Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical ...opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.
The Global Leadership Initiative on Malnutrition (GLIM) created a consensus-based framework consisting of phenotypic and etiologic criteria to record the occurrence of malnutrition in adults. This is ...a minimum set of practicable indicators for use in characterizing a patient/client as malnourished, considering the global variations in screening and nutrition assessment, and to be used across different health care settings. As with other consensus-based frameworks for diagnosing disease states, these operational criteria require validation and reliability testing as they are currently based solely on expert opinion.
Several forms of validation and reliability are reviewed in the context of GLIM, providing guidance on how to conduct retrospective and prospective studies for criterion and construct validity.
There are some aspects of GLIM criteria which require refinement; research using large data bases can be employed to reach this goal. Machine learning is also introduced as a potential method to support identification of the best cut-points and combinations of operational criteria for use with the different forms of malnutrition, which the GLIM criteria were created to denote. It is noted as well that the validation and reliability testing need to occur in a variety of sectors, populations and with diverse persons completing the criteria.
The guidance presented supports the conduct and publication of quality validation and reliability studies for GLIM.
Nutrition risk screening for community-living seniors is of great interest in the health arena. However, to be useful, nutrition risk indices need to be valid and reliable. The following three ...studies describe construct validation, test-retest and inter-rater reliability of SCREEN II.
Study (1) seniors were recruited from the general community and from a geriatrician's clinic to complete a nutritional assessment and SCREEN II. 193 older adults provided medical and nutritional history, 3 days of dietary recall and anthropometric measurements. A dietitian reviewed all information collected and ranked seniors on risk: 1 (low) to 10 (high risk). Receiver operating characteristic curves were completed. An abbreviated SCREEN II was developed through statistical analysis and expert ranking of the 17 items. Studies (2) and (3) seniors were recruited from the community to self-administer (n = 149) or be interviewed (n = 97) using SCREEN II twice within 2 weeks. For self-administration one index was completed via mail. Interviewer administration was completed via telephone with two interviewers. Intra-class correlations were calculated.
(1) Total and abbreviated SCREEN II have increased sensitivity and specificity as compared to SCREEN I in identifying seniors at nutritional risk. (2) Test-retest reliability was adequate (intra-class correlation (ICC) = 0.83). (3) Inter-rater reliability was adequate (ICC = 0.83).
SCREEN II appears to be a valid and reliable tool for the identification of risk for impaired nutritional states in community-living older adults, and is an improvement over SCREEN I.
Context. The ESA Rosetta spacecraft has been orbiting the nucleus of comet 67P/Churyumov-Gerasimenko since August 2014. The rotation axis of the irregularly shaped nucleus has a large obliquity (52°) ...and is oriented such that the southern hemisphere is insolated during perihelion. Aims. We calculate the change in the rotation period as a function of the cometary orbital position due to forces exerted by cometary activity. Methods. We used a detailed shape model of 67P with >105 facets. We calculated the efficiency of the facets to exert a torque based on their radial distance from the center of mass and their orientation. We applied our thermal model to calculate the diurnal water-ice sublimation rate from each facet. The reaction force per facet combined with its torque efficiency creates a torque and changes the angular momentum. The component of the torque parallel to the spin axis changes the rotation period. Results. Our model shows that the rotation period increases slightly during the approach of the comet to the Sun. It reaches a maximum shortly before equinox and drops rapidly during perihelion passage. The magnitude of the change depends on the actual sublimation rates. The change in sign mainly depends on the shape of the nucleus and not much on the sublimation variation. The roughness of the nucleus has little influence. Conclusions. For the given geometry of the rotation axis, the change in the rotation period is mainly influenced by the sublimation activity of the irregular shape of the nucleus. The rotation period increases until shortly before equinox in early May 2015, in good agreement with observations, and will then become shorter rapidly.
Failure of the glomerular filtration barrier, primarily by loss of slit diaphragm architecture, underlies nephrotic syndrome in minimal change disease. The etiology remains unknown. The efficacy of B ...cell-targeted therapies in some patients, together with the known proteinuric effect of anti-nephrin antibodies in rodent models, prompted us to hypothesize that nephrin autoantibodies may be present in patients with minimal change disease.
We evaluated sera from patients with minimal change disease, enrolled in the Nephrotic Syndrome Study Network (NEPTUNE) cohort and from our own institutions, for circulating nephrin autoantibodies by indirect ELISA and by immunoprecipitation of full-length nephrin from human glomerular extract or a recombinant purified extracellular domain of human nephrin. We also evaluated renal biopsies from our institutions for podocyte-associated punctate IgG colocalizing with nephrin by immunofluorescence.
In two independent patient cohorts, we identified circulating nephrin autoantibodies during active disease that were significantly reduced or absent during treatment response in a subset of patients with minimal change disease. We correlated the presence of these autoantibodies with podocyte-associated punctate IgG in renal biopsies from our institutions. We also identified a patient with steroid-dependent childhood minimal change disease that progressed to end stage kidney disease; she developed a massive post-transplant recurrence of proteinuria that was associated with high pretransplant circulating nephrin autoantibodies.
Our discovery of nephrin autoantibodies in a subset of adults and children with minimal change disease aligns with published animal studies and provides further support for an autoimmune etiology. We propose a new molecular classification of nephrin autoantibody minimal change disease to serve as a framework for instigation of precision therapeutics for these patients.
There is increasing awareness of the detrimental health impact of frailty on older adults and of the high prevalence of malnutrition in this segment of the population. Experts in these 2 arenas need ...to be cognizant of the overlap in constructs, diagnosis, and treatment of frailty and malnutrition. There is a lack of consensus regarding the definition of malnutrition and how it should be assessed. While there is consensus on the definition of frailty, there is no agreement on how it should be measured. Separate assessment tools exist for both malnutrition and frailty; however, there is intersection between concepts and measures. This narrative review highlights some of the intersections within these screening/assessment tools, including weight loss/decreased body mass, functional capacity, and weakness (handgrip strength). The potential for identification of a minimal set of objective measures to identify, or at least consider risk for both conditions, is proposed. Frailty and malnutrition have also been shown to result in similar negative health outcomes and consequently common treatment strategies have been studied, including oral nutritional supplements. While many of the outcomes of treatment relate to both concepts of frailty and malnutrition, research questions are typically focused on the frailty concept, leading to possible gaps or missed opportunities in understanding the effect of complementary interventions on malnutrition. A better understanding of how these conditions overlap may improve treatment strategies for frail, malnourished, older adults.
A projected doubling in the global population of people aged ≥60 y by the year 2050 has major health and economic implications, especially in developing regions. Burdens of unhealthy aging associated ...with chronic noncommunicable and other age-related diseases may be largely preventable with lifestyle modification, including diet. However, as adults age they become at risk of “nutritional frailty,” which can compromise their ability to meet nutritional requirements at a time when specific nutrient needs may be high. This review highlights the role of nutrition science in promoting healthy aging and in improving the prognosis in cases of age-related diseases. It serves to identify key knowledge gaps and implementation challenges to support adequate nutrition for healthy aging, including applicability of metrics used in body-composition and diet adequacy for older adults and mechanisms to reduce nutritional frailty and to promote diet resilience. This review also discusses management recommendations for several leading chronic conditions common in aging populations, including cognitive decline and dementia, sarcopenia, and compromised immunity to infectious disease. The role of health systems in incorporating nutrition care routinely for those aged ≥60 y and living independently and current actions to address nutritional status before hospitalization and the development of disease are discussed.
Objectives
Determine if nutrition risk, as measured by SCREEN-8 is predictive of 3-year strength and performance indicators among community-living older adults after adjusting for key demographic and ...health variables. Sex-stratified analyses were also determined.
Design
Cohort study with baseline and 3-year follow-up data from the Canadian Longitudinal Study on Aging (CLSA).
Participants
Participants 55 years and older at baseline were included (n = 22,502); those who reported nasogastric or abdominal tube feeding at either timepoint were excluded (n = 26). The final sample of participants available for analyses slightly varied depending on completion of the three outcome variables. List-wise deletion was used for nutrition risk and covariates to arrive at the sample available for analysis (n = 17,250).
Measurements
The valid and reliable SCREEN-8 tool was used to measure nutrition risk. The minimum and maximum score of SCREEN-8 is 0 and 48, respectively, with lower scores indicating greater nutrition risk. Baseline SCREEN-8 score was used in analyses. Grip strength, chair rise test time and gait speed assessed at the 3-year follow-up were the strength and performance outcomes. Criteria outlined by the European Working Group on Sarcopenia in Older People 2 were used to determine low performance for grip strength (<27 kg for males and <16 kg for females), chair rise test time (>15 seconds) and gait speed (≤0.8 m/s).
Results
Half of participants were female (49.4%) and mean age was 66.7 years (SD 7.9). Mean SCREEN-8 score was 39.2 (SD 6.0). Low grip strength, chair rise test performance and gait speed were found in 18.5%, 19.6% and 29.3% of participants, respectively. After adjusting for covariates (e.g., sex, age, education), SCREEN-8 score was significantly associated with grip strength (F = 11.21, p = .001; OR = 0.98, CI 0.97, 0.99), chair rise time (F = 5.97, p = .015; OR = 0.99, CI 0.97, 0.997), and gait speed (F = 9.99, p = .002; OR = 0.98, CI 0.97, 0.99). Similar interpretation was seen in sex-stratified analyses, although chair rise time was not significant. Age, body mass index, Life Space Index Score and self-rated health were consistently associated with all outcome measures.
Conclusion
Nutrition risk, as measured by SCREEN-8, significantly predicted 3-year strength and performance measures. Greater nutrition risk is associated with an increased odds of low performance on grip strength, chair rise test, and gait speed. Future research should implement nutrition risk screening in primary care settings with subsequent assessment and treatment for at risk clients to determine if nutrition interventions implemented post screening can delay age-related losses in strength and performance.
Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and ...depression. For decades, several in vivo and ex vivo techniques have been used to highlight the mechanisms of the GABA system, however, no studies have currently combined the techniques to create a high-resolution multimodal view of the GABA system.
Here, we present a quantitative high-resolution in vivo atlas of the human brain benzodiazepine receptor sites (BZR) located on postsynaptic ionotropic GABAA receptors (GABAARs), generated on the basis of in vivo 11Cflumazenil Positron Emission Tomography (PET) data. Next, based on ex vivo autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association between BZR protein density and ex vivo mRNA expression for the 19 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein.
This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAAR and the BZR density at each location in the brain.
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