The faecal immunochemical test (FIT) was introduced to triage patients with low-risk symptoms of possible colorectal cancer in English primary care in 2017, underpinned by little primary care ...evidence.
All healthcare providers in the South West of England (population 4 million) participated in this evaluation. 3890 patients aged ≥50 years presenting in primary care with low-risk symptoms of colorectal cancer had a FIT from 01/06/2018 to 31/12/2018. A threshold of 10 μg Hb/g faeces defined a positive test.
Six hundred and eighteen (15.9%) patients tested positive; 458 (74.1%) had an urgent referral to specialist lower gastrointestinal (GI) services within three months. Forty-three were diagnosed with colorectal cancer within 12 months. 3272 tested negative; 324 (9.9%) had an urgent referral within three months. Eight were diagnosed with colorectal cancer within 12 months. Positive predictive value was 7.0% (95% CI 5.1-9.3%). Negative predictive value was 99.8% (CI 99.5-99.9%). Sensitivity was 84.3% (CI 71.4-93.0%), specificity 85.0% (CI 83.8-86.1%). The area under the ROC curve was 0.92 (CI 0.86-0.96). A threshold of 37 μg Hb/g faeces would identify patients with an individual 3% risk of cancer.
FIT performs exceptionally well to triage patients with low-risk symptoms of colorectal cancer in primary care; a higher threshold may be appropriate in the wake of the COVID-19 crisis.
Children exposed to extreme stress are at heightened risk for developing mental and physical disorders. However, little is known about mechanisms underlying these associations in humans. An emerging ...insight is that children's social environments change gene expression, which contributes to biological vulnerabilities for behavioral problems. Epigenetic changes in the glucocorticoid receptor gene, a critical component of stress regulation, were examined in whole blood from 56 children aged 11–14 years. Children exposed to physical maltreatment had greater methylation within exon 1F in the NR3C1 promoter region of the gene compared to nonmaltreated children, including the putative NGFI-A (nerve growth factor) binding site. These results highlight molecular mechanisms linking childhood stress with biological changes that may lead to mental and physical disorders.
Grazing can have considerable ecological impacts when managed inappropriately, however livestock production is a significant contributor to global food security and the removal of land from ...production is not always a viable option. Grazing management practices that incorporate periods of planned rest (i.e. strategic‐rest grazing) may be an alternative to grazing exclusion or continuous grazing that could achieve ecological and animal production outcomes simultaneously.
We conducted a meta‐analysis of global literature to investigate how strategic‐rest grazing mediates ecological (i.e., plant richness and diversity), biophysical (plant biomass and ground cover) and production response variables (animal weight gain and animal production per hectare) compared to continuously grazed or ungrazed areas.
Overall, total ground cover and animal production per hectare were significantly greater under strategic‐rest grazing than continuous grazing management, but biomass, plant richness, plant diversity and animal weight gain did not differ between grazing treatments. Increasing the length of rest relative to graze time under strategic‐rest grazing was associated with an increase in plant biomass, ground cover, animal weight gain and animal production per hectare when compared to continuous grazing.
Synthesis and applications. Understanding both the ecological and animal production trade‐offs associated with different grazing management strategies is essential to make informed decisions about best‐management practices for the world's grazing lands. We show that incorporating periods of rest into grazing regimes improves ground cover and animal production per hectare and that these benefits are more pronounced with increases in the length of time land is rested for. This extended rest also improves biomass production and weight gain compared to continuous grazing systems. Based on these meta‐analyses, we recommend that future research considers the duration of rest compared to graze time in comparisons of grazing systems.
Understanding both the ecological and animal production trade‐offs associated with different grazing management strategies is essential to make informed decisions about best‐management practices for the world's grazing lands. We show that incorporating periods of rest into grazing regimes improves ground cover and animal production per hectare and that these benefits are more pronounced with increases in the length of time land is rested for. This extended rest also improves biomass production and weight gain compared to continuous grazing systems. Based on these meta‐analyses, we recommend that future research considers the duration of rest compared to graze time in comparisons of grazing systems.
Despite the increasing knowledge of the molecular events that induce the glycolysis pathway in effector T cells, very little is known about the transcriptional mechanisms that dampen the glycolysis ...program in quiescent cell populations such as memory T cells. Here we found that the transcription factor Bcl-6 directly repressed genes encoding molecules involved in the glycolysis pathway, including Slc2a1, Slc2a3, Pkm and Hk2, in type 1 helper T cells (TH1 cells) exposed to low concentrations of interleukin 2 (IL-2). Thus, Bcl-6 had a role opposing the IL-2-sensitive glycolytic transcriptional program that the transcription factors c-Myc and HIF-1α promote in effector T cells. Additionally, the TH1 lineage-specifying factor T-bet functionally antagonized the Bcl-6-dependent repression of genes encoding molecules in the glycolysis pathway, which links the molecular balance of these two factors to regulation of the metabolic gene program.
22q11.2 deletion syndrome (22q11.2DS) is a disorder caused by recurrent, chromosome‐specific, low copy repeat (LCR)–mediated copy‐number losses of chromosome 22q11. The Children's Hospital of ...Philadelphia has been involved in the clinical care of individuals with what is now known as 22q11.2DS since our initial report of the association with DiGeorge syndrome in 1982. We reviewed the medical records on our continuously growing longitudinal cohort of 1,421 patients with molecularly confirmed 22q11.2DS from 1992 to 2018. Most individuals are Caucasian and older than 8 years. The mean age at diagnosis was 3.9 years. The majority of patients (85%) had typical LCR22A–LCR22D deletions, and only 7% of these typical deletions were inherited from a parent harboring the deletion constitutionally. However, 6% of individuals harbored other nested deletions that would not be identified by traditional 22q11.2 FISH, thus requiring an orthogonal technology to diagnose. Major medical problems included immune dysfunction or allergies (77%), palatal abnormalities (67%), congenital heart disease (64%), gastrointestinal difficulties (65%), endocrine dysfunction (>50%), scoliosis (50%), renal anomalies (16%), and airway abnormalities. Median full‐scale intelligence quotient was 76, with no significant difference between individuals with and without congenital heart disease or hypocalcemia. Characteristic dysmorphic facial features were present in most individuals, but dermatoglyphic patterns of our cohort are similar to normal controls. This is the largest longitudinal study of patients with 22q11.2DS, helping to further describe the condition and aid in diagnosis and management. Further surveillance will likely elucidate additional clinically relevant findings as they age.
Monogenic causes of autoimmunity provide key insights into the complex regulation of the immune system. We report a new monogenic cause of autoimmunity resulting from de novo germline activating ...STAT3 mutations in five individuals with a spectrum of early-onset autoimmune disease, including type 1 diabetes. These findings emphasize the critical role of STAT3 in autoimmune disease and contrast with the germline inactivating STAT3 mutations that result in hyper IgE syndrome.
The contractile ring is a complex molecular apparatus which physically divides many eukaryotic cells. Despite knowledge of its protein composition, the molecular architecture of the ring is not ...known. Here we have applied super-resolution microscopy and FRET to determine the nanoscale spatial organization of
contractile ring components relative to the plasma membrane. Similar to other membrane-tethered actin structures, we find proteins localize in specific layers relative to the membrane. The most membrane-proximal layer (0-80 nm) is composed of membrane-binding scaffolds, formin, and the tail of the essential myosin-II. An intermediate layer (80-160 nm) consists of a network of cytokinesis accessory proteins as well as multiple signaling components which influence cell division. Farthest from the membrane (160-350 nm) we find F-actin, the motor domains of myosins, and a major F-actin crosslinker. Circumferentially within the ring, multiple proteins proximal to the membrane form clusters of different sizes, while components farther from the membrane are uniformly distributed. This comprehensive organizational map provides a framework for understanding contractile ring function.
American politics in the age of Donald Trump is characterized by negative affect toward politicians of the opposing party and a willingness on the part of citizens to forgive most sins of ...copartisans. Against this backdrop, we ask whether Trump’s numerous high-profile reversals on foreign policy issues matter. Given our polarized political environment, we argue that there is little reason for Trump to worry about looking inconsistent. Drawing on prior scholarship, we contend that when citizens evaluate a leader who has reversed, policy preferences will supersede any consideration of a flip-flop. We also argue that partisan motivated reasoning and preexisting attitudes toward Trump will overwhelm the impact of a reversal on most matters of foreign policy. Using two survey experiments that reflect real-world events, we show that citizens do not change their attitudes toward Donald Trump significantly even when his policy reversals are made explicit.
The Horizontal Wind Model (HWM) has been updated in the thermosphere with new observations and formulation changes. These new data are ground‐based 630 nm Fabry‐Perot Interferometer (FPI) ...measurements in the equatorial and polar regions, as well as cross‐track winds from the Gravity Field and Steady State Ocean Circulation Explorer (GOCE) satellite. The GOCE wind observations provide valuable wind data in the twilight regions. The ground‐based FPI measurements fill latitudinal data gaps in the prior observational database. Construction of this reference model also provides the opportunity to compare these new measurements. The resulting update (HWM14) provides an improved time‐dependent, observationally based, global empirical specification of the upper atmospheric general circulation patterns and migrating tides. In basic agreement with existing accepted theoretical knowledge of the thermosphere general circulation, additional calculations indicate that the empirical wind specifications are self‐consistent with climatological ionosphere plasma distribution and electric field patterns.
Key Points
The horizontal wind model has been updated
New data fill observational gaps
Empirical specifications are consistent with ionospheric models
Realistic modeling of the dynamics and variability in the upper mesosphere and lower thermosphere (UMLT) is critical to understand the coupling between different layers of the whole atmosphere ...system. Here we present simulations of the UMLT temperatures at ∼100 km altitude for one year during 2014 by the Whole Atmosphere Community Climate Model with thermosphere-ionosphere extension (WACCM-X) constrained below ∼90 km using meteorological analysis products of the high-altitude version of Navy Global Environmental Model (NAVGEM-HA). The model results are sampled at the same times and latitudes and longitudes as the satellite observations from Thermosphere Ionosphere and Mesosphere Electric Dynamics/Sounding of the Atmosphere using Broadband Emission Radiometry (TIMED/SABER). Comparisons show that the observed and modeled daily zonal mean temperatures are correlated (r ∼0.5–0.7) at most latitudes between ±50°. Both the observations and simulations show an annual variation at mid-latitudes in two hemispheres with the temperature maximum in summer and the minimum in winter, and at lower latitudes the semiannual variation becomes stronger having the temperature maximums at equinoxes and the minimums during solstices. However, the temperatures observed are on average ∼5–10 K (3%–5%) smaller than the model and the observations show a larger variability. Moreover, migrating tidal amplitudes are mostly overestimated by the model. Though differences are noticed, the WACCM-X simulations with NAVGEM-HA meteorological analyses are overall consistent with the SABER observations. These results support that whole atmosphere models informed by high altitude observations would help to simulate the UMLT variability and the atmosphere and ionosphere coupling.
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