Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate ...involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAG
. To investigate the role of UVRAG
in vivo, we generated mutant mice that inducibly express UVRAG
(iUVRAG
). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAG
mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAG
mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant β-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.
Background Several clinical trials have reported an early reduction in breast cancer incidence in healthy women using tamoxifen to reduce their risk of breast cancer but have not reported longer ...follow-up data for the evaluation of breast cancer prevention. We report the blinded 20-year follow-up (median follow-up = 13 years) of the Royal Marsden trial to identify any long-term prevention of breast cancer associated with tamoxifen treatment. Methods We randomly assigned 2494 healthy women to oral tamoxifen (20 mg/day) or placebo for 8 years. The primary outcome was occurrence of invasive breast cancer. A secondary planned analysis of estrogen receptor (ER)–positive invasive breast cancer was also done. Survival was assessed by use of a Cox proportional hazards model in both univariate and multivariable analyses. The durability of the treatment effect was assessed by use of a Cox regression analysis. All statistical tests were two-sided. Results Among the 2471 eligible participants (1238 participants in the tamoxifen arm and 1233 participants in the placebo arm), 186 developed invasive breast cancer (82 on tamoxifen and 104 on placebo; hazard ratio HR = 0.78, 95% confidence interval CI = 0.58 to 1.04; P = .1). Of these 186 cancers, 139 were ER positive (53 on tamoxifen and 86 on placebo; HR = 0.61, 95% CI = 0.43 to 0.86; P = .005). The risk of ER-positive breast cancer was not statistically significantly lower in the tamoxifen arm than in the placebo arm during the 8-year treatment period (30 cancers in the tamoxifen arm and 39 in the placebo arm; HR = 0.77, 95% CI = 0.48 to 1.23; P = .3) but was statistically significantly lower in the posttreatment period (23 in the tamoxifen arm and 47 in the placebo arm; HR = 0.48, 95% CI = 0.29 to 0.79; P = .004). Fifty-four participants in each arm have died from any cause (HR = 0.99, 95% CI = 0.68 to 1.44; P = .95). The adverse event profiles for both arms were similar to those previously reported and occurred predominantly during the treatment period. Conclusions A statistically significant reduction in the incidence of ER-positive breast cancer was observed in the tamoxifen arm that occurred predominantly during the post treatment follow-up, indicating long-term prevention of estrogen-dependent breast cancer by tamoxifen.
In this paper, synthesis of very high molecular weight (VHMW) polyacrylonitrile-co-methyl acrylate (PAN-co-MA) polymers with weight average molecular weights of at least 1.7 million g/mole were ...repeatedly achieved on a laboratory scale using emulsion polymerization. The development of a hybrid dry-jet gel solution spinning technique for the VHMW PAN-co-MA enabled continuous spinning of 100 filament count tows, 100s of meters in length. Single filaments were analyzed and tested for tensile performance. Experimentally, the hybrid spinning method coupled with VHMW polymers produced precursor fibers with excellent tensile properties, averaging 954 MPa in strength and 15.9 GPa in elastic modulus (N = 296), with small filament diameters (5 μm). Results indicate a strong correlation between decreasing filament diameter, facilitated by high molecular weight polymer, and exponentially increasing tensile properties, using a hybrid dry-jet gel spinning process.
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•Synthesis of copolymers with Mw ≥ 1.7 million g/mole was achieved.•A hybrid dry-jet gel spinning process was developed.•Reduced filament diameters were facilitated by very high molecular weight copolymers.•An exponential relationship between fiber diameter and tensile strength was established.•VHMW polymers produced precursor fibers with excellent tensile properties.
The accumulation of over 30 years of basic research on the biology, genetic variation, and evolution of the wild perennial relatives of soybean (Glycine max) provides a foundation to improve ...cultivated soybean. The cultivated soybean and its wild progenitor, G. soja, have a center of origin in eastern Asia and are the only two species in the annual subgenus Soja. Systematic and evolutionary studies of the ca. 30 perennial species of subgenus Glycine, native to Australia, have benefited from the availability of the G. max genomic sequence. The perennial species harbor many traits of interest to soybean breeders, among them resistance to major soybean pathogens such as cyst nematode and leaf rust. New species in the Australian subgenus continue to be described, due to the collection of new material and to insights gleaned through systematic studies of accessions in germplasm collections. Ongoing studies in perennial species focus on genomic regions that contain genes for key traits relevant to soybean breeding. These comparisons also include the homoeologous regions that are the result of polyploidy in the common ancestor of all Glycine species. Subgenus Glycine includes a complex of recently formed allopolyploids that are the focus of studies aimed at elucidating genomic, transcriptomic, physiological, taxonomic, morphological, developmental, and ecological processes related to polyploid evolution. Here we review what has been learned over the past 30 years and outline ongoing work on photosynthesis, nitrogen fixation, and floral biology, much of it drawing on new technologies and resources.
Telemedicine-the use of technology to deliver care at a distance-is rapidly growing and can potentially expand access for patients, enhance patient-physician collaboration, improve health outcomes, ...and reduce medical costs. However, the potential benefits of telemedicine must be measured against the risks and challenges associated with its use, including the absence of the physical examination, variation in state practice and licensing regulations, and issues surrounding the establishment of the patient-physician relationship. This paper offers policy recommendations for the practice and use of telemedicine in primary care and reimbursement policies associated with telemedicine use. The positions put forward by the American College of Physicians highlight a meaningful approach to telemedicine policies and regulations that will have lasting positive effects for patients and physicians.
BRCA genetic testing has substantial public health impact, yet little is known of the real-world experiences of the more than 100 000 Americans undergoing testing annually.
To identify factors ...associated with use of BRCA testing, assess whether delivery of genetic counseling and testing services adheres to professional guidelines, and measure the impact on patient-reported outcomes.
The American BRCA Outcomes and Utilization of Testing (ABOUT) Study analyzed data from a consecutive national series of 11 159 women whose clinicians ordered BRCA testing between December 2011 and December 2012. Aetna mailed recruitment information across the United States to commercial health plan members whose clinicians had ordered BRCA testing. A total of 3874 women (34.7%) completed questionnaires. Deidentified clinician-reported data from all respondents and a random sample of 2613 nonrespondents were also analyzed.
The proportion of eligible participants who met testing criteria and respondents' report of receiving genetic counseling by a genetics clinician and its association with BRCA knowledge, understanding, and satisfaction were assessed.
Among 3628 women respondents whose clinicians ordered comprehensive BRCA testing, most were white non-Hispanic (2502 69.0%), college educated (2953 81.4%), married (2751 75.8%), and had higher incomes (2011 55.4%). Approximately 16.4% (596) did not meet testing criteria. Mutations were identified in 161 (5.3%) of these women who received comprehensive testing. Only 1334 (36.8%) reported receiving genetic counseling from a genetics clinician prior to testing; the lowest rates (130 12.3%) were among patients of obstetrician/gynecologists. The most commonly reported reason for not receiving this clinical service was lack of clinician recommendation. Those who received it demonstrated greater knowledge about BRCA (mean score difference adjusted for demographics and clinician specialty, β = 0.99 95% CI, 0.83-1.14; P < .001) and expressed greater understanding (β = 0.47 95% CI, 0.41-0.54; P < .001) and satisfaction (β = 2.21 95% CI, 1.60-2.81; P < .001).
Despite improved patient knowledge, understanding, and satisfaction among patients who receive genetic counseling provided by a genetics clinician, as well as multiple guidelines emphasizing the importance of genetic counseling, most US women undergoing BRCA genetic testing do not receive this clinical service. Lack of physician recommendation is the most commonly reported reason. These findings demonstrate important gaps in clinical genetics services. Recently mandated coverage of genetic counseling services as a preventive service without patient cost sharing should contribute to improving clinical genetics services and associated outcomes in the future.
Abstract
Background
Recent studies have shown a decrease in CD4 count during adolescence in young people with perinatally acquired human immunodeficiency virus (HIV, PHIV).
Methods
Young people with ...PHIV in the United Kingdom, followed in the Collaborative HIV Paediatric Study who started antiretroviral therapy (ART) from 2000 onward were included. Changes in CD4 count over time from age 10 to 20 years were analyzed using mixed-effects models, and were compared to published CD4 data for the gerneral population. Potential predictors were examined and included demographics, age at ART start, nadir CD4 z score (age-adjusted) in childhood, and time-updated viral load.
Results
Of 1258 young people with PHIV included, 669 (53%) were female, median age at ART initiation was 8.3 years, and the median nadir CD4 z score was −4.0. Mean CD4 count was higher in young people with PHIV who started ART before age 10 years and had a nadir CD4 z score ≥−4; these young people with PHIV had a decline in CD4 count after age 10 that was comparable to that of the general population. Mean CD4 count was lower in young people with PHIV who had started ART before age 10 and had a nadir CD4 z score <−4; for this group, the decline in CD4 count after age 10 was steeper over time.
Conclusions
In children, in addition to starting ART at an early age, optimizing ART to maintain a higher CD4 z score during childhood may be important to maximizing immune reconstitution later in life.
Young people with human immunodeficiency virus who started antiretroviral therapy before age 10 years and had a nadir CD4 z score <-4 in childhood, had a decline in CD4 count after age 10 steeper than that of the general population.
Graphical Abstract
Graphical Abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/evolution-of-cd4-t-cell-count-with-age-in-a-cohort-of-young-people-growing-up-with-perinatally-acquired-hiv-e628fcfc-4e7a-4d1f-b878-ebf12b31f134
Background
There is a growing evidence base for the importance of spatial reasoning for the development of mathematics. However, the extent to which this translates into practice is unknown.
Aims
We ...aimed to understand practitioners' perspectives on their understanding of spatial reasoning, the extent to which they recognize and implement spatial activities in their practice, and the barriers and opportunities to support spatial reasoning in the practice setting.
Sample
Study 1 (questionnaire) included 94 participants and Study 2 (focus groups) consisted of nine participants. Participants were educational practitioners working with children from birth to 7 years.
Methods
The study was mixed methods and included a questionnaire (Study 1) and a series of focus groups (Study 2).
Results
We found that whilst practitioners engage in a variety of activities that support spatial reasoning, most practitioners reported little confidence in their understanding of what spatial reasoning is.
Conclusion
Informative and accessible resources are needed to broaden understanding of the definition of spatial reasoning and to outline opportunities to support spatial reasoning.
Improved management of pain and co-morbid symptoms (sleep disturbances, psychological distress) among women undergoing surgery for suspected gynecologic malignancies may reach a population vulnerable ...to chronic pain.
Women undergoing surgery for a suspected gynecologic malignancy.
We conducted a pilot randomized controlled trial of eHealth Mindful Movement and Breathing (eMMB) compared to an empathic attention control (AC). Semi-structured interviews were conducted by telephone (n = 23), recorded, transcribed, coded, and analyzed using thematic analysis.
Participants reported overall high acceptability such that all would recommend the study to others. Positive impacts of practicing eMMB included that it relieved tension, facilitated falling asleep, and decreased pain. Participants also reported high adherence to self-directed eMMB and AC writing practices and described facilitators and barriers to practicing.
This qualitative feedback will inform future research to assess the efficacy of eMMB for reducing pain and use of remotely-delivered interventions more broadly.
NCT03681405
Seventy-four post-menopausal women with metastatic breast cancer were treated with a combination hormonal regimen consisting of tamoxifen, aminoglutethimide danazol and medroxyprogesterone acetate ...(POND). 72% of the patients had received no previous treatment. The overall response rate (complete and partial remission) was 43.5% with a median response duration of 19 months and a median survival of 27 months. The most common sites of response were in regional nodes and local chest wall disease. The major side-effects were those expected from the individual agents: nausea, lethargy, rash and oedema.
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