Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

<p>Background: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.</p> <p>Case presentation: Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.</p> <p>Conclusion: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.</p&gt

Gestational age at delivery and special educational need: retrospective cohort study of 407,503 schoolchildren

<STRONG>Background</STRONG> Previous studies have demonstrated an association between preterm delivery and increased risk of special educational need (SEN). The aim of our study was to examine the risk of SEN across the full range of gestation. <STRONG>Methods and Findings</STRONG> We conducted a population-based, retrospective study by linking school census data on the 407,503 eligible school-aged children resident in 19 Scottish Local Authority areas (total population 3.8 million) to their routine birth data. SEN was recorded in 17,784 (4.9%) children; 1,565 (8.4%) of those born preterm and 16,219 (4.7%) of those born at term. The risk of SEN increased across the whole range of gestation from 40 to 24 wk: 37–39 wk adjusted odds ratio (OR) 1.16, 95% confidence interval (CI) 1.12–1.20; 33–36 wk adjusted OR 1.53, 95% CI 1.43–1.63; 28–32 wk adjusted OR 2.66, 95% CI 2.38–2.97; 24–27 wk adjusted OR 6.92, 95% CI 5.58–8.58. There was no interaction between elective versus spontaneous delivery. Overall, gestation at delivery accounted for 10% of the adjusted population attributable fraction of SEN. Because of their high frequency, early term deliveries (37–39 wk) accounted for 5.5% of cases of SEN compared with preterm deliveries (<37 wk), which accounted for only 3.6% of cases. <STRONG>Conclusions</STRONG> Gestation at delivery had a strong, dose-dependent relationship with SEN that was apparent across the whole range of gestation. Because early term delivery is more common than preterm delivery, the former accounts for a higher percentage of SEN cases. Our findings have important implications for clinical practice in relation to the timing of elective delivery

Author Correction: Three-dimensional strain imaging of irradiated chromium using multi-reflection Bragg coherent diffraction

The original version of this Article did not correctly credit and cite relevant previous work. The fifth to seventh sentences of the fifth paragraph of the ‘Three-dimensional imaging of the defects’ section previously read: “In our case, BCDI is sensitive to defects such as voids and dislocations through its strain field sensitivity rather than the spatial resolution46. This is illustrated by the relationship between the continuum representation of the crystal, (Formula presented.) , and the diffraction intensity, I(q) in the far field under a perfectly coherent illumination and in the kinematical scattering approximation given by (Formula presented.). Here, r and q are the real and reciprocal space coordinates respectively, (Formula presented.) is the Fourier transform, Q is the measured Bragg peak, and u(r) is the vector displacement field that is a continuum description of how the atoms are displaced from their equilibrium positions47.” The correct version reads: “In our case, BCDI is sensitive to defects such as voids and dislocations through its strain field sensitivity rather than the spatial resolution46. This is demonstrated by the relationship (Formula presented.). whereby (Formula presented.) is the intensity, (Formula presented.) is the mathematical description of the crystal as a continuum, (Formula presented.) denotes the Fourier transformation operator, Q is the Bragg reflection that was measured, and u(r) is the displacement field47.” The final six sentences of the Results section previously read: “Furthermore, underestimating the defect density prevents TEM from accurately determining the corresponding change in properties. For instance, Weiß et al. show a factor of 2 between measured and calculated change in hardness for neutron irradiated EUROFER9771. Meanwhile, Reza et al. report the same discrepancy between Transient Grating Spectroscopy (TGS)-measured and TEM-determined thermal diffusivity for self-ion irradiated tungsten72. It is important to note that when Reza et al. included small defects from molecular dynamics (MD) simulations, the combination of the TEM and MD data matches TGS measurements. This result confirms the theory that point defects play a significant role in the thermal diffusivity of a material and further reinforces the need to accurately characterize small defects in order to evaluate irradiation-induced changes in properties.” This has been replaced with: ““Hirst et al. opined that the underestimated defects density in TEM measurements comes with a corresponding mischaracterization of the materials properties70. This is demonstrated in a study by Weiß et al. who showed that the hardness values obtained from TEM data of neutron irradiated reduced activation ferritic/martensitic steel is significantly smaller than values from tensile testing. This clearly support the notion that underestimation of point defects from TEM analysis which goes into the dispersed barrier hardening model affects the calculated hardness value71. Hence, the difference in the magnitude of swelling between TEM and BCDI estimates is well justified. In a bid to accurately quantify nanoscale defects in irradiated materials, Meslin et al., used multiple characterization techniques which include TEM, Small Angle Neutron Scattering, Positron Annihilation Spectroscopy and Atom Probe Tomography which are sensitive to different types of nanoscale defects. The study clearly demonstrates the strength and complementarities of each technique72. This further support the need to develop multiple characterization techniques that can complements TEM for defects quantification and building predictive tools.” Consequently, Reference 72, which previously read “Reza, A., Yu, H., Mizohata, K. & Hofmann, F. Thermal diffusivity degradation and point defect density in self-ion implanted tungsten. Acta Mater. 193, 270–279 (2020)”, has been replaced by “Meslin, E. et al. Characterization of neutron-irradiated ferritic model alloys and a RPV steel from combined APT, SANS, TEM, and PAS analyses J. Nucl. Mater. 406, 73–83 (2010).” This has been corrected in both the PDF and HTML versions of the Article

Three-dimensional strain imaging of irradiated chromium using multi-reflection Bragg coherent diffraction

Radiation-induced materials degradation is a key concern in limiting the performance of nuclear materials. The formation of nanoscale void and gas bubble superlattices in metals and alloys under radiation environments can effectively mitigate radiation-induced damage, such as swelling and aid the development of next generation radiation tolerant materials. To effectively manage radiation-induced damage via superlattice formation, it is critical to understand the microstructural changes and strain induced by such superlattices. We utilize multi-reflection Bragg coherent diffraction imaging to quantify the full strain tensor induced by void superlattices in iron irradiated chromium substrate. Our approach provides a quantitative estimation of radiation-induced three-dimensional (3D) strain generated at the microscopic level and predicts the number density of defects with a high degree of sensitivity. Such quantitative evaluation of 3D strain in nuclear materials can have a major impact on predicting materials behavior in radiation environments and can revolutionize design of radiation tolerant materials

Experiential aspects of tourism gift consumption

This article addresses how consumers make use of fantasy, feelings, and fun when deciding, giving, and consuming gifts of tourism and leisure. Despite little industry awareness, consumers are engaging with such behaviour because tourism gifts offer considerable scope for the creative expression of donor–recipient relationships. This UK-based interpretive qualitative study captured data from donors, recipients, and tourism and leisure providers. The feelings (emotions), fantasies (imagination and dreaming), and fun (playfulness) were interrogated through the behavioural phases of gift decision making, gift exchange, post-exchange, and gift consumption. A range of emotions were displayed by donors and recipients at different stages in the gift-giving process; donor decision making in groups for created gifts was particularly charged. Fantasies were evident both for donors planning gifts and for recipients. As an intangible gift, means of exchange allowed for creative mechanisms beyond the classic wrapping strategies associated with physical gifts. The ‘decoy’ strategy stimulated the recipient’s imagination to conjure fantastical scenarios. Fun or playfulness was built into many of the gifts and often related to an element of ‘surprise’, an attribute of the perfect gift (e.g. Belk, 1996) in Western societies

Potentiality in Biology

We take the potentialities that are studied in the biological sciences (e.g., totipotency) to be an important subtype of biological dispositions. The goal of this paper is twofold: first, we want to provide a detailed understanding of what biological dispositions are. We claim that two features are essential for dispositions in biology: the importance of the manifestation process and the diversity of conditions that need to be satisfied for the disposition to be manifest. Second, we demonstrate that the concept of a disposition (or potentiality) is a very useful tool for the analysis of the explanatory practice in the biological sciences. On the one hand it allows an in-depth analysis of the nature and diversity of the conditions under which biological systems display specific behaviors. On the other hand the concept of a disposition may serve a unificatory role in the philosophy of the natural sciences since it captures not only the explanatory practice of biology, but of all natural sciences. Towards the end we will briefly come back to the notion of a potentiality in biology

Global and regional burden of hospital admissions for pneumonia in older adults::A systematic review and meta-analysis

Pneumonia constitutes a substantial disease burden among adults overall and those who are elderly. We aimed to identify all studies investigating the disease burden among older adults (age, ≥65 years) admitted to the hospital with pneumonia. We estimated the hospital admission rate and in-hospital case-fatality ratio (CFR) of pneumonia in older adults, stratified by age and economic status (industrialized vs developing), with data from a systematic review of studies published from 1996 through 2017 and from 8 unpublished population-based studies. We applied these rate estimates to population estimates for 2015 to calculate the global and regional burden in older adults who would have been admitted to the hospital with pneumonia that year. We estimated the number of in-hospital pneumonia deaths by combining in-hospital CFRs with hospital admission estimates from hospital-based studies. We identified 109 eligible studies; 73 used clinical pneumonia as the case definition, and 36 used radiologically confirmed pneumonia as the case definition. We estimated that, in 2015, 6.8 million episodes (uncertainty range [UR], 5.8-8.0 episodes) of clinical pneumonia resulted in hospital admissions of older adults worldwide. The hospital admission rate increased with advancing age and was higher in men. The total disease burden was likely underestimated when using the definition of radiologically confirmed pneumonia. Based on data from 52 hospital studies reporting data on pneumonia mortality, we estimated that about 1.1 million in-hospital deaths (UR, 0.9-1.4 in-hospital deaths) occurred among older adults. The burden of pneumonia requiring hospitalization among older adults is substantial. Appropriate prevention and management strategies should be developed to reduce its impact

Guillain-Barré syndrome: a century of progress

In 1916, Guillain, Barré and Strohl reported on two cases of acute flaccid paralysis with high cerebrospinal fluid protein levels and normal cell counts — novel findings that identified the disease we now know as Guillain–Barré syndrome (GBS). 100 years on, we have made great progress with the clinical and pathological characterization of GBS. Early clinicopathological and animal studies indicated that GBS was an immune-mediated demyelinating disorder, and that severe GBS could result in secondary axonal injury; the current treatments of plasma exchange and intravenous immunoglobulin, which were developed in the 1980s, are based on this premise. Subsequent work has, however, shown that primary axonal injury can be the underlying disease. The association of Campylobacter jejuni strains has led to confirmation that anti-ganglioside antibodies are pathogenic and that axonal GBS involves an antibody and complement-mediated disruption of nodes of Ranvier, neuromuscular junctions and other neuronal and glial membranes. Now, ongoing clinical trials of the complement inhibitor eculizumab are the first targeted immunotherapy in GBS