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Objectives: The purpose of this study was to determine whether a systematic, multiple assessment protocol could increase reporting of prenatal violence compared with a one-time routine assessment. Method: In 1994, the Maternity Care Coordination (MCC) program in a health department prenatal clinic in North Carolina implemented a concise, systematic assessment protocol on all 384 women who enrolled in the program from April 1994 to April 1995. The protocol assessed for violence at three times during pregnancy using the direct question, 'Have you been hit, slapped, kicked, or hurt during this pregnancy?' To determine the effectiveness of the system, we retrospectively examined the 1991-1993 MCC records (n = 1056) in which the care coordinators routinely screened all clients for violence at their first visit only. Results: Compared with the routine assessment approach, the new systematic assessment protocol increased reporting of prenatal violence at the initial prenatal visit from 6.3% to 10.9% (relative risk = 1.7, 95% confidence interval = 1.2, 2.5), and the multiple assessments increased reporting of prenatal violence to 14.1% (relative risk = 2.2, 95% confidence interval = 1.6, 3.1). Conclusions: Our study suggests that a concise and systematic screening technique using direct questions combined with multiple assessments increased reporting of prenatal violence compared with a single routine assessment. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to study the synergy of anti-HER2, trastuzumab, and anti-EGFR, cetuximab, and characterize the tumor microenvironment components that may lead to increased radiation sensitivity with dual anti-HER2/EGFR therapy in head and neck squamous cell carcinoma (HNSCC). Positron emission tomography (PET) imaging ([ 89 Zr]-panitumumab and [ 89 Zr]-pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors. HNSCC cells were treated with trastuzumab, cetuximab, or combination followed by radiation to assess for viability and radiosensitivity (colony forming assay, immunofluorescence, and flow cytometry). In vivo, [ 18 F]-FMISO-PET imaging was used to quantify changes in oxygenation during treatment. Bliss Test of Synergy was used to identify combination treatment synergy. Quantifying EGFR and HER2 receptor expression revealed a 50% increase in heterogeneity of HER2 relative to EGFR. In vitro, dual trastuzumab-cetuximab therapy shows significant decreases in DNA damage response and increased response to radiation therapy (p < 0.05). In vivo, tumors treated with dual anti-HER2/EGFR demonstrated decreased tumor hypoxia, when compared to single agent therapies. Dual trastuzumab-cetuximab demonstrates synergy and can affect tumor oxygenation in HNSCC. Combination trastuzumab-cetuximab modulates the tumor microenvironment through reductions in tumor hypoxia and induces sustained treatment synergy., (© 2024. The Author(s).)

Suicide disproportionately affects many American Indian/Alaska Native (AI/AN) communities. Caring Contacts is one of the few suicide prevention interventions with demonstrated success in diverse populations, but its acceptability and effectiveness have not been evaluated in AI/AN communities. Using community-based participatory research (Phase 1), we conducted focus groups and semi-structured interviews with AI/AN adults, healthcare providers, and leaders in four communities to improve study design and maximize intervention acceptability and effectiveness for implementation in a randomized controlled trial (Phase 2). This paper describes how adaptations made during Phase 1 affected the acceptability, fit, and responsiveness of the study features to the communities' needs. Acceptability of the study procedures and materials in this community appears to be high, with 92% of participants indicating the initial assessment interview was a positive experience. Broadening eligibility criteria with regard to age and possession of a cellular device resulted in the recruitment of an additional 48% and 46% of participants, respectively. Inclusion of locally-informed methods of self-harm allowed us to capture a wider range of suicidal behavior than would have otherwise been identified. Clinical trials would benefit from community-engaged, cultural adaptation studies with populations in which the interventions would eventually be applied., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Wheat is a globally important crop and one of the "big three" US field crops. But unlike the other two (maize and soybean), in the United States its development is commercially unattractive, and so its breeding takes place primarily in public universities. Troublingly, the incentive structures within these universities may be hindering genetic improvement just as climate change is complicating breeding efforts. "Business as usual" in the US public wheat-breeding infrastructure may not sustain productivity increases. To address this concern, we held a multidisciplinary conference in which researchers from 12 US (public) universities and one European university shared the current state of knowledge in their disciplines, aired concerns, and proposed initiatives that could facilitate maintaining genetic improvement of wheat in the face of climate change. We discovered that climate-change-oriented breeding efforts are currently considered too risky and/or costly for most university wheat breeders to undertake, leading to a relative lack of breeding efforts that focus on abiotic stressors such as drought and heat. We hypothesize that this risk/cost burden can be reduced through the development of appropriate germplasm, relevant screening mechanisms, consistent germplasm characterization, and innovative models predicting the performance of germplasm under projected future climate conditions. However, doing so will require coordinated, longer-term, inter-regional efforts to generate phenotype data, and the modification of incentive structures to consistently reward such efforts., (© 2022 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

Objectives: To assess the cost-effectiveness of LEGO-based therapy compared with usual support., Design: Cost-utility analysis alongside randomised control trial., Setting: Mainstream primary and secondary schools in the UK., Participants: 248 children and young people (CYP) with autism spectrum disorder (ASD) aged 7-15 years., Intervention: LEGO-based therapy is a group social skills intervention designed specifically for CYP with ASD. Through play, CYP learn to use the skills such as joint attention, sharing, communication and group problem-solving. CYP randomised to the intervention arm received 12 weekly sessions of LEGO-based therapy and usual support, while CYP allocated to control arm received usual support only., Main Outcome Measures: Average costs based on National Health Service (NHS) and personal social services perspective and quality-adjusted life years (QALYs) measured by EQ-5D-Y over time horizon of 1 year were collected during the trial. Incremental cost-effectiveness ratio (ICER) was calculated, and non-parametric bootstrapping was conducted. The uncertainty around the ICER estimates was presented using cost-effectiveness acceptability curve (CEAC). A set of sensitivity analyses were conducted to assess the robustness of the primary findings., Results: After adjustment and bootstrapping, on average, CYP in LEGO-based therapy group incurred less costs (incremental cost was -£251 (95% CI -£752 to £268)) and gained marginal improvement in QALYs (QALYs gained 0.009 (95% CI -0.008 to 0.028)). The CEAC shows that the probability of LEGO-based therapy being cost-effective was 94% at the willingness-to-pay threshold of £20 000 per QALY gained. Results of sensitivity analyses were consistent with the primary outcomes., Conclusion: Compared with usual support, LEGO-based therapy produced marginal reduction in costs and improvement in QALYs. Results from both primary and sensitivity analyses suggested that LEGO-based therapy was likely to be cost-effective., Trial Registration Number: ISRCTN64852382., Competing Interests: Competing interests: The research team was aware that the LEGO name is a registered trademark and followed the fair use policy in regard to the LEGO brand throughout the duration of the trial. GGdlC co-authored the LEGO-based therapy manual, which formed the basis of the intervention delivered in the trial. The co-authors of the manual have given us full permission to use the manual without license and to develop an abridged version. They have also stated their support for us in writing our own version and will become co-authors on any future publications. GGdlC has also agreed for the team to adapt the fidelity checklist used in her previous study. GGdlC is a Director of Play included a community interest company that offers training and resources for interventions involving play bricks for children. We have provisional agreement with Jessica Kingsley Publishers who have expressed interest in publishing the abridged manual. However, we are not tied to them as a publisher. There are no other financial and/or competing interests to declare., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

The inoculation of one-day-old broiler chicks with the cecal contents from a mature broiler breeder resulted in a highly diverse and uniform cecal bacterial community. CM did not affect feed consumption, weight gain, nor the richness, evenness, or diversity of the cecal bacterial community. However, the structure of the bacterial community was altered in birds fed the CM diet. Although the CM diet was formulated to contain equivalent metabolizable energy to the control diet, it contained more dietary fiber. The abundance of bacterial families, including those that are known to contain species able to metabolize fiber was altered (e.g., bacteria within the families, Methanobacteriaceae , Atopobiaceae , Prevotellaceae , Clostridiales Family XIII, Peptostreptococcaceae , and Succinivibrionaceae ), and concentrations of SCFAs were higher in the ceca of birds fed the CM diet. Moreover, concentrations of isoleucine, isobutyrate, glutamate, and 2-oxoglutarate were higher, whereas concentrations of phenyllactic acid, indole, glucose, 3-phenylpropionate, and 2-oxobutyrate were lower in the digesta of chickens that were fed CM. The metabolic profiles of pancreas, liver, and breast muscle tissues of birds fed the CM diet differed from control birds. Metabolites that were associated with energy production, protection against oxidative stress, and pathways of amino acid and glycerophospholipid metabolism had altered concentrations in these tissues. Some of the observed changes in metabolite levels may indicate an increased disease risk in birds fed the CM diet (e.g., pancreatitis), and others suggested that birds mounted metabolic response to offset the adverse impacts of CM (e.g., oxidative stress in the liver).

Practice of a complex motor gesture involves motor exploration to attain a better match to target, but little is known about the neural code for such exploration. We examine spiking in a premotor area of the songbird brain critical for song modification and quantify correlations between spiking and time in the motor sequence. While isolated spikes code for time in song during performance of song to a female bird, extended strings of spiking and silence, particularly bursts, code for time in song during undirected (solo) singing, or "practice." Bursts code for particular times in song with more information than individual spikes, and this spike-spike synergy is significantly higher during undirected singing. The observed pattern information cannot be accounted for by a Poisson model with a matched time-varying rate, indicating that the precise timing of spikes in both bursts in undirected singing and isolated spikes in directed singing code for song with a temporal code. Temporal coding during practice supports the hypothesis that lateral magnocellular nucleus of the anterior nidopallium neurons actively guide song modification at local instances in time. NEW & NOTEWORTHY This paper shows that bursts of spikes in the songbird brain during practice carry information about the output motor pattern. The brain's code for song changes with social context, in performance versus practice. Synergistic combinations of spiking and silence code for time in the bird's song. This is one of the first uses of information theory to quantify neural information about a motor output. This activity may guide changes to the song.

Background: Given the central role of radiology in patient care, it is important that radiological research is grounded in reproducible science. It is unclear whether there is a lack of reproducibility or transparency in radiologic research., Purpose: To analyze published radiology literature for the presence or lack of key indicators of reproducibility., Methods: This cross-sectional retrospective study was performed by conducting a search of the National Library of Medicine (NLM) for publications contained within journals in the field of radiology. Our inclusion criteria were being MEDLINE indexed, written in English, and published from January 1, 2014, to December 31, 2018. We randomly sampled 300 publications for this study. A pilot-tested Google form was used to record information from the publications regarding indicators of reproducibility. Following peer-review, we extracted data from an additional 200 publications in an attempt to reproduce our initial results. The additional 200 publications were selected from the list of initially randomized publications., Results: Our initial search returned 295,543 records, from which 300 were randomly selected for analysis. Of these 300 records, 294 met inclusion criteria and 6 did not. Among the empirical publications, 5.6% (11/195, [3.0-8.3]) contained a data availability statement, 0.51% (1/195) provided clear documented raw data, 12.0% (23/191, [8.4-15.7]) provided a materials availability statement, 0% provided analysis scripts, 4.1% (8/195, [1.9-6.3]) provided a pre-registration statement, 2.1% (4/195, [0.4-3.7]) provided a protocol statement, and 3.6% (7/195, [1.5-5.7]) were pre-registered. The validation study of the 5 key indicators of reproducibility-availability of data, materials, protocols, analysis scripts, and pre-registration-resulted in 2 indicators (availability of protocols and analysis scripts) being reproduced, as they fell within the 95% confidence intervals for the proportions from the original sample. However, materials' availability and pre-registration proportions from the validation sample were lower than what was found in the original sample., Conclusion: Our findings demonstrate key indicators of reproducibility are missing in the field of radiology. Thus, the ability to reproduce studies contained in radiology publications may be problematic and may have potential clinical implications.

Acupuncture is recognized to induce multifactorial changes in the neuroregulatory aspects of pain physiology. Many aspects overlap with known receptor interactions of commonly used analgesic drugs, and acupuncture can increase the efficacy or replace the use of these pharmacologic pain treatments. This article discusses the currently recognized components of the pain pathways that are modified by acupuncture. It introduces the role of fibroblasts and fascia in mechanotransduction and discusses the ways in which this provides a link between the acupuncture needle and the nervous system and is a conduit for extracellular fluid movement, lymphatics, and the immune system., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Specific phobias (intense, enduring fears of an object or situation that lead to avoidance and severe distress) are highly prevalent among children and young people. Cognitive-behavioural therapy (CBT) is a well-established, effective intervention, but it can be time consuming and costly because it is routinely delivered over multiple sessions during several months. Alternative methods of treating severe and debilitating phobias in children are needed, like one-session treatment (OST), to reduce time and cost, and to prevent therapeutic drift and help children recover quickly. Our study explores whether (1) outcomes with OST are 'no worse' than outcomes with multisession CBT, (2) OST is acceptable to children, their parents and the practitioners who use it and (3) OST offers good value for money to the National Health Service (NHS) and to society., Method: A pragmatic, non-inferiority, randomised controlled trial will compare OST with multisession CBT-based therapy on their clinical and cost-effectiveness. The primary clinical outcome is a standardised behavioural task of approaching the feared stimulus at 6 months postrandomisation. The outcomes for the within-trial cost-effectiveness analysis are quality-adjusted life years based on EQ-5D-Y, and individual-level costs based of the intervention and use of health and social service care. A nested qualitative evaluation will explore children's, parents' and practitioners' perceptions and experiences of OST. A total of 286 children, 7-16 years old, with DSM-IV diagnoses of specific phobia will be recruited via gatekeepers in the NHS, schools and voluntary youth services, and via public adverts., Ethics and Dissemination: The trial received ethical approval from North East and York Research Ethics Committee (Reference: 17/NE/0012). Dissemination plans include publications in peer-reviewed journals, presentations in relevant research conferences, local research symposia and seminars for children and their families, and for professionals and service managers., Trial Registration Number: ISRCTN19883421;Pre-results., Competing Interests: Competing interests: TD receives royalties from the sale of a book on OST. There are no competing interests for the other authors., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY. Published by BMJ.)

Purpose: The purpose of the present study is to evaluate safety, human radiation dosimetry, and optimal imaging time of [ 89 Zr]trastuzumab in patients with HER2-positive breast cancer., Procedures: Twelve women with HER2-positive breast cancer underwent [ 89 Zr]trastuzumab positron emission tomography (PET)/X-ray computed tomography (CT) twice within 7 days post-injection. Biodistribution data from whole-torso PET/CT images and organ time-activity curves were created using data from all patients. Human dosimetry was calculated using OLINDA with the adult female model., Results: High-quality images and the greatest tumor-to-nontumor contrast were achieved with images performed 5 ± 1 day post-injection. Increased [ 89 Zr]trastuzumab uptake was seen in at least one known lesion in ten patients. The liver was the dose-limiting organ (retention of ∼12 % of the injected dose and average dose of 1.54 mSv/MBq). The effective dose was 0.47 mSv/MBq. No adverse effects of [ 89 Zr]trastuzumab were encountered., Conclusion: [ 89 Zr]trastuzumab was safe and optimally imaged at least 4 days post-injection. The liver was the dose-limiting organ., Competing Interests: RB is a consultant for Genentech and has received an honorarium from Genentech and Novartis.

Objective: Using the example of Merck's donations of ivermectin, to show how tax incentives and non-profit collaborators can make corporate largesse consistent with obligations to maximise returns to shareholders., Methods: We obtained information from publicly available data and estimated Merck's tax deductions according to the US Internal Revenue Code. Reviews of Merck-Kitasato contracts and personal interviews provided additional information regarding key lessons from this collaboration., Results: Our best estimate of the direct cost to Merck of the ivermectin tablets donated during 2005-2011 is around US$ 600 million, well below the stated value of US$ 3.8 billion. Our calculation of tax write-offs reduces the net cost to around US$ 180 million in that period. Indirect market benefits and effects on goodwill further enhanced the compatibility of Merck's donation programme with the company's profit-maximising objective. The case offers lessons for effective management of collaborations with public and non-profit organisations., Conclusion: Merck's role in the donation of ivermectin for the treatment of onchocerciasis is widely and justly acknowledged as a prime example of corporate largesse in the public interest. It is nevertheless important to note that several public and non-profit collaborators, and United States taxpayers, played significant roles in increasing Merck's incentives, and indeed ability, to conduct the donation programme that changed so many lives in poor countries, while meeting its responsibilities to shareholders. Overall, the record indicates responsible corporate management of Merck's ivermectin programme and demonstrates the feasibility of socially responsible policies in a manner compatible with obligations to shareholders., (© 2016 John Wiley & Sons Ltd.)

Unlabelled: (89)Zr-labeled antibodies are being investigated in several clinical trials; however, the time requirement for synthesis of clinical doses can hinder patient throughput because of scheduling difficulties. Additionally, low specific activity due to poor labeling efficiency can require larger amounts of the radiopharmaceutical to be administered, possibly leading to adverse side effects. Here, we describe the design and evaluation of a microfluidic reactor capable of synthesizing a single clinical dose of (89)Zr-labeled antibody. (89)Zr-labeled trastuzumab was chosen for this validation because it is currently being evaluated in clinical trials for imaging human epidermal growth factor receptor 2-positive cancer patients., Methods: A microreactor fabricated from polydimethylsiloxane/glass was silanated with trimethoxy(octadecyl) silane to reduce antibody adsorption. Desferrioxamine-p-benzyl-isothiocyanate (DFO-Bz-NCS) was conjugated to trastuzumab in an 8:1 molar ratio following the literature procedures using aseptic techniques. Radiolabeling was performed by pumping (89)Zr-oxalate and DFO-Bz-trastuzumab into the microfluidic reactor at a total rate of 20 μL/min in ratios varying from 1:37 to 1:592 mg:MBq at 37°C to achieve optimal labeling., Results: Silanated reactors showed low antibody adsorption in comparison to unmodified reactors (95% monoclonal antibody recovered vs. 0% recovered). Labeling of the modified trastuzumab was shown to be achievable at a specific activity above the reported literature value of 220 MBq/mg. A high radiochemical purity was achieved without an incubation period at specific activities of less than 148 MBq/mg; however, specific activities up to 592 MBq/mg could be achieved with an incubation period. Clinical doses were able to be prepared and passed all quality control guidelines set by the Food and Drug Administration. Samples were sterile, colorless, and radiochemically pure (100%); maintained the ability to bind to the intended receptor; formed a minimal amount of aggregates (1%-4%); and were completed within 45-60 min., Conclusion: (89)Zr-labeled trastuzumab for use in a clinical setting was synthesized in a microfluidic reactor in under an hour while reducing the amount of handling required by a technician. Use of this compact platform not only could enable the use of radiolabeled antibodies to become a common practice, but also could spread the use of radiolabeled antibodies beyond locations with cyclotron facilities., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Irrespective of the order of the addition of reagents, the reactions of [PCl2N]3 with MX3 (MX3 = AlCl3, AlBr3, GaCl3) in the presence of water or gaseous HX give the air- and light-sensitive superacid adducts [PCl2N]3·HMX4. The reactions are quantitative when HX is used. These reactions illustrate a Lewis acid/Brønsted acid dichotomy in which Lewis acid chemistry can become Brønsted acid chemistry in the presence of adventitious water or HX. The crystal structures of all three [PCl2N]3·HMX4 adducts show that protonation weakens the two P-N bonds that flank the protonated nitrogen atom. Variable-temperature NMR studies indicate that exchange in solution occurs in [PCl2N]3·HMX4, even at lower temperatures than those for [PCl2N]3·MX3. The fragility of [PCl2N]3·HMX4 at or near room temperature and in the presence of light suggests that such adducts are not involved directly as intermediates in the high-temperature ring-opening polymerization (ROP) of [PCl2N]3 to give [PCl2N]n. Attempts to catalyze or initiate the ROP of [PCl2N]3 with the addition of [PCl2N]3·HMX4 at room temperature or at 70 °C were not successful.

Colorectal cancer (CRC) remains a significant cause of mortality. Inhibitors of cyclooxygenase (COX) and thus prostaglandin E2, are promising CRC preventives, but have significant toxicities. Ginger has been shown to inhibit COX, to decrease the incidence and multiplicity of adenomas, and decrease PGE2 concentrations in subjects at normal risk for CRC. This study was conducted to determine the effects of 2.0 g/d of ginger given orally on the levels of PGE2, leukotriene B4 (LTB4), 13-hydroxy-octadecadienoic acids, and 5-, 12-, & 15-hydroxyeicosatetraenoic acid, in the colonic mucosa of subjects at increased risk for CRC. We randomized 20 subjects to 2.0 g/d ginger or placebo for 28 d. At baseline and Day 28, a flexible sigmoidoscopy was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per amount of protein or free arachidonic acid (AA). There was a significant decrease in AA between baseline and Day 28 (P = 0.05) and significant increase in LTB4 (P = 0.04) when normalized to protein, in subjects treated with ginger versus placebo. No other changes in eicosanoids were observed. There was no difference between the groups in total adverse events (AE; P = 0.06). Ginger lacks the ability to decrease eicosanoid levels in people at increased risk for CRC. Ginger did appear to be both tolerable and safe; and could have chemopreventive effects through other mechanisms. Further investigation should focus on other markers of CRC risk in those at increased CRC risk., (© 2014 Wiley Periodicals, Inc.)

The anti-tumor activity of imidazolium salts is highly dependent upon the substituents on the nitrogen atoms of the imidazolium cation. We have synthesized and characterized a series of naphthalene-substituted imidazolium salts and tested them against a variety of non-smallcell lung cancer cell lines. Several of these complexes displayed anticancer activity comparable to cisplatin. These compounds induced apoptosis in the NCI-H460 cell line as determined by Annexin V staining, caspase-3, and PARP cleavage. These results strongly suggest that this class of compounds can serve as potent chemotherapeutic agents.

Phosphatidylinositol 4-phosphate 5-kinases (PIP5Ks) regulate a variety of cellular processes, including signaling through G protein-coupled receptors (GPCRs), endocytosis, exocytosis, and cell migration. These lipid kinases synthesize phosphatidylinositol 4,5-bisphosphate (PIP2) from phosphatidylinositol 4-phosphate [PI(4)P]. Because small-molecule inhibitors of these lipid kinases did not exist, molecular and genetic approaches were predominantly used to study PIP5K1 regulation of these cellular processes. Moreover, standard radioisotope-based lipid kinase assays cannot be easily adapted for high-throughput screening. Here, we report a novel, high-throughput, microfluidic mobility shift assay to identify inhibitors of PIP5K1C. This assay uses fluorescently labeled phosphatidylinositol 4-phosphate as the substrate and recombinant human PIP5K1C. Our assay exhibited high reproducibility, had a calculated adenosine triphosphate Michaelis constant (Km) of 15 µM, performed with z' values >0.7, and was used to screen a kinase-focused library of ~4700 compounds. From this screen, we identified several potent inhibitors of PIP5K1C, including UNC3230, a compound that we recently found can reduce nociceptive sensitization in animal models of chronic pain. This novel assay will allow continued drug discovery efforts for PIP5K1C and can be adapted easily to screen additional lipid kinases., (© 2014 Society for Laboratory Automation and Screening.)

There is an estimated 3 million women in the US living as breast cancer survivors and persistent cancer related fatigue (PCRF) disrupts the lives of an estimated 30% of these women. PCRF is associated with decreased quality of life, decreased sleep quality, impaired cognition and depression. The mechanisms of cancer related fatigue are not well understood; however, preliminary findings indicate dysfunctional activity in the brain as a potential factor. Here we investigate the relationship between PCRF on intrinsic resting state connectivity in this population. Twenty-three age matched breast cancer survivors (15 fatigued and 8 non-fatigued) who completed all cancer-related treatments at least 12 weeks prior to the study, were recruited to undergo functional connectivity magnetic resonance imaging (fcMRI). Intrinsic resting state networks were examined with both seed based and independent component analysis methods. Comparisons of brain connectivity patterns between groups as well as correlations with self-reported fatigue symptoms were performed. Fatigued patients displayed greater left inferior parietal lobule to superior frontal gyrus connectivity as compared to non-fatigued patients (P < 0.05 FDR corrected). This enhanced connectivity was associated with increased physical fatigue (P = 0.04, r = 0.52) and poor sleep quality (P = 0.04, r = 0.52) in the fatigued group. In contrast greater connectivity in the non-fatigued group was found between the right precuneus to the periaqueductal gray as well as the left IPL to subgenual cortex (P < 0.05 FDR corrected). Mental fatigue scores were associated with greater default mode network (DMN) connectivity to the superior frontal gyrus (P = 0.05 FDR corrected) among fatigued subjects (r = 0.82) and less connectivity in the non-fatigued group (r = -0.88). These findings indicate that there is enhanced intrinsic DMN connectivity to the frontal gyrus in breast cancer survivors with persistent fatigue. As the DMN is a network involved in self-referential thinking we speculate that enhanced connectivity between the DMN and the frontal gyrus may be related to mental fatigue and poor sleep quality. In contrast, enhanced connectivity between the DMN and regions in the subgenual cingulate and brainstem may serve a protective function in the non-fatigued group.

Existing analgesics are not efficacious in treating all patients with chronic pain and have harmful side effects when used long term. A deeper understanding of pain signaling and sensitization could lead to the development of more efficacious analgesics. Nociceptor sensitization occurs under conditions of inflammation and nerve injury where diverse chemicals are released and signal through receptors to reduce the activation threshold of ion channels, leading to an overall increase in neuronal excitability. Drugs that inhibit specific receptors have so far been unsuccessful in alleviating pain, possibly because they do not simultaneously target the diverse receptors that contribute to nociceptor sensitization. Hence, the focus has shifted toward targeting downstream convergence points of nociceptive signaling. Lipid mediators, including phosphatidylinositol 4,5-bisphosphate (PIP2), are attractive targets, as these molecules are required for signaling downstream of G-protein-coupled receptors and receptor tyrosine kinases. Furthermore, PIP2 regulates the activity of various ion channels. Thus, PIP2 sits at a critical convergence point for multiple receptors, ion channels, and signaling pathways that promote and maintain chronic pain. Decreasing the amount of PIP2 in neurons was recently shown to attenuate pronociceptive signaling and could provide a novel approach for treating pain. Here, we review the lipid kinases that are known to regulate pain signaling and sensitization and speculate on which additional lipid kinases might regulate signaling in nociceptive neurons.

Medium-sized cyclic oligomeric phosphazenes [PCl2N]m (where m = 5-9) that were prepared from the reaction of PCl5 and NH4Cl in refluxing chlorobenzene have been isolated by a combination of sublimation/extraction and column chromatography from the predominant products [PCl2N]3 and [PCl2N]4. The medium-sized rings [PCl2N]m have been characterized by electrospray ionization-mass spectroscopy (ESI-MS), their (31)P chemical shifts have been reassigned, and their T1 relaxation times have been obtained. Crystallographic data has been recollected for [PCl2N]5, and the crystal structures of [PCl2N]6, and [PCl2N]8 are reported. Halogen-bonding interactions were observed in all the crystal structures of cyclic [PCl2N]m (m = 3-5, 6, 8). The crystal structures of [P(OPh)2N]7 and [P(OPh)2N]8, which are derivatives of the respective [PCl2N]m, are also reported. Comparisons of the intermolecular forces and torsion angles of [PCl2N]8 and [P(OPh)2N]8 with those of three other octameric rings are described. The comparisons show that chlorophosphazenes should not be considered prototypical, in terms of solid-state structure, because of the strong influence of halogen bonding.

Numerous pain-producing (pronociceptive) receptors signal via phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis. However, it is currently unknown which lipid kinases generate PIP2 in nociceptive dorsal root ganglia (DRG) neurons and if these kinases regulate pronociceptive receptor signaling. Here, we found that phosphatidylinositol 4-phosphate 5 kinase type 1C (PIP5K1C) is expressed at higher levels than any other PIP5K and, based on experiments with Pip5k1c(+/-) mice, generates at least half of all PIP2 in DRG neurons. Additionally, Pip5k1c haploinsufficiency reduces pronociceptive receptor signaling and TRPV1 sensitization in DRG neurons as well as thermal and mechanical hypersensitivity in mouse models of chronic pain. We identified a small molecule inhibitor of PIP5K1C (UNC3230) in a high-throughput screen. UNC3230 lowered PIP2 levels in DRG neurons and attenuated hypersensitivity when administered intrathecally or into the hindpaw. Our studies reveal that PIP5K1C regulates PIP2-dependent nociceptive signaling and suggest that PIP5K1C is a therapeutic target for chronic pain., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Elevated tissue levels of prostaglandin E2, produced by cyclooxygenase (COX), are an early event in colorectal cancer (CRC). Data suggest the efficacy of nonsteroidal anti-inflammatory drugs, such as cancer preventives, in the inhibition of COX activity; however, side effects of nonsteroidal anti-inflammatory pose unacceptable limitations. Ginger has been reported to have anti-inflammatory activities with significant CRC preventive potential. We investigated whether consumption of 2.0 g ginger daily regulated the level of two key enzymes that control prostaglandin E2 production, COX-1 and NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase (15-PGDH). Thirty participants at normal and 20 participants at increased risk for CRC were randomized and given 2.0 g/day ginger or placebo for 28 days. Flexible sigmoidoscopy was used to obtain colon biopsies at baseline and the end of the study. Tissue levels of COX-1 and 15-PGDH were assessed using western blotting. After ginger consumption, participants at increased risk for CRC had a significantly reduced colonic COX-1 protein level (23.8±41%) compared with the placebo group (18.9±52%; P=0.03). Protein levels of 15-PGDH in the colon were unchanged. In participants who were at normal risk for CRC, neither protein levels of COX-1 nor 15-PGDH in the colon were altered by ginger consumption. Ginger significantly lowered COX-1 protein expression in participants at increased risk for CRC but not in those at normal risk for CRC. Ginger did not alter 15-PGDH protein expression in either increased or normal-risk participants. Further investigation, in larger studies with a longer ginger intervention, is needed to examine the ability of ginger to impact tissue levels of prostaglandin.

The development of noninvasive imaging techniques using monoclonal antibodies (mAbs) is a quickly evolving field. Immuno-PET uses positron-emitting isotopes to track the localization of mAbs with excellent image quality. Procedures for labeling mAbs with (89)Zr or (124)I using good manufacturing procedures have been established, and therefore these radiopharmaceuticals are being investigated for clinical use. This short review will focus on immuno-PET with full mAbs using long-lived positron-emitting isotopes ((89)Zr and (124)I) over the past 5 y and discuss their progress into clinical use.

Background: A scale validated in one language is not automatically valid in another language or culture. The purpose of this study was to validate the English version of the UNESP-Botucatu multidimensional composite pain scale (MCPS) to assess postoperative pain in cats. The English version was developed using translation, back-translation, and review by individuals with expertise in feline pain management. In sequence, validity and reliability tests were performed., Results: Of the three domains identified by factor analysis, the internal consistency was excellent for 'pain expression' and 'psychomotor change' (0.86 and 0.87) but not for 'physiological variables' (0.28). Relevant changes in pain scores at clinically distinct time points (e.g., post-surgery, post-analgesic therapy), confirmed the construct validity and responsiveness (Wilcoxon test, p < 0.001). Favorable correlation with the IVAS scores (p < 0.001) and moderate to very good agreement between blinded observers and 'gold standard' evaluations, supported criterion validity. The cut-off point for rescue analgesia was > 7 (range 0-30 points) with 96.5% sensitivity and 99.5% specificity., Conclusions: The English version of the UNESP-Botucatu-MCPS is a valid, reliable and responsive instrument for assessing acute pain in cats undergoing ovariohysterectomy, when used by anesthesiologists or anesthesia technicians. The cut-off point for rescue analgesia provides an additional tool for guiding analgesic therapy.

The use of nebulizable, nanoparticle-based antimicrobial delivery systems can improve efficacy and reduce toxicity for treatment of multi-drug-resistant bacteria in the chronically infected lungs of cystic fibrosis patients. Nanoparticle vehicles are particularly useful for applying broad-spectrum silver-based antimicrobials, for instance, to improve the residence time of small-molecule silver carbene complexes (SCCs) within the lung. Therefore, we have synthesized multifunctional, shell cross-linked knedel-like polymeric nanoparticles (SCK NPs) and capitalized on the ability to independently load the shell and core with silver-based antimicrobial agents. We formulated three silver-loaded variants of SCK NPs: shell-loaded with silver cations, core-loaded with SCC10, and combined loading of shell silver cations and core SCC10. All three formulations provided a sustained delivery of silver over the course of at least 2-4 days. The two SCK NP formulations with SCC10 loaded in the core each exhibited excellent antimicrobial activity and efficacy in vivo in a mouse model of Pseudomonas aeruginosa pneumonia. SCK NPs with shell silver cation-load only, while efficacious in vitro, failed to demonstrate efficacy in vivo. However, a single dose of core SCC10-loaded SCK NPs (0.74 ± 0.16 mg Ag) provided a 28% survival advantage over sham treatment, and administration of two doses (0.88 mg Ag) improved survival to 60%. In contrast, a total of 14.5 mg of Ag(+) delivered over 5 doses at 12 h intervals was necessary to achieve a 60% survival advantage with a free-drug (SCC1) formulation. Thus, SCK NPs show promise for clinical impact by greatly reducing antimicrobial dosage and dosing frequency, which could minimize toxicity and improve patient adherence.

Degradable acetalated dextran (Ac-DEX) nanoparticles were prepared and loaded with a hydrophobic silver carbene complex (SCC) by a single-emulsion process. The resulting particles were characterized for morphology and size distribution using scanning electron microscopy (SEM), transmission electron microscopy (TEM), and dynamic light scattering (DLS). The average particle size and particle size distribution were found to be a function of the ratio of the organic phase to the surfactant containing aqueous phase with a 1:5 volume ratio of Ac-DEX CH(2)Cl(2) (organic):PBS (aqueous) being optimal for the formulation of nanoparticles with an average size of 100 ± 40 nm and a low polydispersity. The SCC loading was found to increase with an increase in the SCC quantity in the initial feed used during particle formulation up to 30% (w/w); however, the encapsulation efficiency was observed to be the best at a feed ratio of 20% (w/w). In vitro efficacy testing of the SCC loaded Ac-DEX nanoparticles demonstrated their activity against both Gram-negative and Gram-positive bacteria; the nanoparticles inhibited the growth of every bacterial species tested. As expected, a higher concentration of drug was required to inhibit bacterial growth when the drug was encapsulated within the nanoparticle formulations compared with the free drug illustrating the desired depot release. Compared with free drug, the Ac-DEX nanoparticles were much more readily suspended in an aqueous phase and subsequently aerosolized, thus providing an effective method of pulmonary drug delivery.

Silver N-heterocyclic carbene complexes have been shown to have great potential as antimicrobial agents, affecting a wide spectrum of both Gram-positive and Gram-negative bacteria. A new series of three silver carbene complexes (SCCs) based on 4,5,6,7-tetrachlorobenzimidazole has been synthesized, characterized, and tested against a panel of clinical strains of bacteria. The imidazolium salts and their precursors were characterized by elemental analysis, mass spectrometry, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. The silver carbene complexes, SCC32, SCC33, and SCC34 were characterized by elemental analysis, (1)H and (13)C NMR spectroscopy, and single crystal X-ray diffraction. These complexes proved highly efficacious with minimum inhibitory concentrations (MICs) ranging from 0.25 to 6 μg mL(-1). Overall, the complexes were effective against highly resistant bacteria strains, such as methicillin-resistant Staphylococcus aureus (MRSA), weaponizable bacteria, such as Yersinia pestis, and pathogens found within the lungs of cystic fibrosis patients, such as Pseudomonas aeruginosa, Alcaligenes xylosoxidans, and Burkholderia gladioli. SCC33 and SCC34 also showed clinically relevant activity against a silver-resistant strain of Escherichia coli based on MIC testing.

By using the substituent effect to tune the palladium(II)-involved reactivity, a new probe is found to respond quantitatively to Pd(II). Unexpectedly, the probe gave an emission band in the desirable near-infrared (NIR) region (780 nm), thus providing the first NIR sensor for palladium detection., (This journal is © The Royal Society of Chemistry 2012)

2-(2'-Hydroxyphenyl)benzoxazole (HBO) derivatives represent an important class of luminescent materials, as they can undergo excited state intramolecular proton transfer (ESIPT). The material's ESIPT properties are dependent on the ratio of two different rotamers, whose interconversion is poorly understood. By using HBO derivative 4, the rotational energy barrier of 2- (2',6'-hydroxyphenyl)benzoxazole is determined to be 10.5 kcal/mol by variable-temperature NMR. Although a HBO derivative typically exhibits two rotamers with O···H-O (e.g., 1a) and N···H-O bonding (e.g., 1b), correlation of NMR with fluorescence data reveals that the rotamer with N···H-O bonding is predominant in the solution.

Objectives: Silver carbenes may represent novel, broad-spectrum antimicrobial agents that have low toxicity while providing varying chemistry for targeted applications. Here, the bactericidal activity of four silver carbene complexes (SCCs) with different formulations, including nanoparticles (NPs) and micelles, was tested against a panel of clinical strains of bacteria and fungi that are the causative agents of many skin and soft tissue, respiratory, wound, blood, and nosocomial infections., Methods: MIC, MBC and multidose experiments were conducted against a broad range of bacteria and fungi. Time-release and cytotoxicity studies of the compounds were also carried out. Free SCCs and SCC NPs were tested against a panel of medically important pathogens, including methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant Acinetobacter baumannii (MRAB), Pseudomonas aeruginosa, Burkholderia cepacia and Klebsiella pneumoniae., Results: All four SCCs demonstrated strong efficacy in concentration ranges of 0.5-90 mg/L. Clinical bacterial isolates with high inherent resistance to purified compounds were more effectively treated either with an NP formulation of these compounds or by repeated dosing. Overall, the compounds were active against highly resistant bacterial strains, such as MRSA and MRAB, and were active against the biodefence pathogens Bacillus anthracis and Yersinia pestis. All of the medically important bacterial strains tested play a role in many different infectious diseases., Conclusions: The four SCCs described here, including their development as NP therapies, show great promise for treating a wide variety of bacterial and fungal pathogens that are not easily killed by routine antimicrobial agents.

Inhibitors of COX indicate that upregulation of inflammatory eicosanoids produced by COX, and in particular prostaglandin E(2) (PGE(2)), are early events in the development of colorectal cancer (CRC). Ginger has shown downregulation of COX in vitro and decreased incidence/multiplicity of adenomas in rats. This study was conducted to determine if 2.0 g/d of ginger could decrease the levels of PGE(2), 13-hydroxy-octadecadienoic acids, and 5-, 12-, and 15-hydroxyeicosatetraenoic acid (5-, 12-, and 15-HETE), in the colon mucosa of healthy volunteers. To investigate this aim, we randomized 30 subjects to 2.0 g/d ginger or placebo for 28 days. Flexible sigmoidoscopy at baseline and day 28 was used to obtain colon biopsies. A liquid chromatography mass spectrometry method was used to determine eicosanoid levels in the biopsies, and levels were expressed per protein or per free arachidonic acid. There were no significant differences in mean percent change between baseline and day 28 for any of the eicosanoids, when normalized to protein. There was a significant decrease in mean percent change in PGE(2) (P = 0.05) and 5-HETE (P = 0.04), and a trend toward significant decreases in 12-HETE (P = 0.09) and 15-HETE (P = 0.06) normalized to free arachidonic acid. There was no difference between the groups in terms of total adverse events P = 0.55). On the basis of these results, it seems that ginger has the potential to decrease eicosanoid levels, perhaps by inhibiting their synthesis from arachidonic acid. Ginger also seemed to be tolerable and safe. Further investigation in people at high risk for CRC seems warranted.

Background: Despite being the most commonly used herbal for sleep disorders, chamomile's (Matricaria recutita) efficacy and safety for treating chronic primary insomnia is unknown. We examined the preliminary efficacy and safety of chamomile for improving subjective sleep and daytime symptoms in patients with chronic insomnia., Methods: We performed a randomized, double-blind, placebo-controlled pilot trial in 34 patients aged 18-65 years with DSM-IV primary insomnia for ≥ 6-months. Patients were randomized to 270 mg of chamomile twice daily or placebo for 28-days. The primary outcomes were sleep diary measures. Secondary outcomes included daytime symptoms, safety assessments, and effect size of these measures., Results: There were no significant differences between groups in changes in sleep diary measures, including total sleep time (TST), sleep efficiency, sleep latency, wake after sleep onset (WASO), sleep quality, and number of awakenings. Chamomile did show modest advantage on daytime functioning, although these did not reach statistical significance. Effect sizes were generally small to moderate (Cohen's d ≤ 0.20 to < 0.60) with sleep latency, night time awakenings, and Fatigue Severity Scale (FSS), having moderate effect sizes in favor of chamomile. However, TST demonstrated a moderate effect size in favor of placebo. There were no differences in adverse events reported by the chamomile group compared to placebo., Conclusion: Chamomile could provide modest benefits of daytime functioning and mixed benefits on sleep diary measures relative to placebo in adults with chronic primary insomnia. However, further studies in select insomnia patients would be needed to investigate these conclusions.

Phosphazene polymers are classically synthesized by the high-temperature, ring-opening polymerization (ROP) of [PCl(2)N](3) to give [PCl(2)N](n), followed by functionalization of [PCl(2)N](n) with different side groups. We investigated the interactions of [PCl(2)N](3) with Lewis acids because Lewis acids have been used to induce the high-temperature ROP of [PCl(2)N](3). The reactions of [PCl(2)N](3) with MX(3) (M = group 13, X = halides), under strict anaerobic conditions gave adducts [PCl(2)N](3)·MX(3). Adducts were characterized by X-ray crystallography and multinuclear and variable-temperature NMR studies, and mechanistic understanding of their fluxional behavior in solution was achieved. The properties of the [PCl(2)N](3)·MX(3) adducts at or near room temperature strongly suggests that such adducts are not involved directly as intermediates in the high-temperature ROP of [PCl(2)N](3).

Objective: To describe the technique for performing a coccygeal epidural injection of local anesthetic to facilitate catheterization in male cats with urethral obstructions using low-dose sedation., Significance: Prompt diagnosis and relief of urethral obstructions is important as many cats may have developed marked metabolic abnormalities at the time of presentation. General anesthesia in these patients may be associated with significant risk for complications. Pain management is also an essential treatment goal, and this technique relieves urethral and penile pain during the unblocking process., Conclusion: Coccygeal epidurals can be used safely to provide analgesia to the penis and urethra and to the authors' knowledge, is a novel treatment modality to aid in the relief of urethral obstructions in male cats., (© Veterinary Emergency and Critical Care Society 2011.)

Due to the properties of silver as an antimicrobial, our research group has synthesized many different silver carbene complexes. Two new silver N-heterocyclic carbene complexes derived from 4,5-dichloroimidazole and theobromine bearing methyl benzoate substituents were synthesized by in situ carbene formation using silver acetate as the base in the reaction. The new compounds were fully characterized by several methods including NMR spectroscopy and X-ray crystallography. Preliminary antimicrobial efficacy studies against Pseudomonas aeruginosa, Staphylococcus aureus, and Escherichia coli were conducted. The results of this study demonstrated antimicrobial efficacy of the two complexes comparable to silver nitrate, showing their potential for use in the treatment of bacterial infections.

The increasing incidence of multidrug-resistant (MDR) pulmonary infections in the cystic fibrosis (CF) population has prompted the investigation of innovative silver based therapeutics. The functionalization of the naturally occurring xanthine theobromine at the N(1) nitrogen atom with an ethanol substituent followed by the methylation of the N(9) nitrogen atom gives the N-heterocyclic carbene precursor 1-(2-hydroxyethyl)-3,7,9-trimethylxanthinium iodide. The reaction of this xanthinium salt with silver acetate produces the highly hydrophilic silver carbene complex SCC8. The in vitro antimicrobial efficacy of this newly synthesized complex was evaluated with excellent results on a variety of virulent and MDR pathogens isolated from CF patients. A comparative in vivo study between the known caffeine derived silver carbene SCC1 and SCC8 demonstrated the ability of both complexes to improve the survival rates of mice in a pneumonia model utilizing the clinically isolated infectious strain of Pseudomonas aeruginosa PA M57-15.

An adult male prairie falcon (Falco mexicanus) was presented for evaluation and treatment of self-inflicted wounds along the right proximal patagium. The bird had started self-traumatizing approximately 1 month after fracturing the right metacarpus, although the fracture had stabilized, surface wounds had healed completely, and treatment with a nonsteroidal antiinflammatory drug had been administered. The bird was treated with gabapentin (11 mg/kg p.o. q12h), ketamine (0.5 mg/kg i.m. q24h), and low level laser therapy (LLLT) (<5 mW, 630-680 nm, 5-second application per site) for 3 weeks, but, despite initial improvement, new self-inflicted wounds appeared at the same site. Approximately 1.5 months later, a radial and medianoulnar nerve block was performed by using bupivacaine (2 mg/kg) and medetomidine (0.5 microg/kg). In addition, the dosing interval of ketamine was increased to q12h, and the dose of gabapentin was increased 7.5-fold. A higher energy and wavelength of LLLT (1040 mW, 830 nm, 2 J/cm2) was applied once to the injured region and fracture site, then the original LLLT protocol was applied once daily. After 2.5 months, the wounds healed completely and no further mutilation took place. Once deemed ready for release, the falcon was returned to the wild after 181 days in captivity. This is the first reported application of successful multimodal analgesia in a raptor with uncontrolled neuropathic pain.

Objective: To describe a case of spontaneous ventricular fibrillation in a dog in which biphasic defibrillation was life saving., Case Summary: Ventricular fibrillation occurred in a 7-year-old female Australian Heeler during recovery from anesthesia following pacemaker implantation. Resuscitative efforts including immediate delivery of transthoracic monophasic defibrillation shocks of escalating energy and administration of vasopressors were unsuccessful. However, a single biphasic shock restored sinus rhythm despite prolonged duration of the arrhythmia., New or Unique Information Provided: This case suggests greater efficacy of biphasic defibrillation compared with traditional monophasic defibrillation. In this dog the newer, biphasic technology was life saving after monophasic shocks failed repeatedly to terminate ventricular fibrillation.

A series of N-heterocyclic carbene silver complexes have been synthesized and tested against the select group of bio-safety level 3 bacteria Burkholderia pseudomallei, Burkholderia mallei, Bacillus anthracis, methicillin-resistant Staphylococcus aureus and Yersinia pestis. Minimal inhibitory concentrations, minimal bactericidal and killing assays demonstrated the exceptional efficacy of the complexes against these potentially weaponizable pathogens.

A new survey shows scientists consider the proliferation of intellectual property protection to have a strongly negative effect on research.