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Purpose Resuscitation guidelines have advocated the use of virtual learning as a form of pre-course e-learning. Virtual reality (VR) has been identified to provide a method of constructive learning with instant feedback. There are increasing publications of VR use in cardiopulmonary resuscitation (CPR) training; however, there is a dearth from the dental profession. Therefore, the aim of this exploratory study was to investigate dental students' opinions in CPR training using VR.

We compared the perfomance of SARS-CoV-2 reverse transcriptase real-time polymerase chain reaction (RT-PCR) to droplet digital PCR (ddPCR). 95% and 40% of positive and negative RT-PCR specimens, respectively, were positive on ddPCR yielding sensitivities of 84% (95% CI: 74, 91) and 97% (95% CI: 89, 99), for RT-PCR and ddPCR, respectively. We found that SARS-CoV-2 RT-PCR testing in children has a concerning false-negative rate at lower nucleocapsid gene copy numbers.

Human-induced climate warming by 2100 is expected to thaw large expanses of northern permafrost peatlands. However, the spatio-temporal dynamics of permafrost peatland thaw remain uncertain due to complex permafrost–climate interactions, the insulating properties of peat soils and variation in model projections of future climate. Here we show that permafrost peatlands in Europe and Western Siberia will soon surpass a climatic tipping point under scenarios of moderate-to-high warming (Shared Socioeconomic Pathway (SSP) 2-4.5, SSP3-7.0 and SSP5-8.5). The total peatland area affected under these scenarios contains 37.0–39.5 Gt carbon (equivalent to twice the amount of carbon stored in European forests). Our bioclimatic models indicate that all of Fennoscandia will become climatically unsuitable for peatland permafrost by 2040. Strong action to reduce emissions (SSP1-2.6) by the 2090s could retain suitable climates for permafrost peatlands storing 13.9 Gt carbon in northernmost Western Siberia, indicating that socio-economic policies will determine the rate and extent of permafrost peatland thaw.

Background and Purpose. Gait rehabilitation in patients with severe hemiplegia requires substantial effort. Preliminary studies indicate potential beneficial effects of using multichannel functional electrical stimulation (MFES) for gait rehabilitation in these patients. In this study, a new method of gait rehabilitation for nonambulatory patients with hemiplegia by means of MFES added to conventional therapy was introduced. The results of the method's application were evaluated by comparing it with conventional therapeutic methods. Subjects. The proposed rehabilitation method was tested on a group of 20 patients with severe hemiplegia secondary to cerebrovascular accident. Subjects were randomly assigned to one of two groups. One group received 3 weeks of MFES followed by 3 weeks of conventional therapy. The other group received 3 weeks of conventional therapy followed by 3 weeks of MFES. Methods. The effects of each therapeutic method were evaluated by measurements of temporal-distance variables and ground reaction forces and by assessment of each subject's physical status according to the Fugl-Meyer evaluation scale. Results. There was improved performance of the subjects during MFES combined with conventional therapy was mainly attributed to the enhanced motor learning accomplished by application of MFES. These results, however, are preliminary, and further research is needed., [Bogataj U, Gros N, Kljajic M, et al. The rehabilitation of gait in patients with hemiplegia: a comparison between conventional therapy and multichannel functional electrical stimulation therapy. Phys Ther. 1995;75:490-502.] [...]

Early intervention is regarded as very important for the reduction of illness and death due to lung cancer. Unfortunately, X-rays cannot distinguish between benign and malignant lesions. Although bronchoscopy can provide tissue biopsies which are definitive, it is useful only in those cases where the lesion is accessible. Another possibility is the use of specific antibodies for the evaluation of lung tumors. An antibody which recognizes an antigen specific for cancer cells may be labelled with a radioactive isotope and injected into the patient's circulation. If the antibody binds to the lesion, the increased radioactivity in that area may be detected by scintigraphy. Antibodies to carcinoembryonic antigen (CEA) are candidates for this technique; one particular antibody against CEA, designated ZCE-025, was labelled with the radioactive isotope indium 111 and evaluated in 20 patients scheduled to undergo surgery for lung tumors. After histological examination, nine tumors were found to be squamous cell carcinomas. Of these, eight were positive by scintigraphy after antibody administration. Four of the seven adenocarcinomas were positive by scintigraphy. Of the four tumors which were found to be benign after surgical removal, only one was positive by scintigraphy. The diagnosis based on the scintigraphic detection of radiolabeled antibody was 75 percent accurate for both positives (actual cancers) and negatives, or benign growths. Histological staining of 14 tumors using antibodies to CEA revealed that two tumors negative for CEA by direct staining were positive by scintigraphy, and three tumors positive for CEA by staining were negative by scintigraphy. The location of the tumor, its size, and the penetration of blood vessels into the tumor may all play a role in the detection of lung cancers using the antibody-scintigraphy method. (Consumer Summary produced by Reliance Medical Information, Inc.)

Carboxylesterase Notum is a negative regulator of the Wnt signaling pathway. There is an emerging understanding of the role Notum plays in disease, supporting the need to discover new small-molecule inhibitors. A crystallographic X-ray fragment screen was performed, which identified fragment hit 1,2,3-triazole 7as an attractive starting point for a structure-based drug design hit-to-lead program. Optimization of 7identified oxadiazol-2-one 23ddas a preferred example with properties consistent with drug-like chemical space. Screening 23ddin a cell-based TCF/LEF reporter gene assay restored the activation of Wnt signaling in the presence of Notum. Mouse pharmacokinetic studies with oral administration of 23dddemonstrated good plasma exposure and partial blood–brain barrier penetration. Significant progress was made in developing fragment hit 7into lead 23dd(>600-fold increase in activity), making it suitable as a new chemical tool for exploring the role of Notum-mediated regulation of Wnt signaling.

The COVID-19 pandemic has had an unprecedented health and economic impact and there are currently no approved therapies. We have isolated an antibody, EY6A, from an individual convalescing from COVID-19 and have shown that it neutralizes SARS-CoV-2 and cross-reacts with SARS-CoV-1. EY6A Fab binds the receptor binding domain (RBD) of the viral spike glycoprotein tightly (KDof 2 nM), and a 2.6-Å-resolution crystal structure of an RBD–EY6A Fab complex identifies the highly conserved epitope, away from the ACE2 receptor binding site. Residues within this footprint are key to stabilizing the pre-fusion spike. Cryo-EM analyses of the pre-fusion spike incubated with EY6A Fab reveal a complex of the intact spike trimer with three Fabs bound and two further multimeric forms comprising the destabilized spike attached to Fab. EY6A binds what is probably a major neutralizing epitope, making it a candidate therapeutic for COVID-19.

The Wnt family of proteins are secreted signaling proteins that play key roles in regulating cellular functions. Recently, carboxylesterase Notum was shown to act as a negative regulator of Wnt signaling by mediating the removal of an essential palmitoleate. Here we disclose two new chemical scaffolds that inhibit Notum enzymatic activity. Our approach was to create a fragment library of 250 acids for screening against Notum in a biochemical assay followed by structure determination by X-ray crystallography. Twenty fragments were identified as hits for Notum inhibition, and 14 of these fragments were shown to bind in the palmitoleate pocket of Notum. Optimization of 1-phenylpyrrole 20, guided by structure-based drug design, identified 20zas the most potent compound from this series. Similarly, the optimization of 1-phenylpyrrolidine 8gave acid 26. This work demonstrates that inhibition of Notum activity can be achieved by small, drug-like molecules possessing favorable in vitroADME profiles.

The SARS-CoV-2 virus is more transmissible than previous coronaviruses and causes a more serious illness than influenza. The SARS-CoV-2 receptor binding domain (RBD) of the spike protein binds to the human angiotensin-converting enzyme 2 (ACE2) receptor as a prelude to viral entry into the cell. Using a naive llama single-domain antibody library and PCR-based maturation, we have produced two closely related nanobodies, H11-D4 and H11-H4, that bind RBD (KDof 39 and 12?nM, respectively) and block its interaction with ACE2. Single-particle cryo-EM revealed that both nanobodies bind to all three RBDs in the spike trimer. Crystal structures of each nanobody–RBD complex revealed how both nanobodies recognize the same epitope, which partly overlaps with the ACE2 binding surface, explaining the blocking of the RBD–ACE2 interaction. Nanobody-Fc fusions showed neutralizing activity against SARS-CoV-2 (4–6?nM for H11-H4, 18?nM for H11-D4) and additive neutralization with the SARS-CoV-1/2 antibody CR3022.

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Ex vivoliver machine perfusion (MP) is a promising alternative for preservation of liver grafts from extended criteria donors. Small animal models can be used to evaluate different perfusion conditions. We here describe the development of a miniaturized ex vivoMP system for rat liver grafts, evaluating cell-free and erythrocyte-based perfusion solutions, subnormothermic and normothermic temperatures, and dialysis. A perfusion chamber was designed after a suitable liver position was identified. Normothermic ex vivoliver perfusion (NEVLP) required supplementation of erythrocytes to reduce cell damage. Perfusion with erythrocytes led to rising potassium levels after 12 h (NEVLP, 16.2 mM, interquartile range [IQR]: 5.7 and subnormothermic ex vivoliver perfusion [SNEVLP], 12.8 mM, IQR: 3.5), which were normalized by dialysis using a laboratory dialysis membrane (NEVLP, 6.2 mM, IQR: 0.5 and SNEVLP, 5.3 mM, IQR: 0.1; p= 0.004). Livers treated with NEVLP conditions showed higher bile production (18.52 mg/h/g, IQR: 8.2) compared to livers perfused under SNEVLP conditions (0.4 mg/h/g, IQR: 1.2, p= 0.01). Reducing the perfusion volume from 100 to 50 mL allowed for higher erythrocyte concentrations, leading to significantly lower transaminases (15.75 U/L/mL, IQR: 2.29 vs. 5.97 U/L/mL, IQR: 18.07, p= 0.002). In conclusion, a well-designed perfusion system, appropriate oxygen carriers, dialysis, and miniaturization of the perfusion volume are critical features for successful miniaturized ex vivoliver MP.Impact StatementEx vivoliver machine perfusion (MP) is an emerging preservation alternative to static cold storage. Even though clinical studies have shown benefits for extended criteria donor grafts, standardized systems for perfusion of rat liver grafts are not available, which are inevitable for large-scaled studies on liver reconditioning by ex vivoMP. We here comprehensively describe the development of an ex vivorat liver perfusion system that can be used as modular setting in various approaches of liver MP. We describe pitfalls and techniques that might be of interest when establishing such perfusion systems for basic and translational research.

Solid polymer electrolytes (SPEs) have the potential to improve lithium-ion batteries by enhancing safety and enabling higher energy densities. However, SPEs suffer from significantly lower ionic conductivity than liquid and solid ceramic electrolytes, limiting their adoption in functional batteries. To facilitate more rapid discovery of high ionic conductivity SPEs, we developed a chemistry-informed machine learning model that accurately predicts ionic conductivity of SPEs. The model was trained on SPE ionic conductivity data from hundreds of experimental publications. Our chemistry-informed model encodes the Arrhenius equation, which describes temperature activated processes, into the readout layer of a state-of-the-art message passing neural network and has significantly improved accuracy over models that do not encode temperature dependence. Chemically informed readout layers are compatible with deep learning for other property prediction tasks and are especially useful where limited training data are available. Using the trained model, ionic conductivity values were predicted for several thousand candidate SPE formulations, allowing us to identify promising candidate SPEs. We also generated predictions for several different anions in poly(ethylene oxide) and poly(trimethylene carbonate), demonstrating the utility of our model in identifying descriptors for SPE ionic conductivity.

To analyse prescription of antibodies in emergency dental service according to antibiotic type, working diagnosis, patient visit time and patient demographic characteristics. Additionally, prescription practices among individual dentists were analysed. The data in this retrospective cohort study were collected from electronic medical records and analyzed using descriptive statistics. Statistical analyses were conducted using the chi‐square test and the Z‐test with post‐hoc Bonferroni adjustment (α =0.05). The study covered 20,879 patient visits during a 1.5‐year period (from 1 June 2015 to 1 December 2016). Antibiotics were prescribed in 10,188 (48.8%) visits. In 6,202 (29.7%) visits, no dental treatment was performed and only an antibiotic was prescribed. The antibiotics most frequently prescribed were from the penicillin group and also contained clavulanic acid (70.5%); the second most frequently prescribed antibiotic was clindamycin (15.0%). The most common diagnoses for which an antibiotic was prescribed were acute apical abscess,pericoronitis and retained root; for these diagnoses, an antibiotic was prescribed in 79.8%, 64.3% and 63.3% of visits, respectively. Prescription of an antibiotic was significantly more frequent during Sundays and holidays (55.6% of visits) than during working days (33.2% of visits). Prescription of an antibiotic increased from the age of 1 towards the age of 75 and decreased thereafter. Female dentists prescribed antibiotics slightly but significantly (P< 0.001) more frequently than male dentists (50.8% and 46.8% of visits, respectively). High heterogeneity was observed among dentists regarding their criteria for prescribing antibiotics; individual dentists prescribed antibiotics in 15.0%–72.1% of the total number of visits. Multiple possible issues in the prescription of antibiotics were observed, ranging from administration for inappropriate indications to noncritical and excessive prescription.

Permafrost peatlands are vulnerable to rapid structural changes under climatic warming, including vertical collapse. Peatland water budgets, and therefore peat hydraulic properties, are important determinants of vegetation and carbon fluxes. Measurements of hydraulic properties exist for only a limited number of permafrost peatland locations, primarily concentrated in North America. The impacts of thaw‐induced collapse upon properties such as horizontal saturated hydraulic conductivity (Kh), and thus lateral drainage, remain poorly understood. We made laboratory determinations of Khfrom 82 peat samples from a degrading Swedish palsa mire. We fitted a linear mixed‐effects model (LMM) to establish the controls on Kh, which declined strongly with increasing depth, humification and dry bulk density. Depth exerted the strongest control on Khin our LMM, which demonstrated strong predictive performance (r2= 0.605). Humification and dry bulk density were influential predictors, but the high collinearity of these two variables meant only one could be included reliably in our LMM. Surprisingly, peat Khdid not differ significantly between desiccating and collapsed palsas. We compared our site‐specific LMM to an existing, multi‐site model, fitted primarily to boreal and temperate peatlands. The multi‐site model made less skillful predictions (r2= 0.528) than our site‐specific model, possibly due to latitudinal differences in peat compaction, floristic composition and climate. Nonetheless, low bias means the multi‐site model may still be useful for estimating peat Khat high latitudes. Permafrost peatlands remain underrepresented in multi‐site models of peat hydraulic properties, and measurements such as ours could be used to improve future iterations. Depth and humification are important controls for horizontal saturated hydraulic conductivity in a degrading Swedish palsa complexPeat hydraulic properties did not significantly differ between desiccating and collapsed areas of the palsa complexAn existing model, trained on lower‐latitude peatlands, predicted horizontal saturated hydraulic conductivity adequately, with low bias Depth and humification are important controls for horizontal saturated hydraulic conductivity in a degrading Swedish palsa complex Peat hydraulic properties did not significantly differ between desiccating and collapsed areas of the palsa complex An existing model, trained on lower‐latitude peatlands, predicted horizontal saturated hydraulic conductivity adequately, with low bias

Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi-site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics.

Abstract.Collective nostalgia for the good old days of the country thrives across the world. However, little is known about the social psychological dynamics of this collective emotion across cultures. We predicted that collective nostalgia is triggered by collective angst as it helps people to restore a sense of in-group continuity via stronger in-group belonging and out-group rejection (in the form of opposition to immigrants). Based on a sample (N= 5,956) of individuals across 27 countries, the general pattern of results revealed that collective angst predicts collective nostalgia, which subsequently relates to stronger feelings of in-group continuity via in-group belonging (but not via out-group rejection). Collective nostalgia generally predicted opposition to immigrants, but this was subsequently not related to in-group continuity.

AimsExpression of Claudin-1 has been associated with prognosis in several cancers. Here we investigated the expression pattern of Claudin-1 in borderline tumours of the ovary (BOT).MethodsWe analysed a cohort of 114 cases of borderline tumour (BOT). Claudin-1 expression was studied by immunohistochemistry using a polyclonal antibody and was compared with clinical and histopathological characteristics.ResultsStrong Claudin-1 expression was found in 30 cases (26.3%) independent of histological subtype. Expression was significantly less frequent in International Federation of Gynecology and Obstetrics (FIGO) stage I (p= 0.045), while the presence of microinvasion did not correlate with Claudin-1 expression. In contrast, we detected a highly significant association of Claudin-1 expression with the presence of peritoneal implants (p=0.003) and micropapillary pattern (p=0.047), which are features exclusively seen in serous BOT. Moreover, when we restricted our analysis to the subtype of serous BOT, the association of Claudin-1 expression with peritoneal implants (p<0.001) and micropapillary pattern (p =0.003) remained highly significant.ConclusionsIn conclusion, Claudin-1 expression is associated with the presence of peritoneal implants and micropapillary pattern, which have been shown to be associated with poor prognosis. We speculate that overexpression of Claudin-1 might be linked to the mitogen-activated protein kinase pathway activation in BOT and suggest further studies to define its prognostic and potential therapeutic value.

Substantial changes in terrestrial hydroclimate during the Holocene are recorded in geological archives and simulated by computer models. To identify spatial and temporal patterns during the past 12 ka, proxy records sensitive to changing precipitation and effective moisture (precipitation minus evaporation) were compiled from across the globe (n= 813). Proxy composite timeseries were computed for 30 of the IPCC AR6 regions and compared to two full‐Holocene transient model simulations (TraCE‐21ka and HadCM3) and twelve mid‐Holocene CMIP6 simulations. We find that throughout Northern Hemisphere monsoon regions, proxy and model simulations indicate wetter‐than‐modern conditions during the early and mid‐Holocene while Southern Hemisphere monsoon regions were drier. This insolation driven trend toward modern values began approximately 6,000 years ago, and the clear agreement among proxy records and models may reflect the large magnitude of precipitation change and consistent atmospheric circulation forcing mechanism for these regions. In the midlatitudes, the pattern of change is less certain. Generally, proxy composites show a wetting trend throughout the Holocene for the northern midlatitudes, possibly due to strengthening westerlies from an increasing latitudinal temperature gradient. However, simulations indicate that the magnitude of change was relatively low, and for portions of North America, there is a proxy‐model disagreement. At high latitudes, hydroclimate is positively correlated with temperature in both proxies and models, consistent with projected wetting as temperatures rise. Overall, this large proxy database reveals a coherent pattern of hydroclimate variability despite the challenges associated with reconstructing hydroclimate fields. A new compilation of natural records of past climate (called “proxy records”) characterizes changes to precipitation and moisture conditions during the past 12,000 years. The spatial patterns of climate changes are examined regionally. We also compare the proxy records with climate model simulations to evaluate agreement between these independent data sources. Our results highlight a trend toward modern moisture conditions beginning approximately 6,000 years ago, when Northern Hemisphere monsoon regions in North Africa and Asia started to become dryer and Southern Hemisphere regions in South America and Africa became wetter. These shifts are explained by the seasonal distribution of sunlight associated with slow changes in Earth's orbit. In the Northern Hemisphere midlatitudes, a wetting trend throughout the past 12,000 years is apparent in the proxy records. Changes in the distribution of temperatures may have influenced atmospheric circulation by strengthening winds and increasing moisture delivery to these midlatitude regions. In the polar regions, a covariance between precipitation and temperature are correlated in both models and proxy records. Because modern warming is concentrated on land and in the Arctic, our results provide a partial analogue for the impacts of future warming on hydroclimate. Eight hundred thirteen proxy records characterize terrestrial Holocene hydroclimate. Results are compared to existing paleotemperature data and climate modelsProxy records and models agree on the sign of the precipitation anomaly at 6 ka in 63% of the study regions compared to 26% for temperatureProxy‐model hydroclimate agreement is highest for tropical monsoon regions. Proxies and models disagree about trends in North America Eight hundred thirteen proxy records characterize terrestrial Holocene hydroclimate. Results are compared to existing paleotemperature data and climate models Proxy records and models agree on the sign of the precipitation anomaly at 6 ka in 63% of the study regions compared to 26% for temperature Proxy‐model hydroclimate agreement is highest for tropical monsoon regions. Proxies and models disagree about trends in North America

Colorectal mixed adenoneuroendocrine carcinomas are rare and clinically aggressive neoplasms with considerable morphological heterogeneity. Data on their genomic characteristics and molecular associations to either conventional colorectal adenocarcinomas or poorly differentiated neuroendocrine neoplasms is still scarce, hampering optimized patient treatment and care. Tissue from 19 colorectal mixed adenoneuroendocrine carcinomas and eight colorectal poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas) was microdissected and subjected to next-generation sequencing using a colorectal adenocarcinoma-specific panel comprising 196 amplicons covering 32 genes linked to colorectal adenocarcinoma, and poorly differentiated neuroendocrine neoplasm tumorigenesis. Mixed adenoneuroendocrine carcinomas were also examined for microsatellite instability and MLH-1 promoter methylation status. In three mixed adenoneuroendocrine carcinomas, exocrine and endocrine components were analyzed separately. Genetic testing of colorectal mixed adenoneuroendocrine carcinomas identified 43 somatic mutations clustering in 13/32 genes. Sixteen (84%) tumors harbored at least one somatic mutation, two tumors (11%) displayed high microsatellite instability. Compared with colorectal adenocarcinomas, mixed adenoneuroendocrine carcinomas were more frequently BRAF (37%; P=0.006), and less frequently KRAS (21%; P=0.043) and APC (16%; P=0.001) mutated. Point mutations in neuroendocrine neoplasm-related genes like RB1 or RET were not detected, but one tumor harbored a heterozygous RB1 deletion. Separately analyzed adenocarcinoma and neuroendocrine carcinoma components revealed a shared mutational trunk of driver genes involved in colorectal adenocarcinoma carcinogenesis. Colorectal neuroendocrine carcinomas were similar in their mutation profile to colorectal adenocarcinomas, but compared with mixed adenoneuroendocrine carcinomas, had a higher rate of APC mutations (P=0.027). Our data indicate that colorectal mixed adenoneuroendocrine carcinomas and neuroendocrine carcinomas are genetically closely related to colorectal adenocarcinomas, suggesting that the cells giving rise to these tumors primarily have an intestinal coinage. The identification of BRAF mutations and the frequently present KRAS wild-type status principally render some mixed adenoneuroendocrine carcinomas eligible to targeted treatment strategies used for colorectal adenocarcinomas.

Collapse of ice sheets can cause significant sea level rise and widespread climate change. We examine the climatic response to meltwater generated by the collapse of the Cordilleran‐Laurentide ice saddle (North America) ~14.5 thousand years ago (ka) using a high‐resolution drainage model coupled to an ocean‐atmosphere‐vegetation general circulation model. Equivalent to 7.26 m global mean sea level rise in 340 years, the meltwater caused a 6 sverdrup weakening of Atlantic Meridional Overturning Circulation (AMOC) and widespread Northern Hemisphere cooling of 1–5°C. The greatest cooling is in the Atlantic sector high latitudes during Boreal winter (by 5–10°C), but there is also strong summer warming of 1–3°C over eastern North America. Following recent suggestions that the saddle collapse was triggered by the Bølling warming event at ~14.7–14.5 ka, we conclude that this robust submillennial mechanism may have initiated the end of the warming and/or the Older Dryas cooling through a forced AMOC weakening. Around 50% of the melt from the Cordilleran‐Laurentide ice saddle collapse directly entered the Arctic OceanThe resulting freshwater cap reduced Atlantic Overturning in the model by 6 Sv (40%)This caused widespread Northern Hemisphere cooling (1–5°C), but strong winter warming over eastern North America

Restoration of Gait During Two to Three Weeks of Therapy with Multichannel Electrical Stimulation Soon after the introduction of the first single-channel electrical stimulators for correction of foot drop, attempts [...]

Our limited understanding of millennial‐scale variability in the context of the last glacial period can be explained by the lack of a reliable modeling framework to study abrupt climate changes under realistic glacial backgrounds. In this article, we describe a new set of long‐run Last Glacial Maximum experiments where such climate shifts were triggered by different snapshots of ice‐sheet meltwater derived from the early stages of the last deglaciation. Depending on the location and the magnitude of the forcing, we observe three distinct dynamical regimes and highlight a subtle window of opportunity where the climate can sustain oscillations between cold and warm modes. We identify the Eurasian Arctic and Nordic Seas regions as being most sensitive to meltwater discharge in the context of switching to a cold mode, compared to freshwater fluxes from the Laurentide ice sheets. These cold climates follow a consistent pattern in temperature, sea ice, and convection, and are largely independent from freshwater release as a result of effective AMOC collapse. Warm modes, on the other hand, show more complexity in their response to the regional pattern of the meltwater input, and within them, we observe significant differences linked to the reorganization of deep water formation sites and the subpolar gyre. Broadly, the main characteristics of the oscillations, obtained under full‐glacial conditions with ice‐sheet reconstruction derived meltwater patterns, share similar characteristics with δ18Orecords of the last glacial period, although our experiment design prevents detailed conclusions from being drawn on whether these represent actual Dansgaard‐Oeschger events. During the last glacial period (115,000–12,000 years before present), the baseline cold climate was continuously disturbed by intense and abrupt climate changes. They completely modified the climate for a few thousand years or so, resulting, for instance, in massive temperature shifts and complete reorganizations of ocean circulation. These abrupt changes have been observed in climate records from the Northern Hemisphere and also can be traced in records from the Southern Hemisphere. Yet, we still do not know what triggers these changes, and often cannot simulate them at the right time under known environmental conditions. In the context of the Last Glacial Maximum, a cold period 21,000 years ago with extensive ice over the Northern Hemisphere, this article analyses a new set of climate model simulations that test the effects of freshwater melting from the ice sheets at different periods of the early deglaciation (∼21,000 to 18,000 years before present). Under some conditions, the resulting experiments displayed an Atlantic Ocean that oscillates between strong and collapsed basin‐wide circulation, causing approximately 10°C of temperature change over Greenland; a behavior that resembles observed abrupt climate changes. New set of long‐run Last Glacial Maximum general circulation model experiments showing millennial‐scale variabilityDetailed description of the impact of ice sheet reconstruction‐derived meltwater distributions on abrupt climate changesIntroduction for future studies of the underlying physical processes of abrupt climate changes New set of long‐run Last Glacial Maximum general circulation model experiments showing millennial‐scale variability Detailed description of the impact of ice sheet reconstruction‐derived meltwater distributions on abrupt climate changes Introduction for future studies of the underlying physical processes of abrupt climate changes

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit (PIK3CA) is a central element of a signaling pathway involved in cell proliferation, survival, and growth. Certain mutations in this pathway result in enhanced PI3K signaling, which is associated with oncogenic cellular transformation and cancer. The aims of this study were to characterize different types of PIK3CA mutations in exons 9 and 20 in a series of primary breast carcinomas and to correlate the results with clinicopathologic parameters and survival. We used frozen tissue samples and sequenced exons 9 and 20 for a series of 241 patients with a diagnosis of breast carcinoma. We found that 15.8 of the primary breast carcinomas possessed PIK3CA mutations in either exon 9 or exon 20. The rate of PIK3CA mutations was increased in HRHER2−tumors (18.6), but this difference did not reach a statistical significance. The lowest rate of mutations was observed in HRHER2tumors (5.3). No statistically significant association was found between the presence of PIK3CA mutations and the prognosticclinical features of breast cancer, including histologic subtype, Her2 status, axillary lymph node involvement, tumor grade, and tumor stage. However, the presence of the H1047R mutation in 10 samples was associated with a statistically significantly worse overall survival. PIK3CA mutation was found to be a frequent genetic change in all breast cancer subtypes but occurred with the highest rate in HRHER2−tumors. Further studies are needed to validate the prognostic impact of different PIK3CA mutations.

Osteoporosis frequently remains underrecognized and undertreated in men. Most osteoporosis-related fractures could be prevented if men at risk would be diagnosed, treated, and remained compliant with therapy. Bisphosphonates, the mainstay of osteoporosis treatment, are potent antiresorptive agents that inhibit osteoclast activity, suppress in vivomarkers of bone turnover, increase bone mineral density, decrease fractures, and likely improve survival in men with osteoporosis. The focus of the article is on intravenous zoledronic acid, which may be a preferable alternative to oral bisphosphonate therapy in patients with cognitive dysfunction, the inability to sit upright, polypharmacy, significant gastrointestinal pathology or suspected medication noncompliance. Zoledronic acid is approved in the United States (US) and European Union (EU) as an annual 5 mg intravenous infusion to treat osteoporosis in men. The zoledronic acid 4 mg intravenous dose has been studied in the prevention of bone loss associated with androgen deprivation therapy. This article reviews the evidence for zoledronic acid, currently the most potent bisphosphonate available for clinical use, and its therapeutic effects in the treatment of men with osteoporosis.

The actual nature of spindle cell carcinoma has been debated extensively because of its rarity. It carries a poor prognosis, even when early-stage disease is diagnosed and resected. In view of the rarity and the significance of the histological diagnosis, we report a patient with rapidly progressing spindle cell lung carcinoma with soft tissue metastasis. Diagnosis was confirmed by immunohistochemistry finding. Analysis of the TP53 gene mutations by polymerase chain reaction and DNA sequencing revealed insertion of single thymine resulting in frameshift mutation in the exon 8. Prognosis of spindle cell lung carcinoma might be determined by the sarcoma component of the tumor and, based on that, we wonder if this type of lung carcinoma could be followed-up and treated by strategies for soft tissue sarcomas, because of its rapid, sarcomatous type of growth, beside the properly lung carcinoma oncological treatment.The actual nature of spindle cell carcinoma has been debated extensively because of its rarity. It carries a poor prognosis, even when early-stage disease is diagnosed and resected. In view of the rarity and the significance of the histological diagnosis, we report a patient with rapidly progressing spindle cell lung carcinoma with soft tissue metastasis. Diagnosis was confirmed by immunohistochemistry finding. Analysis of the TP53 gene mutations by polymerase chain reaction and DNA sequencing revealed insertion of single thymine resulting in frameshift mutation in the exon 8. Prognosis of spindle cell lung carcinoma might be determined by the sarcoma component of the tumor and, based on that, we wonder if this type of lung carcinoma could be followed-up and treated by strategies for soft tissue sarcomas, because of its rapid, sarcomatous type of growth, beside the properly lung carcinoma oncological treatment.

Background For patients with two or more primary cancers a correct diagnosis is critically important because prognosis and treatment vary considerably between multiple primary cancers and metastatic disease.Case report Two bilateral synchronous primary lung malignancies of different histological types were diagnosed and immunohistochemically confirmed in a 60-year-old woman. In biopsy specimens of the right lung pure squamous cell carcinoma was detected (stage IIIa). The tumor expressed AE1/AE3, cytokeratin 5 and 34βE12. In biopsy specimens of the left lung small cell carcinoma was detected (stage IIIa). The small cells expressed synaptophysin, chromogranin A and CD56. DNA was extracted from paraffin-embedded tissue of both tumors. Exons 5–9 of the TP53 gene were examined for genetic mutations by polymerase chain reaction and DNA sequencing analysis. Direct sequencing of DNA isolated from the small cell carcinoma revealed a TGC to TTC mutation at codon 404 of TP53 exon 5. In DNA isolated from the squamous cell carcinoma no TP53 mutation was found. The tumors' different response to chemotherapy also suggested that they belonged to different histological types. The patient lived 24 months after the diagnosis, which is more typical for stage III than for stage IV lung carcinoma.Conclusion Discrimination of synchronous primary lung cancers from intrapulmonary metastases based only on clinical findings can be very difficult. Multidisciplinary diagnostic evaluation is therefore very helpful in cases like this, because a correct diagnosis will determine the best treatment for the patient and consequently a better prognosis.

Recientemente, algunas publicaciones pediátricas han planteado la utilidad de la terapia intracoronaria con células progenitoras autólogas (CPA) derivadas de la médula ósea en niños con miocardiopatía dilatada (MCD) e insuficiencia cardiaca. Describimos la utilidad de este tratamiento en dos lactantes con MCD e insuficiencia cardiaca grave, que habían sido trasladados a nuestro centro para valoración de trasplante cardiaco.

Abstract: We present a case of large cell lung carcinoma in sixty-one year old male with typical lung cancer symptoms but unusual radiological presentation and immunophenotype. Tumor morphological finding related to its radiological finding was suggestive for large cell lymphoma or carcinoma, but its immunophenotype made confusion for pathological diagnosis. No p53 mutations were detected in genetic investigation. Multidisciplinar diagnostic approach to some tumors is useful for their final diagnosis.

Notum is a carboxylesterase that suppresses Wnt signaling through deacylation of an essential palmitoleate group on Wnt proteins. There is a growing understanding of the role Notum plays in human diseases such as colorectal cancer and Alzheimer’s disease, supporting the need to discover improved inhibitors, especially for use in models of neurodegeneration. Here, we have described the discovery and profile of 8l(ARUK3001185) as a potent, selective, and brain-penetrant inhibitor of Notum activity suitable for oral dosing in rodent models of disease. Crystallographic fragment screening of the Diamond-SGC Poised Library for binding to Notum, supported by a biochemical enzyme assay to rank inhibition activity, identified 6aand 6bas a pair of outstanding hits. Fragment development of 6delivered 8lthat restored Wnt signaling in the presence of Notum in a cell-based reporter assay. Assessment in pharmacology screens showed 8lto be selective against serine hydrolases, kinases, and drug targets.

Acute graft-versus-host disease (GVHD) was reduced using home care compared with hospital care after allogeneic hematopoietic stem-cell transplantation (ASCT).

Schwannomas of the foot are rare. We describe three cases that mimicked compressive neuropathy, two resembling tarsal tunnel syndrome and a third resembling Morton’s neuroma. All three patients had complete resolution of their pain after resection of the tumor. (J Am Podiatr Med Assoc 96(4): 344–347, 2006)

In this paper we explore the relationship between the public and private savings components of national savings (the ultrarational hypothesis) and between the households and the corporate sector components of private savings (the consolidation effect). We apply pooled cross-section analysis for testing the presence of a unit root in the net savings magnitudes in European Union countries. The empirical evidence suggests no support for the ultrarational hypothesis within the EU. The EU private sector net savings rates show evidence to support the consolidation hypothesis suggesting that private sector constituents act in unison in terms of saving decisions.

In adolescent bone sarcoma patients, bone mass acquisition is potentially compromised at a time in which it should be at a maximum. To evaluate the problem we measured bone mineral density (BMD) and serum markers of bone formation and resorption in a series of pediatric patients with bone tumors. BMD was measured by dual-energy x-ray absorptiometry, at clinical remission, for lumbar spine and the neck of the femur in 38 osteosarcoma and 25 Ewing's sarcoma patients. Mean age was 20.65 and 19.13 y respectively. Serum markers of bone metabolism were: OC, PICP, ICTP, 25-OH vit D and 1,25-(OH)2vit D, IGF-I, IGFBP-3 and intact PTH. Serum was sampled throughout anti-tumoral treatments and follow-up. We analyzed 85 samples from 59 osteosarcoma patients and 54 samples from 36 Ewing's sarcoma patients. Patients had decreased lumbar and femoral BMD. The decrease was more pronounced in pubertal patients compared with those who had completed pubertal development at the time of disease diagnosis. Multivariate analysis indicated that sex, age, weight and BMI were significant in lumbar BMD depletion. Weight and BMI were significant in femoral BMD depletion. Serum markers of bone formation (PICP and OC) and resorption (ICTP) were, throughout, lower than reference values. Significant alterations in other markers were also observed. Up to a third of osteosarcoma and Ewing's sarcoma patients in clinical remission had some degree of BMD deficit. The corresponding increased risk of pathologic bone fractures constitutes a reduction in future quality of life.

The article presents information on two class action lawsuits in the United States by Falun Gong followers against Chinese media defendants. The first case Chen Gang vs. Zhao Zhizhen was filed in the U.S. District Court for the District of Connecticut in the year 2004. Another case Gang Chen vs. China Central Television (CCTV): a P.R.C. State Instrumentality, was filed in January 2006 in the U.S. District Court for the Southern District of New York against the Chinese national television station CCTV. The plaintiffs in these cases claimed violations of international law as a result of speech that allegedly encouraged abuse, detention, torture, and deaths of Falun Gong followers in the People's Republic of China.

Compare the energy expenditure, predicted by anthropometric equations, with that measured by continuous on-line indirect calorimetry in ventilated, critically ill children during the early postinjury period.

The authors' objectives were to compare height at diagnosis of children with bone tumors with that of Spanish reference children; to analyze the frequency of the genotypes for the polymorphisms of the vitamin D receptor (VDR), estrogen receptor (ER), and collagen I1 (COLI1) genes in patients and in healthy controls; and to test the relationship between the genetic markers and height.

To assess bone mineralization in adolescents with bone tumors at remission using quantitative digital ultrasound (QUS) and dual-energy x-ray absorptiometry (DEXA), and to compare the bone mineralization values obtained by both methods.

We studied the evolution of plasma amino acid levels in children with chronic kidney failure after undergoing a renal transplantation. Plasma amino acid profile was studied in 10 children just before surgery, at admission in paediatric intensive care unit and 4, 8, 12, 24, 48 and 72 h after transplantation. Previous to the graft, plasma levels of glutamic acid (p <0.01), hydroxyproline (p <0.01), citrulline (p< 0.01) and arginine (p < 0.05) were significantly increased, whereas plasma levels of serine (p <0.01), glutamine (p <0.03), threonine (p< 0.01), tyrosine (p <0.01), valine (p <0.01), leucine (p <0.01), tryptophan (p<0.01), branched amino acids (BCAA) (p <0.01), aromatic amino acids (AAA) (p <0.01) and essential amino acids (EAA) (p< 0.01) were decreased in relation to control children. The amino acid profile evolution run parallel to the settle down of renal function parameters. Within 72 h after surgery, even before in some cases, all amino acids except tryptophan and arginine reached normal levels.

By means of a reinforced balloon catheter, percutaneous transluminal dilatation was used to treat 48 consecutive cases of atheromatous iliac artery narrowing. With no deaths and little increase in the time and risk of diagnostic arteriography, the procedure was successful in more than 80% of cases, giving immediate luminal enlargement and relief, as judged clinically, for up to six years, the maximum follow-up period. In properly selected patients, this technique should be used in preference to reconstructive vascular surgery.(JAMA 230:117-124, 1974)

Posttransplant lymphoproliferative disorders are infrequent tumors related to chronic immunosuppressive therapy. We present a liver transplant recipient who developed such a tumor in the porta hepatis that provoked obstruction of the entire portal triad. Treatment consisted of systemic chemotherapy, percutaneous dilatation, and placement of Wallstent endoprostheses across both biliary and portal vein stenoses. The patient died 3 weeks later of pneumonia and sepsis. At necropsy, the tumor was completely necrosed and the prostheses in both the common bile duct and the portal vein were patent.

The results of measurements of the magnetic circular dichroism of the optical absorption (MCDA) and optically detected electron paramagnetic resonance (ODEPR) of X-irradiated KBr:In crystals are presented. The MCDA bands and ODEPR parameters of In°(1) centers and In2+ centres have been measured. The mechanism of the energy storage in KBr:In crystals is found not to be simply the formation of correlated F centre-In2+ centre pairs as was assumed previously. Considerable similarities to the storage phosphor BaFBr:Eu2+ were found for the photostimulated emission and read-out properties.

Abstract: Objective: To analyze the actual cost of pediatric intensive care and its different components, particularly the differences between various patient groups, with special reference to the variable cost and the elements included in it. Design: Prospective, observational study. Setting: Multidisciplinary 12-bed pediatric intensive care unit (PICU) in a tertiary university hospital. Patients: 495 admissions to the unit over 17 consecutive months; 64.2 % were medical patients and 35.8 % were surgical patients; the mean (SE) stay in the PICU was 6.6 0.4 days. Measurements and results: The fixed cost per day per patient was calculated, including the costs of physicians, nurses, auxiliary and other personnel who worked during the study period, and the costs of structural depreciation, maintenance, consumption, and disposable material. The variable cost was individually calculated from the costs of routine procedures and also included expenditure on pharmaceuticals, blood products, biochemical, hematological, and bacteriologic tests, radiology, image diagnosis procedures, and other procedures. The Physiologic Stability Index (PSI) was obtained in the first 24 h after admission. The mean fixed cost per patient per day was u. s. $ 608, which represents 72 % of the total patient cost during this study; 86 % of this amount was for personnel (58 % for nurses and auxiliary staff). Variable costs came to 28 % of the total amount, and were $ 218 100 (M SEM) per patient per day. In addition to the costs of their longer stay in the PICU, the daily variable costs of nonsurvivors were higher than those of survivors ($ 542 52 vs $ 179 7; p < 0.001). We classified the patients into four groups according to their PSI score in the first 24 h; variable daily costs increased (p < 0.05) in all comparisons with the PSI level: group I: < 4 points ($ 155 0.5), group II: 5–9 points ($ 210 13), group III: 10–14 points ($ 324 54), group IV: > 15 points ($ 480 42). However, this pattern was not found for all resources: the cost of treatment techniques and biochemical and hematological tests increased, but the consumption of antibiotics, parenteral nutrition, blood products, and bacteriologic tests reached their maximum level in groups I–III and radiology was not significantly influenced by PSI level. Conclusions: The cost of personnel was the biggest factor in intensive care costs: 62.4 % of the total costs. Nonsurvivors generated 3 times the mean variable daily expenditure on survivors and had longer stays in the PICU. The increase in PSI score on the first day was associated with a global increase in variable costs. The cost of treatment techniques significantly increased as the illness became more severe but consumption of antibiotics and parenteral nutrition and use of bacteriologic tests and radiology did not.

The levels of prostaglandin (PG) E2and 6-keto-PGF1a(stable metabolite of prostacyclin) in plasma and gastric juice were determined in 113 critically ill children and adolescent, and compared to those registered in a plasma control group of 24 children and a gastric juice control group of 15. The gastric juice concentration of PGE2is our patients [9.2 × 3.1 (SEM) pg/ml] was significantly lower (p= 0.001) than in the control group [81.1 × 18.1 (SEM) pg/ml]. There were no differences in plasma levels of PGE2and plasma gastric juice levels of 6-ketoPGF1abetween the patients and the control groups. Children who died had lower plasma levels of PGE2[6.2 × 2.2 (SEM) pg/ml] and gastric juice levels of PGE2[2.3 × 0.8 (SEM) pg/ml] than the survivors (p< 0.05). The gastric juice concentration of PGE2was also lower in children who suffered important upper gastrointestinal bleeding, although the difference did not reach statistical significance.

Gianturco-Rösch expandable Z-stents were used in 22 patients with superior vena cava syndrome (SVCS). Stents were placed in all patients in the SVC and in 17 patients, also into the innominate veins. Stent placement resulted in complete relief of symptoms in all patients. Twenty-one patients had no SVCS recurrence from 1 to 16 months, to their death, or to the present time. SVCS recurred only in 1 patient 9 months after stent placement due to tumor ingrowth and secondary thrombosis. Based on ours and on other reported experiences, expandable metallic stents are effective devices for treatment of the SVCS which is difficult to manage by other means.