bluuebunny/crossref_metadata_2025 huggingface dataset:
Early ambulatory Duchenne muscular dystrophy: First symptomatic stage of ambulation - A case report
Authors: Solichin Iman , Prabowo Ido , Laras Sashia , Dwi Putra Nurmansyah Hata , Rhatomy Sholahuddin
Published: May 2021

ABSTRACT

Introduction and importance:

Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease, affected male at young age, progressive and deteriorating symptoms followed the age and usually died in age 20. The early sign of DMD or early ambulatory DMD appeared lately after walking age, and progressively deteriorated by the time of aging.

Case presentation:

A 9 years old boy with symptoms of waddling gait, toe walking and difficulty to climb the stairs came to our center to seek medical help. He initially walked with assistance at 18 months, but always fell down when he tried to walk for distance. No family history of developmental delay. He still has the ability to stand up after sitting on the floor and run even with the difficulty. Behavioral problem or academic achievement was according to his age. The way he did to get down the stairs, he had to sit down and the get back up when he finished. His parents’ status of economic and education is low, which brought them difficult to understand their child is in suffer.

Clinical discussion:

The diagnosis and staging of DMD are quite challenging. A consistency and knowledge to gathered all the information related to history, symptoms, and signs provided the qualified data to overcome the complexity of the case, and to managed the spectrum of the disease appropriately, thus avoid the unnecessary treatment. The symptomatic stage of DMD is distinguished by the spectrum of ambulation. The effective and efficacy of the treatment are depending on good clinical assessment of neuromuscular function. Multidisciplinary team to diagnose and manage the case was needed to create to solve the problem became easier.

Conclusion:

The early ambulatory DMD is the first symptomatic early warning signs to treat DMD. The oral corticosteroids believed could mainstay the functional outcome the upper limb, avoid severe scoliosis, and maintain the respiratory function as normal as possible. Occupational and physical therapies were proposed to maintain the good quality of life.
Does ATLS Training Work? 10-Year Follow-Up of ATLS India Program
Authors: Rattan Amulya , Gupta Amit , Kumar Subodh , Sagar Sushma , Sangi Suresh , Bannerjee Neerja , Nambiar Radhesh , Jain Vinod , Ravi Parli , Misra Mahesh C.
Published: May 2021

BACKGROUND:

Studies evaluating the efficacy of ATLS in low- and middle-income countries are limited. We followed up ATLS providers certified by the ATLS India program over a decade (2009 to 2019), aiming to measure the benefits in knowledge, skills, attitude and their attrition over time.

METHODS:

The survey instrument was developed taking a cue from published literature on ATLS and improvised using the Delphi method. Randomly selected ATLS providers were sent the survey instrument via email as a Google form, along with a statement of purpose. Results are presented descriptively.

RESULTS:

ATLS India trained 7,847 providers over the study period. 2500 providers were selected for the survery using computer-generated random number table. One thousand and thirty doctors (41.2%) responded. Improvement in knowledge (n = 1,013 [98.3%]), psychomotor skills (n = 986 [95.7%]), organizational skills (n = 998 [96.9%]), overall trauma management (n = 1,013 [98.7%]) and self-confidence (n = 939 [91%]) were reported. Majority (904 [87.8%]) started ATLS promulgation at workplace in personal capacity. These benefits lasted beyond 2 years in majority (>60%) of respondents. More than 40% reported cognitive (n = 492 [47.8%]), psychomotor (n = 433 [42%]), and organizational benefits (n = 499 [48.4%]) lasting beyond 3 years. Improvement in self-confidence, ATLS promulgation at the workplace, and retention of organizational skills were more pronounced in ATLS faculties than providers. All other benefits were found to be comparable in both sub-groups. Lack of trained staff (n = 660 [64.1%]) and attitude issues (n = 495 [48.1%]) were the major impediments in implementing ATLS at the workplace. More than a third of respondents (n = 373 [36.2%]) could enumerate one or more incidents where ATLS principles were life- or limb- saving.

CONCLUSIONS:

Cognitive, psychomotor, organizational, and affective impact of ATLS is overwhelmingly positive in the Indian scenario. Until formal trauma systems are established, ATLS remains the best hope for critically injured patients in resource-contrained settings.
A Multi-Platform Approach to Monitoring Negative Dominance for COVID-19 Vaccine-Related Information Online
Authors: Pascual-Ferrá Paola , Alperstein Neil , Barnett Daniel J.
Published: May 2021

Objective:

The aim of this study was to test the appearance of negative dominance in coronavirus disease (COVID-19) vaccine-related information and activity online. We hypothesized that if negative dominance appeared, it would be a reflection of peaks in adverse events related to the vaccine, that negative content would attract more engagement on social media than other vaccine-related posts, and posts referencing adverse events related to COVID-19 vaccination would have a higher average toxicity score.

Methods:

We collected data using Google Trends for search behavior, CrowdTangle for social media data, and Media Cloud for media stories, and compared them against the dates of key adverse events related to COVID-19. We used Communalytic to analyze the toxicity of social media posts by platform and topic.

Results:

While our first hypothesis was partially supported, with peaks in search behavior for image and YouTube videos driven by adverse events, we did not find negative dominance in other types of searches or patterns of attention by news media or on social media.

Conclusion:

We did not find evidence in our data to prove the negative dominance of adverse events related to COVID-19 vaccination on social media. Future studies should corroborate these findings and, if consistent, focus on explaining why this may be the case.
COVID-19 in Patients With a Past History of Chemical War Injury: A Cross-Sectional Study in Southern Iran
Authors: Emami Amir , Pezeshkian FatemehSadat , Javanmardi Fatemeh , Akbari Ali , Asadi-Pooya Ali A.
Published: May 2021

Objective:

This study aimed to determine whether COVID-19 is associated with a different presenting clinical picture or a more severe course of illness in people with a past history of chemical war injury.

Methods:

This is a multicenter retrospective study in Fars Province, Iran, from August 22 to October 4, 2020. People with a past history of chemical war injury and COVID-19 were studied. Two age- and sex-matched control groups, double the size of the patient group each, from the same database of patients with COVID-19 who were hospitalized at the same time (ie, healthy controls and pseudocontrols).

Results:

A total of 46 people with a past history of chemical war injury, 92 healthy controls, and 92 pseudocontrols were studied. People with COVID-19 and a past history of chemical war injury had a significantly higher rate of chest pain compared with others. There were no other clinical differences between the groups. Mortality rate was 17.39%, 15.21%, and 27.17% in people with a past history of chemical war injury, the control group, and the pseudocontrol group, respectively.

Conclusions:

A past history of a chemical war injury does not add to the risk of COVID-19 and does not significantly modify its clinical picture either.
Place-Based Philosophical Activism on the US–Mexico Border
Authors: Alessandri Mariana
Published: May 2021

Before the Department of Homeland Security instituted the Migrant Protection Protocols in January 2019, as many as 1,000 Central American refugees passed each day through Catholic Charities’ Humanitarian Respite Center, where they received food, clothing, a shower, toiletries, and sandwiches for the road. Sister Norma Pimentel founded the Humanitarian Respite Center in 2014 to “restore human dignity” to refugees who had been degraded and vilified during their dangerous journeys north, not least by way of their processing by the US government. Sister Norma has inspired countless people, including me, to engage with the community as a form of place-based philosophical activism, that is, of situated and engaged teaching, scholarship, and service. In this essay I read Sister Norma as a feminist pragmatist in the historical and philosophical lineage of Jane Addams, and I aim to provide an example of how a feminist-pragmatist approach can support and encourage philosophical activism in our communities. Feminist scholars can learn from feminist pragmatism the importance of “being-with,” “sympathetic understanding,” and “a larger social impulse.” Feminist pragmatism encourages academics to become place-based philosophical activists who use their teaching, research, and service in order to press for social justice.
Grace Lee Boggs's Person-Centered Education for Community-Based Change: Feminist Pragmatism, Pedagogy, and Philosophical Activism
Authors: Varner Tess
Published: May 2021

This paper offers an overview of Grace Lee Boggs's community-based and person-centered philosophy and pedagogy, highlighting how education can foster social responsibility and create democratic habits in students, better equipping them to create radical change within their communities. The essay demonstrates Boggs's commitment to philosophical-activist pedagogy and its alignment with a feminist-pragmatist approach, which emphasizes lived experience, pluralism, complexity, and equality, as well as praxis. The essay then considers how Boggs's philosophical activism can be enacted inside and outside the traditional classroom, concluding by describing an educational and activist project called Narrative 4.
Feasibility of implementing antimicrobial stewardship programs in acute-care hospitals: A nationwide survey in Thailand
Authors: Rattanaumpawan Pinyo , Samanloh Surangkana , Thamlikitkul Visanu
Published: May 2021

A nationwide survey was conducted in 399 acute-care hospitals in Thailand. Most had a designated antimicrobial stewardship program (ASP), but <20% had an infectious disease physician on the team. The most frequently cited challenges in ASP implementation were the increased workload, followed by a lack of antimicrobial stewardship knowledge and a lack of hospital administrator concern.
Reconsidering the Age and Typological Character of “Pox Pottery” from Guerrero, Mexico
Authors: Kennett Douglas J. , Voorhies Barbara , Gomez Josue
Published: May 2021

We revisit the age and typological character of “Pox Pottery” that was reported in the 1960s by Charles Brush who considered it to be uniquely early (~2440 BC). Investigating the same two sites in coastal Guerrero where Brush excavated, we recovered Early Formative ceramics, some with the “pox” attribute. Here, we report potsherd frequencies for these deposits at both sites according to regional ceramic typologies, as well as AMS 14C dates used to establish a Bayesian stratigraphic chronology for each site to better constrain the age of these Early Formative period deposits. We argue that “Pox Pottery” is not a ceramic type per se and that the “pox” attribute occurs in multiple Early Formative period ceramic types. The earliest pottery is similar to other Red-on-Buff ceramic traditions from the Central Mexican Highlands and west of the Isthmus of Tehuantepec. Our chronological work demonstrates that these ceramics date between 1820 and 1400 cal BC, consistent with other recent studies indicating an early age of Red-on-Buff ceramics and suggesting shared cultural traditions distinct from the contemporary Locona interaction sphere that emerged in parallel.
Deep in the systematics of Camallanidae (Nematoda): using integrative taxonomy to better understand the phylogeny and consistency of diagnostic traits
Authors: Ailán-Choke Lorena G. , Pereira Felipe B.
Published: May 2021

Due to conflicts between classic and molecular systematics of Camallanidae, different data types were used for the first time, to better understand the evolutionary history and taxa consistency within this family. Genetic [18S and 28S rDNA; cytochrome c oxidase subunit I (COI) mtDNA], morphological and life history traits were used to infer phylogenies using Bayesian inference, reconstructed from separated and concatenated datasets. The consistency of tree and morphological traits was evaluated using the consistency index. Characters were mapped on the trees and the phylogenetic informativeness of genetic markers was estimated. Phylogenetic informativeness of 18S provided better resolution for outer nodes, COI for inners and 28S had an intermediate profile. New sequences for two camallanid species were obtained. Phylogenies of genetic and concatenated data largely agreed, showing more divergence in the COI dataset, due to its higher mutation rate vs stable morphology for diagnosing higher taxa. No genus sustained monophyly. The lack of autapomorphy and phylogenetic proximity supported the partition of Batrachocamallanus as synonym of Procamallanus and Spirocamallanus, which should not be considered as subgenera. Although traits of buccal capsule, male tail, habitat, host and biogeographic were highly consistent, intrinsic patterns varied according to different taxa assemblages. Morphological systematics of Camallanidae, based on buccal capsule, is artificial for certain taxa.
Archibald “Stewart” Hunter MBChB, FRCP(Ed) FRCP(Glas), DCH, 7 March, 1936-18 February, 2021
Authors: Wyllie Jonathan
Published: May 2021

Stewart Hunter was born in 1936 in Comrie, Perthshire. He was the son of Margaret (Peggy) and Archibald Hunter who was a minister in the Church of Scotland and later became Professor of New Testament Theology at the University of Aberdeen. Whilst Stewart chose medicine over the Kirk, he still studied at Aberdeen University. Following qualification in 1960, he chose to specialise in Paediatric Cardiology moving his family to London to learn how to treat children born with heart malformations at Great Ormond Street. Subsequently, he and the family moved back north to Edinburgh to continue that speciality at the Sick Children’s Hospital. In 1969, he was appointed as a lecturer in paediatric cardiology in the academic department of Newcastle University. Between 1972 and 1973, he and the family went to a research post in the United States of America in Pennsylvania where he was part of a team researching and publishing on the use of cineangiography in adults, a technique which he then extended with Dr Mike Tynan to children and infants upon his return to Newcastle. He returned to a second consultant post at Newcastle General Hospital, where the North East Clinical Paediatric Cardiology department was sited before moving to the new purpose built department of Paediatric Cardiology at Freeman Hospital, Newcastle upon Tyne in 1977. His career is a list of achievements which is perhaps most notable for the many clinicians of varying backgrounds with whom he collaborated, supported, taught and developed over the years.
Distinguishing between rumination and intrusive memories in PTSD using a wearable self-tracking instrument: a proof-of-concept case study
Authors: Arendt Ida-Marie T. P. , Riisager Lisa H. G. , Larsen Jakob E. , Christiansen Thomas B. , Moeller Stine B.
Published: May 2021

Rumination has been shown to play a part in post-traumatic stress disorder (PTSD), but its relation to the intrusions characteristic of PTSD has mainly been investigated experimentally. This proof-of-concept case study explored the occurrence, personal experiences, and possible relation between rumination and intrusions in two PTSD patients in their daily living using a mixed method approach. A novel wearable self-tracking instrument was employed which provided fine-grained temporal resolution of observation data and could eliminate recall bias. Furthermore, quantitative and qualitative data were collected on participants’ symptoms, rumination and experiences of using the self-tracking instrument. First, without distinguishing between the two phenomena, the participants tracked both for a week. After receiving psychoeducational training for distinguishing between rumination and intrusions, the differentiated phenomena were tracked for a week. Both participants reported being subjectively able to distinguish between rumination and intrusions and made observations with high adherence during the project. Data hinted at a possible temporal relation between the phenomena in line with theories posing rumination as a maladaptive coping strategy as well as an exacerbator of PTSD symptoms. However, relations to mood were inconclusive. Furthermore, by using the self-tracking instrument, participants gained a heightened awareness of the characteristics of rumination and intrusions and contextual cues for occurrence, as well as a greater sense of momentary agency. Results reveal promising prospects in using the wearable self-tracking instrument for further investigation of the relation between rumination and intrusions in the lived lives of PTSD patients, as well as potential for incorporating this method in clinical treatment.

Key learning aims

(1)

Self-tracking with the One Button Tracker is a novel symptom registration method, particularly suited for use in psychotherapeutic treatment and research.

(2)

Rumination and intrusions appear to the participants as distinct cognitive phenomena and treatment targets in PTSD.

(3)

Registering rumination and intrusions in real-time could reveal important temporal relations between them and the contexts in which they occur.

(4)

The data obtained with this self-tracking method can potentially be used as a tool in, and for the further development of psychotherapy for PTSD.
Hygrometric Control on the Lithosphere‐Asthenosphere Boundary: A 28 Million Year Record From the Canadian Cordillera
Authors: Canil Dante , Hyndman Roy D. , Fode Dominic
Published: May 2021

The depth to the lithosphere‐asthenopshere boundary (LAB) provides a strong control on the temperature and strength of the lithosphere and its susceptibility to tectonic deformation. We probe the nature of the LAB by deriving the depth and source of mantle‐xenolith bearing alkaline lavas aged 28 Ma to 8 ka in the Canadian Cordillera (CC). We document a striking coincidence of the average depth of equilibration of these lavas (65 ± 5 km) with the seismically observed LAB both in the CC and in western USA, and the change in H2O storage capacity at the spinel‐garnet transition of fertile peridotite under the geothermal gradient of hot thin back arc regions. The convergence of these factors show the LAB of hot back arcs is hygrometrically controlled at this phase boundary, limiting the H2O to <150 ppm in the mantle lithosphere. Intraplate regions with a shallower LAB require more H2O and/or less fertile lithosphere.
Interplays Between Mantle Flow and Slab Pull at Subduction Zones in 3D
Authors: Guillaume B. , Funiciello F. , Faccenna C.
Published: May 2021

The understanding of the interactions between subduction‐induced mantle flow and background mantle flow (being global or regional) remains incomplete despite its potential impact on subduction dynamics and associated deformation. Here we present the results of three‐dimensional laboratory models of subduction zones at the scale of the upper mantle in which we systematically vary the plate's width and trench perpendicular background mantle flow. In particular, we test different mantle flow magnitudes and directions of flow, and evaluate their impact on the slab geometry in the vertical plane, trench shape evolution, and the superficial horizontal mantle deformation. While the chosen viscosity ratio between the convective mantle and the subducting plate in our models (∼100) is favorable to the deformation of the slab through mantle displacement, we show that the geometry of the slab in the vertical plane is only marginally affected by the imposed background flow. Instead, the background flow has a larger impact on the horizontal kinematics and deformation of the trench. It reduces along‐trench variations of trench kinematics, which in turn decreases trench curvature, and it largely disturbs the pattern of mantle deformation at slab edges, inhibiting the development of toroidal cells. We also show that the thickness of the convective layer (here, the upper mantle) controls the toroidal component of the mantle flow and the length scale of trench curvature for large subduction zones.
Impacts of Urbanization, Aerodynamic Roughness, and Land Surface Processes on the Extreme Heavy Rainfall Over Chennai, India
Authors: Rajeswari J. R. , Srinivas C. V. , Yesubabu V. , Hari Prasad D. , Venkatraman B.
Published: May 2021

In this study, the impacts of urban land surface processes on the extreme heavy rainfall event on December 01, 2015 over Chennai, located in north coastal Tamil Nadu, India are analyzed using convection permitting WRF simulations. A series of numerical experiments are conducted using different land cover data (USGS‐1992, NRSC‐2004, NRSC‐2015), aerodynamic roughness, and land surface models (LSM) to assess their sensitivity on the predicted rainfall. Results suggest that experiments with NRSC‐2015 with increased urban extent improved the rainfall prediction in terms of rainfall intensity and its distribution. Though temperatures, sensible heat, and planetary boundary layer height (PBLH) increased due to urbanization in both dry and wet phases, the humidity and convective available potential energy (CAPE) reduced during the dry phase suggesting thermal convection played a secondary role in rainfall. Considerable increase of surface drag, momentum transport, wind shear, and turbulent kinetic energy is found in simulations with updated land use and roughness, which determined the location of the cyclonic circulation, convergence, and maximum precipitation. LSM sensitivity experiments indicated that while the five‐layer model substantially increased the sensible heat, temperature, and PBLH, it reduced the moisture convergence and CAPE relative to Noah and Noah‐MP thus resulting in low rainfall. The simulation with Noah‐MP enhanced the low‐level shear and convergence over other LSMs thus produced a wide spread rainfall along the coast. Our results demonstrated that the momentum transport due to urban drag played a vital role by strengthening the low‐level convergence and moist convection, which caused heavy precipitation over Chennai.
Impacts of the Indo‐Pacific Warm Pool on Lower Stratospheric Water Vapor: Seasonality and Hemispheric Contrasts
Authors: Zhou Xin , Chen Quanliang , Li Yang , Zhao Yong , Lin Yuqi , Jiang Yangjie
Published: May 2021

Using time‐slice experiments performed with version 4 of the Whole Atmosphere Community Climate Model (WACCM4) and satellite observations, we investigate hemispheric differences in, and the seasonal dependence of, water vapor transport into the stratosphere in response to Indo‐Pacific warm pool (IPWP) sea‐surface temperature (SST) variations. Specifically, the amplitude of the lower stratospheric water vapor (SWV) response to a warmer (cooler) IPWP (i.e., IPWP Niño [Niña]) occurs mainly in boreal winter when the IPWP SST forcing is identical for different seasons, and the response in the northern tropics (NT) is greater than that in the southern tropics (ST). The seasonality in and hemispheric contrasts of the SWV response to IPWP Niño and IPWP Niña are traced to the tropical cold point temperature, including its zonally symmetric pattern associated with tropical upwelling and its zonally asymmetric features that manifest as the morphology of the coldest point region. Together with the seasonal variations in topical upwelling response, the morphology of the coldest point region, which is affected by equatorial planetary waves and the summer monsoon, determines the seasonality and NT‐ST contrasts in the SWV response to IPWP SST forcing. Among these factors, the importance of the climatological displacement of convective activity from the equator to NT associated with the summer monsoon is highlighted.
Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes
Authors: Modinos Gemma , Richter Anja , Egerton Alice , Bonoldi Ilaria , Azis Matilda , Antoniades Mathilde , Bossong Matthijs , Crossley Nicolas , Perez Jesus , Stone James M. , Veronese Mattia , Zelaya Fernando , Grace Anthony A. , Howes Oliver D. , Allen Paul , McGuire Philip
Published: May 2021

Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labeling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed up for a median of 15 months to determine functional outcomes with the global assessment of function (GAF) scale and clinical outcomes using the comprehensive assessment of at-risk mental states (CAARMS). CHR participants with poor functional outcomes (follow-up GAF < 65, n = 25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF ≥ 65, n = 25) (pfwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe = 0.035); the association was negative in CHR with poor outcomes (pfwe = 0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p = 0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.
EphA2–YES1–ANXA2 pathway promotes gastric cancer progression and metastasis
Authors: Mao Linfeng , Yuan Weijie , Cai Kaimei , Lai Chen , Huang Changhao , Xu Yi , Zhong Shangwei , Yang Chen , Wang Ran , Zeng Pengwei , Huang Heyuan , Chen Zhikang , Chen Zihua
Published: May 2021

Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a key member of the receptor tyrosine kinase (RTK) family, while YES Proto-Oncogene 1 (YES1) is a non-receptor tyrosine kinase (nRTK) and annexin A2 (ANXA2) belongs to the calcium-dependent phospholipid-binding protein family annexins. Here, we show that EphA2, YES1, and ANXA2 form a signal axis, in which YES1 activated by EphA2 phosphorylates ANXA2 at Tyr24 site, leading to ANXA2 activation and increased ANXA2 nuclear distribution in gastric cancer (GC) cells. Overexpression (OE) of YES1 increases, while knockdown (KD) of YES1 or ANXA2 decreases GC cell invasion and migration in vitro and tumor growth in mouse models. Reexpression of wildtype (WT) rather than mutant ANXA2 (Tyr24F) in ANXA2 knockdown (ANXA2-KD) GC cells restores YES1-induced cell invasion and migration, while neither WT nor mutant ANXA2 (Tyr24F) can restore cell invasion and migration in YES1-KD GC cells. In addition, the activation of EphA2–YES1–ANXA2 pathway is correlated with poor prognosis. Thus, our results establish EphA2–YES1–ANXA2 axis as a novel pathway that drives GC invasion and metastasis, targeting this pathway would be an efficient way for the treatment of GC.
Data-driven parcellation and graph theory analyses to study adolescent mood and anxiety symptoms
Authors: Ely Benjamin A. , Liu Qi , DeWitt Samuel J. , Mehra Lushna M. , Alonso Carmen M. , Gabbay Vilma
Published: May 2021

Adolescence is a period of rapid brain development when psychiatric symptoms often first emerge. Studying adolescents may therefore facilitate the identification of neural alterations early in the course of psychiatric conditions. Here, we sought to utilize new, high-quality brain parcellations and data-driven graph theory approaches to characterize associations between resting-state networks and the severity of depression, anxiety, and anhedonia symptoms—salient features across psychiatric conditions. As reward circuitry matures considerably during adolescence, we examined both Whole Brain and three task-derived reward networks. Subjects were 87 psychotropic-medication-free adolescents (age = 12–20) with diverse psychiatric conditions (n = 68) and healthy controls (n = 19). All completed diagnostic interviews, dimensional clinical assessments, and 3T resting-state fMRI (10 min/2.3 mm/TR = 1 s). Following high-quality Human Connectome Project-style preprocessing, multimodal surface matching (MSMAll) alignment, and parcellation via the Cole-Anticevic Brain-wide Network Partition, weighted graph theoretical metrics (Strength Centrality = CStr; Eigenvector Centrality = CEig; Local Efficiency = ELoc) were estimated within each network. Associations with symptom severity and clinical status were assessed non-parametrically (two-tailed pFWE < 0.05). Across subjects, depression scores correlated with ventral striatum CStr within the Reward Attainment network, while anticipatory anhedonia correlated with CStr and ELoc in the subgenual anterior cingulate, dorsal anterior cingulate, orbitofrontal cortex, caudate, and ventral striatum across multiple networks. Group differences and associations with anxiety were not detected. Using detailed functional and clinical measures, we found that adolescent depression and anhedonia involve increased influence and communication efficiency in prefrontal and limbic reward areas. Resting-state network properties thus reflect positive valence system anomalies related to discrete reward sub-systems and processing phases early in the course of illness.
Mesolimbic opioid-dopamine interaction is disrupted in obesity but recovered by weight loss following bariatric surgery
Authors: Karlsson Henry K. , Tuominen Lauri , Helin Semi , Salminen Paulina , Nuutila Pirjo , Nummenmaa Lauri
Published: May 2021

Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central µ-opioid receptor (MOR) downregulation and disruption of the interaction between MOR and dopamine D2 receptor (D2R) system in the ventral striatum. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying 20 healthy non-obese and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and D2R availability were measured using positron emission tomography (PET) with [11C]carfentanil and [11C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed on obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery. In the control subjects, MOR and D2R availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but the unaltered association in dorsal caudate (r = .43). The association between MOR and D2R availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss. Bariatric surgery and concomitant weight loss recover the interaction between MOR and D2R in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioral interventions for treating obesity.
Event-related brain response to visual cues in individuals with Internet gaming disorder: relevance to attentional bias and decision-making
Authors: Kim Bo-Mi , Lee Jiyoon , Choi A. Ruem , Chung Sun Ju , Park Minkyung , Koo Ja Wook , Kang Ung Gu , Choi Jung-Seok
Published: May 2021

This study investigated attentional bias toward game-related cues in Internet gaming disorder (IGD) using electrophysiological markers of late positive potential (LPP) and identifying the sources of LPP. In addition, the association between LPP and decision-making ability was investigated. The IGD (n = 40) and healthy control (HC;n = 39) participants viewed a series of game-related and neutral pictures, while their event-related potentials (ERPs) were recorded. LPPs were calculated as the mean amplitudes between 400 and 700 ms at the centro-parietal (CP3, CP1, Cpz, CP2, and CP4) and parietal (P3, P1, Pz, P2, and P4) electrode sites. The source activations of LPP were estimated using standardized low-resolution brain electromagnetic tomography (sLORETA). In addition, decision-making ability was evaluated by the Cambridge Gambling Task. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HC group. sLORETA showed that the IGD group was more active in the superior and middle temporal gyri, which are involved in social perception, than in the HC group, whereas it was less active in the frontal area. Individuals with IGD have deficits in decision-making ability. In addition, in the HC group, the lower the LPP when looking at the game-related stimuli, the better the quality of decision-making, but not in the IGD group. Enhanced LPP amplitudes are associated with emotional arousal to gaming cues and decision-making deficits in IGD. In addition, source activities suggest that patients with IGD perceive game-related cues as social stimuli. LPP can be used as a neurophysiological marker of IGD.
MicroRNA-dependent control of neuroplasticity in affective disorders
Authors: Martins Helena Caria , Schratt Gerhard
Published: May 2021

Affective disorders are a group of neuropsychiatric disorders characterized by severe mood dysregulations accompanied by sleep, eating, cognitive, and attention disturbances, as well as recurring thoughts of suicide. Clinical studies consistently show that affective disorders are associated with reduced size of brain regions critical for mood and cognition, neuronal atrophy, and synaptic loss in these regions. However, the molecular mechanisms that mediate these changes and thereby increase the susceptibility to develop affective disorders remain poorly understood. MicroRNAs (miRNAs or miRs) are small regulatory RNAs that repress gene expression by binding to the 3ʹUTR of mRNAs. They have the ability to bind to hundreds of target mRNAs and to regulate entire gene networks and cellular pathways implicated in brain function and plasticity, many of them conserved in humans and other animals. In rodents, miRNAs regulate synaptic plasticity by controlling the morphology of dendrites and spines and the expression of neurotransmitter receptors. Furthermore, dysregulated miRNA expression is frequently observed in patients suffering from affective disorders. Together, multiple lines of evidence suggest a link between miRNA dysfunction and affective disorder pathology, providing a rationale to consider miRNAs as therapeutic tools or molecular biomarkers. This review aims to highlight the most recent and functionally relevant studies that contributed to a better understanding of miRNA function in the development and pathogenesis of affective disorders. We focused on in vivo functional studies, which demonstrate that miRNAs control higher brain functions, including mood and cognition, in rodents, and that their dysregulation causes disease-related behaviors.
Genetic predisposition, Aβ misfolding in blood plasma, and Alzheimer’s disease
Authors: Stocker Hannah , Nabers Andreas , Perna Laura , Möllers Tobias , Rujescu Dan , Hartmann Annette M. , Holleczek Bernd , Schöttker Ben , Stockmann Julia , Gerwert Klaus , Brenner Hermann
Published: May 2021

Alzheimer’s disease is highly heritable and characterized by amyloid plaques and tau tangles in the brain. The aim of this study was to investigate the association between genetic predisposition, Aβ misfolding in blood plasma, a unique marker of Alzheimer associated neuropathological changes, and Alzheimer’s disease occurrence within 14 years. Within a German community-based cohort, two polygenic risk scores (clinical Alzheimer’s disease and Aβ42 based) were calculated, APOE genotype was determined, and Aβ misfolding in blood plasma was measured by immuno-infrared sensor in 59 participants diagnosed with Alzheimer’s disease during 14 years of follow-up and 581 participants without dementia diagnosis. Associations between each genetic marker and Aβ misfolding were assessed through logistic regression and the ability of each genetic marker and Aβ misfolding to predict Alzheimer’s disease was determined. The Alzheimer’s disease polygenic risk score and APOE ε4 presence were associated to Aβ misfolding (odds ratio, 95% confidence interval: per standard deviation increase of score: 1.25, 1.03–1.51; APOE ε4 presence: 1.61, 1.04–2.49). No association was evident for the Aβ polygenic risk score. All genetic markers were predictive of Alzheimer’s disease diagnosis albeit much less so than Aβ misfolding (areas under the curve: Aβ polygenic risk score: 0.55; AD polygenic risk score: 0.59; APOE ε4: 0.63; Aβ misfolding: 0.84). Clinical Alzheimer’s genetic risk was associated to early pathological changes (Aβ misfolding) measured in blood, however, predicted Alzheimer’s disease less accurately than Aβ misfolding itself. Genetic predisposition may provide information regarding disease initiation, while Aβ misfolding could be important in clinical risk prediction.
Economic burden of disease progression among multiple myeloma patients who have received transplant and at least one line of therapy in the US
Authors: Fonseca Rafael , Hagiwara May , Panjabi Sumeet , Yucel Emre , Buchanan Jacqueline , Delea Thomas
Published: May 2021

Effects of disease progression on healthcare resource utilization (HRU) and costs among multiple myeloma (MM) patients with ≥1 line of therapy (LOT) who received their first stem cell transplant (SCT) within 1 year of initial MM diagnosis were estimated using a large US claims database. Disease progression was defined as advancement to the next LOT, bone metastasis, hypercalcemia, soft tissue plasmacytoma, skeletal related events, acute kidney disease, or death within 12 months of LOT initiation. Annual HRU and costs in the first three LOTs (L1–L3) were compared for patients with versus without disease progression using inverse probability of treatment weighting to adjust for differences between groups in baseline characteristics. In all LOTs, mean annual hospitalizations and healthcare costs were greater for patients with versus without progression. Total incremental annual costs among patients with versus without progression in L1–L3 were $18,359, $87,055, and $71,917, respectively, among LOTs initiated between 2006 and 2018. In LOTs initiated between 2013 and 2018, the figures were $46,024, $100,329, and $101,942 in L1–L3, respectively. The economic burden of disease progression is substantial in this population of MM patients who underwent SCT and received systemic anti-myeloma therapy.
USP12 promotes CD4+ T cell responses through deubiquitinating and stabilizing BCL10
Authors: Fu Yuling , Wang Peng , Zhao Jingjing , Tan Yunke , Sheng Junli , He Shitong , Du Xialin , Huang Yulan , Yang Yalong , Li Jinling , Cai Yuxiong , Liu Yuxuan , Hu Shengfeng
Published: May 2021

Deubiquitinases (DUBs) regulate diverse biological processes and represent a novel class of drug targets. However, the biological function of only a small fraction of DUBs, especially in adaptive immune response regulation, is well-defined. In this study, we identified DUB ubiquitin-specific peptidase 12 (USP12) as a critical regulator of CD4+ T cell activation. USP12 plays an intrinsic role in promoting the CD4+ T cell phenotype, including differentiation, activation, and proliferation. Although USP12-deficient CD4+ T cells protected mice from autoimmune diseases, the immune response against bacterial infection was subdued. USP12 stabilized B cell lymphoma/leukemia 10 (BCL10) by deubiquitinating, and thereby activated the NF-κB signaling pathway. Interestingly, this USP12 regulatory mechanism was identified in CD4+ T cells, but not in CD8+ T cells. Our study results showed that USP12 activated CD4+ T cell signaling, and targeting USP12 might help develop therapeutic interventions for treating inflammatory diseases or pathogen infections.
MDM2 inhibitor APG-115 exerts potent antitumor activity and synergizes with standard-of-care agents in preclinical acute myeloid leukemia models
Authors: Fang Douglas D. , Tang Qiuqiong , Kong Yanhui , Rong Tao , Wang Qixin , Li Na , Fang Xu , Gu Jiaxing , Xiong Dengkun , Yin Yan , Deng Jing , Yang Dajun , Zhai Yifan
Published: May 2021

Acute myeloid leukemia (AML) is a clinically and genetically heterogeneous clonal disease associated with unmet medical needs. Paralleling the pathology of other cancers, AML tumorigenesis and propagation can be ascribed to dysregulated cellular processes, including apoptosis. This function and others are regulated by tumor suppressor P53, which plays a pivotal role in leukemogenesis. Opposing P53-mediated activities is the mouse double minute 2 homolog (MDM2), which promotes P53 degradation. Because the TP53 mutation rate is low, and MDM2 frequently overexpressed, in patients with leukemia, targeting the MDM2-P53 axis to restore P53 function has emerged as an attractive AML treatment strategy. APG-115 is a potent MDM2 inhibitor under clinical development for patients with solid tumors. In cellular cultures and animal models of AML, we demonstrate that APG-115 exerted substantial antileukemic activity, as either a single agent or when combined with standard-of-care (SOC) hypomethylating agents azacitidine (AZA) and decitabine (DAC), or the DNA-damaging agent cytarabine (Ara-C). By activating the P53/P21 pathway, APG-115 exhibited potent antiproliferative and apoptogenic activities, and induced cell cycle arrest, in TP53 wild-type AML lines. In vivo, APG-115 significantly reduced tumor burden and prolonged survival. Combinations of APG-115 with SOC treatments elicited synergistic antileukemic activity. To explain these effects, we propose that APG-115 and SOC agents augment AML cell killing by complementarily activating the P53/P21 pathway and upregulating DNA damage. These findings and the emerging mechanism of action afford a sound scientific rationale to evaluate APG-115 (with or without SOC therapies) in patients with AML.
Continued anti-VEGF treatment does not prevent recurrences in eyes with stable neovascular age-related macular degeneration using a treat-and-extend regimen: a retrospective case series
Authors: Garweg Justus G. , Traine Peter G. , Garweg Richard A. , Wons Juliana , Gerhardt Christin , Pfister Isabel B.
Published: May 2021

Background

The continuation of anti-vascular endothelial growth factor (anti-VEGF) treatment after achieving stability in patients with neovascular age-related macular degeneration has generally been advocated. In our own patients, we thought to assess whether continued anti-VEGF treatment is capable of preventing recurrences.

Methods

In this retrospective observational case series, patients with stable disease either opted to continue treatment every 12–14 weeks (Group 1) or stopped treatment with subsequent follow-up visits every 8–12 weeks (Group 2).

Results

Of the 103 eyes of 103 patients achieving stability, 49 eyes continued treatment (Group 1), whereas treatment was stopped in 54 eyes undergoing regular follow-up (Group 2). Recurrent disease was observed in 21 (42.9%) and 33 (61.1%) cases in Group 1 and Group 2, respectively (p = 0.08). Time between achieving stable disease and recurrence was comparable between Group 1 and Group 2 (11.1 ± 8.2 months vs. 9.2 ± 6.7 months; p = 0.43). The number of visits between achieving stability and disease recurrence was similar, but not the number of injections (3.5 ± 2.0 vs. 0.2 ± 0.4; p < 0.001).

Conclusions

Continuing anti-VEGF therapy after achieving functional and morphological stability every 12–14 weeks does not prevent recurrences. Patients deserve to be informed of a potential lifetime risk of recurrences, even under continued therapy.
Comparative transcriptome analyses shed light on carotenoid production and plastid development in melon fruit
Authors: Chayut Noam , Yuan Hui , Saar Yuval , Zheng Yi , Sun Tianhu , Zhou Xuesong , Hermanns Anna , Oren Elad , Faigenboim Adi , Hui Maixia , Fei Zhangjun , Mazourek Michael , Burger Joseph , Tadmor Yaakov , Li Li
Published: May 2021

Carotenoids, such as β-carotene, accumulate in chromoplasts of various fleshy fruits, awarding them with colors, aromas, and nutrients. The Orange (CmOr) gene controls β-carotene accumulation in melon fruit by posttranslationally enhancing carotenogenesis and repressing β-carotene turnover in chromoplasts. Carotenoid isomerase (CRTISO) isomerizes yellow prolycopene into red lycopene, a prerequisite for further metabolism into β-carotene. We comparatively analyzed the developing fruit transcriptomes of orange-colored melon and its two isogenic EMS-induced mutants, low-β (Cmor) and yofi (Cmcrtiso). The Cmor mutation in low-β caused a major transcriptomic change in the mature fruit. In contrast, the Cmcrtiso mutation in yofi significantly changed the transcriptome only in early fruit developmental stages. These findings indicate that melon fruit transcriptome is primarily altered by changes in carotenoid metabolic flux and plastid conversion, but minimally by carotenoid composition in the ripe fruit. Clustering of the differentially expressed genes into functional groups revealed an association between fruit carotenoid metabolic flux with the maintenance of the photosynthetic apparatus in fruit chloroplasts. Moreover, large numbers of thylakoid localized photosynthetic genes were differentially expressed in low-β. CmOR family proteins were found to physically interact with light-harvesting chlorophyll a–b binding proteins, suggesting a new role of CmOR for chloroplast maintenance in melon fruit. This study brings more insights into the cellular and metabolic processes associated with fruit carotenoid accumulation in melon fruit and reveals a new maintenance mechanism of the photosynthetic apparatus for plastid development.
Learning a genome-wide score of human–mouse conservation at the functional genomics level
Authors: Kwon Soo Bin , Ernst Jason
Published: May 2021

Identifying genomic regions with functional genomic properties that are conserved between human and mouse is an important challenge in the context of mouse model studies. To address this, we develop a method to learn a score of evidence of conservation at the functional genomics level by integrating information from a compendium of epigenomic, transcription factor binding, and transcriptomic data from human and mouse. The method, Learning Evidence of Conservation from Integrated Functional genomic annotations (LECIF), trains neural networks to generate this score for the human and mouse genomes. The resulting LECIF score highlights human and mouse regions with shared functional genomic properties and captures correspondence of biologically similar human and mouse annotations. Analysis with independent datasets shows the score also highlights loci associated with similar phenotypes in both species. LECIF will be a resource for mouse model studies by identifying loci whose functional genomic properties are likely conserved.