bluuebunny/crossref_metadata_2025 huggingface dataset:
A Unique Approach to Quality Improvement Within the Stroke System of Care Utilizing Developmental Evaluation
Authors: Zusevics Kaija L. , Kaemmerer Nicole (Nikke) , Lang Joshua , Link Jessica , Bluma Dorothy (Dot)
Published: April 2020

Stroke is a significant cause of death that requires multiple systems of care to work together to prevent incidence and improve patient outcomes. The Wisconsin Coverdell Stroke Program partnered with a Model Hospital to understand and improve the stroke system of care in one community. Developmental evaluation (DE) is an approach in which evaluators collaborate closely with project stakeholders to examine complex processes and systems within changeable contexts to develop interventions to improve outcomes. DE was used to assess this community’s stroke systems across the care continuum through process mapping with Model Hospital staff and through key stakeholder interviews with Model Hospital and emergency medical services staff, patients, and caregivers. Process mapping identified how patients and health care data flow through the system of care and highlighted areas where streamlining could improve the movement of patients and data across the care continuum. Interviews with stakeholders unveiled challenges and successes about how patient data are accessed and shared across the care continuum, and ideas for improving systems to be more efficient and supportive of stroke prevention and patient outcomes. Overall, DE was valuable in gaining an in-depth understanding of this complex environment to develop strategies to enhance stroke systems of care.
Ironic Effects of Thought Suppression: A Meta-Analysis
Authors: Wang Deming (Adam) , Hagger Martin S. , Chatzisarantis Nikos L. D.
Published: April 2020

The ironic effect of thought suppression refers to the phenomenon in which individuals trying to rid their mind of a target thought ironically experience greater levels of occurrence and accessibility of the thought compared with individuals who deliberately concentrate on the thought (Wegner, 1994, doi:10.1037/0033-295X.101.1.34). Ironic effects occurring after thought suppression, also known as rebound effects, were consistently detected by previous meta-analyses. However, ironic effects that occur during thought suppression, also known as immediate enhancement effects, were found to be largely absent. In this meta-analysis, we test Wegner’s original proposition that detection of immediate enhancement effects depends on the cognitive load experienced by individuals when enacting thought suppression. Given that thought suppression is an effortful cognitive process, we propose that the introduction of additional cognitive load would compete for the allocation of existing cognitive resources and impair capacity for thought suppression. Studies ( k = 31) consistent with Wegner’s original thought-suppression paradigm were analyzed. Consistent with our predictions, rebound effects were observed regardless of cognitive load, whereas immediate enhancement effects were observed only in the presence of cognitive load. We discuss implications in light of ironic-process theory and suggest future thought-suppression research.
HDL-C is associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose-response fashion: a pooled analysis of 37 prospective cohort studies
Authors: Zhong Guo-Chao , Huang Su-Qun , Peng Yang , Wan Lun , Wu You-Qi-Le , Hu Tian-Yang , Hu Jie-Jun , Hao Fa-Bao
Published: April 2020

Objective

The association between high-density lipoprotein cholesterol (HDL-C) levels and mortality remains controversial. We aimed to investigate the potential dose–response associations between HDL-C levels and mortality from all causes, cardiovascular disease and cancer in the general population.

Methods

PubMed and Embase were searched through April 2019. Prospective cohort studies reporting risk estimates of HDL-C levels and mortality were included. Linear and non-linear dose–response analyses were conducted. A random-effects model was employed to calculate pooled hazard ratio.

Results

Thirty-seven studies, involving 3,524,505 participants and more than 612,027 deaths, were included. HDL-C level was found to be associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose–response pattern, with the lowest risk observed at HDL-C levels of 54–58 mg/dL, 68–71 mg/dL and 64–68 mg/dL, respectively. Compared with HDL-C level of 56 mg/dL, the pooled hazard ratios for all-cause mortality were 1.03 (95% confidence interval (CI) 1.01, 1.05) and 1.10 (95% CI 1.09, 1.12) for each 10-mg/dL increase and decrease in HDL-C levels, respectively; furthermore, compared with the reference category, the pooled hazard ratios for all-cause mortality were 1.21 (95% CI 1.09, 1.36) and 1.36 (95% CI 1.21, 1.53) for the highest and the lowest categories of HDL-C levels, respectively. Similar results were obtained for cardiovascular and cancer mortality.

Conclusions

In the general population, HDL-C level is associated with mortality from all causes, cardiovascular disease and cancer in a J-shaped dose–response manner; both extremely high and low HDL-C levels are associated with an increased risk of mortality.
Concussion Incidence and Impact on Player Performance in Major League Baseball Players Before and After a Standardized Concussion Protocol
Authors: Peterson Joshua G. , Tjong Vehniah K. , Terry Michael A. , Saltzman Matthew D. , Gryzlo Stephen M. , Sheth Ujash
Published: April 2020

Background:

Sports-related concussions have garnered significant attention in recent years because of the negative effects they can have on a player’s cognitive health and performance. In response to this growing concern, Major League Baseball (MLB) introduced a standardized concussion protocol during the 2011-2012 season.

Purpose/Hypothesis:

The purpose of this study was to compare the reported incidence of concussions and the subsequent performance of MLB players before and after the introduction of the standardized concussion protocol. We hypothesized that the introduction of the standardized concussion protocol would not have an impact on player performance postconcussion.

Study Design:

Cohort study; Level of evidence, 3.

Methods:

Players who suffered a concussion between 2001 and 2018 were identified from the MLB transactions page. Incidence and player performance were compared before and after the introduction of the standardized concussion protocol. Player performance was evaluated using traditional data and sabermetric data, which are advanced statistics used in conjunction with standard statistics to better compare players and teams. Player averages were calculated and compared using paired t tests for 30 days before and after concussion, 1 year before and after concussion, and career before and after concussion. Averages were also compared before and after the institution of the standardized concussion protocol using independent-measures t tests.

Results:

There were a total of 114 players who suffered 142 concussions, with 77% of those occurring after the introduction of the concussion protocol (32 before, 110 after). The average time missed because of concussion significantly decreased from 33.7 days (range, 10-122 days) to 18.9 days (range, 6-111 days) after the concussion protocol ( P = .0005). There was no difference in player performance (including batting average, on-base percentage, and slugging for batters; earned run average, fielding-independent pitching, and walks plus hits per inning pitched for pitchers) after concussion at any time point (30 days, 1 year, or career) when comparing these statistics before versus after the MLB concussion protocol. However, batter performance was significantly poorer 1 year after concussion and over the remainder of the players' careers ( P < .05).

Conclusion:

The number of reported concussions increased after the introduction of the MLB concussion protocol. However, players spent significantly less time on the disabled list without any adverse effect on player performance. Despite these changes, long-term batting performance was significantly poorer after concussion.
Book review: Aakash Singh Rathore, Indian Political Theory: Laying the Groundwork for Svaraj
Authors: Yadav Vivek Kumar , Kumar Bharath
Published: April 2020

Aakash Singh Rathore, Indian Political Theory: Laying the Groundwork for Svaraj. New York, NY: Routledge, 2017, 232 pp., ₹495 (paperback). ISBN: 9781138240223.
Do Preoperative and Postoperative Glenoid Retroversion Influence Outcomes After Reverse Total Shoulder Arthroplasty?
Authors: Lansdown Drew , Cheung Edward C , Xiao Weiyuan , Lee Austin , Zhang Alan L , Feeley Brian T , Benjamin Ma C
Published: April 2020

Background

There are limited data on the effect of glenoid retroversion in clinical outcomes following reverse total shoulder arthroplasty (RTSA). The purpose of this study was to evaluate if surgical correction of retroversion affects outcomes following RTSA.

Methods

An institutional database was utilized to identify 177 patients (mean age: 68.2 ± 10.1 years) with minimum 2-year follow-up after primary RTSA. Glenoid version was measured on preoperative and postoperative radiographs. American Shoulder and Elbow Surgeons (ASES) scores and range of motion were collected before and after RTSA. Change in retroversion was determined by comparing preoperative and postoperative glenoid retroversion on radiographs using paired Wilcoxon signed-rank test. Spearman’s rank correlation was used to investigate relationships between ASES scores and glenoid retroversion.

Results

The mean postoperative ASES composite score (75.5 ± 22.7) was significantly higher than preoperative (36.8 ± 19.2; P < .0001). The mean preoperative glenoid retroversion was 9.1 ± 6.7° compared to 6.5 ± 5.1° postoperatively ( P < .0001). There was no correlation between postoperative ASES scores and preoperative retroversion ( r = .014, P = .85) or postoperative retroversion ( r = −.043, P = .57). There was no statistical relationship between postoperative retroversion and range of motion, though there is a risk of inadequate power given the sample size.

Conclusions

Patient-reported outcomes and range of motion measurements following RTSA at short-term follow-up appear to be independent of either preoperative or postoperative glenoid retroversion.
Blinatumomab consolidation and maintenance therapy in adults with relapsed/refractory B-precursor acute lymphoblastic leukemia
Authors: Rambaldi Alessandro , Huguet Francoise , Zak Pavel , Cannell Paul , Tran Qui , Franklin Janet , Topp Max S.
Published: April 2020

In a phase 3 clinical study of heavily pretreated adults with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL), overall survival (OS) following blinatumomab, a BiTE (bispecific T-cell engager) immunooncology therapy, was significantly improved vs chemotherapy following induction (cycles 1 to 2). Here we report the efficacy and safety of those who received additional cycles of blinatumomab. Blinatumomab was administered as a continuous IV infusion for 4 weeks in a 6-week cycle. Patients who achieved a bone marrow response (≤5% blasts) or complete remission (full, partial, or incomplete hematological recovery) during induction could receive additional cycles of blinatumomab. OS and relapse-free survival (RFS) for consolidation (cycles 3 to 5) vs no consolidation, and maintenance (cycles ≥6) vs no maintenance were analyzed using Simon-Makuch and Mantel-Byar odds ratios. Of 267 patients who received blinatumomab induction, 86 (32%) entered consolidation and 36 (13%) entered maintenance. Evidence of longer OS was demonstrated among the maintenance group compared with no-maintenance (median OS [95% confidence interval, CI]: not reached for maintenance vs 15.5 months for no maintenance). Median RFS (months; 95% CI) was numerically longer among maintenance group (14.5; 7.1 to 21.9) compared with no-maintenance (9.8; 8.5 to 11.1). A lower incidence of adverse events was seen during maintenance (72.2%) compared with induction (97.2%) and consolidation (86.1%). Adults with R/R ALL who achieved remission following blinatumomab induction had longer survival on continuation therapy than those who discontinued blinatumomab early, supporting the use of blinatumomab as long-term therapy. No new safety signals were reported. This trial was registered at www.clinicaltrials.gov as #NCT02013167.
Improving inbound logistic planning for large-scale real-world routing problems: a novel ant-colony simulation-based optimization
Authors: Calabrò Giovanni , Torrisi Vincenza , Inturri Giuseppe , Ignaccolo Matteo
Published: April 2020

This paper presents the first results of an agent-based model aimed at solving a Capacitated Vehicle Routing Problem (CVRP) for inbound logistics using a novel Ant Colony Optimization (ACO) algorithm, developed and implemented in the NetLogo multi-agent modelling environment. The proposed methodology has been applied to the case study of a freight transport and logistics company in South Italy in order to find an optimal set of routes able to transport palletized fruit and vegetables from different farms to the main depot, while minimizing the total distance travelled by trucks. Different scenarios have been analysed and compared with real data provided by the company, by using a set of key performance indicators including the load factor and the number of vehicles used. First results highlight the validity of the method to reduce cost and scheduling and provide useful suggestions for large-size operations of a freight transport service.
Functional, neuroplastic and biomechanical changes induced by early Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (e-HABIT-ILE) in pre-school children with unilateral cerebral palsy: study protocol of a randomized control trial
Authors:   Early HABIT-ILE group, Araneda R. , Sizonenko S. V. , Newman C. J. , Dinomais M. , Le Gal G. , Nowak E. , Guzzetta A. , Riquelme I. , Brochard S. , Bleyenheuft Y.
Published: April 2020

Background

Cerebral palsy (CP) causes motor, cognitive and sensory impairment at different extents. Many recent rehabilitation developments (therapies) have focused solely on the upper extremities (UE), although the lower extremities (LE) are commonly affected. Hand-arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) applies the concepts of motor skill learning and intensive training to both the UE and LE. It involves constant stimulation of the UE and LE, for several hours each day over a 2-week period. The effects of HABIT-ILE have never been evaluated in a large sample of young children. Furthermore, understanding of functional, neuroplastic and biomechanical changes in infants with CP is lacking. The aim of this study is to carry out a multi-center randomized controlled trial (RCT) to evaluate the effects of HABIT-ILE in pre-school children with unilateral CP on functional, neuroplastic and biomechanical parameters.

Methods

This multi-center, 3-country study will include 50 pre-school children with CP aged 1–4 years. The RCT will compare the effect of 50 h (two weeks) of HABIT-ILE versus usual motor activity, including regular rehabilitation. HABIT-ILE will be delivered in a day-camp setting, with structured activities and functional tasks that will be continuously progressed in terms of difficulty. Assessments will be performed at 3 intervals: baseline (T0), two weeks later and 3 months later. Primary outcomes will be the Assisting Hand Assessment; secondary outcomes include the Melbourne Assessment-2, executive function assessments, questionnaires ACTIVLIM-CP, Pediatric Evaluation of Disability Inventory, Young Children’s Participation and Environment Measure, Measure of the Process of Care, Canadian Occupational Performance Measure, as well as neuroimaging and kinematics measures.

Discussion

We expect that HABIT-ILE will induce functional, neuroplastic and biomechanical changes as a result of the intense, activity-based rehabilitation process and these changes will impact the whole developmental curve of each child, improving functional ability, activity and participation in the short-, mid- and long-term.

Name of the registry: Changes Induced by Early HABIT-ILE in Pre-school Children With Uni- and Bilateral Cerebral Palsy (EarlyHABIT-ILE).

Trial registration

Trial registration number: NCT04020354-Registration date on the International Clinical Trials Registry Platform (ICTRP): November 20th, 2018; Registration date on NIH Clinical Trials Registry: July 16th, 2019.
Challenges in diagnosis and management of neutropenia upon exposure to immune-checkpoint inhibitors: meta-analysis of a rare immune-related adverse side effect
Authors: Boegeholz J. , Brueggen C. S. , Pauli C. , Dimitriou F. , Haralambieva E. , Dummer R. , Manz M. G. , Widmer C. C.
Published: April 2020

Background

Cancer immunotherapy via immune-checkpoint inhibition (ICI) by antibodies against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and cell death protein 1 (PD-1) have significantly improved the outcome of metastasized melanoma and of a rapidly increasing number of other cancer types. The anti-tumor effect is often accompanied by immune-related adverse events (irAE). Hematological irAE, specifically neutropenia, are rarely observed. However, neutropenia is associated with high morbidity and mortality due to infection complications. Thus, early detection and treatment is crucial.

Methods

We present the clinical course of two patients with severe neutropenia after ICI therapy and demonstrate the difficulty of the diagnosis when a comedication of metamizole, a well-known analgesic drug used to treat cancer pain, is present. Further, we provide a comprehensive descriptive and statistical analysis of published data on diagnostics, treatment and infection complication in patients with at least grade 4 neutropenia by a systematic database search.

Results

Finally, 34 patients were analyzed, including the two case reports from our cohort. The median onset of neutropenia was 10.5 weeks after first ICI administration (interquartile range: 6 weeks). In 76% (N = 26), a normalization of the neutrophil count was achieved after a median duration of neutropenia of 13 days. In a subsample of 22 patients with detailed data, the infection rate was 13%, proven by positive blood culture in 3 cases, but 68% (N = 15) presented with fever > 38 °C. Treatment regime differed relevantly, but mainly included G-CSF and intravenous corticosteroids. Death was reported in 14 patients (41%), 3 of whom (9%) were associated with hematological irAE but only two directly associated with neutropenia.

Conclusion

With an increasing number of cancer patients eligible to ICI therapy, the incidence of severe hematological toxicities may rise substantially over the next years. Clinicians working in the field of cancer immune therapies should be aware of neutropenia as irAE to provide immediate treatment.
Identification of potential molecular targets associated with proliferative diabetic retinopathy
Authors: Shao Dewang , He Shouzhi , Ye Zi , Zhu Xiaoquan , Sun Wei , Fu Wei , Ma Tianju , Li Zhaohui
Published: April 2020

Background

This study aimed to identify and evaluate potential molecular targets associated with the development of proliferative diabetic retinopathy (DR).

Methods

The microarray dataset “GSE60436” generated from fibrovascular membranes (FVMs) associated with proliferative DR was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) from the active FVMs and control or inactive FVMs and control were evaluated and co-DEGs were identified using VEEN analysis. Functional enrichment analysis, and protein-protein interactions (PPI) network and module analyses were performed on the upregulated and downregulated coDEGs. Finally, several predictions regarding microRNAs (miRNAs) and transcription factors (TFs) were made to construct a putative TF-miRNA-target network.

Results

A total of 1475 co-DEGs were screened in active/inactive FVM samples, including 461 upregulated and 1014 downregulated genes, which were enriched for angiogenesis [Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A) and Placental Growth Factor (PGF)] and visual perception, respectively. In the case of the upregulated co-DEGs, Kinesin Family Member 11 (KIF11), and BUB1 Mitotic Checkpoint Serine/Threonine Kinase (BUB1) exhibited the highest values in both the PPI network and module analyses, as well as the genes related to mitosis. In the case of downregulated co-DEGs, several G protein subunits, including G Protein Subunit Beta 3 (GNB3), exhibited the highest values in both the PPI network and module analyses. The genes identified in the module analysis were found to be from the signal transduction-related pathways. In addition, we were able to identify four miRNAs and five TFs, including miR-136 and miR-374.

Conclusions

In brief, HIF1A, PGF, KIF11, G protein subunits, and miR-136, miR-374 may all be involved in angiogenesis, retinal endothelial cell proliferation, and visual signal transduction in proliferative DR. This study provides a number of novel insights that may aid the development of future studies dedicated to discovering novel therapeutic targets in proliferative DR.
Cost-effectiveness of introducing national seasonal influenza vaccination for adults aged 60 years and above in mainland China: a modelling analysis
Authors: Yang Juan , Atkins Katherine E. , Feng Luzhao , Baguelin Marc , Wu Peng , Yan Han , Lau Eric H. Y. , Wu Joseph T. , Liu Yang , Cowling Benjamin J. , Jit Mark , Yu Hongjie
Published: April 2020

Background

China has an aging population with an increasing number of adults aged ≥ 60 years. Influenza causes a heavy disease burden in older adults, but can be alleviated by vaccination. We assessed the cost-effectiveness of a potential government-funded seasonal influenza vaccination program in older adults in China.

Methods

We characterized the health and economic impact of a fully funded influenza vaccination program for older adults using China-specific influenza disease burden, and related cost data, etc. Using a decision tree model, we calculated the incremental costs per quality-adjusted life year (QALY) gained of vaccination from the societal perspective, at a willingness-to-pay threshold equivalent to GDP per capita (US$8840). Moreover, we estimated the threshold vaccination costs, under which the fully funded vaccination program is cost-effective using GDP per capita as the willingness-to-pay threshold.

Results

Compared to current self-paid vaccination, a fully funded vaccination program is expected to prevent 19,812 (95% uncertainty interval, 7150–35,783) influenza-like-illness outpatient consultations per year, 9418 (3386–17,068) severe acute respiratory infection hospitalizations per year, and 8800 (5300–11,667) respiratory excess deaths due to influenza per year, and gain 70,212 (42,106–93,635) QALYs per year. Nationally, the incremental costs per QALY gained of the vaccination program is US$4832 (3460–8307), with a 98% probability of being cost-effective. The threshold vaccination cost is US$10.19 (6.08–13.65). However, variations exist between geographical regions, with Northeast and Central China having lower probabilities of cost-effectiveness.

Conclusions

Our results support the implementation of a government fully funded older adult vaccination program in China. The regional analysis provides results across settings that may be relevant to other countries with similar disease burden and economic status, especially for low- and middle-income countries where such analysis is limited.
Correction to: CircMYO10 promotes osteosarcoma progression by regulating miR-370-3p/RUVBL1 axis to enhance the transcriptional activity of β-catenin/LEF1 complex via effects on chromatin remodeling
Authors: Chen Junxin , Liu Gang , Wu Yizheng , Ma Jianjun , Wu Hongfei , Xie Ziang , Chen Shuai , Yang Yute , Wang Shengyu , Shen Panyang , Fang Yifan , Fan Shunwu , Shen Shuying , Fang Xiangqian
Published: April 2020

Following the publication of the original paper [1], one corresponding author was inadvertently missed.
Effect of cold stress on ovarian & uterine microcirculation in rats and the role of endothelin system
Authors: Wang Di , Cheng Xiumei , Fang Huimin , Ren Yanqing , Li Xinhua , Ren Weiwei , Xue Bing , Yang Cairui
Published: April 2020

Background

Cold, an environmental factor, induces many reproductive diseases. It is known that endothelin (ET) is a potent vasoconstrictor, and cold stress can increase the expression of ET and its receptors. The cold stress rat model was developed to examine two parameters: (1) the effects of cold stress on ovarian and uterine morphology, function, and microvascular circulation and (2) possible mechanisms of ET and its receptors involved in cold stress-induced menstruation disorders.

Methods

The rat cold stress model was prepared with an ice water bath. The estrous cycle was observed by methylene blue and hematoxylin and eosin (H&E) staining. Serum estradiol 2 (E2), testosterone (T), progesterone (P) were detected by radioimmunoassay. Hemorheology indices were measured. The real-time blood flow of auricle and uterine surfaces was measured. Expressions of CD34 and α-SMA in ovarian and uterine tissues were detected by immunohistochemistry. ET-1 contents in serum were tested, and expressions of ET-receptor types A and B (ET-AR and ET-BR) in ovarian tissues were detected via Western blotting.

Results

Cold stress extended the estrous cycle, thereby causing reproductive hormone disorder, imbalance of local endothelin/nitric oxide expression, and microcirculation disturbance. Cold-stress led to up-regulation of ET-AR expression and protein and down-regulation of ET-BR expression in rats.

Conclusions

This study suggests that the reason for cold stress-induced dysfunction in reproductive organs may be closely related to the imbalance of ET-1 and its receptor expressions, leading to microvascular circulation disorders in local tissues.
Why tocilizumab could be an effective treatment for severe COVID-19?
Authors: Fu Binqing , Xu Xiaoling , Wei Haiming
Published: April 2020

A severe pneumonia-associated respiratory syndrome caused by a new coronavirus was identified in December 2019 (COVID-19), spread rapidly and has become a world-wide public health challenge. About 25% of COVID-19 patients experienced severe complications including acute respiratory distress syndrome (ARDS), and even progressed into an intensive care unit (ICU) admission and died. The exploration for the mortality causes and advancing novel therapeutic development of severe COVID-19 is crucial at the moment. The biopsy samples analysis at autopsy suggested that increased alveolar exudate caused by aberrant host immune response and inflammatory cytokine storm probably impedes alveolar gas exchange and contributes to the high mortality of severe COVID-19 patients. Our research has identified that pathogenic T cells and inflammatory monocytes incite inflammatory storm with large amount of interleukin 6, therefore monoclonal antibody that targets the IL-6 pathways may potentially curb inflammatory storm. Moreover, Tocilizumab treatment that blocking IL-6 receptors showed inspiring clinical results including temperature returned to normal quickly and respiratory function improved. Therefore, we suggest that Tocilizumab is an effective treatment in severe patients of COVID-19 to calm the inflammatory storm and reduce mortality.
Chronic morphine regulates TRPM8 channels via MOR-PKCβ signaling
Authors: Iftinca Mircea , Basso Lilian , Flynn Robyn , Kwok Charlie , Roland Corinne , Hassan Ahmed , Defaye Manon , Ramachandran Rithwik , Trang Tuan , Altier Christophe
Published: April 2020

Postoperative shivering and cold hypersensitivity are major side effects of acute and chronic opioid treatments respectively. TRPM8 is a cold and menthol-sensitive channel found in a subset of dorsal root ganglion (DRG) nociceptors. Deletion or inhibition of the TRPM8 channel was found to prevent the cold hyperalgesia induced by chronic administration of morphine. Here, we examined the mechanisms by which morphine was able to promote cold hypersensitivity in DRG neurons and transfected HEK cells. Mice daily injected with morphine for 5 days developed cold hyperalgesia. Treatment with morphine did not alter the expressions of cold sensitive TREK-1, TRAAK and TRPM8 in DRGs. However, TRPM8-expressing DRG neurons isolated from morphine-treated mice exhibited hyperexcitability. Sustained morphine treatment in vitro sensitized TRPM8 responsiveness to cold or menthol and reduced activation-evoked desensitization of the channel. Blocking phospholipase C (PLC) as well as protein kinase C beta (PKCβ), but not protein kinase A (PKA) or Rho-associated protein kinase (ROCK), restored channel desensitization. Identification of two PKC phosphorylation consensus sites, S1040 and S1041, in the TRPM8 and their site-directed mutation were able to prevent the MOR-induced reduction in TRPM8 desensitization. Our results show that activation of MOR by morphine 1) promotes hyperexcitability of TRPM8-expressing neurons and 2) induces a PKCβ-mediated reduction of TRPM8 desensitization. This MOR-PKCβ dependent modulation of TRPM8 may underlie the onset of cold hyperalgesia caused by repeated administration of morphine. Our findings point to TRPM8 channel and PKCβ as important targets for opioid-induced cold hypersensitivity.
Involvement of A13 dopaminergic neurons located in the zona incerta in nociceptive processing: a fiber photometry study
Authors: Moriya Shunpei , Yamashita Akira , Masukawa Daiki , Setoyama Honami , Hwang Yunsu , Yamanaka Akihiro , Kuwaki Tomoyuki
Published: April 2020

The roles of serotonergic and noradrenergic signaling in nociceptive processing in the central nervous system are well known. However, dopaminergic signaling is also relevant to various physical functions, including nociception. The zona incerta is a subthalamic nucleus in which the A13 dopaminergic cell group resides, but how this A13 group affects nociceptive processing remains unknown. Recently, we showed that acute nociceptive stimuli rapidly induce the activity of A10 (ventral tegmental area) dopamine neurons via fiber photometry. In this study, we measured the activity of A13 dopaminergic neurons in response to acute nociceptive stimuli using the same system. Adeno-associated viruses (AAV-CAG-FLEX-G-CaMP6 and AAV-CAG-FLEX-mCherry) were unilaterally injected into the A13 site in transgenic mice carrying a dopamine transporter promotor-regulated Cre recombinase transgene to specifically introduce G-CaMP6/mCherry into A13 dopaminergic cell bodies through site-specific infection. We measured G-CaMP6/mCherry fluorescence intensity in the A13 site to acute nociceptive stimuli (pinch stimulus and heat stimulus). These stimuli significantly induced a rapid increase in G-CaMP6 fluorescence intensity, but non-nociceptive control stimuli did not. In contrast, mCherry fluorescence intensity was not significantly changed by nociceptive stimuli or non-nociceptive stimuli. Our finding is the first report to measure the activity of A13 dopaminergic neurons to aversive stimuli. A13 dopaminergic neurons project to the periaqueductal gray and the central nucleus of the amygdala, which are both well known as key regions in nociceptive processing. Therefore, together with our A10 study, our results indicate that A13 dopaminergic neurons play important roles in nociceptive processing.
Effects of synbiotic supplementation on gut microbiome, serum level of TNF-α, and expression of microRNA-126 and microRNA-146a in patients with type 2 diabetes mellitus: study protocol for a double-blind controlled randomized clinical trial
Authors: Zeinali Fahime , Aghaei Zarch Seyed Mohsen , Vahidi Mehrjardi Mohammad Yahya , Kalantar Seyed Mehdi , Jahan-mihan Alireza , Karimi-Nazari Elham , Fallahzadeh Hossein , Hosseinzadeh-Shamsi-Anar Mahdieh , Rahmanian Masoud , Fazeli Mohammad Reza , Mozaffari-Khosravi Hassan
Published: April 2020

Background

The dramatic increase in the prevalence of type 2 diabetes mellitus (T2DM) is a global major challenge to health. Circulating microRNAs have been suggested as promising biomarkers for different disorders such as diabetes. Imbalances in the gut microbiome have been revealed to contribute to the progression of multiple diseases including T2DM. Recently, the consumption of probiotics and synbiotics in the treatment of various diseases has shown a substantial growth. The anti-diabetes and anti-inflammatory effects of synbiotics have been indicated, which may be due to their beneficial effects on the gut microbiome. However, further research is needed to assess the effects of synbiotics on the microbiota and their impacts on expression of microRNAs relating to T2DM. Thus, we will aim to assess the effects of synbiotics on microbiota, serum level of tumor necrosis factor-α (TNF-α), and expression of microRNA-126 and microRNA-146a in patients with T2DM.

Methods

Seventy-two patients with T2DM will be recruited in this double-blind randomized parallel placebo-controlled clinical trial. After block matching based on age and sex, participants will be randomly assigned to receive 1000 mg/day synbiotic (Familact) or placebo for 12 weeks. The microRNA-126 and microRNA-146a expression levels will be measured by real-time polymerase chain reaction and serum TNF-α level will be assessed by enzyme-linked immunosorbent assay kit at the beginning and at the end of the study. Determination of the gut microbiota will be done by quantitative polymerase chain reaction methods at baseline and at the end of the trial. Biochemical assessments (glycemic and lipid profiles) will also be conducted at onset and end of the study.

Discussion

This is the first randomized controlled trial that will determine the effect of synbiotic supplementation on the gut microbiota and its probable impacts on serum levels of TNF-α and expression of related microRNAs in patients with T2DM.

Trial registration

Iranian Registry of Clinical Trials: IRCT20180624040228N2. Registered on 27 March 2019. http://www.irct.ir/trial/38371.
Goal-Focused Emotion-Regulation Therapy (GET) for young adult survivors of testicular cancer: a pilot randomized controlled trial of a biobehavioral intervention protocol
Authors: Hoyt Michael A. , Wang Ashley Wei-Ting , Ryan Sean J. , Breen Elizabeth C. , Cheavens Jennifer S. , Nelson Christian J.
Published: April 2020

Background

Testicular cancer diagnosis and treatment, especially given its threat to sexuality and reproductive health, can be distressing in the formative period of young adulthood and the majority of young survivors experience impairing, distressing, and modifiable adverse outcomes that can persist long after medical treatment. These include psychological distress, impairment in pursuit of life goals, persistent physical side effects, elevated risk of secondary malignancies and chronic illness, and biobehavioral burden (e.g., enhanced inflammation, dysregulated diurnal stress hormones). However, few targeted interventions exist to assist young survivors in renegotiating life goals and regulating cancer-related emotions, and none focus on reducing the burden of morbidity via biobehavioral mechanisms. This paper describes the methodology of a randomized controlled biobehavioral trial designed to investigate the feasibility and preliminary impact of a novel intervention, Goal-focused Emotion-Regulation Therapy (GET), aimed at improving distress symptoms, emotion regulation, goal navigation skills, and stress-sensitive biomarkers in young adult testicular cancer patients.

Methods

Participants will be randomized to receive six sessions of GET or Individual Supportive Therapy (ISP) delivered over 8 weeks. In addition to indicators of intervention feasibility, we will measure primary (depressive and anxiety symptoms) and secondary (emotion regulation and goal navigation skills, career confusion) psychological outcomes prior to (T0), immediately after (T1), and 12 weeks after (T2) intervention. Additionally, identified biomarkers will be measured at baseline and at T2.

Discussion

GET may have the potential to improve self-regulation across biobehavioral domains, improve overall cancer adjustment, and address the need for targeted supportive care interventions for young adult cancer survivors.

Trial registration

Clinicaltrials.gov, NCT04150848. Registered on 28 October 2019.
Improving the resistance and resilience framework for aging and dementia studies
Authors: Arenaza-Urquijo Eider M. , Vemuri Prashanthi
Published: April 2020

Background

The "resistance vs resilience" to Alzheimer’s disease (AD) framework (coping vs avoiding) has gained interest in the field in the last year. In this viewpoint, our effort is (i) to provide clarity to the usage of the framework in the context of the ATN (amyloid/tau/neurodegeneration) system as well as in lifespan and cognitive aging studies and (ii) to discuss the challenges of matching these concepts to specific biological mechanisms.

Main body

In the context of the ATN system, the main goal of the resistance vs resilience framework is to make a fundamental distinction between risk factors that may help halt the development of AD pathologies (AT) (“resistance”) vs delay processes downstream to AT, i.e., neurodegeneration (N) and the clinical expression of the disease (“resilience”). The process of resilience in dementia and aging research should be envisioned as a process that is developed over the lifespan. Greater neurobiological capital to start with (initial brain reserve), maintaining brain structure and function (brain maintenance), or greater adaptability of cognitive strategies to perform a task (cognitive reserve) could all contribute to higher resilience to pathologies later in life. Simply put, resilience is not only a response to pathological processes (i.e. increased brain function to compensate for increasing AD pathology) but also reflects individual differences in brain structure and function that can be built over the lifespan (e.g., through education, lifetime cognitive, and physical activities). Further, the resistance vs resilience terminology can be extended to study other pathological processes such as cerebrovascular lesions, Lewy body disease, or TDP-43. However, some challenges do exist: (i) when studying multiple neuropathologies, the study design and framework will drive the usage of terminology; (ii) it is unavoidable that the measurements of resilience (brain structure and function) will reflect both the effect of pathologies and the impact of several risk and protective factors throughout the lifespan. Therefore, identifying resilience brain markers across lifespan, aging, and dementia studies, notably with longitudinal study designs, will be an important step towards understanding mechanisms of action.

Conclusions

While the field advances towards consensus definitions of existing concepts, the resistance vs resilience terminology may provide clarity in the communication of results in aging and dementia studies as well as provide a framework for the development of both hypotheses and study designs.
Are ketogenic diets promising for Alzheimer’s disease? A translational review
Authors: Lilamand Matthieu , Porte Baptiste , Cognat Emmanuel , Hugon Jacques , Mouton-Liger François , Paquet Claire
Published: April 2020

Background

Brain amyloid deposition and neurofibrillary tangles in Alzheimer’s disease (AD) are associated with complex neuroinflammatory reactions such as microglial activation and cytokine production. Glucose metabolism is closely related to neuroinflammation. Ketogenic diets (KDs) include a high amount of fat, low carbohydrate and medium-chain triglyceride (MCT) intake. KDs lead to the production of ketone bodies to fuel the brain, in the absence of glucose. These nutritional interventions are validated treatments of pharmacoresistant epilepsy, consequently leading to a better intellectual development in epileptic children. In neurodegenerative diseases and cognitive decline, potential benefits of KD were previously pointed out, but the published evidence remains scarce. The main objective of this review was to critically examine the evidence regarding KD or MCT intake effects both in AD and ageing animal models and in humans.

Main body

We conducted a review based on a systematic search of interventional trials published from January 2000 to March 2019 found on MEDLINE and Cochrane databases. Overall, 11 animal and 11 human studies were included in the present review. In preclinical studies, this review revealed an improvement of cognition and motor function in AD mouse model and ageing animals. However, the KD and ketone supplementation were also associated with significant weight loss. In human studies, most of the published articles showed a significant improvement of cognitive outcomes (global cognition, memory and executive functions) with ketone supplementation or KD, regardless of the severity of cognitive impairments previously detected. Both interventions seemed acceptable and efficient to achieve ketosis.

Conclusion

The KD or MCT intake might be promising ways to alter cognitive symptoms in AD, especially at the prodromal stage of the disease. The need for efficient disease-modifying strategies suggests to pursue further KD interventional studies to assess the efficacy, the adherence to this diet and the potential adverse effects of these nutritional approaches.
Hydralazine-induced antineutrophil cytoplasmic antibody-associated vasculitis with pulmonary–renal syndrome: a case report
Authors: Al-Abdouh Ahmad , Siyal Abdul Muhaymin , Seid Hanan , Bekele Ammer , Garcia Pablo
Published: April 2020

Background

Hydralazine is a common vasodilator which has been used for the treatment of hypertension and heart failure. Hydralazine can induce antineutrophil cytoplasmic antibody-associated vasculitis due to its auto-immunogenic capability and one of the very rare presentations is pulmonary–renal syndrome.

Case presentation

We report a case of a 64-year-old African American woman, who presented to our emergency room with shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, leg swelling, fatigue, loss of appetite, cough with clear sputum, and lightheadedness. On admission, she developed acute hypoxic respiratory failure requiring intubation and acute renal failure requiring hemodialysis. A serologic workup was positive for antineutrophil cytoplasmic antibody, antinuclear antibody, anti-histone, anti-cardiolipin IgM, and anti-double-stranded DNA antibodies. A renal biopsy was done due to persistent deterioration in kidney function and demonstrated classic crescentic (pauci-immune) glomerulonephritis. Hydralazine was empirically discontinued early in the admission and she was started on corticosteroids and cyclophosphamide following biopsy results. She was clinically stable but remained dependent on hemodialysis after discharge.

Conclusion

Hydralazine-induced antineutrophil cytoplasmic antibody-associated vasculitis with pulmonary–renal syndrome is a rare occurrence. In the setting of hydralazine use, multiple positive antigens, and multisystem involvement, clinicians should consider this rare condition requiring prompt cessation of offending drug, early evaluation with biopsy, and contemplate empiric immunosuppressive therapy while biopsy confirmation is pending.
Borderline personality disorder and attention deficit/hyperactivity disorder in adolescence: overlap and differences in a clinical setting
Authors: Akça Ömer Faruk , Wall Kiana , Sharp Carla
Published: April 2020

Background

With increased consensus regarding the validity and reliability of diagnosing Borderline Personality Disorder (BPD) in adolescents, clinicians express concern over the distinction between BPD and Attention-Deficit/Hyperactivity Disorder (ADHD), and its co-morbidity in clinical settings. The goal of this study was to evaluate differences between BPD, ADHD and BPD + ADHD in terms of co-morbid psychiatric disorders and a range of self-reported behavioral problems in adolescents.

Methods

Our sample consisted of N = 550 inpatient adolescents with behavioral and emotional disorders that have not responded to prior intervention. We took a person-centered approach (for increase clinical relevance) and compared adolescents with ADHD, BPD and ADHD+BPD in terms of co-occurring psychiatric disorders and behavioral problems. We performed a regression analysis to test whether BPD symptoms make an incremental contribution to the prediction of psychiatric symptoms over ADHD symptoms.

Results

The severity of almost all co-occurring disorders, aggression, self-harm, suicidal thoughts, and substance use, were higher in the ADHD+BPD group. Borderline symptoms made an incremental contribution to the prediction of psychiatric symptoms beyond the contribution of ADHD.

Conclusion

Severity and co-morbidity may be helpful factors in distinguishing between ADHD and BPD in clinical practice and the co-morbidity of these two disorders may indicate a worse clinical outcome.
The textile products labelling analysis and requirements
Authors: Santos-Roldán Luna , Palacios-Florencio Beatriz , Berbel-Pineda Juan Manuel
Published: April 2020

The textile sector is one of the most representative of Spanish industry, contributing to the wealth of the country with close to 10% of the business fabric in Spain. However, in spite of this daily consumption little is known about the guarantees of traceability clothes labelling must inform about. The purpose of this study is to present a work of analysis of the compliance with the content of the labelling in this sector. For his objective, a research was developed through the consideration of 32 businesses of the textile sector in the city of Córdoba (Spain) where were photographed each label for its later analysis and a confirmation of the regulation. The results show that the majority of labels are incomplete and insufficient. Therefore, it’s necessary the existence of an European public organism with a competence to accredit the manufacturing, distribution and commercialization of textile garments, protecting the rights of workers and the consumers’ access to information.