Endurance exercise has emerged as a powerful intervention that promotes healthy aging by maintaining the functional capacity of critical organ systems. In addition, long-term exercise reduces the incidence of age-related diseases in humans and in model organisms. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare gene expression changes during endurance training in Drosophila melanogaster to gene expression changes during selective breeding for longevity. Microarrays indicate that 65% of gene expression changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training. We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Both interventions generally upregulate stress defense, folate metabolism, and lipase activity, while downregulating carbohydrate metabolism and odorant receptor expression. Several members of the methuselah-like (mthl) gene family are downregulated by both interventions. Knockdown of mthl-3 was sufficient to provide extension of negative geotaxis behavior, endurance and cardiac stress resistance. These results provide support for endurance exercise as a broadly acting anti-aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways.

SUMMARYThe impact of dietary composition on exercise capacity is a subject of intense study in both humans and model organisms. Interactions between diet and genetics are a crucial component of optimized dietary design. However, the genetic factors governing exercise response are still not well understood. The recent development of invertebrate models for endurance exercise is likely to facilitate study designs examining the conserved interactions between diet, exercise and genetics. As a first step, we used the Drosophila model to describe the effects of varying dietary composition on several physiological indices, including fatigue tolerance and climbing speed, cardiac performance, lipid storage and autophagy. We found that flies of two divergent genetic backgrounds optimize endurance and cardiac performance on relatively balanced low calorie diets. When flies are provided with unbalanced diets, diets higher in sugar than in yeast facilitate greater endurance at the expense of cardiac performance. Importantly, we found that dietary composition has a profound effect on various physiological indices, whereas total caloric intake per se has very little predictive value for performance. We also found that the effects of diet on endurance are completely reversible within 48h if flies are switched to a different diet. Supplementary material available online at

Background Messenger RNA in urine supernatant (US-mRNA) might encode information about renal and cardiorenal pathophysiology, including hypertension. However, whether the US-mRNA transcriptome reflects that of renal tissues and whether changes in renal physiology are detectable using US-mRNA is unknown. Methods We compared transcriptomes of human urinary extracellular vesicles and human renal cortex. To avoid similarities attributable to ubiquitously expressed genes, we separately analyzed ubiquitously expressed and highly kidney-enriched genes. To determine whether US-mRNA reflects changes in renal gene expression, we assayed cell-depleted urine for transcription factor activity of mineralocorticoid receptors (MR) using probe-based qPCR. The urine was collected from pre-hypertensive individuals (n=18) after four days on low-sodium diet to stimulate MR activity and again after suppression of MR activity via sodium infusion. Results In comparing this US-mRNA and human kidney cortex, expression of 55 highly kidney-enriched genes correlated strongly (rs=0.82), while 8,457 ubiquitously-expressed genes correlated moderately (rs=0.63). Standard renin-angiotensin-aldosterone system phenotyping confirmed the expected response to sodium loading. Ct values for MR-regulated targets (SCNN1A, SCNN1G, TSC22D3) changed after sodium loading, and MR-regulated targets (SCNN1A, SCNN1G, SGK1, and TSC22D3) correlated significantly with serum aldosterone and inversely with urinary sodium excretion. Conclusions RNA-Seq of urinary extracellular vesicles shows concordance with human kidney. Perturbation in human endocrine signaling (MR activation) was accompanied by changes in mRNA in urine supernatant. Our findings could be useful for individualizing pharmacological therapy in patients with disorders of mineralocorticoid signaling, such as resistant hypertension. More generally, these insights could be used to non-invasively identify putative biomarkers of disordered renal and cardiorenal physiology.

Endurance exercise has received increasing attention as a broadly preventative measure against age-related disease and dysfunction. Improvement of mitochondrial quality by enhancement of mitochondrial turnover is thought to be among the important molecular mechanisms underpinning the benefits of exercise. Interactions between the mitochondrial and nuclear genomes are important components of the genetic basis for variation in longevity, fitness and the incidence of disease. Here, we examine the effects of replacing the mitochondrial genome (mtDNA) of several Drosophila strains with mtDNA from other strains, or from closely related species, on exercise performance. We find that mitochondria from flies selected for longevity increase the performance of flies from a parental strain. We also find evidence that mitochondria from other strains or species alter exercise performance, with examples of both beneficial and deleterious effects. These findings suggest that both the mitochondrial and nuclear genomes, as well as interactions between the two, contribute significantly to exercise capacity.

To address quality control issues identified in the survey, we recommend chain pharmacies incorporate credential checks into annual pharmacy training requirements. Pharmacists may benefit from immunization-related continuing education requirements. State pharmacy organizations may want to take the lead in developing the material to ensure that it is timely and abides by state and federal laws.

Disclaimer In an effort to expedite the publication of articles related to the COVID-19 pandemic, AJHP is posting these manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. Purpose The coronavirus disease 2019 (COVID-19) pandemic has caused health systems across the country to plan for field hospitals to care for patients outside of traditional healthcare settings in the event of a second surge. Here we describe key considerations for the implementation of pharmacy operations and a field hospital formulary at an offsite location within a 2-week time frame. Summary Development of an offsite field hospital formulary is first dependent on the location and patient population defined for the field hospital. Creation of a limited formulary for a planned field hospital in Michigan involved reviewing physical space limitations and drug distribution workflows, assessing current prescribing trends, creating drug categories, and creating formulary guidelines to limit formulary options in each therapeutic category. Ultimately, our institution developed a 140-medication field hospital formulary, a process to enable appropriate use of nonformulary drugs, and a mixed operations model including automated dispensing cabinets and a manual cart-fill process. Although the institution did not have to open the field hospital, the process used for developing the formulary and determining distribution models will allow for an immediate implementation if a second surge occurs. Conclusion A methodical approach to developing limited formularies and pharmacy operations in a field hospital setting will allow health systems to establish efficient and effective medication distribution services in the event of a second surge of COVID-19 cases.

Background Patients diagnosed with acute myeloid leukemia with a FLT3 mutation (FLT3+ AML) have historically had poor outcomes. While the addition of the FLT3 inhibitors to induction therapy has been shown to improve survival outcomes in FLT3+ AML, interactions and overlapping toxicities between FLT3 inhibitors and standard of care medications used during induction therapy (e.g. azole antifungals, anthracyclines) and logistical barriers have complicated their use. To avoid these concerns, our institution has opted to defer initiation of midostaurin until after completion of induction therapy. However, to our knowledge no study confirming the effectiveness of this strategy for real world FLT3 inhibitor use has been published. Methods We performed a single center, propensity-score matched, retrospective cohort study characterizing efficacy and safety of our strategy for use of FLT3 inhibitors in the treatment of FLT3+ AML. The primary outcome was median event-free survival (EFS), while secondary endpoints included median overall survival (OS), overall response rate (ORR), 30-day mortality, duration of neutropenia, duration of thrombocytopenia, consolidation cycle delays, documented infections, and all-cause hospital readmission. Results A total of 83 FLT3+ AML patients treated with intensive induction therapy were included in the study, of whom 48 were propensity-score matched and analyzed. Baseline characteristics were similar between the patients who received a FLT3 inhibitor after induction therapy and the historical control arm. Median EFS was not significantly different but compared favorably between the FLT3 inhibitor cohort and historical controls (not reached vs 8 months, p = 0.343) with 18-month EFS of 54% and 43% for the two cohorts, respectively. Similarly, no significant differences were noted with regard to median OS (not reached vs 28.7 months, p = 0.752), ORR (79.2% vs 79.2%), or safety outcomes between groups. Conclusion Compared to historical controls, addition of a FLT3 inhibitor to intensive chemotherapy post-induction may improve EFS or OS in a real world patient cohort with longer follow-up and a larger sample size. The omission of midostaurin in induction allowed for the use of an azole antifungal and the intensification of anthracycline dose may have contributed to high remission rates in both groups.

Endurance exercise has emerged as a powerful intervention to extend healthy physiology into advanced age. Normal, age‐associated declines in organ structure and function are alleviated in endurance‐trained individuals. Long‐term exercise also reduces age‐related pathologies. Despite these evident benefits, the genetic pathways required for exercise interventions to achieve these effects are still relatively poorly understood. Here, we compare the effects of endurance training on Drosophila melanogaster to the effects of selective breeding for longevity. We find that both selective breeding and endurance training increase endurance, cardiac performance, running speed, flying height, and levels of autophagy in adipose tissue. Microarrays indicate that 73% of transcriptional changes found in flies selectively bred for longevity are also found in flies subjected to three weeks of exercise training. Both endurance training and longevity selection upregulate folate biosynthesis, stress defense and lipid metabolism. Conversely, both interventions downregulate multiple carbohydrate metabolism pathways. methuselah‐like 3 was also transcriptionally reduced in both groups. Altering mthl3 expression in adult flies was able to reproduce a subset of the shared phenotypes. These results provide support for endurance exercise as a broadly acting anti‐aging intervention and confirm that exercise training acts in part by targeting longevity assurance pathways. In addition, these results identify the mthl3 gene as a potential target of exercise training.