bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends of Polypharmacy and Prescription Patterns of Antidepressants in Asia
Authors: Huang Cho-Yin , Yang Shu-Yu , Mojtabai Ramin , Lin Shu-Ku , He Yan-Ling , Chong Mian-Yoon , Ungvari Gabor , Tan Chay-Hoon , Xiang Yu-Tao , Sartorius Norman , Shinfuku Naotaka , Chen Lian-Yu
Published: September 2018

Purpose

Little is known regarding the trend of polypharmacy in Asia. We used data from 5 Asian countries to examine the patterns of antidepressant (AD) prescription and trends of psychotropic polypharmacy over time.

Methods

We used the cross-sectional, pharmacoepidemiological data from 2004 and 2013 REAP-AD (Research on Asian Psychotropic Prescription Patterns for Antidepressants) to examine the patterns of AD prescriptions in clinical settings in China, Japan, Korea, Singapore, and Taiwan. We compared the trend in polypharmacy (ie, concomitant use of ≥2 classes of psychotropic) among individuals receiving AD prescriptions in 2004 and 2013 using multivariable logistic regression models in different diagnostic categories.

Results

The proportion of patients with psychotropic polypharmacy decreased from 2004 to 2013 in all 3 diagnostic categories, including mood disorders (adjusted odds ratio [aOR], 0.44 [0.35–0.56]; P < 0.001), anxiety disorders (aOR, 0.58 [0.36–0.94]; P = 0.028), and psychotic disorders (aOR, 0.18 [0.05–0.60]; P = 0.006). Among individuals with AD prescriptions, concomitant use of anxiolytics (including sedative-hypnotics) decreased in patients with mood disorders (aOR, 0.34 [0.27–0.42]; P < 0.001) and anxiety disorders (aOR, 0.43 [0.27–0.67]; P < 0.001). In contrast, concomitant use of antipsychotics in patients with mood disorders increased (aOR, 1.43 [1.15–1.77]; P = 0.001), and concomitant use of mood stabilizers in patients with psychotic disorders also increased (aOR, 3.49 [1.50–8.14]; P = 0.004).

Conclusions

This is the first study examining trends in psychotropic polypharmacy in East Asia. We found a generally decreasing trend of psychotropic polypharmacy in contrast to the increasing trend reported from Western countries. These findings could offer significant implications for health system reform or policy making.
Self-efficacy as a Mechanism of Action of Imagery Rehearsal Therapy's Effectiveness
Authors: Rousseau Andréanne , Dubé-Frenette Mylène , Belleville Geneviève
Published: September 2018

Imagery rehearsal therapy (IRT) is an empirically validated therapy targeting recurring nightmares, for which the mechanisms of action remain poorly understood. The objective of this study was to investigate how an exploratory measure of self-efficacy could mediate IRT's effectiveness. Thirty-five victims of sexual assault with recurring nightmares were randomly assigned to either IRT or a control condition. Participants completed questionnaires about self-efficacy and nocturnal symptoms at pre- and posttreatment. Regression analyses showed that IRT predicted greater self-efficacy about dreams (β = .578) and that self-efficacy about dreams predicted improvement in insomnia (β = −.378). IRT also predicted greater self-efficacy about nightmares (β = .366), which in turn predicts sleep quality (β = −.412). However, self-efficacy was not a significant mediator of IRT's effectiveness on insomnia and sleep quality. Although IRT did increase patients' self-efficacy over dreams and nightmares, self-efficacy may not be a primary mechanism of action explaining IRT's effectiveness.
Is Tapping on Acupuncture Points an Active Ingredient in Emotional Freedom Techniques? A Systematic Review and Meta-analysis of Comparative Studies
Authors: Church Dawson , Stapleton Peta , Yang Amy , Gallo Fred
Published: September 2018

Emotional Freedom Techniques (EFTs) combine elements of cognitive restructuring and exposure techniques with acupoint stimulation. Meta-analyses indicate large effect sizes for posttraumatic stress disorder, depression, and anxiety; however, treatment effects may be due to components EFT shares with other therapies. This analysis reviewed whether EFTs acupressure component was an active ingredient. Six studies of adults with diagnosed or self-identified psychological or physical symptoms were compared (n = 403), and three (n = 102) were identified. Pretest vs. posttest EFT treatment showed a large effect size, Cohen's d = 1.28 (95% confidence interval [CI], 0.56 to 2.00) and Hedges' g = 1.25 (95% CI, 0.54 to 1.96). Acupressure groups demonstrated moderately stronger outcomes than controls, with weighted posttreatment effect sizes of d = −0.47 (95% CI, −0.94 to 0.0) and g = −0.45 (95% CI, −0.91 to 0.0). Meta-analysis indicated that the acupressure component was an active ingredient and outcomes were not due solely to placebo, nonspecific effects of any therapy, or nonacupressure components.
Mental Health Impact of Homecoming Experience Among 1730 Formerly Deployed Veterans From the Vietnam War to Current Conflicts: Results From the Veterans' Health Study
Authors: Boscarino Joseph A. , Adams Richard E. , Urosevich Thomas G. , Hoffman Stuart N. , Kirchner H. Lester , Boscarino Joseph J. , Withey Carrie A. , Dugan Ryan J. , Figley Charles R.
Published: September 2018

We examined the effects of homecoming support on current mental health among 1730 deployed veterans from Vietnam, Iraq/Afghanistan, Persian Gulf, and other conflicts. The prevalence of current posttraumatic stress disorder (PTSD) was 5.4%, current depression was 8.3%, and 5.4% had suicidal thoughts in the past month. Overall, 26% of veterans had low homecoming support, which was more prevalent among Vietnam veterans (44.3%, p < 0.001). In multivariable logistic regressions, controlling for demographics, combat exposure, number of deployments, trauma history, and operational theater, low postdeployment support was associated with PTSD (odds ratio, 2.13; p = 0.032) and suicidality (odds ratio, 1.91; p < 0.030), but not depression. For suicidality, an interaction was detected for homecoming by theater status, whereby Iraq/Afghanistan veterans with lower homecoming support had a higher probability of suicidal thoughts (p = 0.002). Thus, years after deployment, lower homecoming support was associated with current PTSD and suicidality, regardless of theater and warzone exposures. For suicidality, lower support had a greater impact on Iraq/Afghanistan veterans.
Cognitive Impairment and Personality Traits in Epilepsy
Authors: Wang Xue , Lv Yudan , Zhang Wenxia , Meng Hongmei
Published: September 2018

Cognitive impairment and personality disorders are severe comorbidities commonly observed in patients with epilepsy, and together they decrease the quality of patients' life. This study aimed to evaluate cognitive function and personality traits in patients with epilepsy with the Wechsler Adult Intelligence Scale–Chinese revised and Eysenck Personality Questionnaire and investigate the underlying influencing factors. Compared with the control group, our results showed that patients with epilepsy were presented with significant cognitive impairment and particular personality traits. Epileptic seizure-related factors including earlier age of onset, longer duration of epileptic history, and higher seizure frequency were significantly associated with the observed defects in cognition and personality traits. In addition, the temporal lobe was more likely to affect cognition and personality, and the left hemisphere was closely related to verbal intelligence quotient, which needs to be the focus of future research. These results will be instrumental for guiding the treatment of epilepsy.
Tattoo Recognition in Screening for Victims of Human Trafficking
Authors: Fang Shelley , Coverdale John , Nguyen Phuong , Gordon Mollie
Published: September 2018

There is little information on the secondary prevention of human trafficking and how medical professionals can screen for victims. There is a paucity of validated screening tools for use in clinical settings to identify adult trafficked patients, although one for use in pediatric populations exists. Many victims withhold information about their trafficked status. Because traffickers may mark victims, identification of tattoos provides a useful method for screening patients, which complements history taking, especially when victims are unable to disclose that information. We searched existing medical literature, PsycINFO, PubMed, Google, and JSTOR using keywords “human,” “trafficking,” and “tattoos.” Because there is scant literature on this topic, we also searched the gray literature that enabled preliminary identification of several themes used in trafficking tattoos. We also discussed tattoo placement and quality. Tattoo recognition is a critical factor in identifying victims and setting them on a pathway to freedom and recovery.
Suicide Methods According to Age and Sex
Authors: Han Dae-Guen , Kang Seung-Gul , Cho Seong-Jin , Cho Seo-Eun , Na Kyoung-Sae
Published: September 2018

Because suicide is irreversible, prevention is paramount. For the optimal strategy to reduce lethal means, we sought to investigate age- and sex-associated variations in suicide methods. Data on annual causes of death from 1991 to 2015 in the Republic of Korea were used. Major sociodemographic correlates of the five suicide methods were analyzed by multiple multinominal logistic regression analysis. Among a total of 239,565 suicides from 1991 to 2015, hanging was most common. Gas poisoning sharply increased from 2007 to 2015. The gap between hanging and the second most common method of suicide has increased from 659 in 2004 to 4,433 in 2015. Charcoal burning was most commonly used by males younger than 45 years of age, whereas pesticide was commonly used by both sexes ages 55 years and older. Our results suggest that age- and sex-specific suicide prevention strategies are needed, particularly for gas and pesticide poisoning.
Quality and Safety in Health Care, Part XLVI
Authors: Harolds Jay A.
Published: September 2018

Some of the approaches to prevent and recover from burnout focus on the individual, and others focus on organizational initiatives. A common recommendation for the individual with burnout is to practice meditation and mindfulness. Mindfulness may be defined as focused awareness without judgment regarding the current instance in time. The practice of mindfulness and the outcome of various mindfulness courses will be discussed in this article. Other approaches on the subject of burnout regarding individual efforts and organizational changes will be discussed in subsequent articles in this series.
18F-FDG PET/CT in Isolated Primary Extraskeletal Osteosarcoma
Authors: Parihar Ashwin Singh , Mittal Bhagwant Rai , Vadi Shelvin Kumar , Sood Apurva , Kumar Rajender , Goni Vijay
Published: September 2018

Extraskeletal osteosarcoma is a rare, high-grade soft tissue malignancy, accounting for approximately 1% of all soft tissue sarcomas. Despite the histologic resemblance to osteogenic osteosarcoma, it is considered as a distinct entity because of the differences in clinical behavior and response to treatment. Hence, imaging plays a vital role in establishing the nonskeletal origin of the tumor, differentiating it from osteogenic osteosarcoma. We present 18F-FDG PET/CT findings in a case of isolated primary extraskeletal osteosarcoma confirmed on histopathology.
Socioeconomic Status and Kidney Transplant Outcomes in a Universal Healthcare System: A Population-based Cohort Study
Authors: Naylor Kyla L. , Knoll Gregory A. , Shariff Salimah Z. , McArthur Eric , Garg Amit X. , Van Walraven Carl , Austin Peter C. , McCallum Megan K. , Quinn Robert R. , Tan Vivian S. , Kim S. Joseph
Published: September 2018

Background.

Conflicting evidence exists regarding the relationship between socioeconomic status (SES) and outcomes after kidney transplantation.

Methods.

We conducted a population-based cohort study in a publicly funded healthcare system using linked administrative healthcare databases from Ontario, Canada to assess the relationship between SES and total graft failure (ie, return to chronic dialysis, preemptive retransplantation, or death) in individuals who received their first kidney transplant between 2004 and 2014. Secondary outcomes included death-censored graft failure, death with a functioning graft, all-cause mortality, and all-cause hospitalization (post hoc outcome).

Results.

Four thousand four hundred-fourteen kidney transplant recipients were included (median age, 53 years; 36.5% female), and the median (25th, 75th percentile) follow-up was 4.3 (2.1-7.1) years. In an unadjusted Cox proportional hazards model, each CAD $10000 increase in neighborhood median income was associated with an 8% decline in the rate of total graft failure (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.87-0.97). After adjusting for recipient, donor, and transplant characteristics, SES was not significantly associated with total or death-censored graft failure. However, each CAD $10000 increase in neighborhood median income remained associated with a decline in the rate of death with a functioning graft (adjusted (a)HR, 0.91; 95% CI, 0.83-0.98), all-cause mortality (aHR, 0.92; 95% CI, 0.86-0.99), and all-cause hospitalization (aHR, 0.95; 95% CI, 0.92-0.98).

Conclusions.

In conclusion, in a universal healthcare system, SES may not adversely influence graft health, but SES gradients may negatively impact other kidney transplant outcomes and could be used to identify patients at increased risk of death or hospitalization.
Local Delivery of Regulatory T Cells Promotes Corneal Allograft Survival
Authors: Shao Chunyi , Chen Yihe , Nakao Takeshi , Amouzegar Afsaneh , Yin Jia , Tahvildari Maryam , Lužnik Zala , Chauhan Sunil K. , Dana Reza
Published: September 2018

Background

Regulatory T (Treg) cell-based immunotherapies have been studied as potential cell-based modalities for promoting transplant survival. However, the efficacy of local delivery of Treg cells in corneal transplantation has not been fully elucidated. Herein, we investigated the kinetics of migration of subconjunctivally injected Treg cells and their role in promoting corneal allograft survival.

Methods

GFP+CD4+CD25+Foxp3+ Treg cells were isolated from draining lymph nodes (DLNs) of GFP transgenic mice and were subconjunctivally injected to corneal allograft recipients. Next, Treg cells, conventional T cells (Tconv) or a combination of both was locally injected to graft recipients, and graft survival was determined by evaluating opacity scores for 10 weeks. Transplanted mice without treatment served as controls. The frequencies of major histocompatibility complex-II+CD11b+ antigen-presenting cells, IFNγ+CD4+ Th1 cells, and CD45+ cells in the DLNs and cornea were evaluated at week 2 posttransplantation using flow cytometry. Expressions of IFNγ, IL-10 and TGF-β in the grafts were assessed using reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay.

Results

GFP+ Treg cells were detected in the ipsilateral cornea and DLNs of recipients 6 hours after injection. Subconjunctival injection of Treg cells significantly decreased the frequencies of mature antigen-presenting cells in the graft and DLNs, suppressed Th1 frequencies in DLNs, and inhibited CD45+ cell infiltration to the graft. Finally, locally delivered Treg cells significantly reduced the expression of IFN-γ, enhanced the levels of IL-10 and TGF-β in the graft, and promoted long-term allograft survival.

Conclusions

Our study elucidates the kinetics of migration of locally delivered Treg cells and shows their role in suppressing host immune response against the allograft.
Perspectives on the Optimal Genetically Engineered Pig in 2018 for Initial Clinical Trials of Kidney or Heart Xenotransplantation
Authors: Cooper David K.C. , Ezzelarab Mohamed , Iwase Hayato , Hara Hidetaka
Published: September 2018

For a clinical trial today, what might realistically be the optimal pig among those currently available? Deletion of expression of the 3 pig carbohydrate antigens, against which humans have natural (preformed) antibodies (triple-knockout pigs), should form the basis of any clinical trial. However, because both complement and coagulation can be activated in the absence of antibody, the expression of human complement- and coagulation-regulatory proteins is likely to be important in protecting the graft further. Any genetic manipulation that might reduce inflammation of the graft, for example, expression of hemeoxygenase-1 or A20, may also be beneficial to the long-term survival of the graft. The transgene for human CD47 is likely to have a suppressive effect on monocyte/macrophage and T-cell activity. Furthermore, deletion of xenoantigen expression and expression of a human complement-regulatory protein are both associated with a reduced T-cell response. Although there are several other genetic manipulations that may reduce the T-cell response further, it seems likely that exogenous immunosuppressive therapy, particularly if it includes costimulation blockade, will be sufficient. We would therefore suggest that, with our present knowledge and capabilities, the optimal pig might be a triple-knockout pig that expressed 1 or more human complement-regulatory proteins, 1 or more human coagulation-regulatory proteins, a human anti-inflammatory transgene, and CD47. Absent or minimal antibody binding is important, but we suggest that the additional insertion of protective human transgenes will be beneficial, and may be essential.
Blood Pressure in De Novo Heart Transplant Recipients Treated With Everolimus Compared With a Cyclosporine-based Regimen: Results From the Randomized SCHEDULE Trial
Authors: Andreassen Arne K. , Broch Kaspar , Eiskjær Hans , Karason Kristjan , Gude Einar , Mølbak Dorte , Stueflotten Wenche , Gullestad Lars
Published: September 2018

Background.

Systemic hypertension is prevalent in heart transplant recipients and has been partially attributed to treatment with calcineurin inhibitors (CNIs). SCandinavian HEart transplant De-novo stUdy with earLy calcineurin inhibitors avoidancE trial was the first randomized trial to study early withdrawal of CNIs in de novo heart transplant recipients, comparing an everolimus-based immunosuppressive regimen with conventional CNI-based treatment. As a prespecified secondary endpoint, blood pressure was repeatedly compared across treatment arms.

Methods.

The The SCandinavian HEart transplant De-novo stUdy with earLy calcineurin inhibitors avoidancE trial was a prospective, multicenter, randomized, controlled, parallel-group, open-label trial in de novo adult heart transplant recipients, undertaken at transplant centers in Scandinavia. Blood pressure was assessed with 24-hour ambulatory blood pressure monitoring up to 3 years after heart transplantation (HTx) in 83 patients.

Results.

Overall, systolic blood pressure fell with time, from 138 ± 15 mm Hg 2 weeks after HTx to 134 ± 11 mm Hg after 12 months and 132 ± 14 mm Hg after 36 months (P = 0.003). Diastolic blood pressure did not change over time. After 12 months, there was a numerically larger fall in systolic blood pressure in the everolimus arm (between-group difference 8 mm Hg; P = 0.053), and after 36 months, there was a significant between group difference of 13 mm Hg (P = 0.02) in favor of everolimus.

Conclusions.

In this first, randomized trial with early CNI avoidance in de novo HTx recipients, we observed a modest fall in systolic blood pressure over the first 1 to 3 years after transplantation. The fall in systolic blood pressure was more pronounced in patients allocated to everolimus.
A Randomized Study of Quantiferon CMV-directed Versus Fixed-duration Valganciclovir Prophylaxis to Reduce Late CMV After Lung Transplantation
Authors: Westall Glen P. , Cristiano Yvonne , Levvey Bronwyn J. , Whitford Helen , Paraskeva Miranda A. , Paul Eldho , Peleg Anton Y. , Snell Gregory I.
Published: September 2018

Background.

We provide the results of the first interventional study of cytomegalovirus (CMV)-specific immune monitoring to direct the length of antiviral prophylaxis in lung transplantation (LTx).

Methods.

Patients (n = 118) at risk of CMV infection were randomized 1:2 to either 5 months or variable length valganciclovir prophylaxis (5–11 mo post-LTx), as determined by the QuantiFERON (QFN)-CMV assay. Patients with a negative QFN-CMV assay (< 0.2 IU/mL) received prolonged valganciclovir prophylaxis.

Results.

The primary endpoint that was the incidence of CMV infection in the lung allograft within 18 months of LTx was significantly reduced in the QFN-CMV directed arm (37% versus 58%, P = 0.03). Secondary endpoints that included blood viremia, acute rejection, and chronic lung allograft dysfunction did not differ between the 2 arms. Of the 80/118 patients who ceased antiviral prophylaxis at 5 months, the incidence of viremia (> 600 copies/mL) within the blood was significantly reduced in patients with a positive QFN-CMV assay compared with those without protective immunity (13% versus 67%, P = 0.0003), as was the incidence of severe viremia (> 10 000 copies/mL) (3% versus 50%, P < 0.001). Ceasing antiviral prophylaxis at 11 months in patients with a negative assay was associated with a 25% incidence of late CMV viremia.

Conclusions.

Cytomegalovirus immune monitoring allows an individualized approach to CMV prophylaxis and reduces late CMV infection within the lung allograft.
Effect of the Selective NLRP3 Inflammasome Inhibitor mcc950 on Transplantation Outcome in a Pig Liver Transplantation Model With Organs From Donors After Circulatory Death Preserved by Hypothermic Machine Perfusion
Authors: Yu Yang , Cheng Ying , Pan Qi , Zhang Yi-Jie , Jia De-Gong , Liu Yong-Feng
Published: September 2018

Background

We investigated whether the outcome of organs from donors after circulatory death (DCD) can be improved by the addition of mcc950 to the perfusate of the hypothermic machine perfusion (HMP) system and intravenous mcc950 injection after transplantation in a pig liver transplantation model.

Methods

Thirty-six healthy Bama mini pigs randomized into 3 groups. All the DCD livers were preserved in an HMP system after 2 hours of simple cold storage. In HMP-Postop group, mcc950 was added to the perfusate; in the control group and Postop group, the perfusate was normal LPS. After transplantation, the pigs in the Postop group and HMP-Postop group were intravenously administered 3 mg/kg mcc950, at the time of reperfusion and on day 2 and day 3 after transplantation. During the 3-day follow-up period, general operative characteristics, and serological markers and histological features related to ischemia reperfusion injury were examined.

Results

The HMP-Postop group suffer the lightest ischemia reperfusion injury (IRI), and functioned best after transplantation. Model for the Early Allograft Function Score (predictor of long-term survival), degree of injury in the hepatocytes and rate of apoptosis was lowest in the HMP-Postop group. Further, in the HMP-Postop group, the nucleotide-binding domain leucine-rich repeat containing family pyrin domain containing 3 inflammasome pathway activation was lowest, and the level of IL-1β was lowest. Postop group functioned better than control group, but not comparable with HMP-Postop group.

Conclusions

The outcome of DCD organs can be improved by the addition of mcc950 to the perfusate of the HMP system and intravenous injection of mcc950 after transplantation.
Novel Therapeutic Approaches to Allosensitization and Antibody-mediated Rejection
Authors: Jordan Stanley C. , Ammerman Noriko , Choi Jua , Huang Edmund , Peng Alice , Sethi Supreet , Najjar Reiad , Toyoda Mieko , Lim Kathlyn , Louie Sabrina , Vo Ashley
Published: September 2018

Modification of pathogenic antibodies for autoimmune diseases illuminated the biologic relevance of B cells, plasma cells, and pathogenic antibodies in autoimmunity. They have also rejuvenated interest in how B cells mediate multiple effector functions that include antibody production, antigen presentation to T cells, costimulation, and the production of immune stimulating and immune modulatory cytokines. Repurposing these drugs from autoimmunity and cancer immunotherapy has yielded important advancements in the care of antibody-mediated rejection patients and novel drug development aimed at HLA desensitization have recently emerged. We now stand on an important threshold that promises many advances in the care of our allosensitized patients. We hope that these initial advances will encourage basic scientist, clinical investigators, industry, National Institutes of Health, our academic societies, and the Food and Drug Administration to continue support of these important objectives. These advances clearly have implications for sensitized patients receiving solid organ transplants and antibody-mediated rejection treatment. Modification of alloimmunity and alloantibodies will also have relevance to xenotransplantation where the xenoantibodies present a formidable obstacle to advancement of this important therapy. Working together, we can advance transplant therapeutics where biologic agents are likely to play novel and important roles. Here, we discuss novel drugs emerging in this area.
Recent History of Serious Fall Injuries and Posttransplant Outcomes Among US Kidney Transplant Recipients
Authors: Lynch Raymond J. , Patzer Rachel E. , Pastan Stephen O. , Bowling C. Barrett , Plantinga Laura C.
Published: September 2018

Background.

Serious fall injuries are associated with poor outcomes among dialysis patients, but whether these associations hold in patients with a history of serious fall injury before kidney transplantation is unknown.

Methods.

In national administrative data, 22 474 US adults receiving a first kidney transplant in 2011–2014 with at least 1 year of follow-up before transplant were identified. Serious fall injuries in the year before transplant were identified using diagnostic codes for falls and simultaneous fractures, dislocations, or head trauma in inpatient or outpatient claims. We used multivariable Cox proportional hazards models to estimate associations of incident posttransplant outcomes with serious fall injury in the year before transplant.

Results.

A total of 620 (2.8%) recipients had serious fall injuries before transplant and were more likely to be white, female, and have more comorbid conditions than those without a fall injury. Although posttransplant recipient survival did not differ by recent serious fall injuries (hazard ratio [HR], 1.03; 95% confidence interval [CI], 0.78-1.36), these injuries were associated with 33% higher rates of graft failure (HR, 1.33; 95% CI, 1.03-1.72). Patients with serious fall injuries spent 12.1% of posttransplant follow-up hospitalized, a 3.3-fold higher rate than those without a fall, and had nearly 2-fold higher rates of skilled nursing facility utilization (HR, 1.98; 95% CI, 1.52-2.57).

Conclusions.

Serious fall injuries are independently associated with significantly greater resource requirements and lower graft survival. Further study is needed to delineate the relationship between falls and adverse outcomes in transplant and reduce the incidence and deleterious effects of these events.
The Effect of the Opioid Epidemic on Donation After Circulatory Death Transplantation Outcomes
Authors: Wanis Kerollos Nashat , Madenci Arin L. , Dokus M. Katherine , Tomiyama Koji , Al-Judaibi Bandar M. , Hernán Miguel A. , Hernandez-Alejandro Roberto
Published: September 2018

Background.

The opioid epidemic and the deaths of otherwise healthy individuals due to drug overdose in the United States has major implications for transplantation. The current extent and safety of utilization of liver and kidney grafts from donation after circulatory death (DCD) donors who died from opioid overdose is unknown.

Methods.

Using national data from 2006 to 2016, we estimated the cumulative incidence of graft failure for recipients of DCD grafts, comparing the risk among recipients of organs from donors who died of anoxic drug overdose and recipients of organs from donors who died of other causes.

Results.

One hundred seventy-nine (6.2%) of 2908 liver graft recipients and 944 (6.1%) of 15520 kidney graft recipients received grafts from donors who died of anoxic drug overdose. Grafts from anoxic drug overdose donors were less frequently used compared with other DCD grafts (liver, 25.9% versus 29.6%; 95% confidence interval [CI] for difference, −6.7% to −0.7%; kidney, 81.0% versus 84.7%; 95% CI for difference, −7.3% to −0.1%). However, the risk of graft failure at 5 years was similar for recipients of anoxic drug overdose donor grafts and recipients of other grafts (liver risk difference, 1.8%; 95% CI, −7.8% to 11.8%; kidney risk difference, −1.5%; 95% CI, −5.4% to 3.1%).

Conclusions.

In the context of the current opioid epidemic, utilization of anoxic drug overdose DCD donor grafts does not increase the risk of graft failure and may help to address waitlist demands.
A Case of Musical Hallucinations Related to Mirtazapine
Authors: Lee Grace H. , Stewart Jonathan T.
Published: September 2018

Musical hallucinations (MHs) are relatively uncommon phenomena sometimes encountered in older patients, especially older women. They usually involve popular, overlearned music, either entire songs or repetitive snippets. While MHs are most commonly associated with hearing loss, they may occur in a variety of psychiatric, neurologic, and iatrogenic conditions. We report a 91-year-old man whose MHs were causally related to the antidepressant mirtazapine. Although mirtazapine is generally well tolerated, it may rarely cause MHs or other psychotic symptoms.
Tandospirone-Induced Rhabdomyolysis
Authors: Miyazaki Kensuke , Otaka Masabumi , Yasui-Furukori Norio
Published: September 2018

Background

Rhabdomyolysis involves the release of intracellular contents secondary to muscle cell injury; it generally presents with muscle pain and weakness. Although several psychotropic agents have been documented as causes of rhabdomyolysis, there are no reports of tandospirone-induced rhabdomyolysis.

Case

We present the case of a 15-year-old Japanese girl who had posttraumatic stress disorder after the Great East Japan Earthquake. She received a dose of 60 mg of tandospirone while taking 10 mg of tandospirone and 400 mg of valproic acid every day. She developed appetite loss, muscle weakness, muscle soreness, and general malaise on day 2, and laboratory data revealed a serum creatine phosphokinase level of 17,770 IU/L that reached a peak of 35,530 IU/L on day 4. Lactate dehydrogenase, aspartate aminotransferase, and alanine transaminase levels were also abnormal. After a fluid infusion was initiated and tandospirone was discontinued, most of her symptoms and abnormal laboratory data resolved within 10 days.

Conclusion

This case suggests that careless high dosing of partial 5-HT1A receptor agonists is harmful to at-risk patients, such as adolescent patients with poor mental condition.
Levetiracetam-Induced Seizure Aggravation in Patients With Focal Cortical Dysplasia
Authors: Cvetkovska Emilija , Kuzmanovski Igor , Babunovska Marija , Boshkovski Bojan , Aleksovska Katina , Trencevska Gordana Kiteva
Published: September 2018

Objectives

The choice of antiepileptic drug is typically based on seizure type, and there is no evidence for superior effectiveness or potential deterioration of particular antiepileptic drug in specific etiologic subgroups. The aim of the study was to identify etiological factor(s) associated with increased risk of seizure aggravation with levetiracetam (LEV).

Methods

A retrospective analysis of 139 patients treated with LEV was performed. Seizure aggravation was defined as a 100% or greater increase in seizures frequency, which occurred within 1 month of drug introduction.

Results

Five patients who fulfilled the selection criteria were identified. Seizure aggravation occurred with low doses (500–1000 mg) of LEV. In addition to increased frequency and duration, 2 patients developed new seizure types. Withdrawal of LEV resulted in seizure return to background frequency in all patients. Four of 5 patients have distinctive magnetic resonance imaging finding of focal cortical dysplasia. No patients with paradoxical effect of LEV were detected in the idiopathic epilepsy group or other types of symptomatic epilepsies.

Conclusions

Our results suggest that LEV may possibly induce seizure exacerbation in a subset of patients with focal cortical dysplasia–related epilepsy, although large studies are needed to establish the relation. Underlying causes of epilepsy could impact the treatment choice because electroclinical semiology might be the “final common pathway” of different epileptogenic mechanisms in diverse etiologies.
Increased Risk of Ischemic Stroke in Multiple Myeloma Associated With Lenalidomide Treatment: A Case Report and Review of the Literature
Authors: de Celis Elena , Alonso de Leciñana María , Rodríguez-Pardo Jorge , Fuentes Blanca , Díez-Tejedor Exuperio
Published: September 2018

Objective

The aim of the study was to illustrate the increased risk of ischemic stroke in the context of multiple myeloma (MM) under treatment with lenalidomide combined with dexamethasone.

Methods

This is a case report and literature review.

Results

A 62-year-old woman diagnosed with relapsed MM under treatment with lenalidomide and dexamethasone presented with acute onset disorientation, disturbed behavior, and aphasia. Cranial computed tomography scan revealed an acute cerebral infarction in the left middle cerebral artery territory, and brain magnetic resonance imaging showed additional silent ischemic lesions in other arterial territories. Common stroke etiologies were excluded after an extensive study, leading to a final diagnosis of cerebral infarction of uncommon cause probably related to MM and treatment with lenalidomide plus dexamethasone. A literature review provided 84 reports from the license holder, 2 more cases of stroke in patients with MM receiving lenalidomide and a recurrent stroke in a patient experiencing polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS syndrome) treated with lenalidomide.

Conclusions

Our case exemplifies the need to raise awareness about the risk of ischemic stroke associated with MM that might be increased by treatment with lenalidomide and to establish consistent recommendations regarding thromboprophylaxis to reduce comorbidities and mortality in these patients.
Host JAK-STAT activity is a target of parasitoid wasp virulence strategies
Authors: Brantley Susanna E. , Stouthamer Corinne M. , Kr Pooja , Fischer Mary L. , Hill Joshua , Schlenke Todd A. , Mortimer Nathan T.
Published: September 2018

Innate immune responses that allow hosts to survive infection depend on the action of multiple conserved signaling pathways. Pathogens and parasites in turn have evolved virulence factors to target these immune signaling pathways in an attempt to overcome host immunity. Consequently, the interactions between host immune molecules and pathogen virulence factors play an important role in determining the outcome of an infection. The immune responses ofDrosophila melanogasterprovide a valuable model to understand immune signaling and host-pathogen interactions. Flies are commonly infected by parasitoid wasps and mount a coordinated cellular immune response following infection. This response is characterized by the production of specialized blood cells called lamellocytes that form a tight capsule around wasp eggs in the host hemocoel. The conserved JAK-STAT signaling pathway has been implicated in lamellocyte proliferation and is required for successful encapsulation of wasp eggs. Here we show that activity ofStat92E, theD. melanogasterSTAT ortholog, is induced in immune tissues following parasitoid infection. Virulent wasp species are able to suppressStat92Eactivity during infection, suggesting they target JAK-STAT pathway activation as a virulence strategy. Furthermore, two wasp species (Leptopilina guineaensisandGanaspis xanthopoda) suppress phenotypes associated with a gain-of-function mutation inhopscotch, theD. melanogasterJAK ortholog, indicating that they inhibit the activity of the core signaling components of the JAK-STAT pathway. Our data suggest that parasitoid wasp virulence factors block JAK-STAT signaling to overcome fly immune defenses.

Author Summary

Following infection, host immune responses are triggered to provide protection against the invading pathogen. The proper function of these responses depends on the activity of multiple immune signaling pathways. These pathways act in a coordinated manner to orchestrate the immune response, and any disruption can render the host susceptible to infection. Because of this sensitivity, many pathogen species have evolved virulence mechanisms that target host signaling pathways and disrupt their function. We are using the interaction betweenDrosophila melanogasterandDrosophila-infecting parasitoid wasps to study this relationship between host signaling and pathogen virulence. Parasitoids infect fly larvae, and during infection, transfer virulence protein containing venom into the host, providing a mechanism to alter host signaling. This study is focused on one key immune signaling pathway, the highly conserved JAK-STAT pathway. We find that many virulent parasitoid species restrict the activity of the host JAK-STAT pathway, providing a clue as to their virulence strategy. JAK-STAT signaling plays many additional roles in health and disease, and so this system provides a good model to further understand this important pathway.
GIGANTEApromotes sorghum flowering by stimulating floral activator gene expression
Authors: Harmon Frank G. , Chen Junping , Xin Zhanguo
Published: September 2018

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Funding

This work was supported by USDA-ARS CRIS projects 2030-21000-039-00D and 2030-21000-049-00D to F.G.H.

v.

The C4 grassSorghum bicoloris an important grain and subsistence crop, animal forage, and cellulosic biofuel feedstock that is tolerant of abiotic stresses and marginal soils. Sorghum is short-day flowering, an obstacle for adaptation as a grain crop but a benefit as a biofuel feedstock. To identify genes underlying sorghum photoperiodic flowering behavior this study characterized theSbgi-ems1nonsense mutation in the sorghumGIGANTEA(SbGI) gene from a sequenced M4 EMS-mutagenized BTx623 population.Sbgi-ems1plants had reduced stature and leaf blades exhibiting increased lateral growth combined with reduced proximal-distal growth. Mutant plants flowered later than normal siblings under long-day conditions provided by greenhouse or field. Delayed flowering inSbgi-ems1plants accompanied by an increase in internode number, indicating an extended vegetative growth phase prior to flowering.Sbgi-ems1plants had reduced expression of floral activator genesSbCOandSbEhd1and downstream FT-like florigen genesSbFT, SbCN8, andSbCN12. Therefore,SbGIaccelerates flowering by promotion ofSbCOandSbEhd1expression. Circadian clock-associated genesSbTOC1andSbLHYhad disrupted expression inSbgi-ems1plants. This work demonstratesSbGIis a key upstream activator in the regulatory networks dictating sorghum flowering time and growth, as well as gene expression regulation within the circadian clock.

Summary Statement

SorghumGIGANTEAcontributes to flowering time, growth, and the circadian clock with activities opposite to its maize homolog.GIoccupies a conserved position within regulatory networks but has plastic activity.
Host genetic associations with the gut microbiota in HIV-1-infected subjects: a pilot exploratory study
Authors: Guillén Yolanda , Noguera-Julian Marc , Rivera Javier , Casadellà Maria , Rocafort Muntsa , Parera Mariona , Mothe Beatriz , Coll Josep , Saz Jorge , Navarro Jordi , Crespo Manuel , Negredo Eugènia , Brander Christian , Calle Maria Luz , Clotet Bonaventura , Paredes Roger
Published: September 2018

The impact of host genetics on gut microbial dynamics is debated. No study to date has investigated the possible role of host genetics in shaping the gut microbiota in HIV-1 infected subjects. With the aim of generating preliminary data to inform future host genetic studies, we performed an exploratory host exome analysis of 147 subjects either infected or at risk of becoming infected with HIV-1 from the MetaHIV cohort in Barcelona. Using a DNA microarray chip, we sought to identify host genetic variants associated to three specific microbial features with a potentially inheritable component, and which were previously found to be associated with gut dysbiosis in HIV infection, i.e.: gut enterotype, presence of methanogenic archaea and microbial gene richness. After correction for multiple comparisons, we did not observe any statistically significant association between the host’s genetic landscape and the explored gut microbiome traits. These findings will help design future, adequately-powered studies to assess the influence of host genetics in the microbiome of HIV-1-infected subjects.
Inhibition of the amino-acid transporter LAT1 demonstrates anti-neoplastic activity in medulloblastoma
Authors: Cormerais Yann , Pagnuzzi-Boncompagni Marina , Schrötter Sandra , Giuliano Sandy , Tambutté Eric , Endou Hitoshi , Wempe Michael F. , Pagès Gilles , Pouysségur Jacques , Picco Vincent
Published: September 2018

Most cases of medulloblastoma (MB) occur in young children. While the overall survival rate can be relatively high, current treatments combining surgery, chemo- and radiotherapy are very destructive for patient development and quality of life. Moreover, aggressive forms and recurrences of MB cannot be controlled by classical therapies. Therefore, new therapeutic approaches yielding good efficacy and low toxicity for healthy tissues are required to improve patient outcome. Cancer cells sustain their proliferation by optimizing their nutrient uptake capacities. The L-type amino acid transporter 1 (LAT1) is an essential amino acid carrier overexpressed in aggressive human cancers that was described as a potential therapeutic target. In this study, we investigated the therapeutic potential of JPH203, a LAT1-specific pharmacological inhibitor, on two independent MB cell lines belonging to subgroups 3 (HD-MB03) and Shh (DAOY). We show that while displaying low toxicity towards normal cerebral cells, JPH203 disrupts AA homeostasis, mTORC1 activity, proliferation and survival in MB cells. Moreover, we demonstrate that a long-term treatment with JPH203 does not lead to resistance in MB cells. Therefore, the present study suggests that targeting LAT1 with JPH203 is a promising therapeutic approach for MB treatment.
Leveraging brain cortex-derived molecular data to elucidate epigenetic and transcriptomic drivers of neurological function and disease
Authors: Hatcher Charlie , Relton Caroline L. , Gaunt Tom R. , Richardson Tom G.
Published: September 2018

Integrative approaches which harness large-scale molecular datasets can help develop mechanistic insight into findings from genome-wide association studies (GWAS). We have performed extensive analyses to uncover transcriptional and epigenetic processes which may play a role in neurological trait variation.

This was undertaken by applying Bayesian multiple-trait colocalization systematically across the genome to identify genetic variants responsible for influencing intermediate molecular phenotypes as well as neurological traits. In this analysis we leveraged high dimensional quantitative trait loci data derived from prefrontal cortex tissue (concerning gene expression, DNA methylation and histone acetylation) and GWAS findings for 5 neurological traits (Neuroticism, Schizophrenia, Educational Attainment, Insomnia and Alzheimer’s disease).

There was evidence of colocalization for 118 associations suggesting that the same underlying genetic variant influenced both nearby gene expression as well as neurological trait variation. Of these, 73 associations provided evidence that the genetic variant also influenced proximal DNA methylation and/or histone acetylation. These findings support previous evidence at loci where epigenetic mechanisms may putatively mediate effects of genetic variants on traits, such as KLC1 and schizophrenia. We also uncovered evidence implicating novel loci in neurological disease susceptibility, including genes expressed predominantly in brain tissue such as MDGA1, KIRREL3 and SLC12A5.

An inverse relationship between DNA methylation and gene expression was observed more than can be accounted for by chance, supporting previous findings implicating DNA methylation as a transcriptional repressor. Our study should prove valuable in helping future studies prioritise candidate genes and epigenetic mechanisms for in-depth functional follow-up analyses.
Identification of a novel deltavirus in Boa constrictor
Authors: Hetzel Udo , Szirovicza Leonóra , Smura Teemu , Prähauser Barbara , Vapalahti Olli , Kipar Anja , Hepojoki Jussi
Published: September 2018

Human hepatitis D virus (hHDV) forms the genus Deltavirus which has not been assigned to any virus family. hHDV is a satellite virus and needs hepatitis B virus (HBV) to make infectious particles. Deltaviruses are thought to have evolved in humans, since they have thus far not been identified elsewhere. Herein we report, prompted by a recent observation of HDV-like agent in birds, the identification of a deltavirus in a snake (Boa constrictor) designated as snake-HDV (sHDV). The circular 1711 nt RNA genome of the newly identified virus resembles hHDV in its coding strategy and size. We discovered sHDV when performing a meta-transcriptomic study on brain samples of two boas with central nervous system signs. We did not identify accompanying HBV-like sequences in the samples. By sequence comparison, the putative hepatitis D antigen (HDAg) of sHDV, encoded by one of the two open reading frames (ORFs), is roughly 50% identical to the previously known HDAgs. We used antiserum raised against recombinant snake HDAg to demonstrate a broad viral target cell spectrum, ranging from neurons over epithelial cells to leukocytes. Using RT-PCR, we detected sHDV RNA also in the liver and blood of the two snakes and could show sHDV infection not only in two of their juvenile offspring, but also in a water python (Liasis mackloti savuensis) in the same snake colony, indicating potentially vertical and horizontal transmission. The finding of abundant sHDAg in several tissues suggests that sHDV actively replicated in the studied animals. Our findings suggest that sHDV spread may not be restricted to hepadnavirus co-infection. This would imply that deltaviruses may employ other enveloped viruses for producing infectious particles.