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\"This book is designed to help researchers achieve success in funding their National Science Foundation (NSF) research proposals. The book discuses aspects of the proposal submission and review process that are not typically communicated to the research community. Written by authors with successful track records in grant writing and years of experience as NSF Program Directors, this book provides an insider's view of successful grantsmanship. Written in a practical approach, this book offers tips that will not be found in official paperwork and provides answers to questions frequently asked of NSF Program Directors. The purpose of the book is to improve your NSF grant-writing skills and improve your chances of funding\"-- Provided by publisher.

PurposeMutations in the tumor suppressor gene TP53 are associated with a variety of cancers. Therefore, it is important to know the occurrence and prognostic effects of TP53 mutations in certain cancers.MethodsOver 29,000 cases from the April 2016 release of the International Agency for Research on Cancer (IARC) TP53 Database were analyzed to determine the distribution of germline and somatic mutations in the TP53 gene. Subsequently, 7,893 cancer cases were compiled in cBioPortal for Cancer Genomics from the 33 most recent The Cancer Genome Atlas (TCGA) studies to determine the prevalence of TP53 mutations in cancers and their effects on survival and disease-free survival times.ResultsThe data were analyzed, and it was found that the majority of TP53 mutations were missense and the major mutational hotspots were located at codons 248, 273, 175, and 245 in exons 4–8 for somatic mutations with the addition of codon 337 and other mutations in exons 9–10 for germline mutations. Out of 33 TGCA studies, the effects of TP53 mutations were statistically significant in nine cancers (lung adenocarcinoma, hepatocellular carcinoma, head and neck squamous cell carcinoma, acute myeloid leukemia, clear cell renal cell carcinoma (RCC), papillary RCC, chromophobe RCC, uterine endometrial carcinoma, and thymoma) for survival time and in five cancers (pancreatic adenocarcinoma, hepatocellular carcinoma, chromophobe RCC, acute myeloid leukemia, and thymoma) for disease-free survival time. It was also found that the most common p53 mutation in hepatocellular carcinomas (R249S) was a much better indicator for poor prognosis than TP53 mutations as a whole. In addition, in cases of ovarian serous cystadenocarcinoma, the co-occurrence of TP53 and BRCA mutations resulted in longer survival and disease-free survival times than the presence of neither TP53 nor BRCA mutations.ConclusionTP53 mutations are potential prognostic markers that can be used to further improve the accuracy of predicting survival and disease-free survival times of cancer patients.

Physical exercise and cognitive training have been shown to enhance cognition among older adults. However, few studies have looked at the potential synergetic effects of combining physical and cognitive training in a single study. Prior trials on combined training have led to interesting yet equivocal results. The aim of this study was to examine the effects of combined physical and cognitive interventions on physical fitness and neuropsychological performance in healthy older adults. Seventy-six participants were randomly assigned to one of four training combinations using a 2×2 factorial design. The physical intervention was a mixed aerobic and resistance training program, and the cognitive intervention was a dual-task (DT) training program. Stretching and toning exercises and computer lessons were used as active control conditions. Physical and cognitive measures were collected pre- and postintervention. All groups showed equivalent improvements in measures of functional mobility. The aerobic-strength condition led to larger effect size in lower body strength, independently of cognitive training. All groups showed improved speed of processing and inhibition abilities, but only participants who took part in the DT training, independently of physical training, showed increased task-switching abilities. The level of functional mobility after intervention was significantly associated with task-switching abilities. Combined training did not yield synergetic effects. However, DT training did lead to transfer effects on executive performance in neuropsychological tests. Both aerobic-resistance training and stretching-toning exercises can improve functional mobility in older adults.

Age-related hearing loss is a risk factor for mobility problems and falls, possibly due to poor access to spatial sounds or the higher allocation of attention required to listen, thereby reducing cognitive resources to support mobility. Introducing stabilizing spatial sounds or reducing cognitive load through hearing aids could possibly improve balance performance; however, evidence is mixed. Few studies have evaluated the effects of hearing aids and spatial sounds on balance during realistic, multisensory, dual-tasking conditions. This study used virtual reality to simulate a listening-while-balancing task in 22 older adults with normal hearing and 22 hearing aid users, tested with their aids on versus off. Participants performed a competing digits listening task (two, four digits) and a standing postural task, alone and in combination (dual task) under different visual, postural, and acoustical loads. Listening accuracy and postural outcomes (centre of pressure mean velocity, anterior–posterior standard deviation, medial–lateral standard deviation) were collected. With respect to listening accuracy, as expected, normal hearing adults had higher listening accuracy than those with hearing loss (aided better than unaided) and both groups performed better with eyes closed (vs. open) and under lower postural loads (firm vs. compliant). With respect to postural performance, hearing aids did not remarkably improve balance overall, with no effects on dual-task costs to posture. Other factors related to the complexity of the conditions (i.e., listening, visual, postural demands) differently influenced dual-task costs to posture in individuals with and without hearing loss. Overall, these results contribute to our understanding of how age-related hearing loss and hearing aids affect balance-related outcomes under realistic, complex, multisensory, multitasking conditions.

Despite growing numbers of immune checkpoint blockade (ICB) trials with available omics data, it remains challenging to evaluate the robustness of ICB response and immune evasion mechanisms comprehensively. To address these challenges, we integrated large-scale omics data and biomarkers on published ICB trials, non-immunotherapy tumor profiles, and CRISPR screens on a web platform TIDE ( http://tide.dfci.harvard.edu ). We processed the omics data for over 33K samples in 188 tumor cohorts from public databases, 998 tumors from 12 ICB clinical studies, and eight CRISPR screens that identified gene modulators of the anticancer immune response. Integrating these data on the TIDE web platform with three interactive analysis modules, we demonstrate the utility of public data reuse in hypothesis generation, biomarker optimization, and patient stratification.

Background Individuals with a moderate-to-severe traumatic brain injury (m/sTBI), despite experiencing good locomotor recovery six months post-injury, face challenges in adapting their locomotion to the environment. They also present with altered cognitive functions, which may impact dual-task walking abilities. Whether they present collision avoidance strategies with moving pedestrians that are altered under dual-task conditions, however, remains unclear. This study aimed to compare between individuals with m/sTBI and age-matched control individuals: (1), the locomotor and cognitive costs associated with the concurrent performance of circumventing approaching virtual pedestrians (VRPs) while attending to an auditory-based cognitive task and; (2) gaze behaviour associated with the VRP circumvention task in single and dual-task conditions. Methodology Twelve individuals with m/sTBI (age = 43.3 ± 9.5 yrs; >6 mo. post injury) and 12 healthy controls (CTLs) (age = 41.8 ± 8.3 yrs) were assessed while walking in a virtual subway station viewed in a head-mounted display. They performed a collision avoidance task with VRPs, as well as auditory-based cognitive tasks (pitch discrimination and auditory Stroop), both under single and dual-task conditions. Dual-task cost (DTC) for onset distance of trajectory deviation, minimum distance from the VRP, maximum lateral deviation, walking speed, gaze fixations and cognitive task accuracy were contrasted between groups using generalized estimating equations. Results In contrast to CTLs who showed locomotor DTCs only, individuals with m/sTBI displayed both locomotor and cognitive DTCs. While both groups walked slower under dual-task conditions, only individuals with m/sTBI failed to modify their onset distance of trajectory deviation and maintained smaller minimum distances and smaller maximum lateral deviation compared to single-task walking. Both groups showed shorter gaze fixations on the approaching VRP under dual-task conditions, but this reduction was less pronounced in the individuals with m/sTBI. A reduction in cognitive task accuracy under dual-task conditions was found in the m/sTBI group only. Conclusion Individuals with m/sTBI present altered locomotor and gaze behaviours, as well as altered cognitive performances, when executing a collision avoidance task involving moving pedestrians in dual-task conditions. Potential mechanisms explaining those alterations are discussed. Present findings highlight the compromised complex walking abilities in individuals with m/sTBI who otherwise present a good locomotor recovery.

Importance Exercise, cognitive training, and vitamin D may enhance cognition in older adults with mild cognitive impairment (MCI). Objective To determine whether aerobic-resistance exercises would improve cognition relative to an active control and if a multidomain intervention including exercises, computerized cognitive training, and vitamin D supplementation would show greater improvements than exercise alone. Design, Setting, and Participants This randomized clinical trial (the SYNERGIC Study) was a multisite, double-masked, fractional factorial trial that evaluated the effects of aerobic-resistance exercise, computerized cognitive training, and vitamin D on cognition. Eligible participants were between ages 65 and 84 years with MCI enrolled from September 19, 2016, to April 7, 2020. Data were analyzed from February 2021 to December 2022. Interventions Participants were randomized to 5 study arms and treated for 20 weeks: arm 1 (multidomain intervention with exercise, cognitive training, and vitamin D), arm 2 (exercise, cognitive training, and placebo vitamin D), arm 3 (exercise, sham cognitive training, and vitamin D), arm 4 (exercise, sham cognitive training, and placebo vitamin D), and arm 5 (control group with balance-toning exercise, sham cognitive training, and placebo vitamin D). The vitamin D regimen was a 10 000 IU dose 3 times weekly. Main Outcomes and Measures Primary outcomes were changes in ADAS-Cog-13 and Plus variant at 6 months. Results Among 175 randomized participants (mean [SD] age, 73.1 [6.6] years; 86 [49.1%] women), 144 (82%) completed the intervention and 133 (76%) completed the follow-up (month 12). At 6 months, all active arms (ie, arms 1 through 4) with aerobic-resistance exercise regardless of the addition of cognitive training or vitamin D, improved ADAS-Cog-13 when compared with control (mean difference, −1.79 points; 95% CI, −3.27 to −0.31 points;P = .02;d = 0.64). Compared with exercise alone (arms 3 and 4), exercise and cognitive training (arms 1 and 2) improved the ADAS-Cog-13 (mean difference, −1.45 points; 95% CI, −2.70 to −0.21 points;P = .02;d = 0.39). No significant improvement was found with vitamin D. Finally, the multidomain intervention (arm 1) improved the ADAS-Cog-13 score significantly compared with control (mean difference, −2.64 points; 95% CI, −4.42 to −0.80 points;P = .005;d = 0.71). Changes in ADAS-Cog-Plus were not significant. Conclusions and Relevance In this clinical trial, older adults with MCI receiving aerobic-resistance exercises with sequential computerized cognitive training significantly improved cognition, although some results were inconsistent. Vitamin D supplementation had no effect. Our findings suggest that this multidomain intervention may improve cognition and potentially delay dementia onset in MCI. Trial Registration ClinicalTrials.gov Identifier:NCT02808676

A dual-task paradigm was used to examine the effect of cognitive load on motor reprogramming. We propose that in the face of conflict, both executive control and motor control mechanisms become more interconnected in the process of reprogramming motor behaviors. If so, one would expect a concurrent cognitive load to compromise younger adults’ (YAs) motor reprogramming ability and further exacerbate the response reprogramming ability of older adults (OAs). Nineteen YAs and 14 OAs overlearned a sequence of key presses. Deviations of the practiced sequence were introduced to assess motor reprogramming ability. A Serial Sevens Test was used as the cognitive load. A 3D motion capture system was used to parse finger movements into planning and motor execution times. Global response time analysis revealed that under single-task conditions, during prepotent transitions, OAs responded as quickly as YAs, but they were disproportionately worse than YAs during conflict transitions. Under dual-task conditions, YAs performance became more similar to that of OAs. Movement data were decomposed into planning and movement time, revealing that under single-task conditions, when responding to conflicting stimuli YAs reduced their movement time in order to compensate for delayed planning time; however, additional cognitive load prevented them from exhibiting this compensatory hastening on conflict transitions. We propose that age-related declines in response reprogramming may be linked to reduced cognitive capacity. Current findings suggest that cognitive capacity, reduced in the case of OAs or YAs under divided attention conditions, influences the ability to flexibly adapt to conflicting conditions.

Background Spontaneous walking speed (SWS) is one of the most important indicators of health in older adults. Studies have shown benefits of physical trainings on SWS in older adults but the impact of cognitive training and multidomain interventions remains understudied. Aims This original study aimed at comparing the impact of aerobic/resistance exercise, computerized cognitive training and the combination of both interventions compared with active control conditions on SWS in healthy older adults. Methods Ninety community-dwelling older adults were randomly assigned to four different combinations composed of two active interventions: physical aerobic/resistance and cognitive dual-task trainings, and two active control conditions: stretching exercises and computer lessons. The four combinations were the following: (1) aerobic/resistance and cognitive dual task ( n  = 28), (2) aerobic/resistance and computer lessons ( n  = 21), (3) stretching exercises and cognitive dual task and ( n  = 23), (4) stretching exercises and computer lessons ( n  = 18). Training sessions were held three times/week for three months. SWS for 30 s was assessed before and after the intervention. Results Repeated-measures ANOVA showed a main effect of time and a significant three-way interaction suggesting differential improvement in SWS according to training combinations. A clinical meaningful improvement in SWS was observed in groups 1–3 (0.08–0.14 m/s; effect sizes: small to moderate) but not in the active control group 4. Discussion Results of this study suggest that aerobic/resistance exercise and computerized dual-task training are two non-pharmacological interventions by which SWS, a functional vital sign, can be clinically improved in older adults. Conclusion This original study pointed out different tools to prevent functional decline in older people.

Everyday activities like walking and talking can put an older adult at risk for a fall if they have difficulty dividing their attention between motor and cognitive tasks. Training studies have demonstrated that both cognitive and physical training regimens can improve motor and cognitive task performance. Few studies have examined the benefits of combined training (cognitive and physical) and whether or not this type of combined training would transfer to walking or balancing dual-tasks. This study examines the dual-task benefits of combined training in a sample of sedentary older adults. Seventy-two older adults (≥60 years) were randomly assigned to one of four training groups: Aerobic + Cognitive training (CT), Aerobic + Computer lessons (CL), Stretch + CT and Stretch + CL. It was expected that the Aerobic + CT group would demonstrate the largest benefits and that the active placebo control (Stretch + CL) would show the least benefits after training. Walking and standing balance were paired with an auditory n-back with two levels of difficulty (0- and 1-back). Dual-task walking and balance were assessed with: walk speed (m/s), cognitive accuracy (% correct) and several mediolateral sway measures for pre- to post-test improvements. All groups demonstrated improvements in walk speed from pre- ( = 1.33 m/s) to post-test ( = 1.42 m/s, < 0.001) and in accuracy from pre- ( = 97.57%) to post-test ( = 98.57%, = 0.005).They also increased their walk speed in the more difficult 1-back ( = 1.38 m/s) in comparison to the 0-back ( = 1.36 m/s, < 0.001) but reduced their accuracy in the 1-back ( = 96.39%) in comparison to the 0-back ( = 99.92%, < 0.001). Three out of the five mediolateral sway variables (Peak, SD, RMS) demonstrated significant reductions in sway from pre to post test ( < 0.05). With the exception of a group difference between Aerobic + CT and Stretch + CT in accuracy, there were no significant group differences after training. Results suggest that there can be dual-task benefits from training but that in this sedentary sample Aerobic + CT training was not more beneficial than other types of combined training.