bluuebunny/crossref_metadata_2025 huggingface dataset:
Design of Modular G‐quadruplex Ligands
Authors: Duarte Ana Rita , Cadoni Enrico , Ressurreição Ana S. , Moreira Rui , Paulo Alexandra
Published: March 2018

Guanine‐rich nucleic acid sequences able to form four‐stranded structures (G‐quadruplexes, G4) play key cellular regulatory roles and are considered as promising drug targets for anticancer therapy. On the basis of the organization of their structural elements, G4 ligands can be divided into three major families: one, fused heteroaromatic polycyclic systems; two, macrocycles; three, modular aromatic compounds. The design of modular G4 ligands emerged as the answer to achieve not only more drug‐like compounds but also more selective ligands by targeting the diversity of the G4 loops and grooves. The rationale behind the design of a very comprehensive set of ligands, with particular focus on the structural features required for binding to G4, is discussed and combined with the corresponding biochemical/biological data to highlight key structure–G4 interaction relationships. Analysis of the data suggests that the shape of the ligand is the major factor behind the G4 stabilizing effect of the ligands. The information here critically reviewed will certainly contribute to the development of new and better G4 ligands with application either as therapeutics or probes.
Supramolecular Assembly of Thiolated Cyclodextrin and Ferrocene Derivative for Controlled Drug Delivery
Authors: Cheng Jian‐Guang , Zhang Ying‐Ming , Liu Yu
Published: March 2018

Construction of biocompatible nanoparticles is a significant topic of research at the chemistry/biology interface. Presently, more and more researchers have focused on supramolecular amphiphiles constructed by macrocycle‐induced aggregation, a feasible and universal strategy in the fabrication of functional nanomaterials. In this work, we report a pH‐responsive nanoparticle through a noncovalent complexation between per‐6‐thiolated β‐cyclodextrin sodium salt (SACD) and amphiphilic ferrocene derivative (FC12+Br−) in water. The formation and composition of the obtained supramolecular nanoparticles were comprehensively characterized by UV/Vis absorption, dynamic laser scattering, and microscopic observations. Furthermore, the drug loading and release studies demonstrated that the supramolecular binary nanoparticles could efficiently encapsulate doxorubicin hydrochloride (DOX) in their nanoparticulate cores, and the entrapped DOX could be rapidly released in a low pH environment. The present study suggests that the obtained binary supramolecular amphiphiles with good stability, tunable assembling/disassembling behaviors, and controlled drug loading/release properties have great potential in the construction of on‐demand drug‐delivery systems.
How do Independent Directors Behave with Respect to Sustainability Disclosure?
Authors: García‐Sánchez Isabel‐María , Martínez‐Ferrero Jennifer
Published: March 2018

This paper examines how independent directors behave with respect to sustainability disclosure, attending to its comparability, utility, and reliability, and the moderating effect of the level of socially responsible performance. A large sample of international companies from the period 2006–2014 was used to develop our models of analysis. This research evidences that independent directors show an initial opposition to this voluntary disclosure policy unless there is a higher sustainable development and performance. Several disclosure aspects are examined where, first, utility and comparability of sustainability disclosure are fomented by independent directors only under a greater social and environmental performance. Second, this performance reinforces the positive orientation of independents towards the external assurance of social and environmental disclosure. Thus, the initial opposition of independent directors towards a sustainability disclosure is avoided if there is a greater responsible performance that reduces their reputation risks associated with potentially misleading information. Copyright © 2018 John Wiley & Sons, Ltd and ERP Environment
Selective Hydrodeoxygenation of Vegetable Oils and Waste Cooking Oils to Green Diesel Using a Silica‐Supported Ir–ReOx Bimetallic Catalyst
Authors: Liu Sibao , Simonetti Trent , Zheng Weiqing , Saha Basudeb
Published: March 2018

High yields of diesel‐range alkanes are prepared by hydrodeoxygenation of vegetable oils and waste cooking oils over ReOx‐modified Ir/SiO2 catalysts under mild reaction conditions. The catalyst containing a Re/Ir molar ratio of 3 exhibits the best performance, achieving 79–85 wt % yield of diesel‐range alkanes at 453 K and 2 MPa H2. The yield is nearly quantitative for the theoretical possible long‐chain alkanes on the basis of weight of the converted oils. The catalyst retains comparable activity upon regeneration through calcination. Control experiments using probe molecules as model substrates suggest that C=C bonds of unsaturated triglycerides and free fatty acids are first hydrogenated to their corresponding saturated intermediates, which are then converted to aldehyde intermediates through hydrogenolysis of acyl C−O bonds and subsequently hydrogenated to fatty alcohols. Finally, long‐chain alkanes without any carbon loss are formed by direct hydrogenolysis of the fatty alcohols. Small amounts of alkanes with one carbon fewer are also formed by decarbonylation of the aldehyde intermediates. A synergy between Ir and partially reduced ReOx sites is discussed to elucidate the high activity of Ir–ReOx/SiO2.
Tailored β‐Ketoiminato Complexes of Iron: Synthesis, Characterization, and Evaluation towards Solution‐Based Deposition of Iron Oxide Thin Films
Authors: Sadlo Alexander , Beer Sebastian M. J. , Rahman Shafiqur , Grafen Markus , Rogalla Detlef , Winter Manuela , Ostendorf Andreas , Devi Anjana
Published: March 2018

The synthesis and characterization of five new and closely related homoleptic iron(II) β‐ketoiminate complexes is reported. Molecular structures of compounds 1, 2, and 5 were determined by single‐crystal XRD, which revealed monomeric four‐ and sixfold coordination, depending on the functionalized side chain. The stepwise elimination of the ligand from the complex observed by thermogravimetric analysis and the stability in solution are encouraging features for solution‐based processing of hematite thin films. As a representative example, compound 1 was successfully employed in a straightforward spin‐coating process. The fabricated iron oxide films were characterized in terms of their structure and phase by XRD and Raman spectroscopy, morphology by SEM, and composition by Rutherford backscattering spectrometry accompanied by nuclear reaction analysis, which revealed the formation of crystalline and stoichiometric α‐Fe2O3 films.
Exploring the Corundum Structure as a Host for Colored Compounds – Synthesis, Structures, and Optical Studies of (MM′)3TeO6 (M = Mg, Mn, Co, Ni, Zn; M′ = Mg, Mn, Co, Ni, Cu)
Authors: Bhim Anupam , Gopalakrishnan Jagannatha , Natarajan Srinivasan
Published: March 2018

We describe the syntheses, crystal structures, and optical absorption studies of the transition‐metal‐substituted corundum‐related oxides (MM′)3TeO6 (M = Mg, Mn, Co, Ni, Zn; M′ = Mg, Mn, Co, Ni, Cu). The oxides are readily synthesized by the solid‐state reactions of stoichiometric mixtures of the constituent binaries at 750–860 °C. The Rietveld refinements of the crystal structures from the powder X‐ray diffraction (XRD) data show that the Mg/Mn/Ni/Co/ZnO6 octahedra are distorted. We have interpreted the unique colors and the optical absorption spectra of these materials in terms of the distorted coordination geometries of the Mg/Mn/Ni/Co/ZnO6 chromophores. We have also identified the role that metal‐to‐metal charge transfer (MMCT) from the partially filled transition‐metal 3d orbitals to the empty Mo 4d orbitals plays in the color changes. We believe that the study of these transition‐metal substituted corundum oxides suggests directions for the development of colored inorganic materials featuring distorted octahedra around the 3d transition‐metal ions, as they may be useful as pigments.
A Practical Synthesis of Valuable Strained Eight‐Membered‐Ring Derivatives for Click Chemistry
Authors: Bernard Sabrina , Kumar Ramar Arun , Porte Karine , Thuéry Pierre , Taran Frédéric , Audisio Davide
Published: March 2018

A convenient and cost‐effective synthetic access to cyclooctyne and trans‐cyclooctene derivatives is described. A cyclopropanation step using copper powder in place of Rh2(OAc)4 as catalyst and a symmetric diazomalonate resulted in a drastic decrease in the overall cost of the synthesis. Further derivatizations allowed us to characterize, for the first time, the structure of a BCN analogue by X‐ray crystallography, and to obtain a library of derivatives that could potentially be useful for applications in metal‐free click chemistry.
Thermal effect on surrounding combustibles in minivan passenger car fires
Authors: Okamoto Katsuhiro , Ichikawa Toshikazu , Shimizu Kensuke , Honma Masakatsu
Published: March 2018

In the fire safety design of parking lots and buildings, estimating the possibility of fire spreading to surrounding combustibles, such as neighboring buildings and cars, is essential. The ignition possibility to surrounding combustibles can be predicted from the heat flux from a burning car to the combustibles. In this study, we conducted 2 full‐scale car fire experiments using minivan passenger cars and measured the heat fluxes to their surroundings. The cars were ignited at the rear bumper with 80 g of alcohol gel fuel. The windows were closed. Heat flux gauges were placed around the car to measure the heat flux in various directions. Cedar boards were placed next to the gauges, and burn damage to the boards was observed. When the windows shattered in succession, combustion in the passenger compartment became larger. At a distance of 50 cm from the burning car, the heat flux was greater than 40 kW/m2, and most of the cedar boards were completely burned. At a distance of 1 m, the heat flux was 10 to 20 kW/m2, and some of the cedar boards were burned. We devised a method for modeling the shape and temperature of flames in the burning cars. Furthermore, we propose a method for calculating heat fluxes in the lateral direction of the burning minivan passenger car, and we compared the calculated and measured heat fluxes as a means of verifying the proposed method. The shape of flame in the burning car was approximated as a rectangular prism to calculate the heat flux. The calculation results were in good agreement with the experimental results. The proposed method is expected to be useful for fire safety engineering.
Evaluation of the implementation of the Meeting Centres Support Program in Italy, Poland, and the UK; exploration of the effects on people with dementia
Authors: Brooker Dawn , Evans Simon , Evans Shirley , Bray Jennifer , Saibene Francesca Lea , Scorolli Claudia , Szcześniak Dorota , d'Arma Alessia , Urbańska Katarzyna M. , Atkinson Teresa , Farina Elisabetta , Rymaszewska Joanna , Chattat Rabih , Henderson Catherine , Rehill Amritpal , Hendriks Iris , Meiland Franka , Dröes Rose‐Marie
Published: March 2018

Objectives

MEETINGDEM investigated whether the Dutch Meeting Centres Support Programme (MCSP) could be implemented in Italy, Poland, and the UK with comparable benefits. This paper reports on the impact on people living with dementia attending pilot Meeting Centres in the 3 countries.

Methods

Nine pilot Meeting Centres (MCs) participated (Italy—5, Poland—2, UK—2). Effectiveness of MCSP was compared with Usual Care (UC) on outcomes measuring behavioural and psychological symptoms (NPI), depression (CSDD), and quality of life (DQoL, QOL‐AD), analysed by ANCOVAs in a 6‐month pre‐test/post‐test controlled trial.

Results

Pre/post data were collected for 85 people with dementia and 93 carers (MCSP) and 74 people with dementia /carer dyads' receiving UC. MCSP showed significant positive effects for DQoL [Self‐esteem (F = 4.8, P = 0.03); Positive Affect (F = 14.93, P < 0.00); Feelings of Belonging (F = 7.77, P = 0.01)] with medium and large effect sizes. Higher attendance levels correlated with greater neuropsychiatric symptom reduction (rho = 0.24, P = 0.03) and a greater increase in feelings of support (rho = 0.36, P = 0.001).

Conclusions

MCSPs showed significant wellbeing and health benefits compared with UC, building on the evidence of effectiveness from the Netherlands. In addition to the previously reported successful implementation of MCSP in Italy, Poland, and the UK, these findings suggest that further international dissemination of MCSP is recommended.
Relationships between socio‐clinico‐demographic factors and global cognitive function in the oldest old living in the Tokyo Metropolitan area: Reanalysis of the Tokyo Oldest Old Survey on Total Health (TOOTH)
Authors: Eguchi Yoko , Tasato Kumiko , Nakajima Shinichiro , Noda Yoshihiro , Tsugawa Sakiko , Shinagawa Shunichiro , Niimura Hidehito , Hirose Nobuyoshi , Arai Yasumichi , Mimura Masaru
Published: March 2018

Background

Despite a steady increase in life expectancy, a few studies have investigated cross‐sectional correlates and longitudinal predictors of cognitive function, a core domain of the successful aging, among socio‐clinico‐demographic factors in the oldest‐old exclusively.

Objectives

The aims of this study were to examine socio‐clinico‐demographic characteristics associated with global cognition and its changes in the oldest‐old.

Methods

We reanalyzed a dataset of cognitively preserved community‐dwelling subjects aged 85 years and older in the Tokyo Oldest Old Survey on Total Health, a 6‐year longitudinal observational study. This study consisted of (1) baseline cross‐sectional analyses examining correlates of global cognition (n = 248) among socio‐clinico‐demographic factors and (2) longitudinal analyses examining baseline predictors for changes of global cognition in 3‐year follow‐up (n = 195). The Mini‐Mental State Examination was used as a screening test to assess global cognition.

Results

At baseline, higher weights were related to higher cognitive function in the oldest‐old. The baseline predictors of global cognitive decline in 3‐year follow‐up were higher global cognition, shorter education period, and lower sociocultural activities and lower instrumental activity of daily living, in this order.

Conclusions

The present study suggests that it is crucial to attain higher education during early life and avoid leanness or obesity, participate in sociocultural cognitive activities during late life, and maintain instrumental activity of daily living to preserve optimal cognitive function in the oldest‐old, which will facilitate developing prevention strategies for cognitive decline and promoting successful aging in this increasing population.
Prolonged cenicriviroc therapy reduces hepatic fibrosis despite steatohepatitis in a diet‐induced mouse model of nonalcoholic steatohepatitis
Authors: Kruger Annie J. , Fuchs Bryan C. , Masia Ricard , Holmes Jacinta A. , Salloum Shadi , Sojoodi Mozhdeh , Ferreira Diego S. , Rutledge Stephanie M. , Caravan Peter , Alatrakchi Nadia , Vig Pam , Lefebvre Eric , Chung Raymond T.
Published: March 2018

Nonalcoholic steatohepatitis (NASH) is a progressive liver disease projected to become the leading cause of cirrhosis and liver transplantation in the next decade. Cenicriviroc (CVC), a dual chemokine receptor 2 and 5 antagonist, prevents macrophage trafficking and is under clinical investigation for the treatment of human NASH fibrosis. We assessed the efficacy and durability of short and prolonged CVC therapy in a diet‐induced mouse model of NASH, the choline deficient, L‐amino acid‐defined, high‐fat diet (CDAHFD) model. C57BL/6 mice received 4 or 14 weeks of standard chow or the CDAHFD. CVC (10 mg/kg/day and 30 mg/kg/day for 4 weeks and 20 mg/kg/day and 30 mg/kg/day for 14 weeks) was initiated simultaneously with the CDAHFD. At 4 and 14 weeks, livers were harvested for histology and flow cytometric analyses of intrahepatic immune cells. High‐dose CVC (30 mg/kg/day) therapy in CDAHFD mice for 4 or 14 weeks inhibited intrahepatic accumulation of Ly6Chigh bone marrow‐derived macrophages. Prolonged CVC therapy (14 weeks) yielded no significant differences in the total intrahepatic macrophage populations among treatment groups but increased the frequency of intrahepatic anti‐inflammatory macrophages in the high‐dose CVC group. Despite ongoing steatohepatitis, there was significantly less fibrosis in CDAHFD mice receiving high‐dose CVC for 14 weeks based on histologic and molecular markers, mirroring observations in human NASH CVC trials. CVC also directly inhibited the profibrotic gene signature of transforming growth factor‐β‐stimulated primary mouse hepatic stellate cells in vitro. Conclusion: CVC is a novel therapeutic agent that is associated with reduced fibrosis despite ongoing steatohepatitis. Its ability to alter intrahepatic macrophage populations and inhibit profibrogenic genes in hepatic stellate cells in NASH livers may contribute to its observed antifibrotic effect. (Hepatology Communications 2018;2:529‐545)
Atypical chronic myeloid leukaemia: A case of an orphan disease—A multicenter report by the Polish Adult Leukemia Group
Authors: Drozd‐Sokołowska Joanna , Mądry Krzysztof , Waszczuk‐Gajda Anna , Biecek Przemysław , Szwedyk Paweł , Budziszewska Katarzyna , Raźny Magdalena , Dutka Magdalena , Obara Agata , Wasilewska Ewa , Lewandowski Krzysztof , Piekarska Agnieszka , Bober Grażyna , Krzemień Helena , Stella‐Hołowiecka Beata , Kapelko‐Słowik Katarzyna , Sawicki Waldemar , Paszkowska‐Kowalewska Małgorzata , Machowicz Rafał , Dwilewicz‐Trojaczek Jadwiga
Published: March 2018

Atypical chronic myeloid leukaemia (aCML) belongs to myelodysplastic/myeloproliferative neoplasms. Because of its rarity and changing diagnostic criteria throughout subsequent classifications, data on aCML are very scarce. Therefore, we at the Polish Adult Leukemia Group performed a nationwide survey on aCML. Eleven biggest Polish centres participated in the study. Altogether, 45 patients were reported, among whom only 18 patients (40%) fulfilled diagnostic criteria. Among misdiagnosed patients, myelodysplastic/myeloproliferative syndrome unclassifiable and chronic myelomonocytic leukaemia were the most frequent diagnoses. Thirteen patients were male, median age 64.6 years (range 40.4‐80.9). The median parameters at diagnosis were as follows: white blood cell count 97 × 109/L (23.8‐342) with immature progenitors amounting at 27.5% (12‐72), haemoglobin 8.6 g/dL (3.9‐14.9), and platelet count 66 × 109/L (34‐833). Cytoreductive treatment was used in all patients, and 2 patients underwent allogeneic hematopoietic stem cell transplantation. The median overall survival was 14.1 months (95% CI, 7.2), with median acute myeloid leukaemia‐free survival of 13.3 months (95% CI, 3.6‐22.6). Cumulative incidence of acute myeloid leukaemia transformation after 1 year in aCML group was 12.5% (95% CI, 0%‐29.6%). To conclude, aCML harbours a poor prognosis. Treatment options are limited, with allogeneic hematopoietic stem cell transplantation being the only curative method at present, although only a minority of patients are transplant eligible. Educational measures are needed to improve the quality of diagnoses.
Further evaluation of differential exposure to establishing operations during functional communication training
Authors: Fisher Wayne W. , Greer Brian D. , Mitteer Daniel R. , Fuhrman Ashley M. , Romani Patrick W. , Zangrillo Amanda N.
Published: March 2018

Recent research findings (DeRosa, Fisher, & Steege, ) suggest that minimizing exposure to the establishing operation (EO) for destructive behavior when differential reinforcement interventions like functional communication training (FCT) are introduced may produce more immediate reductions in destructive behavior and prevent or mitigate extinction bursts. We directly tested this hypothesis by introducing FCT with extinction in two conditions, one with limited exposure to the EO (limited EO) and one with more extended exposure to the EO (extended EO) using a combined reversal and multielement design. Results showed that the limited‐EO condition rapidly reduced destructive behavior to low levels during every application, whereas the extended‐EO condition produced an extinction burst in five of six applications. We discuss these findings in relation to the effects of EO exposure on the beneficial and untoward effects of differential reinforcement interventions.
Aluminium foil as an alternative substrate for the spectroscopic interrogation of endometrial cancer
Authors: Paraskevaidi Maria , Morais Camilo L.M. , Raglan Olivia , Lima Kássio M.G. , Paraskevaidis Evangelos , Martin‐Hirsch Pierre L. , Kyrgiou Maria , Martin Francis L.
Published: March 2018

Biospectroscopy has the potential to investigate and characterize biological samples and could, therefore, be utilized to diagnose various diseases in a clinical environment. An important consideration in spectrochemical studies is the cost‐effectiveness of the substrate used to support the sample, as high expense would limit their translation into clinic. In this paper, the performance of low‐cost aluminium (Al) foil substrates was compared with the commonly used low‐emissivity (low‐E) slides. Attenuated total reflection‐Fourier transform infrared spectroscopy was used to analyse blood plasma and serum samples from women with endometrial cancer and healthy controls. The 2 populations were differentiated using principal component analysis with support vector machines with 100% sensitivity in plasma samples (endometrial cancer = 70; healthy controls = 15) using both Al foil and low‐E slides as substrates. The same sensitivity results (100%) were achieved for serum samples (endometrial cancer = 60; healthy controls = 15). Specificity was found higher using Al foil (90%) in comparison to low‐E slides (85%) and lower using Al foil (70%) in comparison to low‐E slides in serum samples. The establishment of Al foil as low‐cost and highly performing substrate would pave the way for large‐scale, multicentre studies and potentially for routine clinical use.

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Synthesis and characterization of four novel palladium(II) and platinum(II) complexes with 1‐(2‐aminoethyl)pyrrolidine, diclofenac and mefenamic acid: In vitro effect of these complexes on human serum paraoxanase1 activity
Authors: Dilek Esra , Caglar Sema , Erdogan Kübra , Caglar Bülent , Sahin Onur
Published: March 2018

In this study, the effects of four novel mononuclear palladium(II) and platinum(II) complexes on the activity of human serum paraoxanase1 were examined. First, four novel mononuclear palladium(II) and platinum(II) complexes were synthesized with a nitrogen donor ligand 1‐(2‐aminoethyl)pyrrolidine and nonsteroidal anti‐inflammatory drugs diclofenac, mefenamic acid. These complexes were characterized by spectroscopic, thermal, and elemental analyses. The crystal structures of complex [Pd(2‐amepyr)2](dicl)2 1 and [Pd(2‐amepyr)2](mef)2 3 were determined by X‐ray crystallography. Then, paraoxonase1 enzyme was purified from human serum. The effects of these complexes on enzyme were evaluated in vitro. The complexes consist of the cationic unit and the counterions. The diclofenac and mefenamic acid acted as a counterion in the complexes. It was observed that all the complexes were stable up to high temperatures. These complexes, even at low doses, inhibited the activity of the enzyme with different inhibition mechanisms.
Ventricular arrhythmias in patients with Takotsubo syndrome
Authors: Möller Christian , Eitel Charlotte , Thiele Holger , Eitel Ingo , Stiermaier Thomas
Published: March 2018

Takotsubo syndrome (TTS) is a unique nonischemic cardiac disease characterized by acute myocardial dysfunction of the left and/or right ventricle. Patients are predominantly postmenopausal women and usually present with symptoms indistinguishable from acute coronary syndrome. Although the exact pathomechanisms of TTS remain elusive, increasing evidence suggests that sympathetic overdrive and catecholamine excess might play a central role. Despite the complete recovery of ventricular dysfunction within several days to weeks, patients with TTS exhibit considerable short‐ and long‐term mortality rates and ventricular arrhythmias have been identified as key contributor to morbidity and mortality. This article summarizes the prevalence, underlying mechanisms, therapeutic strategies, and prognostic implications of ventricular arrhythmias in TTS. Furthermore, the need for implantable cardioverter‐defibrillators is discussed in view of the transient character of the disease.
Long‐term area‐mean temperature series for Switzerland—Combining homogenized station data and high resolution grid data
Authors: Begert Michael , Frei Christoph
Published: March 2018

In this study, we derive new time‐series of monthly‐mean surface air temperature for Switzerland that range back to 1864 and represent area‐mean conditions over the country and three major sub‐regions. The methodology integrates data from a small sample (19 stations) of homogenized long‐term series and from a high‐resolution (2 km) grid dataset over a short (20 years) period. The statistical combination defines an objective weighting of station data that delivers reliable and time‐consistent area‐mean estimates, despite coarse and biased coverage with stations in early years. The methodology also quantifies the uncertainty of the estimates. Validation of the method reveals plausible patterns of station weights, and estimation errors of about 0.1 °C, much smaller than inter‐annual variations. The new series suggest a warming in Switzerland of almost 1.5 °C from the early‐industrial period (1864–1900) till the latest WMO standard period (1981–2010), with a linear trend of 1.29 °C per 100 years between 1864 and 2016. The warming is found to be larger in autumn than in other seasons, larger to the north of the Alps than to the south, and larger below (above) 1000 m asl in winter (summer). In all series, the warming is modulated by inter‐decadal variations. Current global temperature datasets exhibit less warming for Switzerland than the present analysis. The pattern of disagreement suggests that a network‐wide change in Swiss temperature measurements around 1980 may have been missed in the homogeneity adjustments at global data archives. It is desirable that these archives are better aligned with the latest quality processing of the original data owners.
Pembrolizumab‐induced auto‐immune type‐1 diabetes in a patient with metastatic melanoma
Authors: Reslan Zainab , Bennett Michael , Wong Eugene , Jacques Sarah , Lee Adrian
Published: March 2018

Background

Immunotherapy for metastatic melanoma has improved response rates and progression‐free survival significantly compared to traditional chemotherapy. However, our understanding of their unique side‐effect profile remains limited given the novelty of these treatments. Unlike traditional cytotoxic chemotherapy, immunotherapy is often associated with autoimmune‐related toxicities, including colitis, thyroiditis, pneumonitis or hepatitis. However, autoimmune endocrinopathies are much less well described. These experiences are concerning as the use of these agents is becoming more widespread in other cancer subtypes and they require very different approaches in regard to toxicity management. We report a case of pembrolizumab‐induced auto‐immune diabetes and hepatitis in a patient undergoing treatment for metastatic melanoma.

Clinical details

A 79‐year‐old Caucasian man was referred by his general practitioner to the emergency department with hyperglycaemia and elevated liver function tests on a background of recurrent metastatic melanoma on pembrolizumab treatment. The patient had a long history of hypertension but no other significant past medical history. The patient did not have a personal or family history of diabetes or autoimmune disease.

Outcomes

The patient was treated with a basal‐bolus insulin regimen for his new‐onset diabetes and a reducing dose of prednisolone for hepatitis.

Conclusion

New emerging immunotherapy treatments are changing the outcomes of patients with metastatic melanoma; however, their side effect profile differs from traditional chemotherapeutic agents and has not been fully explored. Healthcare professionals and patients should be aware that autoimmune side effects, such as diabetes and hepatitis, do occur in the context of these new treatments.
A qualitative exploration of healthcare providers’ perspectives on patients’ non‐recreational, prescription medicines sharing behaviours
Authors: Beyene Kebede A. , Aspden Trudi J. , Sheridan Janie L.
Published: March 2018

Background

Prescription medicine sharing has been associated with several negative health outcomes. Much of the research has focused on patient perspectives. In this study we explore the views and experiences of health professionals involved in medicines supply.

Aim

To explore healthcare providers’ experiences of, and attitudes toward, factors influencing non‐recreational, prescription medicine‐sharing behaviours, the consequences of sharing, and the types of prescription medicines they believe patients commonly share.

Methods

Face‐to‐face, semi‐structured interviews were conducted with purposively sampled pharmacists (n = 8), doctors (n = 4) and nurses (n = 6) practising in a variety of community or hospital settings in Auckland, New Zealand. The interviews were audio recorded, transcribed verbatim and analysed using a general inductive approach.

Results

Responses fell within three overarching themes: ‘perceived benefits of medicine sharing’ such as saving time and money, and strengthening social relationships; ‘perceived negative consequences of sharing’ such as drug resistance, adverse drug events, delay in seeking professional help, and loss of medicine instructions; ‘reasons for medicine sharing’ such as inadequate medication knowledge, forgetfulness, altruistic reasons, lack of access to health services or medicines, illness denial and embarrassment, and cultural and linguistic barriers.

Conclusions

Prescription medicine sharing, as viewed by healthcare providers, is a multidimensional behaviour with both positive and negative outcomes. Any intervention to reduce the risks/harms of medicine sharing should consider both the healthcare system constraints and the psychosocial, cultural, economic and behavioural aspects of medicine use. The findings can be used to inform development of specific interventions to reduce risks/harms of sharing.
Aftermath of Terror: A Nationwide Longitudinal Study of Posttraumatic Stress and Worry Across the Decade Following the September 11, 2001 Terrorist Attacks
Authors: Garfin Dana Rose , Poulin Michael J. , Blum Scott , Silver Roxane Cohen
Published: March 2018

Research conducted in the early years after the September 11, 2001 (9/11) terrorist attacks in New York, Pennsylvania, and Washington, DC demonstrated adverse psychological outcomes among residents of the United States who were exposed to the attacks both directly and indirectly via the media. However, less is known about the impact of this collective trauma over time. Beginning at the end of December 2006, a longitudinal study of a nationally representative sample of U.S. residents (Cohort 2, N = 1,613) examined the long‐term effects of 9/11, with annual assessments administered every year for 3 years. We assessed rates of 9/11‐related posttraumatic stress (PTS) annually during the first 2 years of the study; during the second and third years of the study, we assessed fear and worry regarding future terrorism. Rates of PTS among participants were compared with those assessed annually in a nationally representative sample between 2002 and 2004 (Cohort 1); results indicated a relatively stable pattern of 9/11‐related PTS symptoms for 6 years following the attacks. Five to six years after 9/11, we found an association between 9/11‐related PTS and both direct, B = 8.45, 95% CI [4.32, 12.59] and media‐based (live television), B = 1.78, 95% CI [0.90, 2.65] exposure to the attacks. Six to 7 years post‐9/11, fear and worry regarding future terrorism were predicted by 9/11‐related PTS symptoms that had been reported approximately 5 years after the attacks, B = 0.04, 95% CI [0.03, 0.05]. The psychological legacy of 9/11 was perceptible among many U.S. residents throughout the decade that followed.
Facial sinus endoscopic evaluation, radiologic assessment, and classification
Authors: Alicandri‐Ciufelli Matteo , Fermi Matteo , Bonali Marco , Presutti Livio , Marchioni Daniele , Todeschini Alessandra , Anschuetz Lukas
Published: March 2018

Objectives

To describe facial sinus anatomy from an endoscopic perspective and present a radiologic classification.

Methods

Facial sinus was studied by endoscopy and high‐resolution computed tomography (HRCT) scan in 39 temporal bones that underwent exclusive transcanal endoscopic approach. A radiomorphologic classification based on the relationship between the facial sinus and the mastoid portion of the facial nerve is created as follows. In type A facial sinus, the pneumatization of the facial sinus did not extend medially or posteriorly to the mastoid portion of the facial nerve. In type B facial sinus, the pneumatization extended posteriorly to the mastoid portion of the facial nerve. In type C facial sinus, the pneumatization extended posteriorly and medially to the mastoid portion of the facial nerve.

Results

In all the specimens that underwent HRCT (n = 31), facial sinus could be identified, and its depth classified, in relation to the facial nerve. In this group, 58% type A, 29% type B, and 13% type C facial sinuses were identified. In all the specimens (n = 39), the facial sinus could be assessed by means of an exclusive endoscopic transcanal approach, and anatomical variants of the chordiculus, previously known as chordal ridge, could be described: ridge (39%), bridge (18%), incomplete (15%), and absent (28%).

Conclusion

Endoscopic exploration of the retrotympanum guarantees a very good exposure of the facial sinus, allowing detailed anatomic descriptions of its conformation and relationships with other structures. Improvement in our knowledge of its anatomy might decrease the possibility of residual disease during cholesteatoma surgery. Angled endoscopes (e.g. 45 °, 70 °) can guarantee a better view of the facial sinus.

Level of Evidence

NA. Laryngoscope, 128:2397–2402, 2018
Dentinogenesis imperfecta type II‐ genotype and phenotype analyses in three Danish families
Authors: Taleb Kawther , Lauridsen Eva , Daugaard‐Jensen Jette , Nieminen Pekka , Kreiborg Sven
Published: March 2018

Background

Dentinogenesis imperfecta (DI) is a rare debilitating hereditary disorder affecting dentin formation and causing loss of the overlying enamel. Clinically, DI sufferers have a discolored and weakened dentition with an increased risk of fracture.

The aims of this study were to assess genotype‐phenotype findings in three families with DI–II with special reference to mutations in the DSPP gene and clinical, histological, and imaging manifestations.

Methods

Nine patients participated in the study (two from family A, four from family B, and three from family C). Buccal swab samples were collected from all participants and extracted for genomic DNA. Clinical and radiographic examinations had been performed longitudinally, and the dental status was documented using photographic images. Four extracted and decalcified tooth samples were prepared for histological analysis to assess dysplastic manifestations in the dentin. Optical coherence tomography (OCT) was applied to study the health of enamel tissue from in vivo images and the effect of the mutation on the function and structure of the DSPP gene was analyzed using bioinformatics software programs.

Results

The direct DNA sequence analysis revealed three distinct mutations, one of which was a novel finding. The mutations caused dominant phenotypes presumably by interference with signal peptide processing and protein secretion. The clinical and radiographic disturbances in the permanent dentition indicated interfamilial variability in DI–II manifestations, however, no significant intrafamilial variability was observed.

Conclusion

The different mutations in the DSPP gene were accompanied by distinct phenotypes. Enamel defects suggested deficit in preameloblast function during the early stages of amelogenesis.
Boundary‐value problems for the third‐order loaded equation with noncharacteristic type‐change boundaries
Authors: Baltaeva Umida , Agarwal Praveen
Published: March 2018

The purpose of this paper is to establish unique solvability for a certain generalized boundary‐value problem for a loaded third‐order integro‐differential equation with variable coefficients. Moreover, the method of integral equations is applied to obtain an equation related to the Riemann‐Liouville operators.
Parent pain catastrophizing predicts child depressive symptoms in youth with sickle cell disease
Authors: Goldstein‐Leever Alana , Cohen Lindsey L. , Dampier Carlton , Sil Soumitri
Published: March 2018

Background

Youth with sickle cell disease (SCD) are at risk for recurrent pain and depressive symptoms, both of which contribute to poorer health outcomes. Furthermore, youth and family coping with child pain, including pain catastrophizing, is known to be associated with poorer psychosocial adjustment and greater functional disability among youth with SCD. In particular, child catastrophizing about pain and parent catastrophizing about their child's pain have been linked to increased pain and depressive symptoms in youth with chronic pain conditions. Despite this, the impact of child and parent pain catastrophizing on depressive symptoms remains unexplored in pediatric SCD.

Procedure

The current study evaluated the predictive value of child and parent pain catastrophizing on child depressive symptoms in a sample of 100 youth with SCD. Differences in child and parent pain catastrophizing across youth with and without clinically elevated depressive symptoms were also examined.

Results

Pain frequency and parent and child pain catastrophizing accounted for 35.9% of variance in child depressive symptoms, with only pain frequency and parent pain catastrophizing emerging as unique predictors of clinically elevated depressive symptoms. Additionally, parents of youth with clinically elevated depressive symptoms showed increased helplessness relative to parents of youth with minimal to mild depressive symptoms.

Conclusions

Findings support the value of depression screening and interventions to promote parent self‐efficacy in managing childhood SCD pain.
Phase 1 trial, pharmacokinetics, and pharmacodynamics of dasatinib combined with crizotinib in children with recurrent or progressive high‐grade and diffuse intrinsic pontine glioma
Authors: Broniscer Alberto , Jia Sujuan , Mandrell Belinda , Hamideh Dima , Huang Jie , Onar‐Thomas Arzu , Gajjar Amar , Raimondi Susana C. , Tatevossian Ruth G. , Stewart Clinton F.
Published: March 2018

Background

Progressive/recurrent high‐grade and diffuse intrinsic pontine gliomas (DIPGs) are fatal. Treatments targeting molecular pathways critical for these cancers are needed.

Methods

We conducted a phase 1 study (rolling‐six design) to establish the safety and maximum tolerated dose (MTD) of dasatinib, an oral platelet‐derived growth factor receptor A (PDGFRA) inhibitor, and crizotinib, an oral c‐Met inhibitor, in such patients. Pharmacokinetics of both agents were performed. Biomarkers of cellular pathway activation in peripheral‐blood mononuclear cells (PBMC) were evaluated before and after administration of dasatinib. PDGFRA and MET amplification, and PDGFRA mutations were studied in tumor samples.

Results

Twenty‐five patients were enrolled in this study (median age: 11.9 years). Eleven patients had DIPG. Glioblastoma accounted for 40% of cases. Dasatinib at 50 mg/m2 and crizotinib at 130 mg/m2 or 100 mg/m2 were poorly tolerated when administered twice daily. Drug administration was then switched to once daily. Dasatinib administered at 50 mg/m2 and crizotinib at 215 mg/m2 once daily was the MTD. Dose‐limiting toxicities consisted of diarrhea, fatigue, proteinuria, hyponatremia, rash, and grade 4 neutropenia. Only two patients received therapy for at least 6 months. No objective radiologic responses were observed. Pharmacokinetics of dasatinib and crizotinib were comparable to previous studies. A statistically significant decrease in the ratio of p‐AKT/total AKT in PBMC occurred after dasatinib administration. PDGFRA and MET amplification were found in four and two cases, respectively. Only one of 10 tumors harbored a PDGFRA mutation.

Conclusions

This drug combination was poorly tolerated and its activity was minimal. We do not recommend further testing of this combination in children.
Intrauterine phenotypic features associated with 16p11.2 recurrent microdeletions
Authors: Lin Shaobin , Shi Shanshan , Zhou Yi , Ji Yuanjun , Huang Peizhi , Wu Jianzhu , Chen Baojiang , Luo Yanmin
Published: March 2018

Objective

To investigate the detection rate of 16p11.2 recurrent microdeletions in fetuses with abnormal ultrasound findings and determine the common abnormal ultrasound findings in fetuses carrying the deletion.

Methods

This study reviewed 2262 consecutive fetuses with abnormal ultrasound findings who underwent prenatal chromosomal microarray analysis between October 2014 and December 2016. Cases carrying the 16p11.2 recurrent microdeletion were further genetically analyzed, and their clinical features were reviewed.

Results

The 16p11.2 recurrent microdeletion was identified in 12 fetuses, who had skeletal malformations (5/12), cardiovascular malformations (4/12), or isolated ultrasound markers (3/12). Approximately 0.5% (12/2262) of the fetuses with abnormal ultrasound findings harbored the deletion. The 5 fetuses with skeletal malformations displayed vertebral defects, particularly in the hemivertebra and butterfly vertebra. The detection rate of the 16p11.2 recurrent microdeletion was statistically significant (P < .05) among fetuses with skeletal malformations (3.6%, 5/140), fetuses with cardiovascular malformations (1.1%, 4/367), and fetuses with isolated ultrasound markers (0.4%, 3/702).

Conclusion

The most frequent ultrasound findings in fetuses with 16p11.2 recurrent microdeletions are skeletal malformations (particularly vertebral malformations), followed by cardiovascular malformations, and isolated ultrasound markers.
Stapled ghrelin peptides as fluorescent imaging probes
Authors: Lalonde Tyler , Shepherd Trevor G. , Dhanvantari Savita , Luyt Leonard G.
Published: March 2018

Fluorescently labelled ghrelin is an effective imaging probe for ex vivo biopsy analysis, in vivo distribution studies, and cell‐based analyses. The objective of our study was to improve the receptor affinity and stability of this ghrelin probe through cyclization, thereby providing a chemical probe with advantages in specificity and sensitivity as compared to immunohistochemical approaches. Truncation of ghrelin to its first 20 essential binding amino acids simplifies chemical synthesis, but reduces the α‐helical content of the peptide, which is important for receptor recognition. To overcome this limitation, we used a “staple scan” to synthesize stable α‐helical cyclic ghrelin(1‐20) analogues using a lactam bridge in either the i, i + 4 or i, i + 7 position. Stapling improved helicity in every case when compared to the linear sequence; however, the binding affinity to the receptor was dependent on the staple position. The peptide with the greatest improvement resulted in a [θ]222/[θ]208 ratio of 0.84, and an IC50 of 7.85 nM. The lead analogue was fluorescently labeled on the C‐terminal lysine of the peptide and microscopy experiments confirmed receptor binding in cells expressing GHS‐R1a. We postulate that the lead stapled peptide can be used as a cancer cell‐specific fluorescent stain with potential research and clinical applications.
Covalent conjugation of cationic antimicrobial peptides with a β‐lactam antibiotic core
Authors: Li Wenyi , O'Brien‐Simpson Neil M. , Holden James A. , Otvos Laszlo , Reynolds Eric C. , Separovic Frances , Hossain Mohammed Akhter , Wade John D.
Published: March 2018

To combat the serious issue of increasing global antibiotic resistance, new antimicrobial therapies are urgently required. As one alternative, previously used antibiotics are being investigated for use in combination with more modern antibiotics including antimicrobial peptides. Towards this goal, 7‐aminocephalosporanic acid, the precursor to the conventional β‐lactam antibiotic, cephalosporin, and the related compound, 7‐aminodesacetoxycephalosporanic acid, were each chemically modified to enable their use in solid phase peptide synthesis for covalent conjugation via their 7‐amino group and a glycolic linker to the N‐terminus of a series of cationic antimicrobial peptides, MSI‐78, CA(1‐7)M(2‐9)NH2 and des‐Chex1‐Arg20. Chemically functionalized Cα‐Fm‐protected 7‐aminocephalosporanic acid and 7‐aminodesacetoxycephalosporanic acid building blocks were separately prepared and attached by their 7‐amino group to the N‐terminus of each peptide on the solid phase via a glutaric anhydride linker. The resulting conjugated AMPs were assessed for antibacterial activity against a panel of six Gram‐negative bacteria, including clinically isolated multi‐drug resistant (MDR) pathogens. Only the conjugated MSI‐78 analogues displayed significant activity against Acinetobacter baumannii and MDR A. baumannii 156 and enhanced activity against Klebsiella pneumoniae. Further work is required to optimize the conjugation of AMPs to 7‐cephalosporanic acid and/or 7‐aminodesacetoxycephalosporanic acid to universally induce an enhanced effect on killing of drug sensitive and MDR bacterial strains that are common causes of hospital‐acquired infections.
Comparison of liquid and liquid‐gas phase plasma reactors for discoloration of azo dyes: Analysis of degradation products
Authors: Kozakova Zdenka , Klimova Edita J. , Obradovic Bratislav M. , Dojcinovic Biljana P. , Krcma Frantisek , Kuraica Milorad M. , Olejnickova Zuzana , Sykora Richard , Vavrova Milada
Published: March 2018

Three plasma systems are used for decomposition of two organic textile dyes. The highest discoloration efficiency over 90% is reached in the water falling film DBD when maximal energy of 270 and 450 kJ L−1 is applied into Reactive Yellow 125 and Direct Red 79 dye solutions, respectively. Decomposition of the dye molecules is confirmed by concentration decreases in dye chromatograms. Similar degradation products are identified in the positive diaphragm discharge and water falling film DBD. In the negative diaphragm discharge, different products are formed due to electrochemical reactions on the anode. Substitution of halogens, hydrogen addition on the azo group and the cleavage of the azo group itself are the main mechanisms contributing to the destruction of the dye molecule in the compared plasma systems.
Using Lipophilic Membrane for Enhanced‐Performance Aqueous Gated Carbon Nanotube Field Effect Transistors
Authors: Joshi Saumya , Bhatt Vijay Deep , Jaworska Ewa , Becherer Markus , Maksymiuk Krzysztof , Michalska Agata , Lugli Paolo
Published: March 2018

Electrolyte gated carbon nanotube field effect transistors have great potential in bio‐sensing applications. However, when the application requires aqueous‐medium electrolytes the performance of field effect based sensors is compromised because of the restriction in the applied voltages. In this work, use of lipophilic poly(vinyl chloride) based membranes containing tetradodecylammonium tetrakis(4‐chlorophenyl)boronate, for encapsulating the channel of the transistor is demonstrated for the first time. This process is performed in ambient atmosphere after fabrication of field effect transistors, hence making it highly lucrative for low cost sensors. A significant improvement in the transistor parameters like increase in on‐off ratio, low hysteresis and reduction in the leakage current are observed, with a negative impact in the on‐current. A comparative study on the impact of membrane composition on the transistor performance is also presented. Toward the end, significant improvement in the performance of a pMOS inverter using membrane on the load and driver transistors is demonstrated.