valproate induces a GAT1 conformation that significantly increases C74 accessibility to the extracellular fluid. Following partial inhibition by MTSET, there was a proportional reduction in both the presteady-state and steady-state macroscopic signals, and the functional and pharmacological properties of the remaining signals were indistinguishable from those of unlabeled GAT1. Therefore, covalent modification of GAT1 at C74 results in completely nonfunctional as well as electrically silent transporters.
Abstract
Background
A high proportion of people with HIV (PWH) in the 2022-2023 mpox outbreak (approx. 40% of US cases) has raised questions about the association between HIV and mpox. Increased ...encounters with the healthcare system may be contributing to this association. This study sought to elucidate whether detection bias drives the relationship between mpox and HIV by determining whether engagement in care and STI screening are associated with having an mpox diagnosis.
Methods
We conducted a 5:1 matched case-control study among DC Cohort participants, a longitudinal cohort of PWH receiving care in Washington, DC. Cases were matched on age (+/-5 years), gender, race/ethnicity, HIV transmission risk factor, time since HIV diagnosis (+/-5 years), years enrolled (+/-3 years), and HIV care site (community or hospital) with up to 5 controls. Engagement in care was defined as two or more CD4 or HIV RNA tests at least 90 days apart during the last year. STI screening was any test for gonorrhea, chlamydia, or syphilis in the past year. Cases were participants with an mpox diagnosis identified by providers or an ICD10 code in the EHR. We used unadjusted conditional logistic regression to assess the relationship between engagement in care, STI screening, and mpox diagnosis.
Results
We identified 68 cases of mpox in the DC Cohort and 65 could be matched to 300 controls (n = 365). Participants were majority male (98.9%), Black (70.7%), MSM (89.3%), and 51.5% of participants had an STI diagnosis since cohort enrollment. Cases were significantly more likely to be engaged in care (50.8% vs. 26.3%; OR: 3.24), receive an STI screening (69.2% vs. 41.3%; OR: 3.45), have a historical STI (72.3% vs. 47.0%; OR: 3.58), and have a CD4 count < 500 (40.4% vs. 21.9%; OR: 2.51).
Conclusion
Among a cohort of PWH, those with an mpox diagnosis were significantly more likely to be engaged in care and received an STI screening in the year prior, suggesting increased encounters for HIV care may account for a higher rate of PWH among mpox cases. The high proportion of CD4 < 500 among mpox cases suggests more clinically evident manifestations in this population. Future analyses should examine unmeasured behavioral factors to explain the association between mpox diagnosis, increased engagement in care and STI screening.
Disclosures
All Authors: No reported disclosures
The aims of this study were to optimize the experimental conditions for labeling extracellularly oriented, solvent-exposed cysteine residues of γ-aminobutyric acid transporter 1 (GAT1) with the ...membrane-impermeant sulfhydryl reagent 2-(trimethylammonium)ethylmethanethiosulfonate (MTSET) and to characterize the functional and pharmacological consequences of labeling on transporter steady-state and presteady-state kinetic properties. We expressed human GAT1 in Xenopus laevis oocytes and used radiotracer and electrophysiological methods to assay transporter function before and after sulfhydryl modification with MTSET. In the presence of NaCl, transporter exposure to MTSET (1-2.5 mM for 5-20 min) led to partial inhibition of GAT1-mediated transport, and this loss of function was completely reversed by the reducing reagent dithiothreitol. MTSET treatment had no functional effect on the mutant GAT1 C74A, whereas the membrane-permeant reagents N-ethylmaleimide and tetramethylrhodamine-6-maleimide inhibited GABA transport mediated by GAT1 C74A. Ion replacement experiments indicated that MTSET labeling of GAT1 could be driven to completion when valproate replaced chloride in the labeling buffer, suggesting that valproate induces a GAT1 conformation that significantly increases C74 accessibility to the extracellular fluid. Following partial inhibition by MTSET, there was a proportional reduction in both the presteady-state and steady-state macroscopic signals, and the functional and pharmacological properties of the remaining signals were indistinguishable from those of unlabeled GAT1. Therefore, covalent modification of GAT1 at C74 results in completely nonfunctional as well as electrically silent transporters.PUBLICATION ABSTRACT
Transmyocardial laser revascularization provides a promising alternative for patients with intractable angina. The concept of blood flow directly from the left ventricular chamber into the myocardium ...is not a new one, and recent studies have found the potential for this application in human hearts. Laser technology has provided an avenue for exploring the possibility of revascularization through channels created in the left ventricle. Early studies have demonstrated improved relief of angina symptoms in patients who are not candidates for traditional medical and surgical revascularization modalities.
BACKGROUND:Poor lifestyle behaviors are leading causes of preventable diseases globally. Added sugars contribute to a diet that is energy dense but nutrient poor and increase risk of developing ...obesity, cardiovascular disease, hypertension, obesity-related cancers, and dental caries.
METHODS AND RESULTS:For this American Heart Association scientific statement, the writing group reviewed and graded the current scientific evidence for studies examining the cardiovascular health effects of added sugars on children. The available literature was subdivided into 5 broad subareaseffects on blood pressure, lipids, insulin resistance and diabetes mellitus, nonalcoholic fatty liver disease, and obesity.
CONCLUSIONS:Associations between added sugars and increased cardiovascular disease risk factors among US children are present at levels far below current consumption levels. Strong evidence supports the association of added sugars with increased cardiovascular disease risk in children through increased energy intake, increased adiposity, and dyslipidemia. The committee found that it is reasonable to recommend that children consume ≤25 g (100 cal or ≈6 teaspoons) of added sugars per day and to avoid added sugars for children <2 years of age. Although added sugars most likely can be safely consumed in low amounts as part of a healthy diet, few children achieve such levels, making this an important public health target.
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