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RAS–MAPK signalling is fundamental for cell proliferation and is altered in most human cancers1–3. However, our mechanistic understanding of how RAS signals through RAF is still incomplete. Although studies revealed snapshots for autoinhibited and active RAF–MEK1–14-3-3 complexes4, the intermediate steps that lead to RAF activation remain unclear. The MRAS–SHOC2–PP1C holophosphatase dephosphorylates RAF at serine 259, resulting in the partial displacement of 14-3-3 and RAF–RAS association3,5,6. MRAS, SHOC2 and PP1C are mutated in rasopathies—developmental syndromes caused by aberrant MAPK pathway activation6–14—and SHOC2 itself has emerged as potential target in receptor tyrosine kinase (RTK)–RAS-driven tumours15–18. Despite its importance, structural understanding of the SHOC2 holophosphatase is lacking. Here we determine, using X-ray crystallography, the structure of the MRAS–SHOC2–PP1C complex. SHOC2 bridges PP1C and MRAS through its concave surface and enables reciprocal interactions between all three subunits. Biophysical characterization indicates a cooperative assembly driven by the MRAS GTP-bound active state, an observation that is extendible to other RAS isoforms. Our findings support the concept of a RAS-driven and multi-molecular model for RAF activation in which individual RAS–GTP molecules recruit RAF–14-3-3 and SHOC2–PP1C to produce downstream pathway activation. Importantly, we find that rasopathy and cancer mutations reside at protein–protein interfaces within the holophosphatase, resulting in enhanced affinities and function. Collectively, our findings shed light on a fundamental mechanism of RAS biology and on mechanisms of clinically observed enhanced RAS–MAPK signalling, therefore providing the structural basis for therapeutic interventions.

Preoperative dysphagia screening is rare. The purpose of this study was to assess the prevalence and potential risk factors of preoperative dysphagia risk in adults preparing for surgery.The Eating Assessment Tool (EAT-10), Patient-Generated Subjective Global Assessment Short Form (PG-SGA SF), and Sarcopenia Screening Tool (SARC-F) were self-administered in adults preparing for surgery to identify dysphagia, malnutrition, and sarcopenia risk, respectively. Other variables collected include clinical demographics, fall risk, and surgical history associated with increased dysphagia risk. Descriptive summary statistics, univariate analysis, and logistic regression were performed as appropriate.The median age was 69 years and preoperative dysphagia risk was 9.6%. Among 357 patients completing both EAT-10 and PG-SGA SF or SARC-F, 7.3% had preoperative dysphagia and malnutrition risk and 7.2% had preoperative dysphagia and sarcopenia risk. Preoperative dysphagia risk was 2.7 times greater in those with prior surgical history associated with increased risk of dysphagia, 2.2 times higher in women, and almost twice as high in Black patients and patients with fall risk. Logistic regression revealed significant odds ratios (ORs) for prior surgical history associated with increased risk of dysphagia (OR, 2.95; 95% CI, 1.62-5.40) and male sex (OR, 0.52; 95% CI, 0.29-0.94), and a significant relationship between preoperative dysphagia and malnutrition risk (OR, 4.56; 95% CI, 2.02-10.28) when controlling for clinical variables.The high prevalence of dysphagia risk alone and in combination with malnutrition and sarcopenia risk in community-dwelling adults underscores the need for standardized preoperative screening and optimization prior to surgery.

The COVID-19 pandemic limited older adults’ access to preventative and diagnostic services and negatively affected accessibility to age-appropriate exercise programs. The purpose of this study was to assess the feasibility of conducting guided virtual functional fitness assessments before and after participation in an 8-week virtual, live fitness program (Vivo) designed for older adults. It was hypothesized there would be no significant difference between in-person and virtual functional fitness assessments and function would improve following the program. Thirteen community-dwelling older adults were recruited, screened, and randomly assigned to in-person-first or virtual-first fitness assessment groups. Validated assessments were delivered using standardized scripts by trained researchers and included Short Physical Performance Battery (SPPB) balance, a 30 s Chair Stand Test, 8 Foot Up-and-Go Test, 30 s Arm Curl Test, and 2 min Step Test. The eight-week, twice-a-week live virtual fitness program involved cardiovascular, balance, agility, Dual-Task, and strength training. Results showed no significant differences between all but one assessment measures, and several measures improved following the eight-week program. Fidelity checks demonstrated the high fidelity of program delivery. These findings illustrate that virtual assessments can be a feasible method to measure functional fitness in community-dwelling older adults.

The onset of the COVID-19 pandemic has presented unique challenges for inpatient psychiatry units (IPUs). IPUs, especially those caring for children and adolescents, rely heavily on milieu group programming to provide care and supervision for patients, and have had to adapt unit policies and procedures to maintain a therapeutic milieu while minimizing COVID-19 transmission.sup1/supSimultaneously providing care while preventing transmission of COVID-19 within IPUs is a formidable task, and many IPUs face the additional challenge of treating youth who have been exposed to, or are actively infected with, COVID-19. In addition, given the need to prevent transmission of COVID-19, recommendations include "mandatory quarantine and isolation when patients refuse to adhere to guidelines,"sup2/suppotentially leading to the use of restraint when patients attempt to leave isolation; thus a conflict between the potential risks of enforcing infection prevention policies in order to reduce virus transmission and best practices of eliminating seclusion and restraint (S/R) creates an ethical dilemma for IPUs.

Introduction: Despite improvements in pharmacologic management of rheumatoid arthritis (RA), patients with RA continue to have an increased risk for CVD - the leading cause of death in this population. RA CVD results from a combination of traditional risk factors - such as hypertension, dyslipidemia, physical inactivity, and obesity - and RA-related systemic inflammation. Although weight loss and physical activity are promising means for improving both traditional and inflammatory risk factors, evidence is lacking for lifestyle interventions targeting these health behaviors in RA. Hypothesis: In the SWET-RA trial, we hypothesized that, as compared to standard of care, a 16-week remotely delivered weight loss and exercise intervention would improve CVD risk factors in older persons with RA and obesity. Methods: Twenty-four patients (age 60-80 years; BMI 28-40 kg/m 2 ) were randomized to one of two groups: 1) supervised weight loss and exercise training (SWET); or 2) counseling health as treatment (CHAT). The SWET intervention - delivered via video conference, the study YouTube channel, and mobile applications - consists of a) dietitian-led caloric restriction diet (7% weight loss goal) with weekly weigh-ins and group support sessions; and b) exercise physiologist-led aerobic (150 min moderate-to-vigorous exercise) and resistance training (twice weekly). CHAT provides initial clinical counseling on healthy diets and physical activity followed by monthly check-ins. Outcomes include body mass; body composition via Air Displacement Plethysmography; peak oxygen consumption [VO 2 (mL/kg/min)] via maximal cardiopulmonary exercise testing; and mean arterial blood pressure (MAP). Within-groups, paired t-tests assessed whether post- minus pre-intervention change scores (mean ± standard deviation) were significant (p Results: To date, 13 patients (61.5% White; 84.6% female) have completed the study; 8 additional patients are expected to complete the study by February 2023. Following the intervention, the CHAT group (n=5) had mean changes in body mass, fat mass, and lean mass of -2.4 ± 4.0%, -3.3 ± 4.3 kg, and 1.0 ± 1.0 kg (all p>0.05). Those randomized to SWET (n=8) had significant improvements in body mass (-5.0 ± 2.9%; p=0.002) and fat mass (-4.3 ± 2.8 kg; p=0.004), and no change in lean mass (0.4 ± 1.2 kg; p=0.36). The CHAT group had a 1.1 ± 6.7% change in peak VO 2 (p=0.81), while the SWET group exhibited a 10.6 ± 16.7% change (p=0.13). There were minimal changes in MAP for both groups (CHAT: -1.0 ± 1.0 mmHg; SWET: -0.4 ± 1.2 mmHg). Conclusions: Preliminary findings indicate that, as compared to CHAT, the SWET intervention elicits beneficial changes in body mass, fat mass, and cardiorespiratory fitness. As the SWET-RA trial is pioneering a remotely delivered program, results from this study will help guide lifestyle intervention implementation to improve CVD risk in larger groups of patients with RA.

Objective Research recruitment through patient portals (ie, patient-facing, web-based clinical interfaces) has the potential to be effective, efficient, and inclusive, but best practices remain undefined. We sought to better understand how patients view this recruitment approach. Materials and Methods We conducted 6 focus groups in Atlanta, GA and Seattle, WA with members of patient advisory committees and the general public. Discussions addressed acceptability of patient portal recruitment and communication preferences. Focus groups were audio-recorded, transcribed, and analyzed using deductive and inductive codes. Iterative team discussions identified major themes. Results Of 49 total participants, 20 were patient advisory committee members. Participants’ mean age was 49 (range 18–74); 59% identified as non-Hispanic White and 31% as Black/African American. Participants were supportive of patient portal recruitment and confident that messages were private and legitimate. Participants identified transparency and patient control over whether and how to participate as essential features. Concerns included the frequency of research messages and the ability to distinguish between research and clinical messages. Participants also discussed how patient portal recruitment might affect diversity and inclusion. Discussion Focus group participants generally found patient portal recruitment acceptable and perceived it as secure and trustworthy. Transparency, control, and attention to inclusiveness were identified as key considerations for developing best practices. Conclusion For institutions implementing patient portal recruitment programs, continued engagement with patient populations can help facilitate translation of these findings into best practices and ensure that implemented strategies accomplish intended goals.

Introduction: The goal of a research ethics consultation service (RECS) is to assist relevant parties in navigating the ethical issues they encounter in conduct of research. The goal of this survey was to describe the current landscape of research ethics consultation and document if and how it has changed over the last decade. Methods: The survey instrument was based on the survey previously circulated. We included a number of survey domains from the previous survey with the goal of direct comparison of outcomes. The survey was sent to 57 RECS in the USA and Canada. Results: Forty-nine surveys were completed for an overall response rate of 86%. With the passing of 10 years, the volume of consults received by RECS surveyed has increased. The number of consults received by a subset of RECS remains low. RECS continues to receive requests for consults from a wide range of stakeholders. About a quarter of RECS surveyed actively evaluate their services, primarily through satisfaction surveys routinely shared with requestors. The number of RECS evaluating their services has increased. We identified a group of eight key competencies respondents find as key to providing RECS. Conclusions: The findings from our survey demonstrate that there have been growth and development of RECS since 2010. Further developing evaluation and competency guidelines will help existing RECS continue to grow and facilitate newly established RECS maturation. Both will allow RECS personnel to better serve their institutions and add value to the research conducted.

The Mediterranean diet (MedD) is a flexible dietary pattern which has such variability that has led to inconsistencies in definitions and assessment. The purpose of this narrative review is to evaluate scoring systems in a cultural and geographic context, from Mediterranean and non-Mediterranean countries, for comparison and application. The early MedD scoring systems (i.e. Trichopoulou’s MedD Scale (T-MDS) and alternative MedD Scale (aMed)) are widely applied throughout the world but use population-specific median cut-offs which limit interpretation and cross-study comparisons. The T-MDS and aMed also do not account for non-traditional MedD foods which are consumed in greater quantities than when the scoring systems were developed. Scoring systems developed after the MedD pyramid publication in 2011 have generally used these recommendations as a basis for food group intake cut-offs, incorporating more foods/food groups as negative components, and some have included dietary and lifestyle behaviours. The different approaches to MedD assessment have created much variability in the foods/food group components included in scoring systems. Assessments that include dietary and lifestyle behaviours may reflect the nutrition transition occurring in Mediterranean countries and better guide clinical intervention approaches. While the new scoring systems are theorised to better capture MedD adherence and behaviours, comparisons are sparse in the literature and none exists outside of Europe. Consensus on food and dietary behaviours to include as well as the methodology for assigning points in MedD scoring systems is needed to advance our understanding of MedD and health relationships to promote public health messaging and clinical application.

Background Risk assessment for hereditary cancer syndromes is recommended in primary care, but family history is rarely collected in enough detail to facilitate risk assessment and referral – a roadblock that disproportionately impacts individuals with healthcare access barriers. We sought to qualitatively assess a literacy-adapted, electronic patient-facing family history tool developed for use in diverse, underserved patient populations recruited in the Cancer Health Assessments Reaching Many (CHARM) Study. Methods Interview participants were recruited from a subpopulation of CHARM participants who experienced barriers to tool use in terms of spending a longer time to complete the tool, having incomplete attempts, and/or providing inaccurate family history in comparison to a genetic counselor-collected standard. We conducted semi-structured interviews with participants about barriers and facilitators to tool use and overall tool acceptability; interviews were recorded and professionally transcribed. Transcripts were coded based on a codebook developed using inductive techniques, and coded excerpts were reviewed to identify overarching themes related to barriers and facilitators to family history self-assessment and acceptability of the study tool. Results Interviewees endorsed the tool as easy to navigate and understand. However, they described barriers related to family history information, literacy and language, and certain tool functions. Participants offered concrete, easy-to-implement solutions to each barrier. Despite experience barriers to use of the tool, most participants indicated that electronic family history self-assessment was acceptable or preferable in comparison to clinician-collected family history. Conclusions Even for participants who experienced barriers to tool use, family history self-assessment was considered an acceptable alternative to clinician-collected family history. Barriers experienced could be overcome with minor adaptations to the current family history tool. Trial registration This study is a sub-study of the Cancer Health Assessments Reaching Many (CHARM) trial, ClinicalTrials.gov, NCT03426878. Registered 8 February 2018.

The changing clinical research recruitment landscape involves practical challenges but introduces opportunities. Researchers can now identify large numbers of eligible patients through electronic health record review and can directly contact those who have authorized contact. Applying behavioral science-driven strategies to design and frame communication could affect patients' willingness to authorize contact and their understanding of these programs. The ethical and practical implications of various strategies warrant empirical evaluation.We conducted an online survey (Compared to the neutral flyer, individuals who received the positive text flyer were numerically more likely to enroll, but this was not statistically significant (24.2% v. 19.0%,This study demonstrated that employing behavioral science-driven communication strategies for authorization for research contact had an effect on likelihood of hypothetical enrollment but did not significantly affect comprehension. Strategies using simple, positive language and visual tools may be effective and ethically appropriate. Further studies should explore how these and other approaches can help to optimize research recruitment.

Summary Background Severe muscle mass (MM) loss is a defining feature of cancer observed across all types and stages of disease and is an independent predictor of poor clinical outcomes including higher incidences of chemotherapy toxicity and decreased survival. Protein is essential to build MM, yet the optimal amount for preventing or treating muscle loss in patients with cancer remains undefined. Methods The Protein Recommendation to Increase Muscle (PRIMe) study is a single-center, two-armed, parallel, randomized, controlled pilot trial that assesses the feasibility of utilizing a high protein (HP) diet to positively impact clinical outcomes in people undergoing chemotherapy to treat colorectal cancer. Forty patients with newly diagnosed stage II-IV colorectal cancer who are scheduled to receive chemotherapy will be included. Participants are randomly assigned to a HP or normal protein (NP) diet for twelve weeks. The HP and NP groups receive nutrition recommendations to achieve 2.0 g of protein per kilogram of body weight per day (g∙kg−1∙d−1) and 1.0 g⋅kg−1⋅d−1, respectively. These values refer to the upper and lower recommended range of protein intake for people with cancer. Energy recommendations are based on measured energy expenditure. Assessments are completed within two weeks of starting chemotherapy (baseline), at week 6, and at week 12. Changes to skeletal MM, physical function, anthropometrics, body composition, muscle strength, physical activity, energy metabolism, metabolic markers, nutritional status, quality of life, readiness to change and psychosocial determinants of behavioural change are assessed between the HP and NP groups. Feasibility of the nutritional intervention is assessed by change in MM as a surrogate marker. Conclusions This evidence-based study investigates the feasibility of increasing protein intake following a diagnosis of cancer on clinical outcomes during treatment for colorectal cancer. This study will inform larger trials assessing the impact of increasing protein intake in cancer to determine their importance and integration into standard clinical care for people with cancer.

Graphical abstract, We study the models submitted to round 12 of the Critical Assessment of protein Structure Prediction (CASP) experiment to assess how well the binding properties are conserved when the X-ray structures of the target proteins are replaced by their models. To explore small molecule binding we generate distributions of molecular probes – which are fragment-sized organic molecules of varying size, shape, and polarity – around the protein, and count the number of interactions between each residue and the probes, resulting in a vector of interactions we call a binding fingerprint. The similarity between two fingerprints, one for the X-ray structure and the other for a model of the protein, is determined by calculating the correlation coefficient between the two vectors. The resulting correlation coefficients are shown to correlate with global measures of accuracy established in CASP, and the relationship yields an accuracy threshold that has to be reached for meaningful binding surface conservation. The clusters formed by the probe molecules reliably predict binding hot spots and ligand binding sites in both X-ray structures and reasonably accurate models of the target, but ensembles of models may be needed for assessing the availability of proper binding pockets. We explored ligand docking to the few targets that had bound ligands in the X-ray structure. More targets were available to assess the ability of the models to reproduce protein–protein interactions by docking both the X-ray structures and models to their interaction partners in complexes. It was shown that this application is more difficult than finding small ligand binding sites, and the success rates heavily depend on the local structure in the potential interface. In particular, predicted conformations of flexible loops are frequently incorrect in otherwise highly accurate models, and may prevent predicting correct protein–protein interactions.

We conducted an online experimental survey to evaluate attitudes toward an authorization for contact (AFC) program allowing researchers to contact patients about studies based on electronic record review. A total of 1070 participants were randomly assigned to 1 of 3 flyers varying in design and framing. Participants were asked to select concerns about and reasons for signing up for AFC. Logistic regression and latent class analysis were conducted. The most commonly selected concerns included needing more information (43%), privacy (40%), and needing more time to think (28%). A minority were not interested in participating in research (16%) and did not want to be bothered (15%). Latent class analysis identified clusters with specific concerns about privacy, lack of interest in research, and not wanting to be bothered. A novel flyer with simple and positive framing was associated with lower odds of both not wanting to be bothered (P = .01) and not being interested in research (P = .01). Many concerns about AFC programs appear nonspecific. Addressing privacy, lack of interest in research, and not wanting to be bothered warrant further study as ways to enhance recruitment.

BACKGROUND: Clinical genomic implementation studies pose challenges for informed consent. Consent forms often include complex language and concepts, which can be a barrier to diverse enrollment, and these studies often blur traditional research-clinical boundaries. There is a move toward self-directed, web-based research enrollment, but more evidence is needed about how these enrollment approaches work in practice. In this study, we developed and evaluated a literacy-focused, web-based consent approach to support enrollment of diverse participants in an ongoing clinical genomic implementation study. METHODS: As part of the Cancer Health Assessments Reaching Many (CHARM) study, we developed a web-based consent approach that featured plain language, multimedia, and separate descriptions of clinical care and research activities. CHARM offered clinical exome sequencing to individuals at high risk of hereditary cancer. We interviewed CHARM participants about their reactions to the consent approach. We audio recorded, transcribed, and coded interviews using a deductively and inductively derived codebook. We reviewed coded excerpts as a team to identify overarching themes. RESULTS: We conducted 32 interviews, including 12 (38%) in Spanish. Most (69%) enrolled without assistance from study staff, usually on a mobile phone. Those who completed enrollment in one day spent an average of 12 minutes on the consent portion. Interviewees found the information simple to read but comprehensive, were neutral to positive about the multimedia support, and identified increased access to testing in the study as the key difference from clinical care. CONCLUSIONS: This study showed that interviewees found our literacy-focused, web-based consent approach acceptable; did not distinguish the consent materials from other online study processes; and valued getting access to testing in the study. Overall, conducting empirical bioethics research in an ongoing clinical trial was useful to demonstrate the acceptability of our novel consent approach but posed practical challenges.

As genomic researchers are encouraged to engage in broad genomic data shar­ing, American Indian/Alaska Native/Native Hawaiian (AI/AN/NH) leaders have raised questions about ownership of data and biospecimens and concerns over emerging challenges and potential threats to tribal sovereignty. Using a community-engaged research approach, we conducted 42 semi-structured interviews with tribal lead­ers, clinicians, researchers, policy makers, and tribal research review board members about their perspectives on ethical issues related to genetics in AI/AN/NH communi­ties. We report findings related to perspec­tives on genetic research, data sharing, and envisioning stronger oversight and manage­ment of data. In particular, participants voiced concerns about different models of data sharing, infrastructure and logistics for housing data, and who should have authority to grant access to data. The results will ultimately guide policy-making and the creation of guidelines and new strategies for tribes to drive the research agenda and promote ethically and culturally appropriate research.Ethn Dis.2019;29(Suppl 3):659-668;doi:10.18865/ed.29.S3.659

This study aimed to evaluate the laboratory-related outcomes of participants who were offered genomic testing based on cancer family history risk assessment tools.Patients from clinics that serve populations with access barriers, who are screened at risk for a hereditary cancer syndrome based on adapted family history collection tools (the Breast Cancer Genetics Referral Screening Tool and PREMMOf all the participants, 87% successfully returned a saliva kit. Overall, 5% had a pathogenic/likely pathogenic cancer risk variant and 1% had a secondary finding. Almost all (14/15, 93%) participants completed recommended consultations with nongenetics providers after an average of 17 months. The recommended actions (eg, breast magnetic resonance imaging) were completed by 17 of 25 participants. Participant personal history of cancer and PREMMThis accessible model of hereditary cancer risk assessment and genetic testing yielded results that were often acted upon by patients and physicians.

We present the results for CAPRI Round 50, the fourth joint CASP-CAPRI protein assembly prediction challenge. The Round comprised a total of twelve targets, including six dimers, three trimers, and three higher-order oligomers. Four of these were easy targets, for which good structural templates were available either for the full assembly, or for the main interfaces (of the higher-order oligomers). Eight were difficult targets for which only distantly related templates were found for the individual subunits. Twenty-five CAPRI groups including eight automatic servers submitted ~1250 models per target. Twenty groups including six servers participated in the CAPRI scoring challenge submitted ~190 models per target. The accuracy of the predicted models was evaluated using the classical CAPRI criteria. The prediction performance was measured by a weighted scoring scheme that takes into account the number of models of acceptable quality or higher submitted by each group as part of their five top-ranking models. Compared to the previous CASP-CAPRI challenge, top performing groups submitted such models for a larger fraction (70–75%) of the targets in this Round, but fewer of these models were of high accuracy. Scorer groups achieved stronger performance with more groups submitting correct models for 70–80% of the targets or achieving high accuracy predictions. Servers performed less well in general, except for the MDOCKPP and LZERD servers, who performed on par with human groups. In addition to these results, major advances in methodology are discussed, providing an informative overview of where the prediction of protein assemblies currently stands., Cancer Research UK, Grant/Award Number: FC001003; Changzhou Science and Technology Bureau, Grant/Award Number: CE20200503; Department of Energy and Climate Change, Grant/Award Numbers: DE-AR001213, DE-SC0020400, DE-SC0021303; H2020 European Institute of Innovation and Technology, Grant/Award Numbers: 675728, 777536, 823830; Institut national de recherche en informatique et en automatique (INRIA), Grant/Award Number: Cordi-S; Lietuvos Mokslo Taryba, Grant/Award Numbers: S-MIP-17-60, S-MIP-21-35; Medical Research Council, Grant/Award Number: FC001003; Japan Society for the Promotion of Science KAKENHI, Grant/Award Number: JP19J00950; Ministerio de Ciencia e Innovación, Grant/Award Number: PID2019-110167RB-I00; Narodowe Centrum Nauki, Grant/Award Numbers: UMO-2017/25/B/ST4/01026, UMO-2017/26/M/ST4/00044, UMO-2017/27/B/ST4/00926; National Institute of General Medical Sciences, Grant/Award Numbers: R21GM127952, R35GM118078, RM1135136, T32GM132024; National Institutes of Health, Grant/Award Numbers: R01GM074255, R01GM078221, R01GM093123, R01GM109980, R01GM133840, R01GN123055, R01HL142301, R35GM124952, R35GM136409; National Natural Science Foundation of China, Grant/Award Number: 81603152; National Science Foundation, Grant/Award Numbers: AF1645512, CCF1943008, CMMI1825941, DBI1759277, DBI1759934, DBI1917263, DBI20036350, IIS1763246, MCB1925643; NWO, Grant/Award Number: TOP-PUNT 718.015.001; Wellcome Trust, Grant/Award Number: FC001003

Millum and Bromwich (2021) provide a thorough and thoughtful analysis of what is required for sufficient informed consent, offering distinct conceptualizations of the ethical requirements of disclo...

Individuals having genomic sequencing can choose to be notified about pathogenic variants in genes unrelated to the testing indication. A decision aid can facilitate weighing one's values before making a choice about these additional results.We conducted a randomized trial (N = 231) comparing informed values-choice congruence among adults at risk for a hereditary cancer syndrome who viewed either the Optional Results Choice Aid (ORCA) or web-based additional findings information alone. ORCA is values-focused with a low-literacy design.Individuals in both arms had informed values-choice congruence (75% and 73% in the decision aid and web-based groups, respectively; odds ratio [OR] = 1.10, 95% CI = 0.58-2.08). Most participants had adequate knowledge (79% and 76% in the decision aid and web-based groups, respectively; OR = 1.20, 95% CI = 0.61-2.34), with no significant difference between groups. Most had information-seeking values (97% and 98% in the decision aid and web-based groups, respectively; OR = 0.59, 95% CI = 0.10-3.61) and chose to receive additional findings.The ORCA decision aid did not significantly improve informed values-choice congruence over web-based information in this cohort of adults deciding about genomic results. Both web-based approaches may be effective for adults to decide about receiving medically actionable additional results.

This article provides pragmatic advice for organizations interested in creating a research ethics consultation service (RECS). A robust RECS has the potential to build capacity among investigators to identify and consider the ethical issues they encounter while conducting their research. Determining whether to establish an RECS should begin with an institutional-needs assessment that includes three key questions: What are the current resources available to research teams to navigate ethical concerns that arise from their research? Is there a demand or perceived need for more resources? Is there institutional support (financial and otherwise) to establish and maintain an RECS? If this results in the decision to establish the consultation service, relevant institutional stakeholders must be identified and consulted, and personnel with the requisite skills recruited. The next step is to establish an RECS and build the infrastructure to process and respond to requests. The RECS's long-term sustainability will depend on a stable source of funding and a mechanism to receive constructive feedback to ensure that the service is meeting the institutional needs it set out to address.

Older veterans with posttraumatic stress disorder (PTSD) are at increased risk of obesity and cardiometabolic disease. Physical activity and healthy eating are two behaviors that impact health, functional independence, and disease risk in later life, yet few studies have examined the relationship between PTSD and diet quality. This secondary analysis aimed to: (a) characterize the diet quality of older veterans with PTSD in comparison to U.S. dietary guidelines and (b) explore if participation in a supervised exercise intervention spurred simultaneous changes in dietary behavior. Diet quality was assessed with the Dietary Screener Questionnaire (DSQ), which measures daily intake of fiber, calcium, added sugar, whole grain, dairy, and fruits/vegetables/legumes. The sample included 54 military veterans ≥ 60 years old with PTSD who participated in a randomized controlled pilot trial comparing 12 weeks of supervised exercise (n = 36) to wait-list usual care (n = 18). The DSQ was administered at baseline and 12 weeks. Consumption of added sugar exceeded U.S. dietary guideline recommendations and consumption of whole grains, fruits/vegetables/legumes, fiber, calcium, and dairy fell short. Participation in the supervised exercise intervention was not associated with changes in diet quality. Results revealed that the diet quality of older veterans with PTSD is poor, and while the exercise intervention improved health through exercise, it did not make veterans any more likely to adopt a more healthful diet. Interventions targeting diet, or diet + exercise, are needed to manage the increased risk of obesity and cardiometabolic disease present in older veterans with PTSD.Older veterans with posttraumatic stress disorder (PTSD) are at risk for several physical health conditions that reduce their quality of life. Physical activity and healthy eating are important behaviors for promoting good health and physical function in later life. The purpose of this study was to examine the diet quality of older veterans with PTSD and explore whether a program designed to increase exercise also improved diet. Diet quality was measured with a self-report survey, the Dietary Screener Questionnaire (DSQ), which measures daily intake of fiber, calcium, added sugar, whole grain, dairy, and fruits/vegetables/legumes. Study participants were 54 military veterans age 60 years and older with PTSD who participated in a randomized controlled pilot trial comparing 12 weeks of supervised exercise to wait-list usual care. The DSQ was administered at baseline and 12 weeks post intervention. Results show that older veterans with PTSD have overall poor diet quality that included consuming too much added sugar and not enough whole grains, fruits/vegetables/legumes, fiber, calcium, and dairy. Participation in the supervised exercise did not lead to simultaneous diet quality changes over 12 weeks. This study shows that diet quality is poor in older veterans with PTSD and future programs are needed to target this health behavior.

There exists a standard approach to developing drugs for adults. The process begins with animal studies focused on toxicity, followed by phase I safety and dosage studies in humans, phase II effica...

As a participant in the joint CASP13-CAPRI46 assessment, the ClusPro server debuted its new template-based modeling functionality. The addition of this feature, called ClusPro TBM, was motivated by the previous CASP-CAPRI assessments and by the proven ability of template-based methods to produce higher quality models, provided templates are available. In prior assessments, ClusPro submissions consisted of models that were produced via free docking of pre-generated homology models. This method was successful in terms of the number of acceptable predictions across targets, however, analysis of results showed that purely template-based methods produced a substantially higher number of medium quality models for targets for which there were good templates available. The addition of template-based modeling has expanded ClusPro’s ability to produce higher accuracy predictions, primarily for homomeric but also for some heteromeric targets. Here we review the newest additions to the ClusPro web server and discuss examples of CASP-CAPRI targets that continue to drive further development. We also describe ongoing work not yet implemented in the server. This includes the development of methods to improve template-based models and the use of co-evolutionary information for data-assisted free docking.

The inhibition of kinases has been pursued by the pharmaceutical industry for over 20 years. While the locations of the sites that bind type II and III inhibitors at or near the adenosine 5'-triphosphate binding sites are well defined, the literature describes 10 different regions that were reported as regulatory hot spots in some kinases and thus are potential target sites for type IV inhibitors. Kinase Atlas is a systematic collection of binding hot spots located at the above ten sites in 4910 structures of 376 distinct kinases available in the Protein Data Bank. The hot spots are identified by FTMap, a computational analogue of experimental fragment screening. Users of Kinase Atlas ( https://kinase-atlas.bu.edu ) may view summarized results for all structures of a particular kinase, such as which binding sites are present and how druggable they are, or they may view hot spot information for a particular kinase structure of interest.

A number of well-established servers perform 'free' docking of proteins of known structures. In contrast, template-based docking can start from sequences if structures are available for complexes that are homologous to the target. On the basis of the results of the CAPRI-CASP structure prediction experiments, template-based methods yield more accurate predictions if good templates can be found, but generally fail without such templates. However, free global docking, or focused docking around even poor quality template-based models, can still generate acceptable docked structures in these cases. In accordance with the analysis of a benchmark set, free docking of heterodimers yields acceptable or better predictions in the top 10 models for around 40% of structures. However, it is likely that a combination of template-based and free docking methods can perform better for targets that have template structures available. Another way of improving the reliability of predictions is adding experimental information as restraints, an option built into several docking servers.

Both aging and obesity are associated with increased levels of pro-inflammatory metabolites, while weight reduction is associated with improvements in inflammatory status. However, few studies have explored the response of key inflammatory markers to the combined settings of weight reduction in an aging population. There are also few studies that have investigated the potential impact of diet composition on inflammatory marker responses. In the MEASUR-UP trial, we evaluated changes in baseline levels of inflammatory markers with post-study levels for a traditional weight loss control group versus a group with generous, balanced protein intake. In this 6-month randomized controlled trial (RCT), older (≥60 yrs) adults with obesity (BMI ≥30 kg/m(2)) and Short Physical Performance Battery (SPPB) score of 4–10 were randomly assigned to either a traditional weight loss regimen, (Control, n=14) or one with higher protein intake (≥30 g) at each meal (Protein, n=25). All participants were prescribed a hypo-caloric diet and attended weekly support and education groups and weigh-ins. Protein participants consumed ≥30 g of high quality protein/meal, including lean and extra lean beef provided to them for two of the three meals per day. Protein intakes were 0.8 and 1.2 g/kg/day for Control and Protein, respectively. Adiponectin, leptin, C-reactive protein (hs-CRP), tumor necrosis factor-α (TNF- α), interleukin-1 (IL-1), IL-6, IL-8, serum amyloid A (SAA), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and glycated serum protein (GSP) levels were measured at 0 and 6-month time points. At the 6-month endpoint, there was significant weight loss and decrease in BMI in both the Control (−4.8 ± 8.2 kg; −2.3 ± 2.4 kg/m(2); P=0.05) and Protein (−8.7 ± 7.4 kg; −2.9 ± 2.3 kg/m(2); P

This study examined the relationship between dysphagia and adverse outcomes across frailty conditions among surgical patients ≥50 years of age. A retrospective cohort analysis of surgical hospitalizations in the Healthcare Cost and Utilization Project's National Inpatient Sample among patients ≥50 years of age undergoing intermediate/high risk surgery not involving the larynx, pharynx, or esophagus. Of 3,298,835 weighted surgical hospitalizations, dysphagia occurred in 1.2% of all hospitalizations and was higher in frail patients ranging from 5.4% to 11.7%. Dysphagia was associated with greater length of stay, higher total costs, increased non-routine discharges, and increased medical/surgical complications among both frail and non-frail patients. Dysphagia may be an independent risk factor for poor postoperative outcomes among surgical patients ≥50 years of age across frailty conditions and is an important consideration for providers seeking to reduce risk in vulnerable surgical populations.