Development, validation, and implementation strategies for the exercise in cancer evaluation and decision support (EXCEEDS) algorithm

2021 Summer.Includes bibliographical references.Background: Clinical practice guidelines recommend referral to cancer rehabilitation or exercise services (CRES) to optimize survivorship. Yet, ability to connect the right survivor with the right CRES at the right time is an ongoing challenge and barrier to utilization of these services. Objective: I aimed to develop a CRES decision support algorithm and used Delphi methodology to systematically: (1) evaluate the algorithm's acceptability and utility; and (2) establish consensus for implementation priorities including key stakeholders, platforms and strategies. Method: I performed a literature review and synthesis, then convened a multidisciplinary expert stakeholder group to participate in algorithm development. We worked iteratively and collaboratively until consensus was reached for content and format of the Exercise in Cancer Evaluation and Decision Support (EXCEEDS) algorithm and conceptual model. Then I recruited international clinical and research experts to participate in the two-part (three survey) online modified Delphi study. In Part 1, participants completed one survey including: (1) CRES recommendations for two randomized case studies in two conditions (using EXCEEDS vs. without EXCEEDS); (2) the Acceptability of Implementation Measure (AIM); and (3) open-ended feedback on the algorithm. Following this survey, I compared decision efficiency (accuracy and duration) between conditions (EXCEEDS vs. independently) for each case study using frequencies (hypothesis ≥75% accurate) and paired samples t-test (p <.05), then calculated consensus for each AIM domain ("meets approval", "is appealing", "welcome in my field/practice"; hypothesis ≥70% agreement) and overall score (hypothesized mean ≥ 4.0). These results were reported to participants in Part 2. I also performed inductive thematic analysis of open-ended feedback. In Part 2 of the Delphi study, participants completed a series of two surveys including ranking the following items using curated lists: (1) stakeholder group (1 -most likely to 7- least likely to benefit), (2) platform (1 - most likely to 6- least likely to be beneficial) and, implementation strategies (1 - most important to 15- least important for successful implementation). I performed preliminary analysis of each ranking using measures of central tendency (median and IQR), then calculated the proportion of participants who ranked each option as a high priority. Ten implementation strategies were ranked as high priority and returned to participants for the final survey where they rated each strategy in terms of effort associated with using the strategy (1 - low effort to 4 - high effort) and potential impact of the strategy on successful implementation of the EXCEEDS algorithm (1 – low impact to 4 - high impact). Following the Eisenhower Urgent-Important Matrix Method, I plotted the effort/impact scores in four quadrants representing effort and impact for each strategy to determine implementation priorities. Results: The final EXCEEDS algorithm combines biomedical and individual characteristics associated with need for supervised skilled CRES into 11 risk-stratified dichotomous (yes/no) questions, organized into two sections: (1) pre-exercise medical clearance recommendation, and (2) CRES triage recommendation. Delphi study participants (N=133) represented all CRES stakeholder groups (oncology, physical medicine and rehabilitation, exercise science, etc.). Loss to follow up between surveys ranged 28% (survey 3) to 43% (survey 2). When using the EXCEEDS algorithm, decision accuracy improved in six (of eight) conditions (75%) and duration improved in all conditions (N=4, p <.05). Consensus was achieved in three AIM domains (75%); overall AIM score was M=3.90 ± 0.473 (range = 1.0 – 5.0). Qualitative themes from participant feedback include: (1) algorithm strengths (n = 123, 40.9%), (2) implementation considerations (n=93, 30.5%), and (3) areas for revision (n=87, 28.5%). Oncology clinicians and administrators were the highest-ranked stakeholder group (Median=2.0, IQR= 1.0 – 3.75, 75.0% agreement) and the only one to achieve consensus. Open-access internet was the highest-ranked implementation platform (Median =2.0, IQR= 1.0 – 3.5, 72.4% agreement) and the only one to achieve consensus. Consensus was achieved for eight of the ten highest-ranked implementation strategies (80%, inter-rater agreement range = 93.4% - 71.1%). Two strategies were categorized as urgent/important: "develop educational materials" and "remind clinicians". Seven strategies were categorized important/not urgent. One strategy, "model and simulate change", was categorized as not important/not urgent. Conclusion: The EXCEEDS algorithm is an acceptable and efficient evidence-based solution to identify and connect the right survivor, with the right CRES, at the right time. Thus, implementation of the EXCEEDS algorithm guided by the consensus-based priorities identified in the Delphi study has the potential to improve CRES coordination and utilization. Future hybrid studies will be used to determine prospective efficacy and best practices for implementation

Senior Sway: Using a Mobile Application to Measure Fall Risk

Background and Purpose: The Senior Sway mobile application uses the iPhone/iPad gyroscope to assess postural sway and motion reaction time. Impairment in postural sway and motion reaction time have the potential to increase risk for future falls. Senior Sway thereby has the potential to provide a quick, easy to use, objective measure for predicting falls in older adults. The purpose of this study was to evaluate the feasibility of the Senior Sway mobile application and its associations with fall risk in community-dwelling older adults. Methods: Adults older than 62 years were recruited from senior centers and community events. Descriptive and bivariate statistics were used to examine feasibility on the basis of enrollment, time required, satisfaction with application, and association with fall risk. Results and Discussion: Fifty-seven adults were recruited. Use of the Senior Sway mobile application was feasible. Ninety-one percent said that they liked the application and reported length of time of assessment was “just right.” The average Senior Sway score was 64.0 (range: 47.8-84.0), which was signifi cantly associated with the 30-second sit-to-stand test. In addition, the motor reaction time score was associated with the Timed Up and Go. Conclusions: Senior Sway is a promising application to improve identifi cation of adults at risk for falls and need for rehabilitation but warrants further research

Training alters the distribution of perilipin proteins in muscle following acute free fatty acid exposure.

KEY POINTS: The lipid droplet (LD)-associated perilipin (PLIN) proteins promote intramuscular triglyceride (IMTG) storage, although whether the abundance and association of the PLIN proteins with LDs is related to the diverse lipid storage in muscle between trained and sedentary individuals is unknown. We show that lipid infusion augments IMTG content in type I fibres of both trained and sedentary individuals. Most importantly, despite there being no change in PLIN protein content, lipid infusion did increase the number of LDs connected with PLIN proteins in trained individuals only. We conclude that trained individuals are able to redistribute the pre-existing pool of PLIN proteins to an expanded LD pool during lipid infusion and, via this adaptation, may support the storage of fatty acids in IMTG. ABSTRACT: Because the lipid droplet (LD)-associated perilipin (PLIN) proteins promote intramuscular triglyceride (IMTG) storage, we investigated the hypothesis that differential protein content of PLINs and their distribution with LDs may be linked to the diverse lipid storage in muscle between trained and sedentary individuals. Trained (n = 11) and sedentary (n = 10) subjects, matched for age, sex and body mass index, received either a 6 h lipid or glycerol infusion in the setting of a concurrent hyperinsulinaemic-euglycaemic clamp. Sequential muscle biopsies (0, 2 and 6 h) were analysed using confocal immunofluorescence microscopy for fibre type-specific IMTG content and PLIN associations with LDs. In both groups, lipid infusion increased IMTG content in type I fibres (trained: +62%, sedentary: +79%; P < 0.05) but did not affect PLIN protein content. At baseline, PLIN2 (+65%), PLIN3 (+105%) and PLIN5 (+53%; all P < 0.05) protein content was higher in trained compared to sedentary individuals. In trained individuals, lipid infusion increased the number of LDs associated with PLIN2 (+27%), PLIN3 (+73%) and PLIN5 (+40%; all P < 0.05) in type I fibres. By contrast, in sedentary individuals, lipid infusion only increased the number of LDs not associated with PLIN proteins. Acute free fatty acid elevation therefore induces a redistribution of PLIN proteins to an expanded LD pool in trained individuals only and this may be part of the mechanism that enables fatty acids to be stored in IMTG

Pairing symmetry and long range pair potential in a weak coupling theory of superconductivity

We study the superconducting phase with two component order parameter scenario, such as, $d_{x^2-y^2} + e^{i\theta}s_{\alpha}$, where $\alpha = xy, x^2+y^2$. We show, that in absence of orthorhombocity, the usual $d_{x^2-y^2}$ does not mix with usual $s_{x^2+y^2}$ symmetry gap in an anisotropic band structure. But the $s_{xy}$ symmetry does mix with the usual d-wave for $\theta =0$. The d-wave symmetry with higher harmonics present in it also mixes with higher order extended $s$ wave symmetry. The required pair potential to obtain higher anisotropic $d_{x^2-y^2}$ and extended s-wave symmetries, is derived by considering longer ranged two-body attractive potential in the spirit of tight binding lattice. We demonstrate that the dominant pairing symmetry changes drastically from $d$ to $s$ like as the attractive pair potential is obtained from longer ranged interaction. More specifically, a typical length scale of interaction $\xi$, which could be even/odd multiples of lattice spacing leads to predominant $s/d$ wave symmetry. The role of long range interaction on pairing symmetry has further been emphasized by studying the typical interplay in the temperature dependencies of these higher order $d$ and $s$ wave pairing symmetries.Comment: Revtex 8 pages, 7 figures embeded in the text, To appear in PR

BCS to Bose Crossover in Anisotropic Superconductors

In this work we use functional integral techniques to examine the nearest neighbour attractive Hubbard model on a quasi-2D lattice. It is a simple phenomenological model for the high-Tc cuprates that allows both extended (non-local) s- and d-wave singlet superconductivity as well as mixed symmetry states. The Hartree-Gor'kov mean field theory of the model has a finite temperature phase diagram which shows a transition from pure s-wave to pure d-wave superconductivity, via a mixed symmetry s+id state, as a function of doping. Including Gaussian fluctuations we examine the crossover from weak-coupling BCS superconductivity to the strong-coupling Bose-Einstein condensation of composite s- or d-wave bosons and comment on the origin and symmetry of the pseudogap.Comment: 20 pages inc. 13 figure

Biofunctionalized Zinc Oxide Field Effect Transistors for Selective Sensing of Riboflavin with Current Modulation

Zinc oxide field effect transistors (ZnO-FET), covalently functionalized with single stranded DNA aptamers, provide a highly selective platform for label-free small molecule sensing. The nanostructured surface morphology of ZnO provides high sensitivity and room temperature deposition allows for a wide array of substrate types. Herein we demonstrate the selective detection of riboflavin down to the pM level in aqueous solution using the negative electrical current response of the ZnO-FET by covalently attaching a riboflavin binding aptamer to the surface. The response of the biofunctionalized ZnO-FET was tuned by attaching a redox tag (ferrocene) to the 3′ terminus of the aptamer, resulting in positive current modulation upon exposure to riboflavin down to pM levels

An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics

For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. Analysis of clinicopathologic annotations for over 11,000 cancer patients in the TCGA program leads to the generation of TCGA Clinical Data Resource, which provides recommendations of clinical outcome endpoint usage for 33 cancer types

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin