bluuebunny/crossref_metadata_2025 huggingface dataset:
Characteristics of patients with atrial fibrillation prescribed edoxaban in Belgium and the Netherlands: insights from the ETNA-AF-Europe study
Authors:   the ETNA-AF-Europe principal investigators from Belgium and the Netherlands*, de Vries T. A. C. , Hemels M. E. W. , Cools F. , Crijns H. J. G. M. , Yperzeele L. , Vanacker P. , Blankoff I. , Lancellotti P. , Mairesse G. H. , de Veer A. , Casado Arroyo R. , Catez E. , de Pauw M. , Vanassche T. , de Asmundis C. , Kirchhof P. , De Caterina R. , de Groot J. R.
Published: January 2021

Background

Studies on the use of non-vitamin K antagonist oral anticoagulants in unselected patients with atrial fibrillation (AF) show that clinical characteristics and dosing practices differ per region, but lack data on edoxaban.

Methods

With data from Edoxaban Treatment in routiNe clinical prActice for patients with AF in Europe (ETNA-AF-Europe), a large prospective observational study, we compared clinical characteristics (including the dose reduction criteria for edoxaban: creatinine clearance 15–50 ml/min, weight ≤60 kg, and/or use of strong p‑glycoprotein inhibitors) of patients from Belgium and the Netherlands (BeNe) with those from other European countries (OEC).

Results

Of all 13,639 patients in ETNA-AF-Europe, 2579 were from BeNe. BeNe patients were younger than OEC patients (mean age: 72.3 vs 73.9 years), and had lower CHA2DS2-VASc (mean: 2.8 vs 3.2) and HAS-BLED scores (mean: 2.4 vs 2.6). Patients from BeNe less often had hypertension (61.6% vs 80.4%), and/or diabetes mellitus (17.3% vs 23.1%) than patients from OEC. Moreover, relatively fewer patients in BeNe were prescribed the reduced dose of 30 mg edoxaban (14.8%) than in OEC (25.4%). Overall, edoxaban was dosed according to label in 83.1% of patients. Yet, 30 mg edoxaban was prescribed in the absence of any dose reduction criteria in 36.9% of 30 mg users (5.5% of all patients) in BeNe compared with 35.5% (9.0% of all patients) in OEC.

Conclusion

There were several notable differences between BeNe and OEC regarding clinical characteristics and dosing practices in patients prescribed edoxaban, which are relevant for the local implementation of dose evaluation and optimisation.

Trial registration

NCT02944019; Date of registration 24 October 2016
Setosphlides A–D, New Isocoumarin Derivatives from the Entomogenous Fungus Setosphaeria rostrate LGWB-10
Authors: Gao Wenbin , Wang Xiaoxia , Chen Fengli , Li Chunqing , Cao Fei , Luo Duqiang
Published: January 2021

Investigation of the entomogenous fungus Setosphaeria rostrate LGWB-10 from Harmonia axyridis led to the isolation of four new isocoumarin derivatives, setosphlides A–D (1–4), and four known analogues (5–8). Their planar structures and the relative configurations were elucidated by comprehensive spectroscopic methods. The absolute configurations of isocoumarin nucleus for 1–4 were elucidated by their ECD spectra. The C-10 relative configurations for the pair of C-10 epimers (1 and 2) were established by comparing the magnitude of the computed 13C NMR chemical shifts (Δδcalcd.) with the experimental 13C NMR values (Δδexp.) for the epimers. All of the isolated compounds (1–8) were evaluated for their cytotoxicities against four human tumor cell lines MCF-7, MGC-803, HeLa, and Huh-7.

Graphic Abstract
Pin-on-disc study of dry sliding behavior of Co-free HVOF-coated disc tested against different friction materials
Authors: Federici Matteo , Menapace Cinzia , Mancini Alessandro , Straffelini Giovanni , Gialanella Stefano
Published: January 2021

The dry sliding behavior of three commercial friction materials (codenamed FM1, FM2, and FM3) tested against a Co-free cermet coating produced by high-velocity oxy-fuel (HVOF) on gray cast-iron discs is investigated. FM1 is a conventional low-metallic friction material, FM2 is developed for using against HVOF-coated discs, and FM3 is a Cu-free friction material with a low content of abrasives and a relatively high concentration of steel fibers. For the tribological evaluation, they are tested on a pin-on-disc (PoD) test rig against Co-free HVOF-coated discs, with particular attention to the running-in stage, which is fundamental for the establishment of a friction layer between the two mating surfaces, i.e., the pin and disc. The PoD tests are performed at room temperature (RT) and a high temperature (HT) of 300 °C. At RT, all materials exhibit a long running-in stage. At HT, no running-in is observed in FM1 and FM2, whereas a shorter running-in period, with respect to the RT case, is observed in FM3 followed by the attainment of a comparatively high coefficient of friction. At RT, the pin wear is mild in all cases but severe at HT. FM3 shows the lowest wear rate at both temperatures. Moreover, the coated disc shows no wear when sliding against the FM3 friction material. All the results are interpreted considering the microstructural characteristics of the friction layers formed on the sliding surfaces. The findings of the present study provide insights into reducing wear in braking system components and hence reducing environmental particulate matter emissions from their wear, through the use of disc coatings.
Clinical Efficacy of a New Robot-assisted Gait Training System for Acute Stroke Patients
Authors: Chien Andy , Chang Fei-Chun , Meng Nai-Hsin , Yang Pei-Yu , Huang Ching , Chou Li-Wei
Published: January 2021

Purpose

Robot-assisted gait rehabilitation has been proposed as a plausible supplementary rehabilitation strategy in stroke rehabilitation in the last decade. However, its exact benefit over traditional rehabilitation remain sparse and unclear. It is therefore the purpose of the current study to comparatively investigate the clinical benefits of the additional robot-assisted training in acute stroke patients compared to standard hospital rehabilitation alone.

Methods

Ninety acute stroke patients (< 3 month) were recruited. All participants received the standard hospital neurorehabilitation comprises 45–60 min sessions daily for 3 weeks. Sixty patients also received an additional 30 min of robot-assisted gait training with the HIWIN MRG-P100 gait training system after each of the standard neurorehabilitation session. Outcome measures included: 1. Berg Balance Scale (BBS); 2. Brunnstrom Stage; 3. Pittsburgh Sleep Quality Index and 4. Taiwanese Depression Questionnaire (TDQ) which were assessed pre-treatment and then after every five training sessions.

Results

Both groups demonstrated significant improvement pre- and post-treatment for the BBS (robotic group p = 0.023; control group p = 0.033) but no significant difference (p > 0.1) between the groups were found. However, the robotic training group had more participants demonstrating larger BBS points of improvement as well as greater Brunnstrom stage of improvement, when compared to the control group. No significant within and between group statistical differences (p > 0.3) were found for Pittsburgh Sleep Quality Index and Taiwanese Depression Questionnaire.

Conclusion

The addition of robotic gait training on top of standard hospital neurorehabilitation for acute stroke patients appear to produce a slightly greater improvement in clinical functional outcomes, which is not transferred to psychological status.
Knowing Women
Authors: Dankwa Serena Owusua
Published: January 2021

Knowing Women is a study of same-sex desire in West Africa, which explores the lives and friendships of working-class women in southern Ghana who are intimately involved with each other. Based on in-depth research of the life histories of women in the region, Serena O. Dankwa highlights the vibrancy of everyday same-sex intimacies that have not been captured in a globally pervasive language of sexual identity. Paying close attention to the women's practices of self-reference, Dankwa refers to them as 'knowing women' in a way that both distinguishes them from, and relates them to categories such as lesbian or supi, a Ghanaian term for female friend. In doing so, this study is not only a significant contribution to the field of global queer studies in which both women and Africa have been underrepresented, but a starting point to further theorize the relation between gender, kinship, and sexuality that is key to queer, feminist, and postcolonial theories. This title is also available as Open Access on Cambridge Core.
Adaptations of the United Kingdom Takeover Panel in Hong Kong and Singapore: Convergence or Divergence?
Authors: ARMSON Emma
Published: January 2021

This article examines the transplantation of the Takeover Panel model from the United Kingdom into the takeover regulatory systems in Hong Kong and Singapore. It focuses on the extent to which this has resulted in formal convergence between the Takeover Panel in the UK and those established in Hong Kong and Singapore. Formal convergence is assessed in terms of the institutional structures of these Panels and is based on their independence and roles, the powers of the Panels and their Executives, and review of their decisions. Applying these criteria, this article concludes that there are medium levels of formal convergence with the UK Panel in both the Hong Kong and Singapore Panels. This article also examines functional convergence, namely the extent to which the Hong Kong and Singapore Panels operate similarly to the UK Panel in practice. In relation to the procedural rules and processes implemented by the Panels, this article concludes that there is a medium form of functional convergence in the case of the Hong Kong Panel, and a weak form of this for the Singapore Panel. Finally, the study of functional convergence in decision-making also includes an examination of the extent to which the Hong Kong and Singapore Panels refer explicitly to the UK approach in their decisions.
Correlation of pre-operative computed tomography, intra-operative findings and surgical outcomes in revision tympanomastoidectomy
Authors: Košec A , Matišić V , Gregurić T , Falak H , Ajduk J , Ries M
Published: January 2021

Objective

To correlate pre-operative computed tomography findings, intra-operative details and surgical outcomes with cholesteatoma recurrence in revision tympanomastoidectomy.

Methods

This retrospective, non-randomised, single-institution cohort study included 42 patients who underwent pre-operative computed tomography imaging and revision surgery for recurrent chronic otitis media. Twelve disease localisations noted during revision surgery were correlated with pre-operative temporal bone computed tomography scans. A matched pair analysis was performed on patients with similar intra-operative findings, but without pre-operative computed tomography scans.

Results

Pre-operative computed tomography identified 25 out of 31 cholesteatoma recurrences. Computed tomography findings correlated with: recurrent cholesteatoma when attic opacification and ossicular chain involvement were present; and revision surgery type. Sinodural angle disease, posterior canal wall erosion and dehiscent dura were identified as predictors of canal wall down tympanomastoidectomy. Patients with pre-operative computed tomography scans had a higher rate of cholesteatoma recurrence, younger age at diagnosis of recurrent disease, more revision surgical procedures and less time between previous and revision surgical procedures (all p < 0.05).

Conclusion

Pre-operative imaging and intra-operative findings have important clinical implications in revision surgery for chronic otitis media. Performing pre-operative computed tomography increases diagnosis accuracy and reduces the time required to diagnose recurrent disease.
Starting a new life in the South? Swiss, Dutch and Flemish ageing in Morocco: a lifecourse perspective
Authors: Bolzman Claudio , Fokkema Tineke , Guissé Ibrahima , van Dalen Danique
Published: January 2021

This article focuses on European migrants living in Morocco and now near retirement or retired. Using a lifecourse approach we are interested in whether their timing of migration to Morocco made a difference in terms of their motivations to settle there and subsequently with the social relationships at the destination. To this end, we conducted 36 biographical interviews with Swiss, Dutch and Belgian Flemish migrants aged 50 and older. Findings show the relevance of a lifecourse perspective for international migration studies. Early adulthood migrants to Morocco had no strong obligations in their home country and were ready to explore new affective or professional experiences in a new country. They had the time to discover and find a place in Moroccan society and to develop long-lasting social relationships with kin and non-kin. Middle-adulthood migrants moved with the intention of rapidly accessing a higher standard of living thanks to the tourism economy, with hedonistic perspectives in a setting with a better climate. Their social life is limited to interaction with business clients and a few like-minded migrants from Europe, and their communication with personnel is a daily challenge. Most late-in-life migrants experienced disruptive life events before migrating, and expected to find in Morocco a second chance to build a better life. They generally move in select circles of European expatriates.
Constructions of older people's identities in Indonesian regional ageing policies: the impacts on micro and macro experiences of ageing
Authors: Lestari Made Diah , Stephens Christine , Morison Tracy
Published: January 2021

As Indonesia experiences rapid growth of the ageing population, the government's attention has turned to the wellbeing of older people. This study aims to review critically the construction of older people's identity and care within regional ageing policies in Indonesia. Working from a critical gerontology perspective, a critical discourse analysis of 16 regional ageing policies identified two constructions, labelled ‘material’ and ‘cultural’ ageing, which were used to position older people. The analysis showed that ‘material ageing’ positions older people at the intersection of ‘decline’ and ‘successful ageing’ discourses, while ‘cultural ageing’ positions older people's welfare at the intersection of ‘public responsibility’ and ‘family obligation’ discourses. These discursive constructions in the policy documents have both micro (interpersonal) and macro (structural) constructive effects. At the micro-level, the regional ageing policies stand at a crossroad between empowering and marginalising older people and their families. While the dominant discourse of ‘successful ageing’ encourages older people to be healthy, it marginalises those who do not, or cannot, meet its criteria, undermining a rehabilitative approach as a policy priority. In addition, the rights of the family are overlooked, despite being a pivotal element of cultural ageing. At the macro level, a moral dilemma appears in defining the public and private domains of older people's welfare. Eligibility requirements for state assistance (due to budgetary constraints) ensure that elder care is often relegated to the private sphere, without support. Recommendations for policy improvement are discussed, including the recognition of families’ rights and the importance of local cultural practices in providing care for older people.
THE RELEVANCE OF PROPRIETY AND SELF-COMMAND IN ADAM SMITH’S THEORY OF MORAL SENTIMENTS
Authors: Montes Leonidas
Published: January 2021

Propriety and self-command are distinctive and complex Smithian concepts. This essay attempts to shed more light on the meaning and significance of propriety and the virtue of self-command. After a brief introduction on the recent reappraisal of The Theory of Moral Sentiments (TMS), a short analysis of Smith’s crucial idea of sympathy follows. Then the relevance of propriety is discussed and some connections between propriety and the virtue of self-command are explored. Finally, the importance of Smith’s self-command is reassessed, paying attention to its origins and philosophical implications. It is noteworthy that, through self-command and propriety, TMS stresses the role of intentions and motivations. By doing so, Adam Smith opens up new threads to rethink personal liberty and its ethical importance for political economy.
The Adaptation of Japanese Economic Statecraft: Trade, Aid, and Technology
Authors: Govella Kristi
Published: January 2021

This article examines how Japan has adapted economic statecraft to serve changing strategic aims through case studies of trade arrangements, official development assistance, and dual-use technology. After World War II, Japan continuously adapted these economic tools to pursue shifting non-economic goals related to international reintegration, comprehensive security, human security, and traditional security. More recently, in response to escalating US–China strategic competition, Japan has employed economic statecraft to simultaneously reduce international instability and to counter China in targeted ways as part of a broader hedging approach. First, Japan has attempted to bolster multilateral trade arrangements amid a volatile policy environment, while also using them to both engage and counter China. Second, Japan has used official development assistance to stabilize and build defense capacity in Asian countries facing pressure from China. Third, Japan has increasingly militarized its dual-use technologies to enhance its ability to respond to Chinese activity in outer space.
Re-emergence of Great Power Conflict and US Economic Statecraft
Authors: Weiss Linda
Published: January 2021

After almost two decades of dealing with asymmetric threats, America's strategic focus on technological superiority carefully honed during the Cold War, began to fracture, eroding its military and economic advantage. But China's recent emergence as a credible geopolitical rival has reinvigorated US efforts to sustain high-tech leadership as the basis of its military primacy. At the center of these efforts are the defense and defense-related agencies of the national security state (NSS) whose mission is to dominate the new technological frontiers of military power and achieve future competitive advantage. Alongside the quest for breakthroughs in foundational technologies, NSS agencies are seeking to correct long neglected deficiencies in advanced manufacturing, by rebuilding the industrial ecosystem's supply chains depleted after decades of offshoring. With this suite of initiatives, the US is following a course of action more consistent with the exercise of (economic) statecraft than industrial policy. However, unlike its authoritarian rival, the US faces the challenge of having to balance security imperatives with commercial interests and, not least, having to contend with a dysfunctional and maladapted presidency.
Backfire suppressed low profile aperture coupled stacked patch antenna backed by a high impedance surface (HIS) reflector for UHF RFID reader applications
Authors: Kim Sangkil
Published: January 2021

In this paper, a backfire suppressed aperture coupled circularly polarized (CP) stacked patch antenna for universal ultra-high frequency (UHF) radio frequency identification applications is presented. Cross-polarized backfire radiation patterns were successfully suppressed by a planar high impedance surface (HIS) reflector. The size of the fabricated antenna is 250 × 250 × 26.9 mm3 (0.71λ0 × 0.71λ0 × 0.076λ0) and its peak gain value of 7.1 dBi is measured. The distance between the antenna and the HIS reflector is only 4.8 mm (0.014 λ0). The HIS reflector suppressed cross-pol backfire radiations by about 10 dB. Detailed antenna and HIS reflector design are discussed thoroughly in this paper. The presented backfire suppression technique using the HIS reflector is scalable to other applications and frequency bands. This paper demonstrates the feasibility of the HIS structure at UHF band.
Hair cortisol levels in pregnancy as a possible determinant of fetal sex: a longitudinal study
Authors: Romero-Gonzalez Borja , Puertas-Gonzalez Jose A. , Gonzalez-Perez Raquel , Davila Marta , Peralta-Ramirez Maria Isabel
Published: January 2021

Stress during pregnancy has been widely studied and associated to different variables, usually with negative results for the health of the mother and the newborn, such as having a higher risk of suffering postpartum depression, premature birth, obstetrics complications or low birthweight, among others. However, there are not many lines of research that study the role that the sex of the baby plays on this specific stress and vice versa. Thus, the main objective was to analyse the relationship between the sex of the offspring and the stress of the mothers in the first trimester of pregnancy. In order to achieve this, 108 women had their biological stress measured (trough hair cortisol levels) and psychological stress evaluated (the Prenatal Distress Questionnaire (PSS), the Perceived Stress Scale (PDQ) and the Stress Vulnerability Inventory (IVE)). The results revealed significant differences in maternal hair cortisol levels in the first trimester based on the sex of the baby they had given birth to (t = −2.04; P < 0.05): the concentration of the hormone was higher if the baby was a girl (164.36:54.45-284.87 pg/mg) than if it was a boy (101.13:37.95-193.56 pg/mg). These findings show that the sex of the future baby could be conditioned, among many other variables, by the mother´s stress levels during conception and first weeks of pregnancy. Further research is needed in this area to support our findings.
Where do pre-service teachers' educational psychological misconceptions come from?
Authors: Menz Cordelia , Spinath Birgit , Seifried Eva
Published: January 2021

Abstract. Previous research has found a high prevalence of some (educational) psychological misconceptions (i.e., incorrect but often popular assumptions that contradict results from psychological research) among (pre-service) teachers. However, the number of topics that have been investigated is limited. Additionally, knowing the sources of misconceptions might be helpful for rebutting them. Furthermore, anecdotal evidence has been found to be important for informing (pre-service) teachers' practice, but personal experiences also are among the main sources of misconceptions. Therefore, we hypothesized that pre-service teachers would predominantly view sources of anecdotal evidence as the origin of their educational psychological beliefs in general and the main source of their misconceptions in particular. In an online survey (with correlational and quasi-experimental elements) of N = 836 pre-service teachers, we found that educational psychological misconceptions were less prevalent than expected but that pre-service teachers indeed mainly based their beliefs on sources of anecdotal evidence (personal experiences and narratives from other people) and that these nonscientific sources turned out to be the main sources of their misconceptions (comparison with scientific sources: d = 0.19 and d = 0.23). Furthermore, referring more to sources of anecdotal than scientific evidence (research and lectures) was associated with undesirable aspects, that is, more misconceptions ( d = 0.21) and less reduction of misconception endorsement through empirical refutation-style information ( d = 0.30) but not with a lower judgment of the view that it is possible to examine educational psychological topics scientifically. In sum, our results indicate that basing one's beliefs more on sources of anecdotal than scientific evidence is associated with outcomes that stand in contrast to evidence-based education. Future research should investigate why pre-service teachers concentrate on sources of anecdotal evidence, how to make sources of scientific evidence more tempting, and whether counteracting misconceptions by showing the downside of nonscientific sources is effective.
Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis
Authors: Kantarjian Hagop M. , Hughes Timothy P. , Larson Richard A. , Kim Dong-Wook , Issaragrisil Surapol , le Coutre Philipp , Etienne Gabriel , Boquimpani Carla , Pasquini Ricardo , Clark Richard E. , Dubruille Viviane , Flinn Ian W. , Kyrcz-Krzemien Slawomira , Medras Ewa , Zanichelli Maria , Bendit Israel , Cacciatore Silvia , Titorenko Ksenia , Aimone Paola , Saglio Giuseppe , Hochhaus Andreas
Published: January 2021

In the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.
A glycaemic index compendium of non-western foods
Authors: Henry Christiani Jeyakumar , Quek Rina Yu Chin , Kaur Bhupinder , Shyam Sangeetha , Singh Harvinder Kaur Gilcharan
Published: January 2021

Current international tables published on the glycaemic index (GI) of foods represent valuable resources for researchers and clinicians. However, the vast majority of published GI values are of Western origin, notably European, Australian and North American. Since these tables focus on Western foods with minimal inclusion of other foods from non-Western countries, their application is of limited global use. The objective of this review is to provide the GI values for a variety of foods that are consumed in non-Western countries. Our review extends and expands on the current GI tables in an attempt to widen its application in many other regions of the world.
Efficacy of telemedicine for persons with type 1 diabetes during Covid19 lockdown
Authors: Boscari Federico , Ferretto Sara , Uliana Ambra , Avogaro Angelo , Bruttomesso Daniela
Published: January 2021

Background

Starting March 2020 the Italian Government imposed a lockdown to limit the spread of SARS-CoV-2. During lockdown outpatient visits were limited and telemedicine (TM) was encouraged.

Methods

We retrospectively analyzed data from continuous or flash glucose monitoring systems shared through different cloud systems during the lockdown by subjects with type 1 diabetes and compared data obtained 4 weeks before and 4 weeks after structured telephonic visit. Variables considered were mean glucose, time spent in target (70–180 mg/dl), hypoglycemia (<70 mg/dl) and hyperglycemia (>180 mg/dl), coefficient of variation, and length of sensor use.

Results

During the 4 weeks following the telephonic visit there was an improvement of glycemic control, with a significant reduction of mean glucose values (161.1 before vs 156.3 mg/dl after, p = 0.001), an increase of the time spent in target (63.6 vs 66.3, p = 0.0009) and a reduction of time spent in hyperglycemia (33.4 vs 30.5, p = 0.002). No changes were observed regarding glucose variability, time spent in hypoglycemia, and length of sensor use. Similar results were observed in subjects treated with multiple daily injections or continuous subcutaneous insulin infusion.

Conclusions

A structured telephonic visit appears to be an effective way to replace or integrate routine visits in particular conditions.
Shifting uncertainty intolerance: methylphenidate and attention-deficit hyperactivity disorder
Authors: Mandali Alekhya , Sethi Arjun , Cercignani Mara , Harrison Neil A. , Voon Valerie
Published: January 2021

Risk evaluation is a critical component of decision making. Risk tolerance is relevant in both daily decisions and pathological disorders such as attention-deficit hyperactivity disorder (ADHD), where impulsivity is a cardinal symptom. Methylphenidate, a commonly prescribed drug in ADHD, improves attention but has mixed reports on risk-based decision making. Using a double-blinded placebo protocol, we studied the risk attitudes of ADHD patients and age-matched healthy volunteers while performing the 2-step sequential learning task and examined the effect of methylphenidate on their choices. We then applied a novel computational analysis using the hierarchical drift–diffusion model to extract parameters such as threshold (‘a’—amount of evidence accumulated before making a decision), drift rate (‘v’—information processing speed) and response bias (‘z’ apriori bias towards a specific choice) focusing specifically on risky choice preference. Critically, we show that ADHD patients on placebo have an apriori bias towards risky choices compared to controls. Furthermore, methylphenidate enhanced preference towards risky choices (higher apriori bias) in both groups but had a significantly greater effect in the patient population independent of clinical scores. Thus, methylphenidate appears to shift tolerance towards risky uncertain choices possibly mediated by prefrontal dopaminergic and noradrenergic modulation. We emphasise the utility of computational models in detecting underlying processes. Our findings have implications for subtle yet differential effects of methylphenidate on ADHD compared to healthy population.
A genome-wide methylation study reveals X chromosome and childhood trauma methylation alterations associated with borderline personality disorder
Authors: Arranz María J. , Gallego-Fabrega Cristina , Martín-Blanco Ana , Soler Joaquim , Elices Matilde , Dominguez-Clavé Elisabet , Salazar Juliana , Vega Daniel , Briones-Buixassa Laia , Pascual Juan Carlos
Published: January 2021

Borderline personality disorder (BPD) is a severe and highly prevalent psychiatric disorder, more common in females than in males and with notable differences in presentation between genders. Recent studies have shown that epigenetic modifications such as DNA methylation may modulate gene × environment interactions and impact on neurodevelopment. We conducted an epigenome wide study (Illumina Infinium HumanMethylation450k beadchip) in a group of BPD patients with (N = 49) and without (N = 47) childhood traumas and in a control group (N = 44). Results were confirmed in a replication cohort (N = 293 BPD patients and N = 114 controls) using EpiTYPER assays. Differentially methylated CpG sites were observed in several genes and intragenic regions in the X chromosome (PQBP1, ZNF41, RPL10, cg07810091 and cg24395855) and in chromosome 6 (TAP2). BPD patients showed significantly lower methylation levels in these CpG sites than healthy controls. These differences seemed to be increased by the existence of childhood trauma. Comparisons between BPD patients with childhood trauma and patients and controls without revealed significant differences in four genes (POU5F1, GGT6, TNFRSF13C and FAM113B), none of them in the X chromosome. Gene set enrichment analyses revealed that epigenetic alterations were more frequently found in genes controlling oestrogen regulation, neurogenesis and cell differentiation. These results suggest that epigenetic alterations in the X chromosome and oestrogen-regulation genes may contribute to the development of BPD and explain the differences in presentation between genders. Furthermore, childhood trauma events may modulate the magnitude of the epigenetic alterations contributing to BPD.
Polygenic overlap and shared genetic loci between loneliness, severe mental disorders, and cardiovascular disease risk factors suggest shared molecular mechanisms
Authors: Rødevand Linn , Bahrami Shahram , Frei Oleksandr , Lin Aihua , Gani Osman , Shadrin Alexey , Smeland Olav B. , Connell Kevin S. O’ , Elvsåshagen Torbjørn , Winterton Adriano , Quintana Daniel S. , Hindley Guy F. L. , Werner Maren C. F. , Djurovic Srdjan , Dale Anders M. , Lagerberg Trine V. , Steen Nils Eiel , Andreassen Ole A.
Published: January 2021

Clinical and epidemiological evidence suggest that loneliness is associated with severe mental disorders (SMDs) and increases the risk of cardiovascular disease (CVD). However, the mechanisms underlying the relationship between loneliness, SMDs, and CVD risk factors remain unknown. Here we explored overlapping genetic architecture and genetic loci shared between SMDs, loneliness, and CVD risk factors. We analyzed large independent genome-wide association study data on schizophrenia (SCZ), bipolar disorder (BD), major depression (MD), loneliness and CVD risk factors using bivariate causal mixture mode (MiXeR), which estimates the total amount of shared variants, and conditional false discovery rate to evaluate overlap in specific loci. We observed substantial genetic overlap between SMDs, loneliness and CVD risk factors, beyond genetic correlation. We identified 149 loci jointly associated with loneliness and SMDs (MD n = 67, SCZ n = 54, and BD n = 28), and 55 distinct loci jointly associated with loneliness and CVD risk factors. A total of 153 novel loneliness loci were found. Most of the shared loci possessed concordant effect directions, suggesting that genetic risk for loneliness may increase the risk of both SMDs and CVD. Functional analyses of the shared loci implicated biological processes related to the brain, metabolic processes, chromatin and immune system. Altogether, the study revealed polygenic overlap between loneliness, SMDs and CVD risk factors, providing new insights into their shared genetic architecture and common genetic mechanisms.
White matter anisotropy and response to cognitive behavior therapy for posttraumatic stress disorder
Authors: Korgaonkar Mayuresh S. , Felmingham Kim L. , Klimova Aleksandra , Erlinger May , Williams Leanne M. , Bryant Richard A.
Published: January 2021

Trauma-focused cognitive behavior therapy (TF-CBT) is the gold standard treatment for posttraumatic stress disorder (PTSD), up to one-half of PTSD patients remain treatment non-responders. Although studies have used functional MRI to understand the neurobiology of treatment response, there is less understanding of the role of white matter brain structures in response to TF-CBT. Thirty-six treatment-seeking PTSD patients and 33 age-gender matched healthy controls completed diffusion-weighted imaging scans at baseline. Patients underwent nine sessions of TF-CBT treatment and PTSD symptom severity was assessed with the Clinician-Administered PTSD Scale before and after completing treatment. Patients were assessed to estimate the reduction in overall symptoms and also specifically fear and dysphoric symptoms of PTSD. Tract-based spatial statistical analyses were performed for the PTSD group to evaluate whole-brain correlations of fractional anisotropy (FA) with improvement in overall, fear, and dysphoric symptoms using non-parametric permutation inference testing (pFWE < 0.05). Next, we evaluated if these significant measures also characterized PTSD from controls. Greater improvement in dysphoric symptoms was found correlated with lower FA in white matter regions associated with the limbic system, frontal cortex, thalamic association and projection fibers, corpus callosum, and tracts related to the brainstem. White matter anisotropy was not found associated with either overall or fear symptoms. FA in the significant clusters was similar between PTSD and controls. White-matter related to key functional regions may also play an important role in response to TF-CBT. Our results underscore the heterogeneity of PTSD and the need to evaluate distinct symptom phenotypes in treatment studies.
PET evaluation of light-induced modulation of microglial activation and GLP-1R expression in depressive rats
Authors: Liu Yu , Wang Lizhen , Pan Donghui , Li Mingzhu , Li Yaoqi , Wang Yan , Xu Yuping , Wang Xinyu , Yan Junjie , Wu Qiong , Lu Lin , Yuan Kai , Yang Min
Published: January 2021

Light therapy has been accepted as a promising therapeutic choice for depression. Positron emission tomography (PET) combined with specific radiotracers has great benefits for revealing pathogenesis and developing therapeutics. This study aimed to investigate the influences of light therapy on microglial activation and glucagon-like peptide-1 receptor (GLP-1R) expression in the brain of depressive rats using [18F]DPA-714 and [18F]exendin-4 PET. The results showed that chronic unpredictable mild stress (CUMS)-induced depressive rats had poorer performance in behavioral tests compared to normal rats (p < 0.05) and the depressive-like behavior could be ameliorated by light therapy. Besides, depressive rats had significantly higher [18F]DPA-714 uptake and lower [18F]FDG uptake compare to normal rats in 11 and 9 regions of interest (ROIs) of the brain, respectively (p < 0.05). After 5 weeks of light therapy, higher [18F]FDG and [18F]exendin-4 uptake was observed in most ROIs of light therapy-treated depressive rats compared to untreated depressive rats (p < 0.05) and no significant differences existed in [18F]DPA-714 uptake between the two groups. This study demonstrated that light therapy can ameliorate depressive-like behavior, improve glucose metabolism, and halt the decline of brain GLP-1R expression of depressive rats, but have no effects on microglial activation caused by CUMS. Besides, this study validated that [18F]DPA-714 and [18F]exendin-4 PET have the potential for noninvasive evaluation of microglial activation and GLP-1R expression in the brain of depression.
Biallelic mutations in the death domain of PIDD1 impair caspase-2 activation and are associated with intellectual disability
Authors: Sheikh Taimoor I. , Vasli Nasim , Pastore Stephen , Kharizi Kimia , Harripaul Ricardo , Fattahi Zohreh , Pande Shruti , Naeem Farooq , Hussain Abrar , Mir Asif , Islam Omar , Girisha Katta Mohan , Irfan Muhammad , Ayub Muhammad , Schwarzer Christoph , Najmabadi Hossein , Shukla Anju , Sladky Valentina C. , Braun Vincent Zoran , Garcia-Carpio Irmina , Villunger Andreas , Vincent John B.
Published: January 2021

PIDD1encodes p53-Induced Death Domain protein 1, which acts as a sensor surveilling centrosome numbers and p53 activity in mammalian cells. Early results also suggest a role in DNA damage response where PIDD1 may act as a cell-fate switch, through interaction with RIP1 and NEMO/IKKg, activating NF-κB signaling for survival, or as an apoptosis-inducing protein by activating caspase-2. Biallelic truncating mutations in CRADD—the protein bridging PIDD1 and caspase-2—have been reported in intellectual disability (ID), and in a form of lissencephaly. Here, we identified five families with ID from Iran, Pakistan, and India, with four different biallelic mutations inPIDD1, all disrupting the Death Domain (DD), through which PIDD1 interacts with CRADD or RIP1. Nonsense mutations Gln863* and Arg637* directly disrupt the DD, as does a missense mutation, Arg815Trp. A homozygous splice mutation in the fifth family is predicted to disrupt splicing upstream of the DD, as confirmed using an exon trap. In HEK293 cells, we show that both Gln863* and Arg815Trp mutants fail to co-localize with CRADD, leading to its aggregation and mis-localization, and fail to co-precipitate CRADD. Using genome-edited cell lines, we show that these threePIDD1mutations all cause loss of PIDDosome function.Pidd1null mice show decreased anxiety, but no motor abnormalities. Together this indicates thatPIDD1mutations in humans may cause ID (and possibly lissencephaly) either through gain of function or secondarily, due to altered scaffolding properties, while complete loss of PIDD1, as modeled in mice, may be well tolerated or is compensated for.
AgRP neurons trigger long-term potentiation and facilitate food seeking
Authors: Wang Chunmei , Zhou Wenjun , He Yang , Yang Tiffany , Xu Pingwen , Yang Yongjie , Cai Xing , Wang Julia , Liu Hesong , Yu Meng , Liang Chen , Yang Tingting , Liu Hailan , Fukuda Makoto , Tong Qingchun , Wu Qi , Sun Zheng , He Yanlin , Xu Yong
Published: January 2021

Sufficient feeding is essential for animals’ survival, which requires a cognitive capability to facilitate food seeking, but the neurobiological processes regulating food seeking are not fully understood. Here we show that stimulation of agouti-related peptide-expressing (AgRP) neurons triggers a long-term depression (LTD) of spontaneous excitatory post-synaptic current (sEPSC) in adjacent pro-opiomelanocortin (POMC) neurons and in most of their distant synaptic targets, including neurons in the paraventricular nucleus of the thalamus (PVT). The AgRP-induced sEPCS LTD can be enhanced by fasting but blunted by satiety signals, e.g. leptin and insulin. Mice subjected to food-seeking tasks develop similar neural plasticity in AgRP-innervated PVT neurons. Further, ablation of the majority of AgRP neurons, or only a subset of AgRP neurons that project to the PVT, impairs animals’ ability to associate spatial and contextual cues with food availability during food seeking. A similar impairment can be also induced by optogenetic inhibition of the AgRP→PVT projections. Together, these results indicate that the AgRP→PVT circuit is necessary for food seeking.
Alcohol use disorder causes global changes in splicing in the human brain
Authors: Van Booven Derek , Mengying Li  , Sunil Rao J. , Blokhin Ilya O. , Dayne Mayfield R. , Barbier Estelle , Heilig Markus , Wahlestedt Claes
Published: January 2021

Alcohol use disorder (AUD) is a widespread disease leading to the deterioration of cognitive and other functions. Mechanisms by which alcohol affects the brain are not fully elucidated. Splicing constitutes a nuclear process of RNA maturation, which results in the formation of the transcriptome. We tested the hypothesis as to whether AUD impairs splicing in the superior frontal cortex (SFC), nucleus accumbens (NA), basolateral amygdala (BLA), and central nucleus of the amygdala (CNA). To evaluate splicing, bam files from STAR alignments were indexed with samtools for use by rMATS software. Computational analysis of affected pathways was performed using Gene Ontology Consortium, Gene Set Enrichment Analysis, and LncRNA Ontology databases. Surprisingly, AUD was associated with limited changes in the transcriptome: expression of 23 genes was altered in SFC, 14 in NA, 102 in BLA, and 57 in CNA. However, strikingly, mis-splicing in AUD was profound: 1421 mis-splicing events were detected in SFC, 394 in NA, 1317 in BLA, and 469 in CNA. To determine the mechanism of mis-splicing, we analyzed the elements of the spliceosome: small nuclear RNAs (snRNAs) and splicing factors. While snRNAs were not affected by alcohol, expression of splicing factor heat shock protein family A (Hsp70) member 6 (HSPA6) was drastically increased in SFC, BLA, and CNA. Also, AUD was accompanied by aberrant expression of long noncoding RNAs (lncRNAs) related to splicing. In summary, alcohol is associated with genome-wide changes in splicing in multiple human brain regions, likely due to dysregulation of splicing factor(s) and/or altered expression of splicing-related lncRNAs.
Effects of cortisol administration on craving during in vivo exposure in patients with alcohol use disorder
Authors: Soravia Leila M. , Moggi Franz , de Quervain Dominique J.-F.
Published: January 2021

Alcohol-associated memories and craving play a crucial role in the development and maintenance of alcohol use disorder (AUD). As treatment options are limited in AUD, novel treatment strategies focus on the manipulation of alcohol-associated memories. The stress hormone cortisol affects various memory processes, and first clinical studies have shown that it inhibits the retrieval of disorder-specific memories and enhances extinction memory. This study aimed to investigate the effects of a single oral administration of cortisol on craving in patients with AUD during repeated in vivo exposure to alcohol pictures and the preferred alcoholic drink. In a double-blind, block-randomized, placebo-controlled cross-over design, 46 patients with AUD were treated with two sessions of in vivo exposure to alcohol. Cortisol (20 mg) or placebo was orally administered 1 h before each test day. Craving, stress, and cortisol were repeatedly measured during exposure sessions. Results show, that cortisol administration had distinct effects on craving depending on the severity of AUD and test day. While cortisol administration significantly enhanced craving during exposure on the first test day in patients with less severe AUD, it reduced craving in patients with more severe AUD. Independent of the cortisol administration, repeated in vivo exposure reduced craving from test day 1 to test day 2. In conclusion, adding cortisol to in vivo exposure might be a promising approach for reducing the strength of alcohol-associated memories and might promote the consolidation of extinction memory in patients with severe AUD. However, the differential effect of cortisol on craving depending on AUD severity cannot be conclusively explained and highlights the need for future studies elucidating the underlying mechanism.
Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma
Authors: Merdan Selin , Subramanian Kritika , Ayer Turgay , Van Weyenbergh Johan , Chang Andres , Koff Jean L. , Flowers Christopher
Published: January 2021

The clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.