bluuebunny/crossref_metadata_2025 huggingface dataset:
“The Most Common Sickness of Our Time”: Tocqueville on Democratic Restlessness
Authors: Stauffer Dana Jalbert
Published: June 2018

In volume 1 ofDemocracy in America, Tocqueville argues that the energy unleashed by democracy is one of democracy's greatest benefits. In volume 2, his portrait of democracy turns darker, and he recasts the dynamism of American society as an expression of an underlying restlessness. In this paper, I argue that restlessness (inquiétude) is a key element of Tocqueville's mature view of democratic man. Whereas previous scholarship on Tocqueville's view of restlessness either treats the theme instrumentally, by subordinating it to other themes, or seeks to illuminate Tocqueville's debt to other thinkers, this paper examines Tocqueville's treatment of restlessness as an important theme in its own right. Treating this theme in full requires examining his discussions of materialism, envy, democratic morality, and democratic peoples’ experiences of literature and art. Through this examination we see how, in Tocqueville's view, democracy, for all its merits, obstructs the path to human happiness.
WHERE ARE WE NOW?
Authors: Shlomowitz Matthew
Published: June 2018

This article offers generalised reflections on current aesthetic interests and values within the field of new music. Critical composition and postmodernism are considered for the relevance these historic positions might hold today. Then two important trends of the past decade are presented: first, music that draws attention toward the sounding shape and act of listening, reflecting the recent surge of interest in materialism across academic and artistic disciplines; and second, pieces that include aspects such as physical action, lighting and theatrical approaches to expand the possibilities of concert hall work beyond the purely sonic.
PERFORMANCE OF SMARTPHONE-BASED DIGITAL IMAGES FOR CERVICAL CANCER SCREENING IN A LOW-RESOURCE CONTEXT
Authors: Tran Phuong Lien , Benski Caroline , Viviano Manuela , Petignat Patrick , Combescure Christophe , Jinoro Jeromine , Herinianasolo Josea Lea , Vassilakos Pierre
Published: June 2018

Objectives:

Colposcopes are expensive, heavy, and need specialized technical service, which may outreach the capacity of low-resource settings. Our aim was to assess the performance of smartphone-based digital images for the detection of cervical intraepithelial neoplasia grade 2 or worse (CIN2+).

Methods:

Human papillomavirus (HPV)-positive women recruited through a cervical cancer screening campaign had VIA/VILI assessment (visual inspection after application of acetic acid/lugol's iodine). Cervical digital images were captured with a smartphone camera, randomly coded with no prior selection and distributed on an online database (Google Forms) for evaluation. Healthcare providers were invited to evaluate the images and identify CIN2+. The gold standard was the histopathological diagnosis. The sensitivity and specificity for the detection of CIN2+ was assessed for each reader and reported with the 95 percent confidence interval (Clopper-Pearson method).

Results:

One hundred twenty-five consecutive HPV-positive women were included, with 19 CIN2+ (15.2 percent). Forty-five gynecologists completed the assessment, one-third were considered as experts (>50 colposcopies) and two-thirds as novices (<50 colposcopies). The sensitivity and specificity for CIN 2+ detection was 71.3 percent (67.0–75.7 percent) and 62.4 percent (57.5–67.4 percent), respectively. The performance of novices and experts was similar. The readers assessed 73.1 percent of images as acceptable for diagnostic.

Conclusion:

Smartphone-based digital images, with its high portability, have a great potential for the diagnosis of CIN2+ in low-resource context.
Produce-associated foodborne disease outbreaks, USA, 1998–2013
Authors: Bennett S. D. , Sodha S. V. , Ayers T. L. , Lynch M. F. , Gould L. H. , Tauxe R. V.
Published: June 2018

The US Food Safety Modernization Act (FSMA) gives food safety regulators increased authority to require implementation of safety measures to reduce the contamination of produce. To evaluate the future impact of FSMA on food safety, a better understanding is needed regarding outbreaks attributed to the consumption of raw produce. Data reported to the US Centers for Disease Control and Prevention's Foodborne Disease Outbreak Surveillance System during 1998–2013 were analysed. During 1998–2013, there were 972 raw produce outbreaks reported resulting in 34 674 outbreak-associated illnesses, 2315 hospitalisations, and 72 deaths. Overall, the total number of foodborne outbreaks reported decreased by 38% during the study period and the number of raw produce outbreaks decreased 19% during the same period; however, the percentage of outbreaks attributed to raw produce among outbreaks with a food reported increased from 8% during 1998–2001 to 16% during 2010–2013. Raw produce outbreaks were most commonly attributed to vegetable row crops (38% of outbreaks), fruits (35%) and seeded vegetables (11%). The most common aetiologic agents identified were norovirus (54% of outbreaks), Salmonella enterica (21%) and Shiga toxin-producing Escherichia coli (10%). Food-handling errors were reported in 39% of outbreaks. The proportion of all foodborne outbreaks attributable to raw produce has been increasing. Evaluation of safety measures to address the contamination on farms, during processing and food preparation, should take into account the trends occurring before FSMA implementation.
Use of gender distribution in routine surveillance data to detect potential transmission of gastrointestinal infections among men who have sex with men in England
Authors: Mook P. , Gardiner D. , Kanagarajah S. , Kerac M. , Hughes G. , Field N. , McCarthy N. , Rawlings C. , Simms I. , Lane C. , Crook P. D.
Published: June 2018

Detecting gastrointestinal (GI) infection transmission among men who have sex with men (MSM) in England is complicated by a lack of routine sexual behavioural data. We investigated whether gender distributions might generate signals for increased transmission of GI pathogens among MSM. We examined the percentage male of laboratory-confirmed patient-episodes for patients with no known travel history for 10 GI infections of public health interest in England between 2003 and 2013, stratified by age and region. An adult male excess was observed forShigellaspp. (annual maximum 71% male); most pronounced for those aged 25–49 years and living in London, Brighton and Manchester. An adult male excess was observed every year forEntamoeba histolytica(range 59.8–76.1% male),Giardia(53.1–57.6%) andCampylobacter(52.1–53.5%) and for a minority of years for hepatitis A (max. 69.8%) and typhoidal salmonella (max. 65.7%). This approach generated a signal for excess male episodes for six GI pathogens, including a characterised outbreak ofShigellaamong MSM. Stratified analyses by geography and age group were consistent with MSM transmission forShigella. Optimisation and routine application of this technique by public health authorities elsewhere might help identify potential GI infection outbreaks due to sexual transmission among MSM, for further investigation.
104 Valproate-Induced Hyperammonemic Encephalopathy: Case Studies
Authors: Matthews Dan , Matthews Glenda
Published: June 2018

BACKGROUND

Hyperammonemia and carnitine deficiency with concomitant encephalopathy have been reported to result from valproic acid administration (Coulter DL, J Child Neurol 1991Jan; 6(1); 7-14 and Mock, CM, et al, Am J Health Syst Pharm, 2012 Jan; 69(1):35-9). Although there have been numerous publications regarding this adverse event in the neurology literature, there have been very few reports published in the psychiatric literature. The reported incidence of hyperammonemia in children treated with valproate is 19%. It is important that prescribers be aware of the risk of valproic acid induced hyperammonemic encephalopathy, as well as its diagnosis and management.

OBJECTIVE

The current study explores the feasibility of reversing Valproate Induced Hyperammonemic Encephalopathy (VHE) by discontinuing valproic acid and normalizing the carnitine level via L-carnitine supplementation.

METHODS

Three males (ages 10-16 years), are reported with 12 - 24 month histories of cognitive decline during treatment for “Bipolar Disorder of Childhood” with valproate. All were referred with multi-year histories of explosive/impulsive aggression and multiple unsuccessful psychopharmacological regimes. The one consistent medication throughout treatment was sodium valproate. The subjects received serial neuropsychological testing, complex EEG, MRI, valproic acid, carnitine, and ammonia blood levels. Oxcarbazepine titrated to 30-50 mg/kg/day was substituted for valproate after initial testing was completed. Normative reference laboratory levels were as follows: (1) ammonia (reference interval 15-45 mcg/dl), (2) total carnitine (reference interval 34-77 nmol/ml), and (3) valproic acid (reference interval 50-125 mcg/ml).

RESULTS

Case Study 1: Male, 10 years old, ammonia 78 mcg/dl; carnitine 17 nmol/ml; valproic acid 92 mcg/ml. IQ 79 (compared to 105 one year earlier); MRI cerebral atrophy; EEG - left temporal aberrancies.

Case Study 2: Male, 12 years old, ammonia 76 mcg/dL; carnitine 14 nmol/ml; valproic acid 104 mcg/ml. IQ 89 (compared to 109); MRI normal; EEG - left temporal aberrancies.

Case Study 3: Male, 16 years old, ammonia 72 mcg/dl; carnitine 24 nmol/ml; valproic acid 125 mcg/ml. IQ 45 (compared to 65); MRI normal; EEG - left temporal aberrancies.

In all three subjects, after valproate was removed (oxcarbazepine substituted) and supplemental L-carnitine added, ammonia and total carnitine levels normalized. At one year follow up, IQ’s returned to previous baselines, and MRI atrophy (Case 1) normalized. EEG aberrancies were unchanged. Patients were mood and behaviorally stable on oxcarbazepine.

CONCLUSION

Evidence of cognitive decline while on valproate warrants ammonia and carnitine level testing. If these levels are abnormal, VHE should be diagnosed and valproate should be removed as rapidly as feasible; L-carnitine supplementation (the lesser of 100 mg/kg/day or 2 grams/day) should be implemented to normalize the carnitine level.

Funding Acknowledgements

No funding.
127 Cardiovascular Safety Assessment of Deutetrabenazine in Healthy Volunteers and Implications for Patients With Huntington Disease or Tardive Dyskinesia
Authors: Cox Donna S. , Levi Micha , Rabinovich-Guilatt Laura , Truong David , Stamler David
Published: June 2018

Introduction

Deutetrabenazine is approved for treating Huntington disease (HD) chorea and is being evaluated for tardive dyskinesia (TD).

Objective

To assess the effect of deutetrabenazine on cardiac repolarization.

Methods

A QT interval study was performed to evaluate effects of deutetrabenazine 12 and 24 mg on cardiac repolarization, as assessed by time-matched change from baseline, placebo-adjusted, in Fridericia-corrected QT interval (ΔΔQTcF). Moxifloxacin (400 mg) and tetrabenazine (50 mg) were the positive control and comparator, respectively. An exposure–response analysis was developed from this study to predict maximal effects on QTcF at maximum recommended dosing based on CYP2D6 status, an approach consistent with regulatory guidance at predicting QT interval effects.

Results

Maximal ΔΔQTcF between the least-squares mean (90% two-sided confidence interval) of deutetrabenazine 12 and 24 mg (n=45 in each group) were 2.8 (0.7–4.8) ms and 4.5 (2.4–6.5) ms, respectively. The ΔΔQTcF increase with tetrabenazine (n=45) was 7.6 (5.6–9.5) ms. Assay sensitivity was verified with moxifloxacin (n=47), which produced a maximal effect on ΔΔQTcF of 14.0 (11.9–16.0) ms. A linear model was developed that described a correlation between plasma concentrations from pivotal HD andTD trials (n=101) and QT interval prolongation. Using that model and the individual predicted Cmax for HD and TD patients, the placebo-adjusted change from baseline inQTcF for deutetrabenazine at maximal recommended daily doses was found to be 5.4 (2.5–9.5) ms.

Conclusions

Patients receiving the maximal recommended doses of deutetrabenazine are predicted to have a QTcF increase below the level of regulatory concern.

Presented at: Psych Congress; September 16–19, 2017; New Orleans, Louisiana, USA.

Funding Acknowledgements

This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel
129 Effect of DR/ER-MPH on Caregiver-Reported ADHD Symptom Improvement in Children With ADHD and Caregiver Strain: Results From a Phase 3 Trial
Authors: Pliszka Steven R. , Arnold Valerie K. , Marraffino Andrea , DeSousa Norberto J. , Incledon Bev , Sallee F. Randy , Wilens Timothy E. , Newcorn Jeffrey H.
Published: June 2018

Objective

Evening-dosed DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, was designed to provide efficacy upon awakening and through the evening. The objective was to evaluate whether treatment with DR/ER-MPH in children with attention-deficit/hyperactivity disorder (ADHD): (1) improves caregiver-rated ADHD symptoms, and (2) reduces caregiver strain, versus placebo.

Method

Caregiver-rated ADHD symptoms (Conners’ Global Index–Parent [CGI-P]) and caregiver strain (Caregiver Strain Questionnaire [CGSQ]) were assessed as secondary endpoints following 3 weeks of treatment in a randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) with ADHD (NCT02520388). Using the 10-item CGI-P, parents rated their child’s ADHD symptoms on a 4-point scale (0=never/seldom; 3=very often/frequently). Caregivers also rated the impact of caring for a child with emotional and behavioral challenges on the 21-item CGSQ (5-point scale: 1=not at all; 5=very much). A reduction on individual item and total scores for both measures indicated an improvement.

Results

Of 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose after 3 weeks of treatment was 68.1 mg. Mean CGI-P scores at baseline and CGSQ scores at screening (ie, before washout of prior ADHD therapy) were comparable for both DR/ER-MPH (CGI-P: 22.8, CGSQ: 54.5) and placebo (CGI-P: 21.8; CGSQ: 54.9) groups. After 3 weeks of treatment, caregivers of children onDR/ER-MPH reported significant reductions in CGI-P scores versus those on placebo (least-squares [LS] mean: 12.3 vs 17.4; P<0.001). Additionally, there was a significant reduction in CGSQ scores after 3 weeks of treatment with DR/ER-MPH versus placebo (LS mean: 41.2 vs 49.1; P<0.001). Post hoc analyses on the effect of DR/ER-MPHversus placebo on individual items of CGI-P and CGSQ, and the two subscales of CGI-P will be presented. No serious TEAEs were reported and all TEAEs were consistent with those of MPH.

Conclusions

Caregivers reported significant improvements in their child’s ADHD symptoms and these improvements coincided with reductions in caregiver strain after 3 weeks of treatment on evening-dosed DR/ER-MPH versus placebo.

Funding Acknowledgements

Ironshore Pharmaceuticals & Development, Inc.
130 Consistent Efficacy of DR/ER-MPH on Early Morning Functioning in Children With ADHD: Analysis of BSFQ Item Ratings From a Pivotal Phase 3 Trial
Authors: Wilens Timothy E. , Pliszka Steven R. , Arnold Valerie K. , Marraffino Andrea , DeSousa Norberto J. , Incledon Bev , Sallee F. Randy , Newcorn Jeffrey H.
Published: June 2018

Objective

In a phase 3 trial of children with attention-deficit/hyperactivity disorder (ADHD), DR/ER-MPH (formerly HLD200), a delayed-release and extended-release methylphenidate, improved ADHD symptoms and reduced at-home early morning and late afternoon/evening functional impairment versus placebo. The validated Before School Functioning Questionnaire (BSFQ), a key secondary endpoint, was used to measure early morning functional (EMF) impairment. This post hoc analysis evaluated the effect of DR/ER-MPH versus placebo on individual BSFQ item scores from baseline.

Method

Data were analyzed from a pivotal, randomized, double-blind, multicenter, placebo-controlled, parallel-group, phase 3 trial of DR/ER-MPH in children (6-12 years) withADHD (NCT02520388). Using the 20-item BSFQ, investigators evaluated EMF impairment by scoring each item on a severity scale of 0 to 3, with 0 denoting “no impairment” and 3 denoting “severe impairment”. For post hoc analyses, treatment comparisons between DR/ER-MPH and placebo at endpoint were determined by using least squares mean changes from baseline on individual BSFQ items score derived from an analysis of covariance (ANCOVA) model with treatment as the main effect, and study center and baseline score as covariates.

Results

Of 163 children enrolled across 22 sites, 161 were included in the intent-to-treat population (DR/ER-MPH, n=81; placebo, n=80) and 138 completed the study. The mean DR/ER-MPH dose achieved after 3 weeks of treatment was 68.1 mg. Following 3 weeks of treatment, DR/ER-MPH significantly reduced mean BSFQ item scores frombaseline on 18 out of 20 items versus placebo (P<0.001 in 8 items [listening, following directions, attention, forgetfulness, talkativeness, silliness, time awareness, getting to school]; P<0.01 in 7 items [overall organization, being quiet, distraction, interrupt/blurt out, breakfast, hygiene, independence]; P<0.05 in 3 items [procrastination, hyperactivity, awaiting turn]). Only “dressing” and “misplacing/losing items” showed no significant between-group differences (P=0.171 and P=0.175, respectively). Distributions of the severity ratings for each item will be presented. No serious TEAEs were reported; TEAEs were consistent with methylphenidate.

Conclusions

Post hoc analyses revealed that DR/ER-MPH significantly reduced 18 out of 20 individual BSFQ item scores versus placebo in children with ADHD. These findings are worth further exploration.

Funding Acknowledgements

Ironshore Pharmaceuticals & Development, Inc.
132 Effects of Valbenazine on Depression and Suicidality in Adults With Tardive Dyskinesia: Pooled Results of 3 Double-Blind, Placebo-Controlled Trials
Authors: Remington Gary , Thai-Cuarto Dao , Burke Joshua , Siegert Scott , Liang Grace S.
Published: June 2018

Study Objectives

Valbenazine (INGREZZA; VBZ) is a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor that is approved for the treatment of tardive dyskinesia (TD) in adults. The randomized, double-blind, placebo (PBO)-controlled trials of VBZ evaluated the treatment of TD in patients with a primary psychiatric diagnosis (schizophrenia/schizoaffective disorder or mood disorder) while on concomitant psychiatric medications to manage these disorders. Since treatment-emergent depression and suicidal ideation/behavior are important clinical concerns in psychiatric patient populations, data from these trials were analyzed to assess the effectsof once-daily VBZ on depression and suicidality.

Methods

Data were pooled from three 6-week trials: KINECT (NCT01688037), KINECT 2 (NCT01733121), KINECT 3 (NCT02274558). Outcome data were analyzed in the safety population by pooled VBZ doses (40 mg, 80 mg) and PBO. Outcomes of interest included: treatment-emergent adverse events (TEAEs) related to depression or suicidality; mean score change from baseline to Week 6 in the Calgary Depression Scale for Schizophrenia (CDSS, for participants with schizophrenia/schizoaffective disorder) or the Montgomery-Åsberg Depression Rating Scale (MADRS, for participants with mood disorder); and, worsening from baseline in Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation scores. All outcomes were analyzed descriptively.

Results

There were 400 total participants in the pooled safety population; 286 participants had schizophrenia/schizoaffective disorder (40 mg, n=82; 80 mg, n=70; PBO, n=134) and 114 had a mood disorder (40 mg, n=28; 80 mg, n=42; PBO, n=44). Over one-third of participants had a lifetime history of suicidal ideation or behavior (40 mg, 45%; 80 mg, 39%; PBO, 37%). Few participants had a depression- or suicide-related TEAE, with no apparent differences between VBZ and PBO: suicidal ideation (40 mg, 3.6%; 80 mg, 0.9%; PBO, 2.2%); depression (40 mg, 0%; 80 mg, 1.8%; PBO, 1.1%); depressive symptom (40 mg, 0.9%; 80 mg, 0%; PBO, 0.6%); suicide attempt (40 mg, 0%; 80 mg, 0.9%; PBO, 0%). Mean changes from baseline to Week 6 in depression scale scores were generally small and similar across treatment groups: CDSS total score (40 mg, -0.5; 80 mg, -0.6; PBO, -0.3); MADRS total score (40 mg, -0.2; 80 mg, -1.7; PBO, 0.6). Few participants had a shift from no suicidal ideation at baseline (C-SSRS score=0) to any suicidal ideation during treatment (C-SSRS score=1-5): 40 mg, 3.9% (4/103); 80 mg, 0.9% (1/111); PBO, 2.9% (5/174).

Conclusion

Data from 3 double-blind, placebo-controlled trials indicate that once-daily VBZ treatment was not associated with a worsening in depression-related symptoms or an increased risk of suicidal ideation or behavior.

Funding Acknowledgements

This study was funded by Neurocrine Biosciences, Inc.
158 Long-Term Safety of Deutetrabenazine for the Treatment of Tardive Dyskinesia: Results From an Open-Label, Long-Term Study
Authors: Anderson Karen E. , Davis Mat D. , Factor Stewart A. , Hauser Robert A. , Jarskog L. Fredrik , Jimenez-Shahed Joohi , Kumar Rajeev , Ochudlo Stanislaw , Ondo William G. , Fernandez Hubert H.
Published: June 2018

Introduction

In the 12-week ARM-TD and AIM-TD studies, deutetrabenazine showed clinically significant improvements in Abnormal Involuntary Movement Scale (AIMS) scores at Week 12 compared with placebo, and was generally well tolerated.

Objective

To evaluate the long-term safety/tolerability and efficacy of deutetrabenazine in patients with TD. Week 54 open-labelresults are reported in this interim analysis.

Methods

Patients with TD who completed ARM-TD or AIM-TD were included in this open-label, single-arm extension study, in which all patients restarted/started deutetrabenazine 12 mg/day, titrating up to a maximum total daily dose of 48 mg/day based on dyskinesia control and tolerability. The study comprised a 6-week titration period and a long-term maintenance phase. Safetymeasures included incidence of adverse events (AEs), serious AEs (SAEs), drug-related AEs, and AEs leading to withdrawal, dose reduction, or dose suspension. This analysis reports results up to Week 54.

Results

304 patients enrolled in the extension study. There were 215 patient-years of exposure in this analysis, and exposure-adjusted incidence rates (EAIRs) of AEs (incidence/patient-years) were comparable to or lower than those observed with short-term deutetrabenazine treatment and placebo. The frequency of SAEs (EAIR 0.14) was similar to rates observed with short-termplacebo (EAIR 0.33) and deutetrabenazine (EAIR range 0.06–0.33) treatment. AEs leading to study discontinuation (EAIR 0.08), dose reduction (EAIR 0.17), and dose suspension (EAIR 0.09) were uncommon.

Conclusions

Long-term treatment with deutetrabenazine was generally safe and well tolerated in patients with TD, and did not result in cumulative toxicity.

Presented at: The American Psychiatric Association 2017 Annual Meeting; May 20–24, 2017; San Diego, California, USA.

Funding Acknowledgements

This study was funded by Teva Pharmaceutical Industries, Petach Tikva, Israel.
199 Cardiac Safety and QTc Intervals With DM/Q Treatment for Pseudobulbar Affect: A Review of Clinical Trial Data
Authors: Mason Jay W. , Hugentobler Emmanuelle , Formella Andrea E. , Pope Laura E.
Published: June 2018

OBJECTIVE

Dextromethorphan hydrobromide and quinidine sulfate (DM/Q) 20mg/10mg is FDA approved to treat pseudobulbar affect (PBA), a neurological condition characterized by sudden, frequent, involuntary crying or laughing. Although the total dose of quinidine (20 mg) from twice daily DM/Q for PBA is well below the antiarrhythmic dose (600-1600 mg/day), clinicians may be reticent to use DM/Q due to concerns for cardiac safety.

METHOD

DM/Q cardiac safety was evaluated in two thorough QTc (TQT) studies and by ECG monitoring in DM/Q phase 3 clinical trials. In the TQT studies, twice daily DM/Q 30mg/10mg (Study 08-AVR-126; N=50 enrolled) and supratherapeutic doses 30mg/30mg and 60mg/60mg (Study 05-AVR-119; N=36 enrolled) were studied in healthy volunteers. In phase 3 controlled clinical trials, the effects of DM/Q on Fridericia’s corrected QT intervals (QTcF) were assessed, as was the incidence of ECG outliers. Adverse events (AEs) were monitored in all clinical trials.

RESULTS

Overall, 47/50 participants completed TQT study 08-AVR-126 and 36/36 completed TQT study 05-AVR-119. Time-matched, placebo-corrected mean maximal changes in QTcF for DM/Q 30mg/10mg and 30mg/30mg occurred 3h post-dose (10.3 and 10.1ms, respectively) vs moxifloxacin (12.2 and 14.4ms at 1.5 and 1.0h). For the supratherapeutic DM/Q 60/60 mg dose, mean maximal QTcF change was 18.8ms. No participant had a QTcF >480 ms or QTc increase >60 ms. In PBA phase 3 controlled trials, mean changes in QTcF were similar for DM/Q containing Q 10 mg (0.4 to 3.5 ms; n=217) andplacebo (0.4 to 3.1 ms; n=183), but greater for DM/Q with Q 30 mg (2.9 to 7.6 ms; n=146). In an outlier analysis, a similar percentage of DM/Q-treated participants (3.9%) had a QTcF shift from <450 ms at baseline to ≥450 ms during treatment vs placebo (2.9%). No participant with PBA had a QTc change from baseline >60 ms or an absolute QTc interval >480 ms. No dose- or time-related trends in cardiac arrhythmias or other cardiac-related AEs were observed.

Of 2552 DM/Q-treated patients and healthy participants across all controlled and open-label trials for any indication, 11 deaths due to any cardiovascular AE have been reported; none were attributable to DM/Q treatment and none occurred in placebo-controlled PBA clinical trials in any treatment group. Overall 16 patients had a QTcF that exceeded 500 ms at any ECG measurement.

CONCLUSIONS

The TQT studies demonstrated that DM/Q has the potential to prolong the QT interval in a dose-dependent manner, but that the risk for QTc prolongation and arrhythmias with Q 10 mg formulations is low. In clinical trials with PBA patients, the cardiac safety profile of DM/Q 20mg/10mg or 30/10 mg was indistinguishable from placebo.

Funding Acknowledgements

Avanir Pharmaceuticals, Inc.
Decentralised clinical training in optometry: a developmental strategy for eye health in KwaZulu Natal?
Authors: van Staden Diane
Published: June 2018

Background

Decentralised clinical training (DCT) in optometry is an emerging concept in South Africa. In 2016, the University of KwaZulu Natal (UKZN) implemented this adaptive model of clinical training for undergraduate health professions. The initiative, which emanated through an agreement between UKZN’s College of Health Sciences and the KwaZulu Natal Department of Health, centres on the placement of undergraduate optometry students within public health facilities for clinical training purposes. Optometry services in South Africa have, however, had a historical bias towards a private sector model of training and a curative practice approach resulting in access barriers for the rural poor and high levels of unmet need. It has further contributed to a general state of underdevelopment of eye health services within the public sector.

Discussion

DCT challenges historical undergraduate programme structures and modes of teaching and learning in optometry. It is largely underpinned by a need to strengthen health service delivery through a primary health care-centred, community-based training approach and produce ‘fit-for-purpose’ graduates who have contextually appropriate competencies for effective, local health service delivery. The historical absence of optometry services within the public sector has, however, contributed to limited planning for, and development of eye health services in this sector. This has inadvertently contributed to the burden of avoidable vision impairment in the country. The public health system in South Africa, therefore, faces various developmental challenges which impact eye health services and student clinical training.

Conclusion

While the model is still in a developmental state and resourcing challenges potentially affecting DCT are noted, early experiences of the Discipline of Optometry at the UKZN are that DCT shows promise in terms of its potential contribution towards the development of eye health services within the public health sector from graduate readiness, resource strengthening, access improvement and health service development perspectives.
Cover crop nitrogen contribution to organic broccoli production
Authors: Luna John M. , Sullivan Dan , Garrett Amy M. , Xue Lan
Published: June 2018

Nitrogen (N) is a difficult nutrient to manage in organic farming systems, and yield reductions related to N deficiency have been reported in organic systems. Legume-based cover crops offer opportunities for biologically fixed N; however, improved quantification of N contribution is needed for cost-effective N management. A 2-yr experiment was conducted near Corvallis, OR, USA, in 2007 and 2008 to (1) evaluate biomass production and N accumulation from selected cover crop treatments, (2) compare the effects of fall-planted cover crops on broccoli [(Brassica oleraceaeL. (Italica group)] yield, (3) estimate the quantity of feather meal-N replaced by cover crops. Cover crop treatments included common vetch (Vicia sativaL.), phacelia (Phacelia tanacetifoliaBenth), oats (Avena sativaL.) and the mixtures phacelia plus vetch, oats plus vetch and a no-cover crop (fallow) treatment as the control. Using feather meal as an N source, four rates of N fertilizer (0, 100, 200 and 300 kg N ha−1) were randomized within each cover crop treatment in a randomized, split-plot design. Cover crop biomass and N accumulation differed between the 2 yr of the study. In 2007, total biomass accumulation ranged from 5000 to 10,000 kg ha−1, whereas in 2008, cover crop accumulation was 1500 to 5000 kg ha−1. Biomass of both phacelia and vetch (in mixtures or as sole crops) was reduced by 80% from 2007 to 2008, whereas oat biomass and weed biomass in the fallow plots was reduced by only 40% between the 2 yr. The accumulation of N was also reduced in 2008, with vetch (either as a sole crop or in mixtures) contributing less than a third of total N produced in 2007. In 2007, vetch and vetch-based cover crop mixtures increased broccoli yield compared with the fallow, providing 100–135 kg fertilizer equivalent N ha−1. But due to decreased cover crop biomass and N accumulation in 2008, vetch and vetch-based mixtures failed to increase broccoli yield, providing <20 kg N ha−1fertilizer equivalence. In 2007, oats grown as a sole cover crop reduced broccoli yield when no supplemental N was applied. In 2008, both phacelia and oats reduced broccoli yield at all N levels, with estimated N fertilizer equivalence values of −80 to −95 kg N ha−1. Although legume and legume mixtures increased broccoli yield in only 1 yr of the experiment, addition of vetch to the mixtures reduced yield loss in both years compared with oats and phacelia grown as sole crops.
Infektionen unter Immunsuppression
Authors: Depmeier Carsten , Günthard Huldrych F. , Steiner Urs C.
Published: June 2018

Zusammenfassung. Immunmodulierende und immunsuppressive Therapien werden immer häufiger eingesetzt. Je nach Wirkungsmechanismus und Grunderkrankung besteht unter diesen Therapien ein erhöhtes Infektionsrisiko. Im klinischen Alltag ist das individuelle Infektionsrisiko abhängig von einer Vielzahl von Patienten-, Umwelt- und Erreger-spezifischen Faktoren. Ältere und multimorbide Patienten unterliegen einem besonderen Infektionsrisiko. Klassische bakterielle Infektionen mit eventuell atypischer Manifestation, Hepatitis-B-Virus, Herpesviren, Mykobakterien und andere granulomatöse Infektionen stehen im Vordergrund. Typische klinische Infektionszeichen können fehlen und laborchemische Parameter können als diagnostisches Tool versagen. Ein systematisches Screening auf latente oder chronische Infektionen vor Einleitung und eine engmaschige Betreuung der Patienten während einer immunmodulierenden oder immunsuppressiven Therapie sind nötig, um Morbidität und Mortalität zu senken.
Mercury in Active‐Layer Tundra Soils of Alaska: Concentrations, Pools, Origins, and Spatial Distribution
Authors: Olson C. , Jiskra M. , Biester H. , Chow J. , Obrist D.
Published: June 2018

Tundra soils serve as major sources of mercury (Hg) input to the Arctic Ocean via river runoff and coastal erosion; yet little information is available on tundra soil Hg concentrations, pool sizes, origins, and dynamics. We present a detailed investigation of Hg in the active layer (upper ~100 cm subject to seasonal thaw) of tundra soils across 11 sites in Alaska. Soil Hg concentrations in organic horizons (151 ± 7 μg/kg) were in the upper range of temperate soil organic horizons, and concentrations in mineral horizons (98 ± 6 μg/kg) were much higher than in temperate soils. Soil Hg concentrations declined from inland to coastal sites, in contrast to a hypothesized northward increase expected because of proximity to coastal atmospheric mercury depletion events. Principle component analyses and elemental ratios results show that exogenic sources dominated over geogenic sources—in A‐horizons (66 ± 4%) and mineral B‐horizons (51 ± 1%). 14C age‐dating suggested recent origins of Hg in surface soils but showed that mineral soils (more than 7,300 years old) must have accumulated atmospheric inputs across millennia leading to high soil concentrations and pools. We estimated a total Northern Hemisphere active‐layer tundra soil Hg pool of 184 Gg (range of 136 to 274 Gg), suggesting a globally important Hg storage pool. Tundra soils are subject to seasonal thaw and freeze dynamics, thereby providing large inputs to rivers, lakes, and the Arctic Ocean. Understanding processes that mobilize Hg from tundra soils will be critical to understanding future Arctic wildlife and human Hg exposures.
Concomitant Double Ion and Electron Populations in the Earth's Magnetopause Boundary Layers From Double Reconnection With Lobe and Closed Field Lines
Authors: Lavraud Benoit , Jacquey Christian , Achilli Timothée , Fuselier Stephen A. , Grigorenko Elena , Phan Tai D. , Øieroset Marit , McFadden James , Angelopoulos Vassilis
Published: June 2018

While double ion populations, with a cold population originating from the solar wind and a hotter one from the magnetosphere, are frequently observed in the low‐latitude boundary layers at the Earth's magnetopause, similar double electron populations are observed less often. A preliminary study of magnetopause crossings characteristics was used to determine the typical locations and energy spectra of ion and electron populations near the magnetopause. Then, we set up an automated detection algorithm for identifying regions with concomitant double populations in both ion and electron energy spectra. The statistical study was carried out on 7 years of Time History of Events and Macroscale Interactions during Substorms particle data, to determine the interplanetary magnetic field conditions in the upstream solar wind for these double populations. The results suggest that such concomitant ion and electron double population boundary layers form preferentially in the subsolar region and under northward interplanetary magnetic field but with a significant BY component. We interpret this finding as the result of reconnection of the same magnetosheath field line in both hemispheres with at least one end reconnecting in its hemisphere at lower latitude with a closed magnetospheric field line that already contains a hot electron source.
Boundary Layer Diabatic Processes, the Virtual Effect, and Convective Self‐Aggregation
Authors: Yang Da
Published: June 2018

The atmosphere can self‐organize into long‐lasting large‐scale overturning circulations over an ocean surface with uniform temperature. This phenomenon is referred to as convective self‐aggregation and has been argued to be important for tropical weather and climate systems. Here we present a boundary layer centric framework based on the available potential energy budget of convective self‐aggregation. We show that boundary layer diabatic processes dominate the available potential energy production and are, therefore, essential to convective self‐aggregation. We further show that the enhanced virtual effect of water vapor can lead to convective self‐aggregation.
A TKE‐Based Framework for Studying Disturbed Atmospheric Surface Layer Flows and Application to Vertical Velocity Variance Over Canopies
Authors: Chamecki Marcelo , Dias Nelson L. , Freire Livia S.
Published: June 2018

We propose an approach to study disturbed surface layer flows based on a simplified form of the turbulent kinetic energy (TKE) budget equation (the reduced TKE budget), which can be represented by a two‐dimensional phase space. The phase space provides a way to quantify relative contributions of shear and buoyancy production/destruction of TKE, as well as the local imbalance between local production and dissipation. In this framework, Monin‐Obukhov Similarity Theory represents one possible approach to reduce the dimensionality of the phase space. We apply this framework to study the vertical velocity variance in the canonical surface layer and in the canopy roughness sublayer above the Amazon forest. Results reveal interesting insight into the behavior of the vertical velocity variance over forests, linking its magnitude to the imbalance between local production and dissipation of TKE.
Enhancing the Predictability of Seasonal Streamflow With a Statistical‐Dynamical Approach
Authors: Slater Louise J. , Villarini Gabriele
Published: June 2018

Seasonal streamflow forecasts facilitate water allocation, reservoir operation, flood risk management, and crop forecasting. They are generally computed by forcing hydrological models with outputs from general circulation models (GCMs) or using large‐scale climate indices as predictors in statistical models. In contrast, hybrid statistical‐dynamical forecasts (combining statistical methods with dynamical climate predictions) are still uncommon, and their skill is largely unknown. Here we conduct systematic forecasting of seasonal streamflow using eight GCMs from the North American Multi‐Model Ensemble, 0.5–9.5 months ahead, at 290 stream gauges in the U.S. Midwest. Probabilistic forecasts are developed for low to high streamflow using predictors that reflect climatic and anthropogenic influences. Results indicate that GCM forecasts of climate and antecedent climatic conditions enhance seasonal streamflow predictability; while land cover and population density predictors decrease biases or enhance skill in certain catchments. This paper paves the way for novel forecasting approaches using dynamical GCM predictions within statistical frameworks.
Eddy Tracking in the Northwestern Indian Ocean During Southwest Monsoon Regimes
Authors: Trott Corinne B. , Subrahmanyam Bulusu , Chaigneau Alexis , Delcroix Thierry
Published: June 2018

The northwestern Indian Ocean exhibits a relatively highly energetic eddy field during the southwest monsoon season between June and September. This study analyzes the seasonal and interannual variability of the eddy characteristics and their trajectories in the northwestern Indian Ocean using altimetric sea surface height observations from 1993 to 2014. Although the highest number of eddies is found in the Arabian Peninsula coastal region, the strongest eddies, characterized by large radii, amplitudes, and eddy kinetic energies are found along the Somali Current. Trajectories of anticyclonic and cyclonic eddies are investigated to provide insight on the generation and propagation of eddies of varying amplitudes. The largest annual eddy in the Somali Current system corresponds to the Great Whirl, for which the year‐to‐year variability with respect to shape, size, generation, and propagation was examined, as was the development of these characteristics over the Great Whirl's lifetime.
Security of Deep Groundwater in the Coastal Bengal Basin Revealed by Tracers
Authors: Lapworth D. J. , Zahid A. , Taylor R. G. , Burgess W. G. , Shamsudduha M. , Ahmed K. M. , Mukherjee A. , Gooddy D. C. , Chatterjee D. , MacDonald A. M.
Published: June 2018

Uncertainty persists regarding the vulnerability of deep groundwater across Asia's megadeltas. In the coastal Bengal Basin aquifer system, shallow groundwater (<100 m) commonly features high salinity or arsenic concentrations, and deep, better‐quality, groundwater supplies drinking water to >80 million people. Here we report new radiocarbon evidence from a network of nine dedicated, multilevel monitoring wells, which indicates residence times of between 103 and 104 years for groundwater at depths >150 m. Modern groundwater detected in some deep abstraction wells using anthropogenic tracers (SF6, CFCs) is attributed to short circuiting of shallow groundwater within wells. Age‐depth profiles and hydrochemical data in monitoring wells confirm the regional resilience of deep groundwater to ingress of shallow contaminated groundwater. Our results are consistent with high regional anisotropy in the aquifer and support continued use of deep groundwater though the potential for leakage of shallow contaminated groundwater in deep abstraction wells requires careful monitoring.
Can Formulas Derived From Pyroxenes and/or HEDs Be Used to Determine the Mineralogies of V‐Type Asteroids?
Authors: Burbine T. H. , Buchanan P. C. , Klima R. L. , Binzel R. P.
Published: June 2018

We compare methods for determining the pyroxene mineralogies of V‐type near‐Earth asteroids from their reflectance spectra. We evaluate whether band centers derived from the spectra of synthetic pyroxenes can be used to achieve greater analytical accuracy than is achieved through the use of band centers derived from the spectra of basaltic achondrites (howardites, eucrites, diogenites or HEDs). We conclude that band centers derived from the reflectance spectra of synthetic pyroxenes with known mineralogies do not provide useful diagnostic information to derive equations for determining accurate pyroxene compositions of V‐type asteroids. Band centers from the reflectance spectra of HEDs with known pyroxene mineralogies can be used to derive equations for determining accurate pyroxene compositions of V‐type asteroids. HEDs are physical mixtures of a number of different types of pyroxenes and best simulate the surfaces of V‐type asteroids. Formulas using the Band I center appear best for determining asteroid pyroxene mineralogies for V‐type asteroids due to the current difficulty in doing accurate temperature corrections to the Band II center. Most of the observed V‐type near‐Earth asteroids have interpreted mineralogies similar to eucrites or howardites. One of the observed near‐Earth asteroids could possibly have a surface mineralogy similar to diogenites.
Image Reconstruction Techniques in Neutron and Gamma Ray Spectroscopy: Improving Lunar Prospector Data
Authors: Wilson J. T. , Lawrence D. J. , Peplowski P. N. , Cahill J. T. S. , Eke V. R. , Massey R. J. , Teodoro L F. A.
Published: June 2018

We present improved resolution maps of the Lunar Prospector Neutron Spectrometer thermal, epithermal, and fast neutron data and gamma ray spectrometer Th‐line fluxes via global application of pixon image reconstruction techniques. With the use of mock data sets, we show that the pixon image reconstruction method compares favorably with other methods that have been used in planetary neutron and gamma ray spectroscopy. The improved thermal neutron maps are able to clearly distinguish variations in composition across the lunar surface, including within the lunar basins of Hertzsprung and Schrödinger. The improvement in resolution reveals a correlation between albedo and thermal neutron flux within the basins. The consequent increase in dynamic range confirms that Hertzsprung basin contains one of the most anorthositic parts of the lunar crust, including nearly pure anorthite over a region tens of kilometers in diameter. At Orientale, the reconstructed epithermal neutron data show broad overlap with circular polarization ratio but there remains a mismatch between measures of regolith maturity that sample the surface and those that probe the near subsurface, which is consistent with a complex layering scenario.
Towards a More Earth‐Like Circulation in Idealized Models
Authors: Wu Zheng , Reichler Thomas
Published: June 2018

Idealized models are useful for the investigation of dynamical phenomena in which physical processes play a secondary role. Typically, such models employ highly idealized topography and zonally symmetric equilibrium temperatures as forcings. However, these simplifications are somewhat unrealistic and make these models unfit for investigations in which similarity with the real atmosphere is crucial. In this study, we present a new idealized model of the stratosphere‐troposphere system which has a more Earth‐like circulation than previous models. We accomplish this by introducing into the dry dynamical core of the Geophysical Fluid Dynamics Laboratory realistic topography and equilibrium temperatures with zonal asymmetries. We then explore the model's sensitivity to the prescribed strength of the surface momentum drag. We find improvements in the model's circulation when validating against reanalysis. Most notably, the strength and structure of the winds, the spectrum of planetary waves, and the frequency of stratospheric sudden warming events are more realistic than in traditional idealized models. In the extratropics, the diagnosed diabatic forcing of the model also compares favorably against the observations. We further find that variations in the surface momentum damping exert an important control on the model's circulation, including the frequency of stratospheric sudden warming events. We believe that the new model reduces the gap between traditional idealized models and full models and that it is useful for the investigation of phenomena in which greater similarity with the real system is needed. The code for the new model and its equilibrium temperature data set is published on GitHub.
A strong link between marine microbial community composition and function challenges the idea of functional redundancy
Authors: Galand Pierre E , Pereira Olivier , Hochart Corentin , Auguet Jean Christophe , Debroas Didier
Published: June 2018

Marine microbes have tremendous diversity, but a fundamental question remains unanswered: why are there so many microbial species in the sea? The idea of functional redundancy for microbial communities has long been assumed, so that the high level of richness is often explained by the presence of different taxa that are able to conduct the exact same set of metabolic processes and that can readily replace each other. Here, we refute the hypothesis of functional redundancy for marine microbial communities by showing that a shift in the community composition altered the overall functional attributes of communities across different temporal and spatial scales. Our metagenomic monitoring of a coastal northwestern Mediterranean site also revealed that diverse microbial communities harbor a high diversity of potential proteins. Working with all information given by the metagenomes (all reads) rather than relying only on known genes (annotated orthologous genes) was essential for revealing the similarity between taxonomic and functional community compositions. Our finding does not exclude the possibility for a partial redundancy where organisms that share some specific function can coexist when they differ in other ecological requirements. It demonstrates, however, that marine microbial diversity reflects a tremendous diversity of microbial metabolism and highlights the genetic potential yet to be discovered in an ocean of microbes.