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PurposeWe propose a novel compensator-based IMRT system designed to provide a simple, reliable, and cost-effective adjunct technology, with the goal of expanding global access to advanced radiotherapy techniques. The system would employ easily reusable tungsten bead compensators that operate independent of a gantry (e.g., mounted in a ring around the patient). Thereby the system can be retrofitted to existing linac and cobalt teletherapy units. This study explores the quality of treatment plans from the proposed system and the dependence on associated design parameters.MethodsWe considered 60 Co-based plans as the most challenging scenario for dosimetry and benchmarked them against clinical MLC-based plans delivered on a linac. Treatment planning was performed in the Pinnacle treatment planning system with commissioning based on Monte Carlo simulations of compensated beams. 60 Co-compensator IMRT plans were generated for five patients with head-and-neck cancer and five with gynecological cancer and compared to respective IMRT plans using a 6 MV linac beam with an MLC. The dependence of dosimetric endpoints on compensator resolution, thickness, position, and number of beams was assessed. Dosimetric accuracy was validated by Monte Carlo simulations of dose distribution in a water phantom from beams with the IMRT plan compensators.ResultsThe 60 Co-compensator plans had on average equivalent PTV coverage and somewhat inferior OAR sparing compared to the 6 MV-MLC plans, but the differences in dosimetric endpoints were clinically acceptable. Calculated treatment times for head-and-neck plans were 7.6 ± 2.0 min vs 3.9 ± 0.8 min (6 MV-MLC vs 60 Co-compensator) and for gynecological plans were 8.7 ± 3.1 min vs 4.3 ± 0.4 min. Plan quality was insensitive to most design parameters over much of the ranges studied, with no degradation found when the compensator resolution was finer than 6 mm, maximum thickness at least 2 tenth-value-layers, and more than five beams were used. Source-to-compensator distances of 53 and 63 cm resulted in very similar plan quality. Monte Carlo simulations suggest no increase in surface dose for the geometries considered here. Simulated dosimetric validation tests had median gamma pass rates of 97.6% for criteria of 3% (global)/3 mm with a 10% threshold.ConclusionsThe novel ring-compensator IMRT system can produce plans of comparable quality to standard 6 MV-MLC systems. Even when 60 Co beams are used the plan quality is acceptable and treatment times are substantially reduced. 60 Co-compensator IMRT plans are adequately modeled in an existing commercial treatment planning system. These results motivate further development of this low-cost adaptable technology with translation through clinical trials and deployment to expand the reach of IMRT in low- and middle-income countries.

Identifying effective treatment(s) for sarcopenia and sarcopenic obesity is of paramount importance as the global population advances in age and obesity continues to be a worldwide concern. Evidence has shown that a ketogenic diet can be beneficial for the preservation of muscle quality and function in older adults, but long-term adherence is low due in part to the high-fat (≥80%), very low carbohydrate (<5%) composition of the diet. When provided in adequate amounts, exogenous ketone esters (KEs) can increase circulating ketones to concentrations that exceed those observed during prolonged fasting or starvation without significant alterations in the diet. Ketone esters first emerged in the mid-1990s and their use in preclinical and clinical research has escalated within the past 10–15 years. We present findings from a narrative review of the existing literature for a proposed hypothesis on the effects of exogenous ketones as a therapeutic for preservation of skeletal muscle and function within the context of sarcopenic obesity and future directions for exploration. Much of the reviewed literature herein examines the mechanisms of the ketone diester (R,S-1,3-butanediol diacetoacetate) on skeletal muscle mass, muscle protein synthesis, and epigenetic regulation in murine models. Additional studies are needed to further examine the key regulatory factors producing these effects in skeletal muscle, examine convergent and divergent effects among different ketone ester formulations, and establish optimal frequency and dosing regimens to translate these findings into humans. [ABSTRACT FROM AUTHOR]

This paper employs panel estimators with data on the 50 American states for the years 1963 to 2006 to test the relationship between Unemployment Insurance (UI) trust fund solvency and UI benefit generosity. We find that both average and maximum weekly UI benefit amounts, as ratios to the average weekly wage, are higher in states and in years with more highly solvent trust funds. This result holds after controlling for state-level unemployment rate, gross domestic product, population growth, legislative political ideology, partisan control of the executive and legislative branches, and gubernatorial election year across multiple specifications, including fixed-effects and dynamic panel estimators. We propose a theory of moderate coupling as the causal mechanism, whereby UI program benefits and financing are directly related but are not as tightly linked as in other social insurance programs, such as Medicaid. The findings have important policy implications for the funding of states' UI systems. As a consequence of moderate coupling, the countercyclicality of the UI program is dampened. (Contains 3 tables, 2 figures, and 12 footnotes.)

Interventions for animal lifespan extension like caloric restriction (CR) have identified physiologic and biochemical pathways related to hunger and energy‐sensing status as possible contributors, but mechanisms have not been fully elucidated. Prior studies using ghrelin agonists show greater food intake but no effect on lifespan in rodent models. This experiment in male C57BL/6J mice tested the influence of ghrelin agonism for perceived hunger, in the absence of CR, on longevity. Mice aged 4 weeks were allowed to acclimate for 2 weeks prior to being assigned (N = 60/group). Prior to lights off daily (12:12 cycle), animals were fed a ghrelin agonist pill (LY444711; Eli Lilly) or a placebo control (Ctrl) until death. Treatment (GhrAg) animals were pair‐fed daily based on the group mean food intake consumed by Ctrl (ad libitum feeding) the prior week. Results indicate an increased lifespan effect (log‐rank p = 0.0032) for GhrAg versus placebo Ctrl, which weighed significantly more than GhrAg (adjusted for baseline weight). Further studies are needed to determine the full scope of effects of this ghrelin agonist, either directly via increased ghrelin receptor signaling or indirectly via other hypothalamic, systemic, or tissue‐specific mechanisms. [ABSTRACT FROM AUTHOR]

Calorie restriction (CR) has been known for more than 70 years to extend life span and delay disease in rodent models. Metformin administration in rodent disease models has been shown to delay cancer incidence and progression, reduce cardiovascular disease and extend life span. To more directly test the potential of metformin supplementation (300 mg/ kg/day) as a CR mimetic, life-span studies were performed in Fischer-344 rats and compared with ad libitum feeding and CR (30%). The CR group had significantly reduced food intake and body weight throughout the study. Body weight was significantly reduced in the metformin group compared with control during the middle of the study, despite similar weekly food intake. Although CR significantly extended early life span (25th quantile), metformin supplementation did not significantly increase life span at any quantile (25th, 50th, 75th, or 90th), overall or maximum life span (p > .05) compared with control. Key Words: Calorie restriction--Metformin--Mimetic--Life span--Aging. doi: 10.1093/gerona/glq033

The histone deacetylase activity of Sir2p is dependent on [NAD.sup.+] and inhibited by nicotinamide (NAM). As a result, Sir2p-regulated processes in Saccharomyces cerevisiae such as silencing and replicative aging are susceptible to alterations in cellular [NAD.sup.+] and NAM levels. We have determined that high concentrations of NAM in the growth medium elevate the intracellular [NAD.sup.+] concentration through a mechanism that is partially dependent on NPT1, an important gene in the Preiss--Handler [NAD.sup.+] salvage pathway. Overexpression of the nicotinamidase, Pnclp, prevents inhibition of Sir2p by the excess NAM while maintaining the elevated [NAD.sup.+] concentration. This growth condition alters the epigenetics of rDNA silencing, such that repression of a URA3 reporter gene located at the rDNA induces growth on media that either lacks uracil or contains 5-fluoroorotic acid (5-FOA), an unusual dual phenotype that is reminiscent of telomeric silencing (TPE) of URA3. Despite the similarities to TPE, the modified rDNA silencing phenotype does not require the SIR complex. Instead, it retains key characteristics of typical rDNA silencing, including RENT and Pol I dependence, as well as a requirement for the Preiss--Handler [NAD.sup.+] salvage pathway. Exogenous nicotinamide can therefore have negative or positive impacts on rDNA silencing, depending on the PNC1 expression level.