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Selective serotonin reuptake inhibitors (SSRIs) are widely used for treating neuropsychiatric disorders. However, the exact mechanism of action and why effects can take several weeks to manifest is not clear. The hypothesis of neuroplasticity is supported by preclinical studies, but the evidence in humans is limited. Here, we investigate the effects of the SSRI escitalopram on presynaptic density as a proxy for synaptic plasticity. In a double-blind placebo-controlled study (NCT04239339), 32 healthy participants with no history of psychiatric or cognitive disorders were randomized to receive daily oral dosing of either 20 mg escitalopram (n= 17) or a placebo (n= 15). After an intervention period of 3–5 weeks, participants underwent a [11C]UCB-J PET scan (29 with full arterial input function) to quantify synaptic vesicle glycoprotein 2A (SV2A) density in the hippocampus and the neocortex. Whereas we find no statistically significant group difference in SV2A binding after an average of 29 (range: 24–38) days of intervention, our secondary analyses show a time-dependent effect of escitalopram on cerebral SV2A binding with positive associations between [11C]UCB-J binding and duration of escitalopram intervention. Our findings suggest that brain synaptic plasticity evolves over 3–5 weeks in healthy humans following daily intake of escitalopram. This is the first in vivo evidence to support the hypothesis of neuroplasticity as a mechanism of action for SSRIs in humans and it offers a plausible biological explanation for the delayed treatment response commonly observed in patients treated with SSRIs. While replication is warranted, these results have important implications for the design of future clinical studies investigating the neurobiological effects of SSRIs.

This article reviews developments in international mergers, acquisitions, and joint ventures during the year 2011. (l) Because of space limitations, this year's article reviews only six selected jurisdictions: Australia, Denmark, [...]

This article reviews developments in 2010 in international mergers and acquisitions (M&As) and joint ventures (JVs) in Argentina, Australia, Austria, Denmark, Germany, India, Israel, New Zealand, the United Kingdom, and [...]

Poor performance is common in the delivery of large-scale transport infrastructure. Despite previous studies examining the management of transport megaprojects, there is a lack of systematic reviews on performance Controls and Accountability in Megaprojects (CAMP). We analyze research on CAMP in Africa. Out of the 947 records retrieved, 35 articles published between 1980 and 2022 meet our inclusion criteria. We identify four main research themes: “project governance,” “performance management,” “project conceptual management,” and “complexity management.” Our findings indicate significant weaknesses in project governance and a lack of proper project conception. Practical implications involve restructuring project governance policies and implementing a multi-level project governance model. The research supports recognizing corruption as a characteristic of megaprojects, implementing project governance as a standard management practice, and improving governance in public-private partnerships. Additionally, future research should prioritize integrating and developing policies, strengthening institutions, implementing participatory governance mechanisms, and building capacity for project management.

Structural engineering is the first step toward changing properties of materials. While this can be at relative ease done for bulk materials, for example, using ion irradiation, similar engineering of 2D materials and other low-dimensional structures remains a challenge. The difficulties range from the preparation of clean and uniform samples to the sensitivity of these structures to the overwhelming task of sample-wide characterization of the subjected modifications at the atomic scale. Here, we overcome these issues using a near ultrahigh vacuum system comprised of an aberration-corrected scanning transmission electron microscope and setups for sample cleaning and manipulation, which are combined with automated atomic-resolution imaging of large sample areas and a convolutional neural network approach for image analysis. This allows us to create and fully characterize atomically clean free-standing graphene with a controlled defect distribution, thus providing the important first step toward atomically tailored two-dimensional materials.

A nonvolatile fluorine-18 aldehyde prosthetic group was developed from [18F]SFB, and used for site-specific labeling of active site inhibited factor VII (FVIIai). FVIIai has a high affinity for tissue factor (TF), a transmembrane protein involved in angiogenesis, proliferation, cell migration, and survival of cancer cells. A hydroxylamine N-glycan modified FVIIai (FVIIai-ONH2) was used for oxime coupling with the aldehyde [18F]2under mild and optimized conditions in an isolated RCY of 4.7 ± 0.9%, and a synthesis time of 267 ± 5 min (from EOB). Retained binding and specificity of the resulting [18F]FVIIai to TF was shown in vitro. TF-expression imaging capability was evaluated by in vivo PET/CT imaging in a pancreatic human xenograft cancer mouse model. The conjugate showed exceptional stability in plasma (>95% at 4 h) and a binding fraction of 90%. In vivo PET/CT imaging showed a mean tumor uptake of 3.8 ± 0.2% ID/g at 4 h post-injection, a comparable uptake in liver and kidneys, and low uptake in normal tissues. In conclusion, FVIIai was labeled with fluorine-18 at the N-glycan chain without affecting TF binding. In vitro specificity and a good in vivo imaging contrast at 4 h postinjection was demonstrated.

The radionuclide copper-64 is widely used in combination with biomolecules, such as antibodies, for positron emission tomography (PET). Copper-64 is ideal for the imaging of biomolecules with long circulation times due to its relatively long half-life, and when conjugated to an antibody, specific cells can be targeted in vivo. Here, we have prepared a trastuzumab–chelator conjugate by using affinity-guided conjugation, in which an azide was attached to the antibody prior to a strain promoted azide–alkyne cycloaddition reaction with DBCO-PEG4-NOTA. The conjugate was benchmarked against a standard nonspecific labeled trastuzumab–NOTA conjugate. The conjugates were tested for incorporation of copper-64, stability in buffer and plasma, and tumor targeting in vivousing PET imaging of mice with xenograft tumors expressing HER2. Both conjugates showed good incorporation of copper-64 and a high stability with less than 10% degradation after 36 h. Furthermore, both conjugates showed accumulation at the tumor site with mean uptake of 7.2 ± 2.4%ID/g and 5.2 ± 1.3%ID/g after 40 h for the affinity-guided labeled trastuzumab and the nonspecific labeled trastuzumab, respectively.

Background:Studies investigating the transfer of endotracheal intubation skills from simulation training to out-of-hospital patient scenarios are limited.Aims:The aim was to evaluate the outcome of endotracheal intubation simulation training among paramedics and the safe transfer of skills to out-of-hospital cardiac arrest (OHCA) patients.Methods:Paramedics participated in a 1-day simulation training course including five Airtraq endotracheal intubation attempts using three different types of mannequins (n=15 attempts). Performance and outcome of transfer of intubation skills to patients were monitored for the next 35 months. European Resuscitation Council international advanced cardiopulmonary resuscitation guidelines (Nolan et al, 2005) were followed to ensure patient safety.Findings:Endotracheal intubation was attempted in a total of 417 patients with OHCA by 51 (96%) of the 53 participating paramedics. In 366 (88%) patients, intubation was successfully performed in the first or second attempt. Aspiration, airway secretion, a high modified Cormack Lehane score and insecure verification of tube placement were the most common reasons for failed intubation.Conclusion:Endotracheal intubation with Airtraq in adult patients with OHCA can be performed safely by paramedics after receiving a 1-day simulation-based training course.

ABSTRACTA number of existing contributions within occupational science have explored the situatedness of occupation by asking what. We identify this perspective as limiting understandings of the relationship of situation and occupation. Instead, we propose using John Dewey’s theory of inquiry to explore the situatedness of occupation from the perspective of howsituation and occupation work together. We argue that this approach can provide a theoretical understanding of engagement in occupation as a natural inquiry process. Viewing occupation from this perspective, we suggest, reveals its transformative capacity, situating it in the doing of explorative actions, depending on contextual cues. The implications of the suggested situatedness of occupation are discussed, and the authors present ‘enacted situated inquiry’ as a way to further understandings of the relationship of occupation and situation, along with proposals for moving forward.

ABSTRACTIn their article “Filling in the gaps: A case for enhancing Madsen and Josephsson’s assertions about occupation, situation, and inquiry”, Aldrich and Cutchin (2017) responded to our article “Engagement in occupation as an inquiring process: Exploring the situatedness of occupation” with the ambition to enhance our assertions on occupation. In this reply, we argue that their text does not address the main arguments of our article. We further argue that their response confirms that further steps in exploring the situatedness of occupation by asking howsituation and occupation are related is a necessary step in avoiding dualistic perspectives on occupation.

We have experienced rapid development in Augmented Reality (AR) systems and platforms in the world of cultural heritage, namely in cultural settings and historical museums. However, we still face a range of challenges to design an AR system that meets the requirements for an AR installation working autonomously in a cultural heritage setting for an extended duration. This article describes the development of two installations for the visualization of a 3D reconstruction of a castle chapel, running autonomously during open hours in the location of a castle museum. We present a convincing 3D visualization running at interactive frame-rates on modern tablets. In one installation, the tablet is connected to a large screen TV for an immersive experience, and, in another, the tablet is hand-held, thus facilitating translational freedom in the chapel. Both installations allow unsupervised usage during museum visiting hours. Based on in-field observations and on-device logging of application usage, user behavior is analyzed and evaluated. Results indicate that users spent a limited amount of time using the application and did not fully explore the visual area of the chapel. In order for the user to spend more time with the application, additional information must be presented to the user.

The urokinase-type plasminogen activator receptor (uPAR) is implicated in cancer invasion and metastatic development in prostate cancer and provides therefore an attractive molecular target for both imaging and therapy. In this study, we provide the first in vivo data on an antimetastatic effect of uPAR radionuclide targeted therapy in such lesions and show the potential of uPAR positron emission tomography (PET) imaging for identifying small foci of metastatic cells in a mouse model of disseminating human prostate cancer. Two radiolabeled ligands were generated in high purity and specific activity: a uPAR-targeting probe (177Lu-DOTA-AE105) and a nonbinding control (177Lu-DOTA-AE105mut). Both uPAR flow cytometry and ELISA confirmed high expression levels of the target uPAR in PC-3M-LUC2.luc cells, and cell binding studies using 177Lu-DOTA-AE105 resulted in a specific binding with an IC50value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted 177Lu groups (p< 0.05) using bioluminescence imaging. Moreover, we found a significantly longer metastatic-free survival, with 65% of all mice without any disseminated metastatic lesions present at 65 days after first treatment dose (p= 0.047). In contrast, only 30% of all mice in the combined control groups treated with 177Lu-DOTA-AE105mut or vehicle were without metastatic lesions. No treatment-induced toxicity was observed during the study as evaluated by observing animal weight and H&E staining of kidney tissue (dose-limiting organ). Finally, uPAR PET imaging using 64Cu-DOTA-AE105 detected all small, disseminated metastatic foci when compared with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of metastatic lesions in a human metastatic prostate cancer model. Furthermore, we have provided the first evidence of the potential for identification of small metastatic lesions using uPAR PET imaging in disseminated prostate cancer, illustrating the promising strategy of uPAR theranostics in prostate cancer.

Two novel radioligands for the serotonin transporter (SERT), [125I]{3‐[5‐iodo‐1‐[4‐fluorophenyl)‐1,3‐dihydroisobenzofuran‐1‐yl]‐propyl}‐dimethylamine ([125I]‐2) and S‐[125I]{3‐[5‐iodo‐1‐(4‐fluorophenyl)‐1,3‐dihydroisobenzofuran‐1‐yl]‐propyl}‐dimethylamine ([125I]‐(S)‐2) were synthesized in a Br/125I exchange reaction. Binding experiments in rats yielded Kdvalues of 0.7 ± 0.06 and 0.52 ± 0.02 nM for [125I]‐2 and [125I]‐(S)‐2, respectively. One hour after intravenous injection of [125I]‐2, 0.34% of the injected dose had accumulated in the brain. The highest hypothalamus‐to‐cerebellum ratio was reached 2 h after injection of [125I]‐(S)‐2 and amounted to 2.4. Pre‐treatment experiments with paroxetine resulted in effective reduction of the target‐to‐cerebellum ratios.

Coagulation in blood is initiated when coagulation factor VII (FVII) binds to exposed TF and is activated to FVIIa, and the TF/FVIIa complex may therefore provide a marker of vascular injury potentially applicable in diagnostic imaging of acute gastrointestinal (GI) bleeding. Methods: Recombinant FVIIa (rFVIIa) was radiolabeled with technetium‐99 m in a direct labeling reaction using the ‘carbonyl approach’ using the IsoLink®carbonyl labeling agent. The properties of 99 mTc(CO)3‐rFVIIa complex was analyzed by TCA precipitation, HPLC and FVIIa functional integrity was tested in in vitroassays. Results: Labeling of rFVIIa was possible without tagging with a chelater. Incorporation of radioactivity depended strongly on rFVIIa concentration and temperature. More than 95% incorporation was achieved after 30 min at 45°C with 0.76 mg/ml rFVIIa. 99 mTc(CO)3‐rFVIIa was obtained in 46% radiochemical yield and in >95% radiochemical purity. Pull down experiments showed that the biological activity (binding to tissue factor and to anti‐FVII antibody) of the radiolabelled product remained intact in the formulation mixture as well as in human serum. By computer modeling analysis, two candidate sites for stabilizing the 99 mTc(CO)+3‐ligand structure in FVIIa were identified. Conclusion: Radiolabelled rFVIIa derivatives may represent a novel tool for the diagnosis of acute gastrointestinal bleeding lesions. Copyright © 2010 John Wiley & Sons, Ltd.

Preparative HPLC methods have been developed for a number of 11Cmethylated PET tracers, which enable elution of the labelled compounds prior to their precursors, thus reducing the overall synthesis time and avoiding contamination of the final product with precusor. This reversal of retention order has been achieved for 11CDASB, 11Craclopride, 11CFLB 457, 11Ccarfentanil, and 2fluoroNmethyl11Capomorphine, enabling collection of the purified radiopharmaceuticals from the HPLC system after 5–7 min. Furthermore, by using ethanol as the organic modifier, residual solvent analysis prior to human injection could be avoided and three of the radiopharmaceuticals could be injected directly following simple dilution and sterile filtration. Copyright © 2009 John Wiley & Sons, Ltd.

Three ¹¹C-labelled tracers for the serotonin reuptake site, S-[N-methyl-¹¹C]citalopram ([¹¹C]-4), S-[N-methyl-d3-¹¹C]citalopram ([¹¹C]-12), and S-[N-methyl-¹¹C]citalopram-α,α-d2 ([¹¹C]-13) were synthesized and the distribution of radioactivity after injection of radioligand was examined ex vivo in rats. The deuterated analogue of (S)-desmethylcitalopram, (S)-1-(4-fluorophenyl)-1-(3-methylamino-[3-d2]-propyl)-1,3-di-hydro-isobenzofuran-5-carbonitrile (11), was synthesized in a multi-step synthesis from escitalopram (4) and used as precursor in the synthesis of [¹¹C]-13. In analogy with the reported gas phase synthesis of [¹¹C]methyl iodide the first gas phase synthesis of [¹¹C]Methyl iodide-d3 is reported. The ¹H/²H kinetic isotope effect related to the synthesized compounds were investigated in ex vivo rat studies, where the brain regions of interest to cerebellum ratios of the tracers [¹¹C]-4, [¹¹C]-12 and [¹¹C]-13 were compared. The ex vivo data indicated no significant differences in binding in any of the investigated brain regions after injection of the three tracers. Copyright © 2004 John Wiley & Sons, Ltd.

A new selective method for the deprotection of benzyl ethers situated next to alcohols in the α, β, or γposition is presented which uses either NIS or DIB/I2as a reagent. After initial formation of a hypoiodite intermediate, the reaction is believed to follow a radical pathway to resemble the Hoffman‐Löffler‐Freytag reaction. The formation of the intermediate hypoiodite is suggested on the basis of NMR studies. Depending on the substrate, the corresponding benzylidene derivatives or diols are isolated.

The precise positioning of dopant atoms within bulk crystal lattices could enable novel applications in areas including solid-state sensing and quantum computation. Established scanning probe techniques are capable tools for the manipulation of surface atoms, but at a disadvantage due to their need to bring a physical tip into contact with the sample. This has prompted interest in electron-beam techniques, followed by the first proof-of-principle experiment of bismuth dopant manipulation in crystalline silicon. Here, we use first-principles modeling to discover a novel indirect exchange mechanism that allows electron impacts to non-destructively move dopants with atomic precision within the silicon lattice. However, this mechanism only works for the two heaviest group V donors with split-vacancy configurations, Bi and Sb. We verify our model by directly imaging these configurations for Bi and by demonstrating that the promising nuclear spin qubit Sb can be manipulated using a focused electron beam.

Gespannte Benzylidenacetale wie 1 können mit einer neuen intramolekularen Reaktion synthetisiert werden. Sie ermöglicht auch die selektive Abspaltung von Benzylschutzgruppen, die freien OH-Gruppen benachbart sind, ohne andere Benzylgruppen anzugreifen. Der Mechanismus dieser für Kohlenhydratsynthesen nützlichen Reaktion verläuft wahrscheinlich über ionische Zwischenstufen unter Beteiligung der Nachbargruppe.

Strained benzylidene acetals such as 1 can be prepared with a new intramolecular reaction that allows the selective removal of benzyl protecting groups neighboring free OH groups, without attacking other benzyl groups. The mechanism of this reaction, which is useful for carbohydrate synthesis, probably proceeds via ionic intermediates with neighboring group participation.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.