bluuebunny/crossref_metadata_2025 huggingface dataset:
Utilization of transdermal fentanyl in German nursing home residents from 2010 to 2014
Authors: Jobski Kathrin , Bantel Carsten , Hoffmann Falk
Published: March 2019

Purpose

Transdermal fentanyl (TF) is the most commonly used opioid in Germany although it is associated with an increased risk for hypoventilation and potentially life‐threatening respiratory depression if used inappropriately. The objective of this study was to characterize nursing home residents newly receiving TF with regards to (1) patients' conditions at patch initiation, (2) previous analgesic treatment, and (3) the initial TF dose.

Methods

Using claims data (2010‐2014), we studied a cohort of new nursing home residents aged greater than or equal to 65 years initiating TF.

Results

TF was the most commonly prescribed opioid in nursing home residents. During their nursing home stay, 8571 persons (median age: 86 years, 79.2% female and 28.6% with a diagnosis of cancer) started TF (6.7% of all residents). Almost half of the new TF users were opioid‐naïve and 56.2% of those who had been treated with opioids in the 180 days before TF initiation had only received low potency opioids such as tilidine/naloxone or tramadol. Opioid‐naïve TF users more often were care dependent and had a higher prevalence of dementia than patients previously treated with opioids. Overall, patients often received anxiolytic/hypnotic (29.7%) or antipsychotic (31.4%) comedication. About 61% of opioid‐naïve users started with the lowest available dose (12.5 μg/h), followed by 32% treated with 25 μg/h.

Conclusions

TF as a noninvasive treatment option is the first‐choice opioid in German nursing homes. Although initial doses seemed more appropriate than those identified in previous studies, the large proportion of opioid‐naïve patients in this vulnerable population warrants attention, given the limited controllability of the treatment.
Camera‐Based Observation in Laser Material Processing
Authors: Friedrich Katharina
Published: March 2019

Today, laser material processing is a well‐established technology for contact‐less cutting, drilling, and welding of materials. To increase the performance of laser based manufacturing processes, camera‐based observation plays an important role. Camera‐based imaging enables an observation during laser processing, a quick analysis and thus an immediate reaction.
The Industrial Camera Modules Market
Authors: González Ana Belén , Pozo Jose
Published: March 2019

Camera modules have now taken a major share of the camera industry due to becoming a key part of an important consumer electronic device, the smartphones. In this article, an analysis of the camera module industry is offered including market forecast, company ecosystem, and consumer trends. The focus is on camera modules serving consumer electronics such as mobile phones, but we also give an overview of other applications, in particular the automotive ones.
Janus Nanoparticle Emulsions as Chiral Nanoreactors for Enantiomerically Selective Ligand Exchange
Authors: Lu Jia En , Peng Yi , Chen Shaowei
Published: March 2019

Janus nanoparticles capped with a hydrophobic and hydrophilic hemisphere of mercapto ligands can self‐assemble into hollow, emulsion‐like nanostructures in controlled media. As the nanoparticle emulsions are chiroptically active exhibiting a plasmonic circular dichroism absorption in the visible range, they can be exploited as a unique chiral nanoreactor by selective encapsulation of d‐enantiomer into the water phase of the water‐in‐oil emulsions for directional functionalization of the nanoparticles and endow the resulting nanoparticles with select chirality. This is demonstrated in the present study with gold Janus nanoparticles functionalized with (hydrophobic) hexanethiolates and (hydrophilic) 3‐mercapto‐1,2‐propandiol, and d,l‐cysteine is used as the molecular probe. Experimental results demonstrate that d‐cysteine is the preferred enantiomers entrapped within the nanoparticle emulsions, where the ensuing ligand exchange reaction is initially confined to the hydrophilic face of the Janus nanoparticles. This suggests that with a deliberate control of the reaction time, chiral Janus nanoparticles can be readily prepared by ligand exchange reactions even with a racemic mixture of ligands.
An ensemble of lipoxygenase structures reveals novel conformations of the Fe coordination sphere
Authors: Pakhomova Svetlana , Boeglin William E. , Neau David B. , Bartlett Sue G. , Brash Alan R. , Newcomer Marcia E.
Published: March 2019

The regio‐ and stereo‐specific oxygenation of polyunsaturated fatty acids is catalyzed by lipoxygenases (LOX); both Fe and Mn forms of the enzyme have been described. Structural elements of the Fe and Mn coordination spheres and the helical catalytic domain in which the metal center resides are highly conserved. However, animal, plant, and microbial LOX each have distinct features. We report five crystal structures of a LOX from the fungal plant pathogen Fusarium graminearum. This LOX displays a novel amino terminal extension that provides a wrapping domain for dimerization. Moreover, this extension appears to interfere with the iron coordination sphere, as the typical LOX configuration is not observed at the catalytic metal when the enzyme is dimeric. Instead novel tetra‐, penta‐, and hexa‐coordinate Fe2+ ligations are apparent. In contrast, a monomeric structure indicates that with repositioning of the amino terminal segment, the enzyme can assume a productive conformation with the canonical Fe2+ coordination sphere.
Relationship Between the Boson Heat Capacity Peak and the Excess Enthalpy of a Metallic Glass
Authors: Mitrofanov Yurii P. , Makarov Andrei S. , Afonin Gennadii V. , Zakharov Konstantin V. , Vasiliev Alexander N. , Kobelev Nikolai P. , Wilde Gerhard , Khonik Vitaly A.
Published: March 2019

The authors measure the low temperature heat capacity of a Pd‐based metallic glass and derive the Boson peak height in relation with the enthalpy changes occurring upon structural relaxation and crystallization. The Boson peak height was also calculated within the framework of the Interstitialcy theory as a function of the excess enthalpy of glass with respect to the maternal crystal. A good agreement between experiment and calculation is found.
Language ideologies in science education
Authors: Lemmi Catherine , Brown Bryan A. , Wild Andrew , Zummo Lynne , Sedlacek Quentin
Published: March 2019

Drawing on sociolinguistics research regarding common beliefs and justifications about language, we applied notions of language ideology to an analysis of the formative assessment practices of secondary science teachers from linguistically diverse schools. We identified two language ideologies that were demonstrated by teachers as they engaged in the formative assessment of student work. Here, we introduce the termslanguage‐exclusive ideologyandlanguage‐inclusive ideology. Alanguage‐exclusive ideologyholds that certain forms of language are expected in a science class, and others are not appropriate. What we have termed alanguage‐inclusive ideologysuggests that multiple forms of language use are acceptable in science classrooms, and this approach finds synergies with the literature on translanguaging, or the integration of multiple languages for complex communicative purposes. We argue that science teacher educators should consider teachers’ language ideologies as they prepare professional development and preservice teacher education curriculum materials, and we discuss potential implications for science education and teacher education. Finally, we call for more explicit consideration of issues of language ideology within the science education community to understand how various approaches to language can provide affordances or barriers to content learning and language development.
Production of medium chain length polyhydroxyalkanoate from acetate by engineered Pseudomonas putida KT2440
Authors: Yang Songyuan , Li Suhang , Jia Xiaoqiang
Published: March 2019

Pseudomonas putida was metabolically engineered to produce medium chain length polyhydroxyalkanoate (mcl-PHA) from acetate, a promising carbon source to achieve cost-effective microbial processes. As acetate is known to be harmful to cell growth, P. putida KT2440 was screened from three Pseudomonas strains (P. putida KT2440, P. putida NBRC14164, and P. aeruginosa PH1) as the host with the highest tolerance to 10 g/L of acetate in the medium. Subsequently, P. putida KT2440 was engineered by amplifying the acetate assimilation pathway, including overexpression of the acs (encoding acetyl-CoA synthetase) route and construction of the ackA-pta (encoding acetate kinase-phosphotransacetylase) pathway. The acs overexpressing P. putida KT2440 showed a remarkable increase of mcl-PHA titer (+ 92%), mcl-PHA yield (+ 50%), and cellular mcl-PHA content (+ 43%) compared with the wild-type P. putida KT2440, which indicated that acetate could be a potential substrate for biochemical production of mcl-PHA by engineered P. putida.
When working memory is in a mood: Combined effects of induced affect and processing of emotional words
Authors: Rączy Katarzyna , Orzechowski Jarosław
Published: March 2019

It is already well established that the working memory system can be influenced by moods or emotional stimuli. However, the exact combined impact of these two on the performance of working memory remains a puzzle. To examine the effect that the emotional content of stimuli has on working memory performance, 90 participants performed a 2-back task with emotional content (positive, neutral, and negative words) when they were in a positive, neutral, or negative mood. Repeated-measures ANOVA with mood as between-subjects factor and emotional load as within-subjects factor revealed a main effect of emotional content for both performance accuracy and reaction times in a 2-back task, and a main effect of mood for performance accuracy. Participants reacted significantly faster to negative words independently of their mood state. They were significantly more accurate when they were in the positive mood, but when they processed positive words they were less accurate. Additionally, to test whether loading the working memory system can reset the combined effect of mood and emotional stimuli, we measured the participants’ mood before and after they performed the n-back task; this revealed a significant effect of the n-back task on the mood. Together, these results suggest that although mood and emotional content do have a robust effect on working memory, in some instances combining them does not heighten their individual effects. Moreover, the results also show that participants might be easily distracted from moods by simply performing an n-back task.
The Red Bird River Shelter (15CY52) Revisited: The Archaeology of the Cherokee Syllabary and of Sequoyah in Kentucky
Authors: Simek Jan F. , Carroll Beau Duke , Reed Julie , Cressler Alan , Belt Tom , Adams Wayna , White Mary
Published: March 2019

This article reanalyzes petroglyphs from the Red Bird River Shelter (15CY52), a small sandstone shelter in Kentucky. In 2009–2013, it was claimed that some of the carvings at the site represented the earliest known examples of Cherokee Syllabary writing, dating to the first two decades of the nineteenth century. It was also suggested that Sequoyah, the Cherokee artist and intellectual who invented the Cherokee Syllabary in the early nineteenth century, had made these petroglyph versions during a visit to see his white paternal family living in Kentucky. Our reanalysis categorically contests this interpretation. We do not see Cherokee Syllabary writing at Red Bird River Shelter. We do not believe that historical evidence supports the notion that Sequoyah had white relatives in Kentucky whom he visited there at the time required for him to have authored those petroglyphs. We also believe that this account misrepresents Sequoyah's Cherokee identity by tying him to white relatives for whom there is no historical warrant. We argue that the Red Bird River Shelter is a significant precontact petroglyph site with several panels of line-and-groove petroglyphs overlain by numerous examples of modern graffiti, but there is no Sequoyan Syllabary inscription there.
Nudges that should fail?
Authors: TOR AVISHALOM
Published: March 2019

Professor Sunstein (2017) discusses the possible causes for and policy implications of the failure of nudges, with special attention to defaults. Though he focuses on nudges that fail when they should succeed, Sunstein recognizes that some failures reveal that a nudge should not have been attempted to begin with. ‘Nudges that fail’, however, does not consider fully the relationship between the outcomes of nudging and their likely welfare effects, most notably neglecting the troubling case of nudges that succeed when they should fail. Hence, after clarifying the boundaries of legitimate nudging within a libertarian-paternalistic approach and noting the fourfold relationship between the efficacy of nudging and its normative desirability, this article evaluates more fully the case of failed nudges and examines the hitherto unaddressed problem of successful yet undesirable nudges. This analysis shows that the failure of nudging bears only limited diagnostic value, while the success of a nudge is even less indicative of its normative status. The article concludes with recommendations for policy-makers who wish to employ nudges that are not only efficacious, but also likely to advance the subjective well-being of the individuals they target.
A Simultaneous Cluster Analysis of Cognitive, Emotional, and Personality Factors and Insomnia and Sleep Quality Among Earthquake Victims
Authors: Khazaie Habibolah , Zakiei Ali , Komasi Saeid
Published: March 2019

Objective

The current study compares the measures of sleep quality and intensity of insomnia based on the clustering analysis of variables including dysfunctional beliefs and attitudes about sleep, experiential avoidance, personality traits of neuroticism, and complications with emotion regulation among the individuals struck by an earthquake in Kermanshah Province.

Methods

This study is a cross-sectional study that was carried out among earthquake victims of Kermanshah Province (western Iran) in 2017. Data were gathered starting 10 days after the earthquake and lasted for 2 weeks; of 1,200 standard questionnaires distributed, 1,001 responses were received, and the analysis was performed using 999 participants. The data analysis was carried out using a cluster analysis (K-mean method).

Results

Two clusters were identified, and there is a significant difference between these two clusters in regard to all of the variables. The cluster with higher mean values for the selected variables shows a higher intensity of insomnia and a lower sleep quality.

Conclusions

Considering the current results, it can be concluded that variables of dysfunctional attitudes and beliefs about sleep, experiential avoidance, the personality traits of neuroticism, and complications with emotion regulation are able to identify the clusters where there is a significant difference in regard to sleep quality and the intensity of insomnia. (Disaster Med Public Health Preparedness. 2019;13:745–752)
COMPUTABILITY IN UNCOUNTABLE BINARY TREES
Authors: JOHNSTON REESE
Published: March 2019

Computability, while usually performed within the context of ω, may be extended to larger ordinals by means of α-recursion. In this article, we concentrate on the particular case of ω1-recursion, and study the differences in the behavior of ${\rm{\Pi }}_1^0$-classes between this case and the standard one.

Of particular interest are the ${\rm{\Pi }}_1^0$-classes corresponding to computable trees of countable width. Classically, it is well-known that the analog to König’s Lemma—“every tree of countable width and uncountable height has an uncountable branch”—fails; we demonstrate that not only does it fail effectively, but also that the failure is as drastic as possible. This is proven by showing that the ω1-Turing degrees of even isolated paths in computable trees of countable width are cofinal in the ${\rm{\Delta }}_1^1\,{\omega _1}$-Turing degrees.

Finally, we consider questions of nonisolated paths, and demonstrate that the degrees realizable as isolated paths and the degrees realizable as nonisolated ones are very distinct; in particular, we show that there exists a computable tree of countable width so that every branch can only be ω1-Turing equivalent to branches of trees with ${\aleph _2}$-many branches.
New Clues on the Origin of the “Inca Mirror” at the Museum National d'Histoire Naturelle in Paris
Authors: Calligaro Thomas , Chiappero Pierre-Jacques , Gendron François , Poupeau Gérard
Published: March 2019

Since at least 1742, the mineralogical collection of the Muséum National d'Histoire Naturelle (MNHN) in Paris has hosted, under the reference number 22.U, a biconvex lens-shaped obsidian artifact, also described as a mirror, measuring 250 mm in diameter and finely polished on both faces. It has usually been ascribed to the shipment sent by Hernán Cortez in 1522 to the Emperor Charles V, which was captured by a French privateer. We investigated the object using modern techniques. The elemental composition of the obsidian determined by the particle induced X-ray emission (PIXE) method showed that the raw material originates from the Mullumica deposit (Ecuador). Documentary investigations revealed that the lens (renumbered No. 176.101) was sent in 1737 from Quito, Ecuador (at that time part of the viceroyalty of Peru), to France by members of the Godin–La Condamine geodesic expedition (1735–1743). The mirror is thus among the rare Ecuadorian archeological or colonial artifacts to have reached the Old World during the eighteenth century.
Standing waves of modified Schrödinger equations coupled with the Chern–Simons gauge theory
Authors: d'Avenia Pietro , Pomponio Alessio , Watanabe Tatsuya
Published: March 2019

We are interested in standing waves of a modified Schrödinger equation coupled with the Chern–Simons gauge theory. By applying a constraint minimization of Nehari-Pohozaev type, we prove the existence of radial ground state solutions. We also investigate the nonexistence for nontrivial solutions.
The Futurists of Beijing: Alvin Toffler, Zhao Ziyang, and China's “New Technological Revolution,” 1979–1991
Authors: Gewirtz Julian
Published: March 2019

This article examines former Chinese Premier and General Secretary Zhao Ziyang's policies to respond to a “New Technological Revolution,” which resulted from a most unlikely influence: the prominent American writer Alvin Toffler and other futurists. Drawing on previously unstudied materials and internal Chinese sources, this article demonstrates how Zhao and other senior Chinese officials interpreted and deployed these ideas to advocate for distinctive and influential policies. This policy vision of actionable futurism shaped science and technology policy during the 1980s—especially the major 863 Program to develop advanced technologies—and had great importance in China's economic transformation. In explicating Zhao's role, this account revises the often-repeated Deng Xiaoping–centered story of the 863 Program's origins and reassesses this major initiative, which exemplifies how new expectations about the future, shaped by the transnational movement of ideas, became centrally important to the Chinese leadership's decades-long agenda for China's modernization. This examination also illustrates the distinctiveness of Zhao's policy vision, frequently effaced by official Deng-centered narratives, and the fluidity of conceptions of modernization in this period. The article concludes by suggesting the enduring relevance of these ideas about the future for the current era of Chinese state-led investment in new technologies.
Virtual Earthquakes and Real-World Survival in Japan'sDisaster ReportVideo Game
Authors: Whaley Ben
Published: March 2019

This article analyzes the first video game in theZettai Zetsumei Toshi(2002, Disaster Report) series for Sony's PlayStation 2 console against the backdrop of the 2011 Tōhoku earthquake and tsunami. In the game, players must use limited resources to escape from an earthquake-stricken city while rescuing other survivors. The article argues that the game makes visible the marginal victims and narratives of survival often erased under the collective rhetoric of national trauma. This is explored in relation to disaster photography and artistic representations of 3.11. The article suggests that the game's narrative rejects governmental rhetoric about nuclear energy and that the gameplay mechanisms utilize “limited engagement” or a form of operationalized weakness in order to communicate victimhood to players. The article concludes with an examination of how the in-game disaster photography inscribes players’ actions, making it more difficult to subsume these images into a generalized account of natural disaster trauma.
Glucose-restriction increasesTrichomonas vaginaliscellular damage towards HeLa cells and proteolytic activity of cysteine proteinases (CPs), such as TvCP2
Authors: Miranda-Ozuna Jesús F. T. , Rivera-Rivas Luis Alberto , Cárdenas-Guerra Rosa Elena , Hernández-García Mar Sarai , Rodríguez-Cruz Sarahí , González-Robles Arturo , Chavez-Munguía Bibiana , Arroyo Rossana
Published: March 2019

Trichomonas vaginalisinduces cellular damage to the host cells (cytotoxicity) through the proteolytic activity of multiple proteinases of the cysteine type (CPs). Some CPs are modulated by environmental factors such as iron, zinc, polyamines, etc. Thus, the goal of this study was to assess the effect of glucose onT. vaginaliscytotoxicity, proteolytic activity and the particular role of TvCP2 (TVAG_057000) during cellular damage. Cytotoxicity assays showed that glucose-restriction (GR) promotes the highest HeLa cell monolayers destruction (~95%) by trichomonads compared to those grown under high glucose (~44%) condition. Zymography and Western blot using different primary antibodies showed that GR increased the proteolytic activity, amount and secretion of certain CPs, including TvCP2. We further characterized the effect of glucose on TvCP2. TvCP2 increases in GR, localized in vesicles close to the plasma membrane and on the surface ofT. vaginalis. Furthermore, pretreatment of GR-trichomonads with an anti-TvCP2r polyclonal antibody specifically reduced the levels of cytotoxicity and apoptosis induction to HeLa cells in a concentration-dependent manner. In conclusion, our data show that GR, as a nutritional stress condition, promotes trichomonal cytotoxicity to the host cells, increases trichomonad proteolytic activity and amount of CPs, such as TvCP2 involved in cellular damage.
Addressing the constraints of Tritrichomonas foetus sample collection in remote areas: lyophilized modified Diamond's media as a substitute for liquid medium
Authors: Rush Gemma , Reynolds Michael William , Calvani Nichola Eliza Davies , Šlapeta Jan
Published: March 2019

Bovine trichomoniasis is a notifiable, reproductive disease of cattle caused by the parasite Tritrichomonas foetus. Culturing with modified Diamond's medium (MDM) is required to increase the low number of organisms received from a preputial sample, but is limited in application to remote areas as it requires continuous cold chain storage. This study utilized lyophilization to sustain the viability of MDM during transport in lieu of a continuous cold chain. All lyophilized MDM was able to sustain T. foetus after storage for 42 days at 24 °C, and the results demonstrated that lyophilized MDM was equally as viable as refrigerated liquid MDM. Storage of lyophilized MDM at room temperature for 1 and 7 days did not impact T. foetus yield, both with and without exposure to light. A limitation of the lyophilized MDM was demonstrated with a significant decrease in T. foetus yield when the media was stored at 37 and 58 °C. The lyophilization of MDM provides a robust method of transporting and storing medium prior to reconstitution and inoculation, for use in T. foetus diagnosis and surveillance in remote areas.
Village Reconstruction in Rural China: The Importance of Being Urban
Authors: Wilson Saul , Zhang Xiaorong
Published: March 2019

Using examples from village reconstruction programmes in rural China, we show that local cadres often prioritize project visibility over publicized policy goals. While central policies and the academic literature emphasized land reclamation or rural welfare, local cadres – and the projects they designed – tended instead to focus on projecting an image of urban, wealthy villagers. Where such image-driven behaviour is most deleterious to villagers, it can evince opposition. We observe that some areas avoid conflict by making these projects voluntary or adjusting projects to local conditions. However, we provide a case study of a village with strong village leadership, showing that contrary to recent claims that village cadres are increasingly impotent, some maintain the authority to override widespread objections from villagers.
Seroprevalence of HCV, HBV and HIV in two inner-city London emergency departments
Authors: Cieply L. , Simmons R. , Ijaz S. , Kara E. , Rodger A. , Rosenberg W. , McGuinness A. , Mbisa J. L. , Ledesma J. , Ohemeng-Kumi N. , Dicks S. , Potts H. , Lattimore S. , Mandal S.
Published: March 2019

Summary: In this paper we build on work investigating the feasibility of human immunodeficiency virus (HIV) testing in emergency departments (EDs), estimating the prevalence of hepatitis B, C and HIV infections among persons attending two inner-London EDs, identifying factors associated with testing positive in an ED. We also undertook molecular characterisation to look at the diversity of the viruses circulating in these individuals, and the presence of clinically significant mutations which impact on treatment and control.

Blood-borne virus (BBV) testing in non-traditional settings is feasible, with emergency departments (ED) potentially effective at reaching vulnerable and underserved populations. We investigated the feasibility of BBV testing within two inner-London EDs. Residual samples from biochemistry for adults (⩾18 years) attending The Royal Free London Hospital (RFLH) or the University College London Hospital (UCLH) ED between January and June 2015 were tested for human immunodeficiency virus (HIV)Ag/Ab, anti-hepatitis C (HCV) and HBsAg. PCR and sequence analysis were conducted on reactive samples. Sero-prevalence among persons attending RFH and UCLH with residual samples (1287 and 1546), respectively, were 1.1% and 1.0% for HBsAg, 1.6% and 2.3% for anti-HCV, 0.9% and 1.6% for HCV RNA, and 1.3% and 2.2% for HIV. For RFH, HBsAg positivity was more likely among persons of blackvs.white ethnicity (odds ratio 9.08; 95% confidence interval 2.72–30), with anti-HCV positivity less likely among females (0.15, 95% CI 0.04–0.50). For UCLH, HBsAg positivity was more likely among non-white ethnicity (13.34, 95% CI 2.20–80.86 (Asian); 8.03, 95% CI 1.12–57.61 (black); and 8.11, 95% CI 1.13–58.18 (other/mixed)). Anti-HCV positivity was more likely among 36–55 year oldsvs.⩾56 years (7.69, 95% CI 2.24–26.41), and less likely among females (0.24, 95% CI 0.09–0.65). Persons positive for HIV-markers were more likely to be of blackvs.white ethnicity (4.51, 95% CI 1.63–12.45), and less likely to have one ED attendance (0.39, 95% CI 0.17–0.88), or female (0.12, 95% CI 0.04–0.42). These results indicate that BBV-testing in EDs is feasible, providing a basis for further studies to explore provider and patient acceptability, referral into care and cost-effectiveness.
The sources of electrophysiological variability in the retina ofPeriplaneta americana
Authors: Frolov Roman V.
Published: March 2019

Variability in the electrophysiological properties of homotypic photoreceptors is widespread and is thought to facilitate functioning under disparate illumination conditions. Compound eyes of insects have three sources of variability: inter-individual, intra-individual, and intra-ommatidial, the latter two overlapping. Here, I explored the causes of variability inPeriplaneta americana, a nocturnal insect characterized by highly variable photoreceptor responses. By recording from photoreceptors in dissociated ommatidia, including consecutive recordings from photoreceptors in the same ommatidium (SO), I studied the variability of six properties: whole-cell membrane capacitance (Cm), phototransduction latency, maximal conductance (Gmax) and the slope factor of the sustained Kv current, absolute sensitivity in dim light, and sustained light-induced current (LIC) amplitude in bright light. Coefficient of variation (CV) metrics were used to compare variances in four experimental groups: SO, same animal (SA), all data combined “full sample” (FS), and full sample of all SO recordings (FSSO). For the normally distributed parametersCm,Gmax, slope factor, and latency, the highest CV values were found in FS and FSSO, intermediate in SA, and the lowest in SO. On average, SO variance accounted for 47% of the full-sample variance in these four parameters. Absolute sensitivity and LIC values were not normally distributed, and the differences in variability between SO and FS/FSSO groups were smaller than for the other four parameters. These results indicate two main sources of variability, intra-ommatidial and inter-individual. Inter-individual variability was investigated by exposing adult cockroaches to constant light or dark for several months. In both groups, the majority of CV measures for the six parameters decreased compared to control, indicating substantial contribution of phenotypic plasticity to inter-individual differences. Analysis of variability of resting potential and elementary voltage responses revealed that resting potential is mainly determined by the sustained Kv conductance, whereas voltage bump amplitude is mainly determined by current bump amplitude andCm.
12 Impact of Aripiprazole Long-acting Injectable (ALAI) Initiation on Hospitalizations and Visits to Emergency
Authors: Parro-Torres Carlos , Ros-Cucurull Elena , Arques-Egea Sergio
Published: March 2019

Background

Aripiprazole once-monthly is an LAI formulation of aripiprazole that is currently approved in the USA and Europe for the treatment of schizophrenia. Some studies have reported a decline in hospital admissions and emergency use after initiation on long-acting injectable (LAI) antipsychotics, but the effects of using recently commercialised LAI aripiprazole remains uncertain.

Aims

To characterize the impact of ALAI initiation on number of hospitalizations and visits to the emergency service, among patients suffering from schizophrenia attending regularly to psychiatric consultations of Gregorio Marañón University General Hospital (Madrid, Spain).

Methods

Patients initiated on (ALAI) were studied in an observational mirror-image design to assess changes in number of hospitalizations and visits to the emergency service in the 12months pre- vs 12months post-depot initiation. Other sociodemographic, physical and clinical variables such as age, gender, weight, blood pressure and presence of dual disorders were also gathered. Variables were collected reviewing clinical records.

Wilcoxon test was used to assess hospitalizations and visits to the emergency. Paired t-tests were used to assess changes in weight and blood pressure. Non parametric Mann-Whitney U test was used to compare aripiprazole doses between genders and in order to assess de influence of dual disorders. In order to perform the statistical analysis, IBM SPSS statistics v.20 was used.

Results

31 patients were included in the final analysis. Mean age was 44.67 (SD=15.57) years. Most of the patients were male (54.8% vs 45.2%). 71% were previously receiving oral antipsychotics treatment, whereas 29% were receiving other LAI antipsychotic: no significant differences were observed when comparing hospitalizations (p=0.74) or emergency use (p=0.98) in the 12months post-initiation between these groups. Mean dosage was 352.67mg/28days (SD=0.461), and 38.7% needed an adjustment during the first year of treatment (dosage increased in 76.9%). A combination of two or more antipsychotics was prescribed in 64.5% of the patients. Mean psychiatric number of hospitalizations a year declined from 0.483/year pre-initiation to 0.224/year post-initiation (P<0.05), whereas mean visits a year to the emergency psychiatric service declined from 1.419 pre-initiation to 1.032 post-initiation (P<0.1). No significant changes in weight (p=0.82), systolic (p=0.56) or diastolic (p=0.29) blood pressure were observed. No gender differences in dosage were observed (p=0.246). Suffering from dual disorders had no influence on dosage either (p=0.68).

Conclusions

LAI aripiprazole initiation appears to provide a benefit decreasing hospitalization needs and emergency services consumption and it was well tolerated. This data supports previous evidence indicating superiority of LAI antipsychotics.
20 The Need for Speed: Adjunctive Triple Chronotherapy in the Accelerated Treatment of Acute Depression and Suicidality in the Adolescent Population
Authors: Hurd Diane , Arzubi Eric , Herrera Mariela Rojas , Coombs Nicholas , Brant Jeannine
Published: March 2019

Objective

This pilot study aims to explore the feasibility and proof of concept of triple chronotherapy (TCT) as a non-pharmacological, adjunctive intervention in the treatment of acute depression and suicidality in the adolescent population.

Method

Thirty-one adolescents with moderate to severe depression were included in the study. Each participant underwent a 4-day intervention (TCT) which consisted of one night of sleep deprivation followed by three days of sleep phase advancement and daily bright light therapy. Primary outcomes were feasibility and depression, as measured by Hamilton Depression Scale-17 (HAMD-17) scores. Secondary outcomes included severity of illness, anxiety, self-harm, insomnia, and suicidality.

Results

Twenty-nine (94%) adolescents completed the TCT protocol. Twenty-six (84%) of the 31 enrolled patients experienced a reduction in depressive symptoms of at least 50% from baseline; 24 (77%) achieved remission, defined as a HAMD-17 score less than 8. Secondary outcomes showed significant improvement following the 4-day TCT intervention; improvement was sustained through the 7–10 day and 1-month follow-up periods.

Conclusion

This pilot study determined TCT to be a feasible, safe, accelerated, and promising adjunctive treatment for acute depression in the adolescent population. This study has been submitted for publication and is currently under review.
22 Using Light to Unveil Depression: The Role of Optogenetics
Authors: Diniz Aurelio Lourenco , Escobar-Montealegre Freddy , Peçanha Marcela Pellegrini
Published: March 2019

Introduction

Major depressive disorder (MDD) is a highly prevalent and often debilitating condition with a vast impact on modern societies worldwide. Although it interferes significantly with functioning, MDD is frequently unresponsive to conventional treatment approaches and pharmacotherapy failure has been reported in approximately one third of patients. Current knowledge of the exact underlying disease mechanisms is insufficient, and may thus largely contribute to such therapeutic limitations. Optogenetics, a novel study field employing the expression of genetically-encodable light-sensitive proteins in specific cell types, circumvents the limitations of other forms of neuromodulation and enables temporally precise, bidirectional control of cellular activity in well-defined neuronal populations. This strategy has been used successfully to dissect neural pathways and circuitries involved in complex mental diseases such as MDD.

Methods

A systematic literature search was conducted using the terms “Optogenetics”, “Depression” and “Major depressive disorder” on the databases MEDLINE, LILACS, SciELO, Pubmed and BIREME. Inclusion criteria were adopted: articles published in the English language from 1971 (description of bacteriorhodopsin as a light-activated regulator of transmembrane ion flow) to 2017 and articles based on experimental studies were selected.

Results

By using highly validated animal models based on the exposure of phenotypically susceptible rodents to different forms of chronic stress, researchers have been able to reproduce the hallmark symptoms of Depression as well as the histopathological abnormalities found in human brain specimens post-mortem. Several brain regions and neuron populations involved in MDD have been identified by use of a variety of molecular resources including viral vectors, genetically engineered animals, multiple promoters and bacterial opsins. Important areas of dysfunction underlying depression including the medial prefrontal cortex, the ventral tegmental area, the nucleus accumbens, the hippocampus and the basolateral amygdala have been investigated by using optogenetic neuromodulation, yielding new insights into the pathological processes underlying MDD. Researchers have been able to pinpoint affected circuitries and employ time-precise light modulation to successfully revert symptoms of MDD, restoring normal function. It is important to highlight that although promising, studies using optogenetics are controversial, largely due to the variable set tools, models and tests employed in research.

Conclusion

Light modulation using optogenetics has greatly aided to establish accurate models to unveil the neurobiological basis of Depression. Further research will continue to help build more complete pathophysiological constructs and pave the way for new treatment strategies.
27 A New Method for Initiating Treatment with the Long-acting Antipsychotic Aripiprazole Lauroxil
Authors: Meyer Jonathan , Jain Rakesh , Wehr Angela , Rege Bhaskar , von Moltke Lisa , Weiden Peter J
Published: March 2019

STUDY OBJECTIVE

Slow release is a fundamental feature of long-acting injectable (LAI) antipsychotics. This property allows continuous drug exposure between dosing intervals. However, there can be a significant delay between giving the first LAI dose and achievement of efficacious plasma concentrations. This time period requires additional pharmacologic intervention. Until now, this delay was addressed with one of two strategies: 1) continuing with supplemental oral antipsychotic, or 2) giving more LAI up front (e.g. loading dose). A third strategy has now been developed to reduce the time needed for oral supplementation when starting the LAI aripiprazole lauroxil (AL) from 21days to 1day. A nano-crystalline milled dispersion of AL (ALNCD; brand name ARISTADA INITIO™) was formulated by reducing the AL particle diameter from micron-size particles to nanometer- sized particles. ALNCD has faster dissolution and a shorter half-life than AL and is designed to be used as a single injection along with a single oral aripiprazole dose of 30mg as a 1-day alternative to the 21days of oral aripiprazole supplementation. Here we provide an overview of the new 1-day initiation regimen for starting AL treatment, and demonstrate the relative contributions of each of its components.

METHODS

A blinded, randomized, phase 1, pharmacokinetic (PK), and safety study compared the 1-day initiation regimen with the 21-day oral aripiprazole regimen. A combination of observed data, and population pharmacokinetic model–based simulations were used to plot plasma aripiprazole concentrations of single doses of ALNCD, 30mg oral aripiprazole, and AL, individually, and all three combined.

RESULTS

The PK profiles of the 1-day and 21-day initiation regimens (both in conjunction with either 441mg or 882mg doses of AL) were comparable, with therapeutically relevant aripiprazole levels achieved within 4days of treatment initiation. The safety profile of the 1-day initiation regimen was similar to the 21-day initiation regimen, and consistent with that of AL. Aripiprazole concentration–time profiles demonstrated that each component delivered aripiprazole to the systemic circulation at different time periods, with the 30mg dose of oral aripiprazole predominant in the first week, followed by ALNCD, and then AL.

CONCLUSIONS

The 1-day initiation regimen is well-tolerated and a suitable alternative to 21days of oral aripiprazole supplementation for starting AL. Each component of the 1-day initiation regimen, together with AL, is necessary to provide continuous coverage from treatment initiation until the next regularly scheduled AL injection.

Funding Acknowledgements: This study was funded by Alkermes Inc.
36 Too Scared to Blink: Pseudoparkinsonism due to Nyctophobia
Authors: Janjua Khurram , Hirsch Alan R.
Published: March 2019

Introduction

A hallmark of Parkinson’s disease is facial akinesia with decrease in blink frequency (Karson, 1984). A markedly decreased blink frequency from nyctophobia, a fear of the dark, has not heretofore been reported.

Method

Case Study: A 26-year-old right handed male presented with a 20-year history of phantasmagoria. Visual hallucinations of strangers appeared several to a hundred times a day, seconds to minutes in duration. These morbid images were horrific, of dead people or ghosts, suddenly appearing in his visual space, actively attacking real people. Examples included a little girl, decapitated, cradling her head in her arm or Freddy Krueger like apparitions, shooting, stabbing, strangling or maiming actual people who were within the patient’s visual field. He was able to differentiate between the hallucinations and real people, either from the context (a non hallucination would not be murdering someone else), or he would wait for the hallucinations to vanish, allowing him to then interact with the person who is actually there. The images were so disturbing to him that he fled his home state to run away from the hallucinations, but to his chagrin, they persisted. There were diurnal variations to his hallucinations, which were more frequent at night, or when he closed his eyes, and the fear of these has induced nyctophobia. In order to avoid these, he attempted to curtail closing his eyes or blinking. He had been treated with 9 different psychotropic medications, which had no effect on his hallucinations. Phenytoin was begun, and once therapeutic levels were achieved, all of his hallucinations resolved, as did his nyctophobia, with return to normal blink frequency.

Results

Physical examination: Bilateral palmar erythema. Facial expression with decreased blink frequency, approximately 1/per minute, but not otherwise hypomimetic. Neurological examination: Cranial Nerve (CN) Examination: CN III, IV and VI: bilateral ptosis. Motor Examination: Normal tone without cogwheel rigidity. No bradykinesia. Drift Testing: Right upward-outward drift, right cerebellar spooning, and Abductor Digiti Minimi sign. Gait: Normal without instability or retropulsion. Reflexes: 1+ throughout. Hoffman Reflex: positive bilaterally. Other: Magnetic Resonance Imaging of brain with/without infusion: Normal. Five-day Electroencephalogram: Temporal Lobe Status Epilepticus with bilateral foci.

Discussion

In this individual, the sheer terror of phantasmagoria with his eyes closed, forced him to maintain them in the open position as long as possible, reducing his blink frequency to once a minute or less. The return to a normal rate of blink frequency with treatment using phenytoin, with resolution of his horrific hallucinations, further validates this as the origin for his infrequent blinking. In those with low nictation, without other manifestations of Parkinson’s disease, query as to volitional inhibition of blink frequency and nyctophobia is warranted.
50 Adjunctive Buprenorphine/Samidorphan Combination in Patients with Major Depressive Disorder: Phase 3 Long-term Extension Study Results
Authors: Thase Michael , Stanford Arielle D. , Memisoglu Asli , Martin William , Claxton Amy , Bodnik J. Alexander , Trivedi Madhukar H. , Fava Maurizio , Pathak Sanjeev
Published: March 2019

Introduction

Buprenorphine/samidorphan (BUP/SAM), a combination of BUP (a µ-opioid receptor partial agonist and κ-antagonist) and SAM (a sublingually bioavailable µ-opioid antagonist), is an investigational opioid system modulator for depression. BUP/SAM has shown efficacy versus placebo as an adjunctive treatment for major depressive disorder (MDD) and a consistent safety profile in previously reported, placebo-controlled clinical studies.1,2

Study Objective(s)

1. To characterize the safety profile following long-term treatment with BUP/SAM

2. To explore depression symptoms and remission rates in patients with MDD following long-term treatment with BUP/SAM

Methods

FORWARD-2 (Clinicaltrials.gov ID: NCT02141399) enrolled patients who had participated in 1 of 4 controlled studies as well as de novo patients. All patients had a confirmed diagnosis of MDD, had a history of inadequate response to standard antidepressant therapies (ADTs), and had been treated with an adequate dose of an established ADT for ≥8weeks before BUP/SAM initiation. ADT dosage could be titrated, but the ADT could not be changed. During the study, patients received open-label, sublingual BUP/SAM 2mg/2mg as adjunctive treatment for up to 52weeks. Safety (primary objective) was assessed via adverse events (AEs), vital signs, laboratory analytes, and electrocardiography. Suicidal ideation or behavior (SIB) was evaluated by the Columbia Suicide Severity Rating Scale. Abuse potential, dependence, and withdrawal were assessed by AEs and the Clinical Opiate Withdrawal Scale. Exploratory efficacy endpoints included mean Montgomery–Åsberg Depression Rating Scale (MADRS) scores and remission rate (MADRS ≤10).

Results

Of 1454 total patients, 49% completed the 52-week study, 11% discontinued due to an AE, and 40% discontinued because of other reasons as of the interim data cutoff date (April 30, 2017). Most AEs were of mild/moderate severity. Serious AEs were reported in 3.2% of patients. AEs occurring in ≥10% of patients were nausea, headache, constipation, dizziness, and somnolence. There was no evidence of increased risk of SIB with BUP/SAM. Incidence of euphoria-related events was low (1.2%). After abrupt discontinuation of BUP/SAM, there was little evidence of withdrawal. BUP/SAM was not associated with meaningful changes in laboratory or metabolic parameters or in bodyweight. The mean MADRS score decreased from 22.9 (±9.7) at baseline to 9.8 (±8.8) after 52weeks. The remission rate at 52weeks was 52.5%.

Conclusions

Long-term treatment with BUP/SAM did not reveal any new safety findings and confirmed that the risk of abuse and dependence with BUP/SAM was low. BUP/SAM maintained an antidepressant effect for up to 52weeks of treatment in patients with MDD.

Funding Acknowledgements: Alkermes, Inc.