Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized ...OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.
An international group of neurologists and radiologists developed revised guidelines for standardized brain and spinal cord MR imaging for the diagnosis and follow-up of MS. A brain MR imaging with ...gadolinium is recommended for the diagnosis of MS. A spinal cord MR imaging is recommended if the brain MR imaging is nondiagnostic or if the presenting symptoms are at the level of the spinal cord. A follow-up brain MR imaging with gadolinium is recommended to demonstrate dissemination in time and ongoing clinically silent disease activity while on treatment, to evaluate unexpected clinical worsening, to re-assess the original diagnosis, and as a new baseline before starting or modifying therapy. A routine brain MR imaging should be considered every 6 months to 2 years for all patients with relapsing MS. The brain MR imaging protocol includes 3D T1-weighted, 3D T2-FLAIR, 3D T2-weighted, post-single-dose gadolinium-enhanced T1-weighted sequences, and a DWI sequence. The progressive multifocal leukoencephalopathy surveillance protocol includes FLAIR and DWI sequences only. The spinal cord MR imaging protocol includes sagittal T1-weighted and proton attenuation, STIR or phase-sensitive inversion recovery, axial T2- or T2*-weighted imaging through suspicious lesions, and, in some cases, postcontrast gadolinium-enhanced T1-weighted imaging. The clinical question being addressed should be provided in the requisition for the MR imaging. The radiology report should be descriptive, with results referenced to previous studies. MR imaging studies should be permanently retained and available. The current revision incorporates new clinical information and imaging techniques that have become more available.
Objective
Hearing loss affects over 1.23 billion people globally. It has been proposed that hearing impairment negatively impacts on cognition. Some studies have demonstrated a faster rate of decline ...in cognition, and increased risk of incident all‐cause dementia. This finding is not ubiquitous. This study used meta‐analysis to examine the evidence‐base regarding the relationship between hearing and cognition.
Design
A systematic review of the literature and meta‐analyses of study findings were conducted. Published and grey literature was reviewed. Papers were included if they studied the relationship between hearing and cognition in adults with and without hearing impairment.
Main outcome measures
Meta‐analyses examined evidence for and against seven questions. Is cognition poorer in individuals with normal hearing compared to (i) untreated or (ii) treated hearing impairment, is cognition associated with degree of hearing impairment in (iii) untreated and/or (iv) treated hearing, is cognition (v) different in untreated compared to treated hearing impairment, (vii) does cognition improve after intervention, and (vii) how is hearing impairment differentially associated with cognitive ability across six domains of cognition?
Results
The 33 included studies contributed 40 samples, with a total of 602 participants with untreated hearing impairment, 672 participants with treated hearing impairment, 176 healthy controls, and 4260 individuals with a range of hearing impairment with/without treatment. The results demonstrated that cognition is significantly poorer in (i) individuals with untreated hearing and remains poorer in (ii) treated hearing impairment compared to normal hearers. The degree of cognitive deficit is significantly associated with the degree of hearing impairment in both (iii) untreated and (iv) treated hearing impairment. Furthermore, (v) hearing intervention significantly improves cognition. Finally, (vii) hearing impairment impacted on all domains of cognition.
Conclusions
This meta‐analysis suggests that hearing impairment is associated with cognitive problems. However, due to diversity within studies, small sample sizes, the failure to control for premorbid and other health factors, this conclusion may be premature.
The application of physiologically based pharmacokinetic (PBPK) modeling has developed rapidly within the pharmaceutical industry and is becoming an integral part of drug discovery and development. ...In this study, we provide a cross pharmaceutical industry position on “how PBPK modeling can be applied in industry” focusing on the strategies for application of PBPK at different stages, an associated perspective on the confidence and challenges, as well as guidance on interacting with regulatory agencies and internal best practices.
During the last 12 years, over 80 countries have introduced national HPV vaccination programs. The majority of these countries are high or upper-middle income countries. The barriers to HPV vaccine ...introduction remain greatest in those countries with the highest burden of cervical cancer and the most need for vaccination. Innovation and global leadership is required to increase and sustain introductions in low income and lower-middle income countries.
Operating Room Fires and Surgical Skin Preparation Jones, Edward L., MD, MS; Overbey, Douglas M., MD; Chapman, Brandon C., MD ...
Journal of the American College of Surgeons,
07/2017, Letnik:
225, Številka:
1
Journal Article
Recenzirano
Abstract Background Operating room fires are “never” events that remain an under-reported source of devastating complications. One common set-up which promotes fires is the use of surgical skin ...preparations combined with electrosurgery and oxygen. Limited data exist examining the incidence of fires and surgical skin preps. Study Design A standardized, ex-vivo model was created with a 15x15cm section of clipped, porcine skin. An electrosurgical “Bovie” pencil was activated for 2 seconds on 30Watts coagulation mode in 21% oxygen (room air) both immediately and 3 minutes following skin prep application. Skin preps with and without alcohol were tested. Preps were applied with and without pooling. Alcohol-based skin preps included 70% isopropyl alcohol (IPA) with 2% chlorhexidine gluconate, 74% IPA with 0.7% iodine povacrylex and plain 70% IPA. Results No fires occurred with non-alcohol based preps (p<0.001 vs. alcohol-based preps). Alcohol-based preps caused flash flames at 0 minutes in 22% (13/60) and at 3 minutes in 10% (6/60) of tests. When examining pooling of alcohol-based preps, fires occurred in 38% (23/60) at 0 minutes and 27% (16/60) at 3 minutes. Conclusion Alcohol-based skin preps fuel operating room fires in common clinical scenarios. Following manufacturer guidelines and allowing 3 minutes for drying, surgical fires were still created in one in ten cases without pooling and over one quarter of cases with pooling. Surgeons can decrease the risk of an operating room fire by using non-alcohol based skin preps or avoiding pooling of the prep solution.
The fourth orbit of Parker Solar Probe (PSP) reached heliocentric distances down to 27.9
R
⊙
, allowing solar wind turbulence and acceleration mechanisms to be studied in situ closer to the Sun than ...previously possible. The turbulence properties were found to be significantly different in the inbound and outbound portions of PSP’s fourth solar encounter, which was likely due to the proximity to the heliospheric current sheet (HCS) in the outbound period. Near the HCS, in the streamer belt wind, the turbulence was found to have lower amplitudes, higher magnetic compressibility, a steeper magnetic field spectrum (with a spectral index close to –5/3 rather than –3/2), a lower Alfvénicity, and a ‘1∕
f
’ break at much lower frequencies. These are also features of slow wind at 1 au, suggesting the near-Sun streamer belt wind to be the prototypical slow solar wind. The transition in properties occurs at a predicted angular distance of ≈4° from the HCS, suggesting ≈8° as the full-width of the streamer belt wind at these distances. While the majority of the Alfvénic turbulence energy fluxes measured by PSP are consistent with those required for reflection-driven turbulence models of solar wind acceleration, the fluxes in the streamer belt are significantly lower than the model predictions, suggesting that additional mechanisms are necessary to explain the acceleration of the streamer belt solar wind.
The land and ocean absorb on average just over half of the anthropogenic emissions of carbon dioxide (CO2) every year. These CO2 "sinks" are modulated by climate change and variability. Here we use a ...suite of nine dynamic global vegetation models (DGVMs) and four ocean biogeochemical general circulation models (OBGCMs) to estimate trends driven by global and regional climate and atmospheric CO2 in land and oceanic CO2 exchanges with the atmosphere over the period 1990–2009, to attribute these trends to underlying processes in the models, and to quantify the uncertainty and level of inter-model agreement. The models were forced with reconstructed climate fields and observed global atmospheric CO2; land use and land cover changes are not included for the DGVMs. Over the period 1990–2009, the DGVMs simulate a mean global land carbon sink of −2.4 ± 0.7 Pg C yr−1 with a small significant trend of −0.06 ± 0.03 Pg C yr−2 (increasing sink). Over the more limited period 1990–2004, the ocean models simulate a mean ocean sink of −2.2 ± 0.2 Pg C yr−1 with a trend in the net C uptake that is indistinguishable from zero (−0.01 ± 0.02 Pg C yr−2). The two ocean models that extended the simulations until 2009 suggest a slightly stronger, but still small, trend of −0.02 ± 0.01 Pg C yr−2. Trends from land and ocean models compare favourably to the land greenness trends from remote sensing, atmospheric inversion results, and the residual land sink required to close the global carbon budget. Trends in the land sink are driven by increasing net primary production (NPP), whose statistically significant trend of 0.22 ± 0.08 Pg C yr−2 exceeds a significant trend in heterotrophic respiration of 0.16 ± 0.05 Pg C yr−2 – primarily as a consequence of widespread CO2 fertilisation of plant production. Most of the land-based trend in simulated net carbon uptake originates from natural ecosystems in the tropics (−0.04 ± 0.01 Pg C yr−2), with almost no trend over the northern land region, where recent warming and reduced rainfall offsets the positive impact of elevated atmospheric CO2 and changes in growing season length on carbon storage. The small uptake trend in the ocean models emerges because climate variability and change, and in particular increasing sea surface temperatures, tend to counter\\-act the trend in ocean uptake driven by the increase in atmospheric CO2. Large uncertainty remains in the magnitude and sign of modelled carbon trends in several regions, as well as regarding the influence of land use and land cover changes on regional trends.
To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and ...education-matched controls.
We analyzed task-free-fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ε4 allele matched for age, education, and gender.
The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance.
The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.
During the course of 9 months, the human placenta develops into a highly vascular organ. Vasculogenesis starts during the third week post-conception. Hemangioblastic cell cords differentiate in situ ...from mesenchymal cells in the villous cores, most probably under the influence of vascular endothelial growth factor (VEGFA) secreted by the overlying trophoblast. The cords elongate through proliferation and cell recruitment, and connect with the vasculature of the developing fetus. A feto-placental circulation starts around 8 weeks of gestation. Elongation of the capillaries outstrips that of the containing villi, leading to looping of the vessels. The obtrusion of both capillary loops and new sprouts results in the formation of terminal villi. Branching and non-branching angiogenesis therefore play key roles in villous morphogenesis throughout pregnancy. Maternal circulating levels of VEGFA and placental growth factor vary across normal pregnancy, and in complicated pregnancies. Determining the impact of these changes on placental angiogenesis is difficult, as the relationship between levels of factors in the maternal circulation and their effects on fetal vessels within the placenta remains unclear. Furthermore, the trophoblast secretes large quantities of soluble receptors capable of binding both growth factors, influencing their bioavailability. Villous endothelial cells are prone to oxidative stress, which activates the apoptotic cascade. Oxidative stress associated with onset of the maternal circulation, and with incomplete conversion of the spiral arteries in pathological pregnancies, plays an important role in sculpting the villous tree. Suppression of placental angiogenesis results in impoverished development of the placenta, leading ultimately to fetal growth restriction.
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