bluuebunny/crossref_metadata_2025 huggingface dataset:
Qualitative Clinical Trial Exit Interviews Evaluating Treatment Benefit, Burden, and Satisfaction in Patients with Schizophrenia
Authors: Simmons Adam , Carpenter-Conlin Julia , Bessonova Leona , O’Sullivan Amy K. , McDonnell David , Saucier Cory , White Michelle K. , Foster April M. , Bjorner Jakob B. , Lapeyra Olga , Walling David P.
Published: May 2021

Objective

An open-label extension study (NCT02873208) evaluated the long-term tolerability, safety, and efficacy of combination olanzapine/samidorphan (OLZ/SAM) treatment in patients with schizophrenia. This qualitative sub study explored perceptions of benefit, burden, and satisfaction with previous medications and OLZ/SAM.

Methods

Semi-structured interviews (60 minutes; audio-recorded) were conducted. Interviewer sensitivity training, senior interviewer oversight, and a list of common medications to aid recall supported data collection. Interview transcripts were content coded and analyzed (NVivo v11.0).

Results

All 41 patients reported a lifetime burden with schizophrenia adversely impacting employment, relationships, emotional health, social activities, and daily tasks. Hospitalization for schizophrenia management was another reported aspect of disease burden. Although most (n=32) patients reported previous medication benefits, side effects affecting physical, emotional/behavioral, and cognitive functioning were reported by all (n=41). Following OLZ/SAM treatment, 39/41 patients (95%) reported improvements in symptoms including hallucinations, paranoia, depression, sleep, and concentration. Furthermore, patients described improvements in self-esteem, social activities, relationships, and daily activities. Twenty-three patients (56%) reported side effects attributed to OLZ/SAM; lack of energy (n=12 [29%]) and dry mouth (n= 5 [12%]) were most common. Twenty-four (59%) patients were “very satisfied” with OLZ/SAM; most (n=35 [85%]) preferred to continue OLZ/SAM vs switching to another medication. As most substudy patients (n=40; 98%) completed the extension study, satisfied patients may be overrepresented in this analysis.

Conclusion

This qualitative interview approach provided valuable insight into patients’ experiences with previous medications and OLZ/SAM. Overall, most patients reported treatment satisfaction and improvements in symptoms, function, and health-related quality of life with OLZ/SAM.

Funding

Alkermes, Inc.
Long-Term Safety and Efficacy of Deutetrabenazine in Younger and Older Patients With Tardive Dyskinesia
Authors: Sajatovic Martha , Wilhelm Amanda , Finkbeiner Stacy , Barkay Hadas , Chaijale Nayla , Gross Nicholas , Gordon Mark Forrest
Published: May 2021

Background

Tardive dyskinesia (TD) is an involuntary movement disorder that is more prevalent in older patients. However, there is limited information on TD treatment for this population. In two 12-week pivotal trials (ARM-TD and AIM-TD), TD patients demonstrated significant improvements in Abnormal Involuntary Movement Scale (AIMS) score with deutetrabenazine versus placebo.

Methods

Patients who completed ARM-TD or AIM-TD enrolled in an open-label extension (OLE) study. This post hoc analysis assessed change and percent change from baseline in AIMS score, response rates for ≥50% AIMS improvement, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety in younger (<55 years) and older (≥55 years) patients.

Results

This analysis included 119 younger and 218 older patients enrolled in the OLE. Data presented at Week 145 (mean±SE): total deutetrabenazine dose was 39.4±1.39mg/day and 39.5±1.04mg/day in younger and older patients, respectively. Changes from baseline in AIMS score were –6.7±0.62 and –6.5±0.47, respectively (percent changes of –61.4%±4.10% and –54.6%±3.01%). The majority of younger and older patients achieved treatment success per CGIC (67% and 76%) and PGIC (64% and 63%) and achieved ≥50% AIMS response (76% and 62%). Deutetrabenazine was generally well tolerated in both groups. Exposure-adjusted incidence rates (incidence/patient-years) were <0.01 and 0.02 for akathisia, 0.07 (both) for somnolence and sedation, 0.04 and 0.11 for parkinson-like events, and 0.06 and 0.09 for depression in younger and older patients, respectively.

Conclusions

Deutetrabenazine treatment was associated with sustained improvements in AIMS score and was well tolerated in both younger and older TD patients.

Funding

Teva Pharmaceutical Industries Ltd., Petach Tikva, Israel
Single-Dose Pharmacokinetics of Amphetamine Extended-Release Oral Suspension (AMPH EROS) in 6–12-Year-Old Children with ADHD
Authors: Pardo Antonio , Childress Ann C. , King Thomas R. , Rafla Eman , Kando Judith C.
Published: May 2021

Methods

This Phase 1, open-label, single-dose, one-period, one-treatment PK study enrolled 12 children 6–12 y with ADHD. PK parameters for d- and l-amphetamine in plasma (Cmax, tmax, AUC0–8, and t1/2) were calculated and expressed as means, geometric means, and standard deviations. The primary endpoint was all objective PK measurements at 28 hours post-dose. PK was evaluated for 2 cohorts (6 pts ages 6–9 y and 6 pts aged 10–12 y). Safety was monitored continuously and assessed based on occurrence of adverse events.

Results

A single dose of 10 mg (4 ml) AMPH EROS (2.5 mg/ml) administered under fasted conditions resulted in a rapid rise in mean plasma concentration in d-amphetamine, reaching maximum concentrations within 5 hours. The overall study population mean (SD) plasma AUC0–8 (d-amphetamine) was 1061.2 (309) h*ng/mL, and for l-amphetamine was 380.5 (112) h*ng/mL. The mean maximum concentration (Cmax) for the overall study population was 54.91 ng/mL and 17.1 (5.2) ng/mL for d- and l-amphetamine, respectively. The overall study population median time to maximum concentrations (Tmax) for d-amphetamine were reached at 3.4 hours, and for l-amphetamine at 4.1 hours. The elimination half-life (t1/2) for the entire study cohort was 10.6 (2.0) hours for d-amphetamine, and 12.5 (3.2) hours for l-amphetamine. Directionally, a higher mean Cmax, AUC0–8, AUCt, and median Tmax were observed in the younger (6 to 9-year-old) age group, and this result was consistent with both the d- and l-amphetamine enantiomers. The mean elimination t1/2 for both d- and l-amphetamine was higher in the older cohort (10–12 years) than in the 6 to 12-year-olds. Study drug was well-tolerated by the subjects in this study. Two TEAEs were reported in one subject TEAEs (diarrhea and rash on legs) occurred approximately 12 hours postdose.

Conclusions

This study confirmed that the PK profile of AMPH EROS in 6 to 12-year-olds provided a consistent, predictable extended-release profile in a highly titratable liquid formulation, and this finding was relatively consistent and directionally predictable between the age groups assessed, with higher maximum concentrations and AUCs and shorter elimination half-lives noted in the younger population, with no anomalous parameters demonstrated, and no untoward or unexpected safety issues noted.

Funding

Tris Pharma, Inc.
Challenges in Treating Tardive Dyskinesia: Assessing the Impact of Virtual Medical Education
Authors: Glazar Amanda , Peterson Cecilia , Lemon Michael , Shah Chirag , Masand Prakash
Published: May 2021

Introduction

Tardive Dyskinesia (TD) refers to abnormal, involuntary, choreoathetoid movements of the tongue, lips, face, trunk, and extremities and is associated with long-term exposure to dopamine-blocking agents, such as antipsychotic medications. Once established, these movements usually persist. The movements are disfiguring and can bring unwanted attention to affected individuals. When severe, especially if the respiratory muscles are affected, the movements can be disabling, limit activity, and reduce quality of life. The prevalence is 7.2% in individuals on newer antipsychotics who have never been exposed to older neuroleptics. Until recently, there were no effective treatments for TD. In recent years, many new treatments have been investigated for the treatment of TD, including valbenazine, deutetrabenazine, and branched chain amino acids. Valbenazine first, followed by deutetrabenazine are FDA approved to treat TD. A virtual broadcast was developed to assess the ability of continuing medical education (CME) to improve awareness of the recognition and treatment of TD among psychiatrists.

Methods

The virtual broadcast (May 9, 2020) consisted of a two-hour, live-streamed discussion between two expert faculty. Impact of the educational activity was assessed by comparing psychiatrists’ responses to four identical questions presented before and directly after activity participation. A follow-up survey was sent to all participants six-weeks post-activity to measure performance in practice changes. A chi-square test was used to identify significant differences between pre- and post-assessment responses. Cohen’s d was used to calculate the effect size of the virtual broadcast.

Results

Activity participation resulted in a noticeable educational effect among psychiatrists (n=621; d=6.12, P<.001). The following areas showed significant (P<0.05) pre- vs post-educational improvements: recognition of movements in patients with TD, rate of TD in SGA exposed patients, treatment options for TD (on and off-label), and treatment of TD using VMAT inhibitors. Additionally, 54% of psychiatrists reported a change in practice performance as a result of the education received in the activity, including utilization of a standard scale to evaluate movement disorders and educate patients and family members about potential for TD, how to recognize symptoms, and when to treat.

Conclusions

The results indicated that a CME-certified two-hour virtual broadcast was effective at improving knowledge among psychiatrists for the recognition and treatment of TD. This knowledge also resulted in positive changes in practice performance post-activity. Future education should continue to address best practices in the diagnosis, treatment and management of patients with TD, as there remains an increased need for tailored CME among psychiatrists.

Funding

Neurocrine Biosciences, Inc.
The Incidence and Economic Burden of Extrapyramidal Symptoms in Patients with Schizophrenia Treated with Atypical Antipsychotics
Authors: Kadakia Aditi , Brady Brenna L. , Huang Huan , Dembek Carole , Williams G. Rhys , Kent Justine M.
Published: May 2021

Objective

Extrapyramidal symptoms (EPS), including movement disorders, tremors, and muscle contractions are common side effects of atypical antipsychotic (AAP) drugs in patients with schizophrenia. This study examined the incidence and burden of EPS in patients with schizophrenia initiating AAPs.

Methods

Patients with schizophrenia initiating AAPs with no prior EPS were identified in the MarketScan Multi-state Medicaid database from 1/1/2012-12/31/2018. Incidence of EPS (identified via ICD-9/ICD-10 diagnoses and medications) was assessed during the 12-months following AAP initiation. Cohorts with and without EPS were defined. Demographics, clinical characteristics, and healthcare resource use and costs over 12 months following the first EPS claim (EPS) or randomly assigned index date (Non-EPS) were assessed.

Results

A total of 11,642 patients with schizophrenia were identified; 21.2% developed EPS in the 12-months following AAP initiation. EPS and Non-EPS cohorts included 2,295 (mean age 38, 61% male, CCI 0.6) and 5,607 (mean age 39, 57% male, CCI 0.7) patients, respectively. Over the 12-month post-index period, EPS cohort had significantly higher rates of all-cause (30.2% vs. 24.6%, p<0.001) and schizophrenia-related hospitalizations (22.5% vs. 12.9%, p<0.001) and schizophrenia-related emergency room visits (25.5% vs. 16.7%, p<0.001) compared to Non-EPS cohort. All-cause ($25,911 vs. $21,550, p<0.001) and schizophrenia-related healthcare costs ($12,134 vs. $6,230, p<0.001) were significantly higher in EPS vs. Non-EPS cohort.

Conclusions

In the 12 months following AAP initiation, over 20% of schizophrenia patients developed EPS, which was associated with increased healthcare resource utilization and costs. Treatment options that minimize EPS may reduce the economic burden of schizophrenia.

Funding

Sunovion Pharmaceuticals Inc.
Hospitalization Risk Among Adults with Bipolar I Disorder Treated with Oral Atypical Antipsychotics: A Long-Term Data Analysis of Medicaid Claims Data
Authors: Niu Xiaoli , Veeranki Phani , Dennen Syvart , Liu Yanmei , Shafrin Jason , Dembek Carole , Laubmeier Kimberly , Williams G. Rhys
Published: May 2021

Objective

To compare the risk of hospitalization for adult Medicaid beneficiaries with bipolar I disorder (BPD-I) when treated with lurasidone compared to other atypical antipsychotics (AAPs) as monotherapy.

Methods

Using IBM MarketScan Multi-State Medicaid Claims database, a retrospective cohort study was conducted on adult BPD-I patients who initiated an AAP (index date) between January 1, 2014 and June 30, 2019. Patients were required to be continuously enrolled during the 12-month pre- and 24-month post-index date. Marginal structural models were performed to estimate the risk of hospitalization (all-cause, BPD-I-related, and psychiatric-related) associated with each AAP and the average length of stay.

Results

The analysis included 8262 adult BPD-I patients, of whom AAP use was divided between lurasidone (14%), aripiprazole (17%), olanzapine (8%), quetiapine (29%), risperidone (10%), no/minimal (1%) or other (21%) during each month of post-index period. The adjusted odds ratios (aORs) for all-cause hospitalization were significantly higher for olanzapine (aOR=1.60, 95% CI=1.09–2.10) and quetiapine (aOR=1.54, 95% CI=1.18–1.89), compared to lurasidone. The aORs for BPD-I-related hospitalization were significantly higher for quetiapine (aOR=1.57, 95% CI=1.10–2.04) and risperidone (aOR=1.80, 95% CI=1.04–2.56) compared to lurasidone. The average length of hospital stay was more than twice as high for quetiapine compared to lurasidone (aRR=2.12, 95% CI=1.32–2.92). The risk of psychiatric-related hospitalization was numerically lower for lurasidone compared to all other AAPs.

Conclusion

Over a 24-month follow-up period, lurasidone-treated adult BPD-1 patients had significantly lower risk of all-cause hospitalization than those treated with olanzapine and quetiapine, lower risk of BPD-I-related hospitalization than quetiapine and risperidone, and fewer hospital days than quetiapine in a Medicaid population.

Funding

Sunovion Pharmaceuticals Inc.
Could Improved Microcirculation Reverse the Effects of Fetal Alcohol Syndrome? A Review
Authors: Yavari Arman Phillipe
Published: May 2021

Fetal alcohol spectrum disorders, (FASDs) are a spectrum of neurodevelopmental and cognitive conditions, caused by the consumption of alcohol in varying amounts in utero that affect an estimated 1 - 5% of the general population in the United States. The effects of the spectrum of disorders are lifelong, resulting in often significant learning difficulties, cognitive deficits, and behavioral issues. It is known that blood flow and microcirculation to the brain are affected by the consumption of alcohol in utero, and that microcirculation and neurology are intimately linked, with changes in the former having drastic effects on the latter. The purpose of the current review is to analyze whether improvement in microcirculation in the infant or child with FASDs could affect quality of clinical outcomes in the spectrum of disorders, or lead to the improvement of disorder-related symptoms. Scientific evidence from the literature suggests that, in theory, improving cerebral microcirculation in the infant or young child with FASDs could lead to a corresponding improvement in neurological health, and potentially an improvement in cerebral development, which may in theory lead to a lessening of symptoms. Further review into the connection between microcirculation and neurological health, and correspondingly, clinical outcomes in patients with neurological deficits, is warranted.
Perampanel-Induced Cataplexy in a Young Male with Generalized Epilepsy
Authors: Kenaan Kelsey , Zafar Mohsin , Bond Ronnie , Gracious Barbara
Published: May 2021

Perampanel is an anti-epileptic drug reported to exert its effects in the central never system (CNS) by inhibiting post-synaptic glutamate receptors. The most commonly reported neuropsychiatric side effects are affective dysregulation with some reports of psychosis. However, the precise therapeutic mechanism is unknown. We report on a 32-year-old African American male with recurring generalized tonic-clonic (GTC) seizures, who presented to our hospital with onset of mood lability for several months, subsequent to adding perampanel to his antiepileptic medications. On presentation, perampanel administration was temporarily withheld, and subsequently, noted to be coincident with neuropsychiatric symptomatology, including motor weakness in emotional contexts. The mechanisms underlying cataplexy are complex and, in our patient, most likely induced by an interaction between perampanel and the wakeful inhibition of the sublaterodorsal nucleus projections.
Untreated Insomnia in Corrections and Increased Risk of Death
Authors: Collins Caiti , Wallis Richard
Published: May 2021

Study Objectives

This review discusses the potential negative consequences of untreated insomnia in correctional settings.

Methods

A literature review was conducted on the association between insomnia and negative health outcomes, the best practices for treating insomnia with and without medications, and common practices that prohibit the treatment of insomnia in correctional settings.

Results

Untreated insomnia was associated with increased psychiatric distress, increased risk for suicide, and increased all-cause mortality. Common practices in many correctional institutions impose restrictions on treating insomnia. These practices lead to an increased likelihood for negative health outcomes, including suicide and an increase in all-cause death.

Conclusions

Practices that prohibit the treatment of sleep in correctional settings increase the risk of death by suicide and other adverse health outcomes. The practices are often put in place due to pressure from the security staff who have trouble controlling the black-market trade of prescribed medications and other contraband within jails and prisons. Healthcare professionals in the correctional setting must advocate for the importance of treating sleep problems in jails and prisons and work with security staff on ways to overcome the problems of pill diversion and the trade of contraband in order to provide quality healthcare to this protected population.
Evaluation of MADRS Severity Thresholds in Patients With Bipolar Depression
Authors: Thase Michael E. , Harrington Amanda , Calabrese Joseph , Montgomery Stuart , Niu Xiaomeng , Patel Mehul
Published: May 2021

Introduction

The Montgomery-Åsberg Depression Rating Scale (MADRS) is commonly used for the assessment of depressive symptom changes in patients with major depressive disorder (MDD) or bipolar depression. Categories of depression severity that correspond to ranges of MADRS total score have been previously reported in patients with MDD, but it appears that MADRS severity ranges have not been reported for patients with bipolar I disorder. The objective of this study was to evaluate MADRS total score ranges that correspond with different grades of depression severity in patients with bipolar I depression.

Methods

Data were pooled from 3 randomized, double-blind, placebo-controlled, 6- or 8-week trials of cariprazine in patients with bipolar I depression. MADRS severity ranges were evaluated using an anchor-based approach with the clinician-rated, 7-category Clinical Global Impression-Severity (CGI-S) scale. CGI-S has previously been used to determine severity thresholds in MDD. Correlations between MADRS total score and CGI-S score were assessed in the pooled dataset at week 6; placebo and active treatment arms were pooled together. Youden index from receiver operating characteristic (ROC) curves was used to determine the optimal threshold for MADRS total score corresponding to each CGI-S severity level.

Results

The pooled dataset included 1523 patients with bipolar depression. Mean CGI-S scores were highly correlated with mean MADRS total scores at week 6 (r=.87; P<.0001), with MADRS total scores increasing with CGI-S severity. Using the ROC curves, MADRS total score ranges corresponding to each CGI-S severity category were estimated as follows: score of 0-6 for “normal, not at all ill”, 7-12 for “borderline mentally ill”, 13-18 for “mildly ill”, 19-23 for “moderately ill”, 24-36 for “markedly ill”, 37-39 for “severely ill”, and 40 or greater for “extremely ill”. Area under the curve (AUC) values for these cutoffs ranged from 0.930 to 0.997, representing outstanding sensitivity and specificity.

Conclusions

Utilizing data from 3 recent clinical trials of subjects with bipolar depression, we were able to identify MADRS severity thresholds. These empirical findings may help clinicians to understand and contextualize MADRS results from bipolar clinical research and apply to their patients in practice.

Funding

AbbVie Inc.
Assessment of iodine nutrition of schoolchildren in Gonda, India, indicates improvement and effectivity of salt iodisation
Authors: Gaurav Kushagra , Yadav Subhash , Kumar Sheo , Mishra Anjali , Godbole Madan M , Singh Uttam , Mishra Saroj K
Published: May 2021

Objective:

To study the total goitre rate (TGR), urinary iodine concentration (UIC) and salt iodine content among schoolchildren in a previously endemic area for severe iodine deficiency disorder (IDD).

Design:

Cross-sectional epidemiological study.

Setting:

The study was carried out in the Gonda district (sub-Himalayan region) of North India.

Participants:

Nine hundred and seventy-seven schoolchildren (6–12 years) were studied for parameters such as height, weight, UIC and salt iodine content. Thyroid volume (TV) was measured by ultrasonography to estimate TGR.

Results:

The overall TGR in the study population was 2·8 % (95 % CI 1·8, 3·8). No significant difference in TGR was observed between boys and girls (3·5 % v. 1·9 %, P = 0·2). There was a non-significant trend of increasing TGR with age (P = 0·05). Median UIC was 157·1 μg/l (interquartile range: 94·5–244·9). At the time of the study, 97 % of salt sample were iodised and nearly 86 % of salt samples had iodine content higher than or equal to 15 part per million. Overall, TGR was significantly lower (2·8 % v. 31·0 %, P < 0·001), and median UIC was significantly higher (157·1 v. 100·0 μg/l, P < 0·05) than that reported in the same area in 2009.

Conclusions:

A marked improvement was seen in overall iodine nutrition in the Gonda district after three and a half decades of Universal Salt Iodisation (USI). To sustainably control IDD, USI and other programmes, such as health education, must be continuously implemented along with putting mechanisms to monitor the programme at regular intervals in place.
An efficient and novel treatment regimen including temozolomide for medulloblastoma: a case study
Authors: Arbabi-Kalati Farshid , Dadras Ali , Nami Mohammad
Published: May 2021

Background:

The central nervous system (CNS) embryonal tumour is a rare malignancy reported in adults and more commonly in children. The most available treatments may cause neurological dysfunctions requiring clinical attention.

Case presented:

A 29-year-old male was referred with ataxia and diplopia, and brain imaging revealed a posterior fossa lesion suggesting medulloblastoma. The tumour and related symptoms were notably alleviated following treatment with dexamethasone. Following the recurrence of tumour, a biopsy and pathology report, the diagnosis of desmoplastic/nodular medulloblastoma was confirmed. The patient underwent 18 fractions of 180 cGy spine and whole-brain radiation therapy (RT). In addition, 5400 cGy irradiation in 12 fractions was given to the posterior fossa together with 2 mg/m2 intravenous vincristine (VCR) weekly over 6 weeks. Following a 3-week break, the patient was scheduled to receive 150 mg/m2/day temozolomide for 5 days, 2 mg VCR and 65 mg/m2/day cisplatin every 3 weeks for 8 cycles.

Conclusion:

The patient gained survival benefit to date (60 months since diagnosis) with favourable life quality. The promising response in this one exemplary case study proposes that a combined chemotherapy regimen including temozolomide, vincristine and cisplatin is an effective treatment choice for CNS embryonal tumours following RT; however, the further evaluation and a randomised clinical trial are needed.
Development of a 50-Item Abridged Form of the Junior Spanish Version	of the NEO Questionnaire (JS NEO-A50)
Authors: Ortet-Walker Jordi , Mezquita Laura , Vidal-Arenas Verónica , Ortet Generós , Ibáñez Manuel I.
Published: May 2021

Abstract. The aim of this psychometric study was to construct an abridged 50-item form, 10 for each of the five factors of personality, of the Junior Spanish version of the NEO-PI-R (JS NEO-A50). Two separate studies were conducted. In Study 1, 400 high school students completed two personality scales to examine the factor structure (exploratory factor analysis), convergent validity, and reliability of the JS NEO-A50. In Study 2, an independent sample of 385 adolescents completed the JS NEO-A50 and several outcome measures to replicate the factor structure (exploratory structural equation model) and examine criterion validity, respectively. The five-factor structure found in Study 1 was satisfactorily replicated in the second, independent sample. Sources of reliability (internal consistency and test-retest) and validity (convergent) were adequate. Also, the outcome measures assessed in Study 2 were related to personality traits in the expected direction. Life satisfaction was significantly predicted by emotional stability; symptoms of behavioral problems were predicted by low scores in both agreeableness and conscientiousness while internalizing emotional symptoms were mainly predicted by emotional instability; finally, academic performance was mainly predicted by conscientiousness. We conclude that the JS NEO-A50 is a sound inventory to measure the five broad personality domains in Spanish-speaking adolescents.
High‐Resolution Numerical Modeling of Barotropic Global Ocean Tides for Satellite Gravimetry
Authors: Sulzbach R. , Dobslaw H. , Thomas M.
Published: May 2021

The recently upgraded barotropic tidal model TiME is employed to study the influence of fundamental tidal processes, the chosen model resolution, and the bathymetric map on the achievable model accuracy, exemplary for the M2 tide. Additionally, the newly introduced pole‐rotation scheme allows to estimate the model’s inherent precision (open ocean rms: 0.90 cm) and enables studies of the Arctic domain without numerical deviations originating from pole cap handling. We find that the smallest open ocean rms with respect to the FES14‐atlas (3.39 cm) is obtained when tidal dissipation is carried out to similar parts by quadratic bottom friction, wave drag, and parametrized eddy‐viscosity. This setting proves versatile to obtaining high accuracy values for a diverse ensemble of additional partial tides. Using the preferred model settings, we show that for certain minor tides it is possible to obtain solutions that are more accurate than results derived with admittance assumptions from data‐constrained tidal atlases. As linear admittance derived minor tides are routinely used for de‐aliasing of satellite gravimetric data, this opens the potential for improving gravity field products by employing the solutions from TiME.
Pathomechanisms of ALS8: altered autophagy and defective RNA binding protein (RBP) homeostasis due to the VAPB P56S mutation
Authors: Tripathi Priyanka , Guo Haihong , Dreser Alice , Yamoah Alfred , Sechi Antonio , Jesse Christopher Marvin , Katona Istvan , Doukas Panagiotis , Nikolin Stefan , Ernst Sabrina , Aronica Eleonora , Glaß Hannes , Hermann Andreas , Steinbusch Harry , Feller Alfred C. , Bergmann Markus , Jaarsma Dick , Weis Joachim , Goswami Anand
Published: May 2021

Mutations in RNA binding proteins (RBPs) and in genes regulating autophagy are frequent causes of familial amyotrophic lateral sclerosis (fALS). The P56S mutation in vesicle-associated membrane protein-associated protein B (VAPB) leads to fALS (ALS8) and spinal muscular atrophy (SMA). While VAPB is primarily involved in the unfolded protein response (UPR), vesicular trafficking and in initial steps of the autophagy pathway, the effect of mutant P56S-VAPB on autophagy regulation in connection with RBP homeostasis has not been explored yet. Examining the muscle biopsy of our index ALS8 patient of European origin revealed globular accumulations of VAPB aggregates co-localised with autophagy markers LC3 and p62 in partially atrophic and atrophic muscle fibres. In line with this skin fibroblasts obtained from the same patient showed accumulation of P56S-VAPB aggregates together with LC3 and p62. Detailed investigations of autophagic flux in cell culture models revealed that P56S-VAPB alters both initial and late steps of the autophagy pathway. Accordingly, electron microscopy complemented with live cell imaging highlighted the impaired fusion of accumulated autophagosomes with lysosomes in cells expressing P56S-VAPB. Consistent with these observations, neuropathological studies of brain and spinal cord of P56S-VAPB transgenic mice revealed signs of neurodegeneration associated with altered protein quality control and defective autophagy. Autophagy and RBP homeostasis are interdependent, as demonstrated by the cytoplasmic mis-localisation of several RBPs including pTDP-43, FUS, Matrin 3 which often sequestered with P56S-VAPB aggregates both in cell culture and in the muscle biopsy of the ALS8 patient. Further confirming the notion that aggregation of the RBPs proceeds through the stress granule (SG) pathway, we found persistent G3BP- and TIAR1-positive SGs in P56S-VAPB expressing cells as well as in the ALS8 patient muscle biopsy. We conclude that P56S-VAPB-ALS8 involves a cohesive pathomechanism of aberrant RBP homeostasis together with dysfunctional autophagy.
Mutations inhibiting KDM4B drive ALT activation in ATRX-mutated glioblastomas
Authors: Udugama M. , Hii L. , Garvie A. , Cervini M. , Vinod B. , Chan F.-L. , Das P. P. , Mann J. R. , Collas P. , Voon H. P. J. , Wong L. H.
Published: May 2021

Alternative Lengthening of Telomeres (ALT) is a telomere maintenance pathway utilised in 15% of cancers. ALT cancers are strongly associated with inactivating mutations in ATRX; yet loss of ATRX alone is insufficient to trigger ALT, suggesting that additional cooperating factors are involved. We identify H3.3G34R and IDH1/2 mutations as two such factors in ATRX-mutated glioblastomas. Both mutations are capable of inactivating histone demethylases, and we identify KDM4B as the key demethylase inactivated in ALT. Mouse embryonic stem cells inactivated for ATRX, TP53, TERT and KDM4B (KDM4B knockout or H3.3G34R) show characteristic features of ALT. Conversely, KDM4B over-expression in ALT cancer cells abrogates ALT-associated features. In this work, we demonstrate that inactivation of KDM4B, through H3.3G34R or IDH1/2 mutations, acts in tandem with ATRX mutations to promote ALT in glioblastomas.
Systematic inference and comparison of multi-scale chromatin sub-compartments connects spatial organization to cell phenotypes
Authors: Liu Yuanlong , Nanni Luca , Sungalee Stephanie , Zufferey Marie , Tavernari Daniele , Mina Marco , Ceri Stefano , Oricchio Elisa , Ciriello Giovanni
Published: May 2021

Chromatin compartmentalization reflects biological activity. However, inference of chromatin sub-compartments and compartment domains from chromosome conformation capture (Hi-C) experiments is limited by data resolution. As a result, these have been characterized only in a few cell types and systematic comparisons across multiple tissues and conditions are missing. Here, we present Calder, an algorithmic approach that enables the identification of multi-scale sub-compartments at variable data resolution. Calder allows to infer and compare chromatin sub-compartments and compartment domains in >100 cell lines. Our results reveal sub-compartments enriched for poised chromatin states and undergoing spatial repositioning during lineage differentiation and oncogenic transformation.
Discontinuous epidemic transition due to limited testing
Authors: Scarselli Davide , Budanur Nazmi Burak , Timme Marc , Hof Björn
Published: May 2021

High impact epidemics constitute one of the largest threats humanity is facing in the 21st century. In the absence of pharmaceutical interventions, physical distancing together with testing, contact tracing and quarantining are crucial in slowing down epidemic dynamics. Yet, here we show that if testing capacities are limited, containment may fail dramatically because such combined countermeasures drastically change the rules of the epidemic transition: Instead of continuous, the response to countermeasures becomes discontinuous. Rather than following the conventional exponential growth, the outbreak that is initially strongly suppressed eventually accelerates and scales faster than exponential during an explosive growth period. As a consequence, containment measures either suffice to stop the outbreak at low total case numbers or fail catastrophically if marginally too weak, thus implying large uncertainties in reliably estimating overall epidemic dynamics, both during initial phases and during second wave scenarios.
Emerging concepts in intestinal immune control of obesity-related metabolic disease
Authors: Khan Saad , Luck Helen , Winer Shawn , Winer Daniel A.
Published: May 2021

The intestinal immune system is an important modulator of glucose homeostasis and obesity-associated insulin resistance. Dietary factors, the intestinal microbiota and their metabolites shape intestinal immunity during obesity. The intestinal immune system in turn affects processes such as intestinal permeability, immune cell trafficking, and intestinal hormone availability, impacting systemic insulin resistance. Understanding these pathways might identify mechanisms underlying treatments for insulin resistance, such as metformin and bariatric surgery, or aid in developing new therapies and vaccination approaches. Here, we highlight evolving concepts centered on intestinal immunity, diet, and the microbiota to provide a working model of obesity-related metabolic disease.
Magnetization control by angular momentum transfer from surface acoustic wave to ferromagnetic spin moments
Authors: Sasaki R. , Nii Y. , Onose Y.
Published: May 2021

Interconversion between electron spin and other forms of angular momentum is useful for spin-based information processing. Well-studied examples of this are the conversion of photon angular momentum and rotation into ferromagnetic moment. Recently, several theoretical studies have suggested that the circular vibration of atoms work as phonon angular momentum; however, conversion between phonon angular momentum and spin-moment has yet to be demonstrated. Here, we demonstrate that the phonon angular momentum of surface acoustic wave can control the magnetization of a ferromagnetic Ni film by means of the phononic-to-electronic conversion of angular momentum in a Ni/LiNbO3 hybrid device. The result clearly shows that the phonon angular momentum is useful for increasing the functionality of spintronic devices.
Breathing-driven prefrontal oscillations regulate maintenance of conditioned-fear evoked freezing independently of initiation
Authors: Bagur Sophie , Lefort Julie M. , Lacroix Marie M. , de Lavilléon Gaëtan , Herry Cyril , Chouvaeff Mathilde , Billand Clara , Geoffroy Hélène , Benchenane Karim
Published: May 2021

Brain–body interactions are thought to be essential in emotions but their physiological basis remains poorly understood. In mice, regular 4 Hz breathing appears during freezing after cue-fear conditioning. Here we show that the olfactory bulb (OB) transmits this rhythm to the dorsomedial prefrontal cortex (dmPFC) where it organizes neural activity. Reduction of the respiratory-related 4 Hz oscillation, via bulbectomy or optogenetic perturbation of the OB, reduces freezing. Behavioural modelling shows that this is due to a specific reduction in freezing maintenance without impacting its initiation, thus dissociating these two phenomena. dmPFC LFP and firing patterns support the region’s specific function in freezing maintenance. In particular, population analysis reveals that network activity tracks 4 Hz power dynamics during freezing and reaches a stable state at 4 Hz peak that lasts until freezing termination. These results provide a potential mechanism and a functional role for bodily feedback in emotions and therefore shed light on the historical James–Cannon debate.
Oriented arrangement of simple monomers enabled by confinement: towards living supramolecular polymerization
Authors: Zong Yingtong , Xu Si-Min , Shi Wenying , Lu Chao
Published: May 2021

The living supramolecular polymerization technique provides an exciting research avenue. However, in comparison with the thermodynamic spontaneous nucleation, using simple monomers to realize living supramolecular polymerization is hardly possible from an energy principle. This is because the activation barrier of kinetically trapped simple monomer (nucleation step) is insufficiently high to control the kinetics of subsequent elongation. Here, with the benefit of the confinement from the layered double hydroxide (LDH) nanomaterial, various simple monomers, (such as benzene, naphthalene and pyrene derivatives) successfully form living supramolecular polymer (LSP) with length control and narrow dispersity. The degree of polymerization can reach ~6000. Kinetics studies reveal LDH overcomes a huge energy barrier to inhibit undesired spontaneous nucleation of monomers and disassembly of metastable states. The universality of this strategy will usher exploration into other multifunctional molecules and promote the development of functional LSP.
Deforestation reduces rainfall and agricultural revenues in the Brazilian Amazon
Authors: Leite-Filho Argemiro Teixeira , Soares-Filho Britaldo Silveira , Davis Juliana Leroy , Abrahão Gabriel Medeiros , Börner Jan
Published: May 2021

It has been suggested that rainfall in the Amazon decreases if forest loss exceeds some threshold, but the specific value of this threshold remains uncertain. Here, we investigate the relationship between historical deforestation and rainfall at different geographical scales across the Southern Brazilian Amazon (SBA). We also assess impacts of deforestation policy scenarios on the region’s agriculture. Forest loss of up to 55–60% within 28 km grid cells enhances rainfall, but further deforestation reduces rainfall precipitously. This threshold is lower at larger scales (45–50% at 56 km and 25–30% at 112 km grid cells), while rainfall decreases linearly within 224 km grid cells. Widespread deforestation results in a hydrological and economic negative-sum game, because lower rainfall and agricultural productivity at larger scales outdo local gains. Under a weak governance scenario, SBA may lose 56% of its forests by 2050. Reducing deforestation prevents agricultural losses in SBA up to US$ 1 billion annually.
A rich catalog of C–C bonded species formed in CO2 reduction on a plasmonic photocatalyst
Authors: Devasia Dinumol , Wilson Andrew J. , Heo Jaeyoung , Mohan Varun , Jain Prashant K.
Published: May 2021

The understanding and rational design of heterogeneous catalysts for complex reactions, such as CO2 reduction, requires knowledge of elementary steps and chemical species prevalent on the catalyst surface under operating conditions. Using in situ nanoscale surface-enhanced Raman scattering, we probe the surface of a Ag nanoparticle during plasmon-excitation-driven CO2 reduction in water. Enabled by the high spatiotemporal resolution and surface sensitivity of our method, we detect a rich array of C1–C4 species formed on the photocatalytically active surface. The abundance of multi-carbon compounds, such as butanol, suggests the favorability of kinetically challenging C–C coupling on the photoexcited Ag surface. Another advance of this work is the use of isotope labeling in nanoscale probing, which allows confirmation that detected species are the intermediates and products of the catalytic reaction rather than spurious contaminants. The surface chemical knowledge made accessible by our approach will inform the modeling and engineering of catalysts.
Overtemperature-protection intelligent molecular chiroptical photoswitches
Authors: Yao Jiabin , Wu Wanhua , Xiao Chao , Su Dan , Zhong Zhihui , Mori Tadashi , Yang Cheng
Published: May 2021

Stimuli-responsive intelligent molecular machines/devices are of current research interest due to their potential application in minimized devices. Constructing molecular machines/devices capable of accomplishing complex missions is challenging, demanding coalescence of various functions into one molecule. Here we report the construction of intelligent molecular chiroptical photoswitches based on azobenzene-fused bicyclic pillar[n]arene derivatives, which we defined as molecular universal joints (MUJs). The Z/E photoisomerization of the azobenzene moiety of MUJs induces rolling in/out conformational switching of the azobenzene-bearing side-ring and consequently leads to planar chirality switching of MUJs. Meanwhile, temperature variation was demonstrated to also cause conformational/chiroptical inversion due to the significant entropy change during the ring-flipping. As a result, photo-induced chiroptical switching could be prohibited when the temperature exceeded an upper limit, demonstrating an intelligent molecular photoswitch having over-temperature protection function, which is in stark contrast to the low-temperature-gating effect commonly encountered.
Outpatient prescribing pattern for acute bronchitis in primary healthcare settings in China
Authors: Fu Mengyuan , Wushouer Haishaerjiang , Hu Lin , Li Nan , Guan Xiaodong , Shi Luwen , Ross-Degnan Dennis
Published: May 2021

Inappropriate prescribing for acute bronchitis in primary healthcare settings (PHSs) is commonly seen worldwide. Here we describe the prescribing patterns and antibiotic use for acute bronchitis in PHSs across China. We conduct a nationwide cross-sectional survey to collect outpatient prescriptions from PHSs in 2017. Patients diagnosed with acute bronchitis without other infections are eligible for this study. Generalized estimating equations are used for analysis. Overall, 10,678 prescriptions for acute bronchitis from 214 institutions are included. The antibiotic prescription rate is 44.5% for total prescriptions, and differs significantly by region and urban/rural status (p < 0.05). Among all single-antibiotic prescriptions, 91.5% are broad-spectrum. Two-thirds of the prescriptions contain medicines for symptom management. The overall guideline compliance rate of acute bronchitis treatment for adults is 31.0%. Prescribing antibiotics, especially broad-spectrum ones, for acute bronchitis is commonly observed in Chinese PHSs. Targeted interventions are urgently needed for Chinese primary clinicians, especially in western rural areas.
Vibratory behaviour produces different vibration patterns in presence of reproductives in a subterranean termite species
Authors: Pailler Louis , Desvignes Samuel , Ruhland Fanny , Pineirua Miguel , Lucas Christophe
Published: May 2021

Vibratory behaviours are widespread in social insects, but the produced vibrations remain poorly explored. Communication using vibrations is an efficient way to transmit information in subterranean environments where visual and odorant signals are less efficient. In termites, different vibratory behaviours are performed in different contexts like reproductive regulation and alarm signalling, but only few studies explored the structure of the produced vibrations (i.e., duration, number of pulses, amplitude). Here, we described several types of vibrations produced by a vibratory behaviour widespread in termites (body-shaking), which can be transmitted through the substrate and detected by other colony members. We analysed the structures of the emitted vibrations and the occurrence of the body-shaking events in presence/absence of reproductives and/or in presence/absence of a stress stimuli (flashlight) in the subterranean termiteReticulitermes flavipes. Interestingly, only the presence of the reproductives did influence the number of pulses and the duration of the emitted vibrations. Moreover, the first part of the emitted vibrations seems to be enough to encode reproductive information, but other parts might hold other type of information. Body-shaking occurrence did increase in presence of reproductives but only briefly under a flashlight. These results show that vibratory cues are complex in termites and their diversity might encode a plurality of social cues.
Markedly poor physical functioning status of people experiencing homelessness admitted to an acute hospital setting
Authors: Kiernan S. , Ní Cheallaigh C. , Murphy N. , Dowds J. , Broderick J.
Published: May 2021

Adults who are homeless experience poor health and frequently require hospital in-patient care but the physical functioning ability of this group is rarely considered. The objective of this study was to evaluate a broad range of physical functioning variables to enable better future planning of targeted health and accommodation services for this group. This cross-sectional, observational study was conducted in a large acute hospital in Dublin, Ireland. A comprehensive ward-based test battery evaluated physical functioning in 65 in-patients registered as homeless with an age range of 23–80 years. Less than 10% (n = 5) were > 70 years. 58/65 (83%) of participants had mobility limitations and 35/65 (54%) reported at least one fall in the previous six months. Only 25/66 (35%) were able to walk for 6 min and 20/65 (31%) were able to climb one flight of stairs. 45/63 (70%) of participants were pre-frail or frail. Muscular mass was normal in the majority of participants but grip strength was low. This study revealed hospital in-patients registered as homeless displayed particularly poor physical functioning levels and mobility regardless of age. Health and housing services should address the unmet physical functioning needs of this vulnerable group.
Salivary caffeine in Parkinson’s disease
Authors: Leodori Giorgio , De Bartolo Maria Ilenia , Belvisi Daniele , Ciogli Alessia , Fabbrini Andrea , Costanzo Matteo , Manetto Simone , Conte Antonella , Villani Claudio , Fabbrini Giovanni , Berardelli Alfredo
Published: May 2021

We aimed to investigate salivary caffeine content, caffeine absorption and metabolism in Parkinson’s disease (PD) and verify whether salivary caffeine can be used as a biomarker of PD. We enrolled 98 PD patients and 92 healthy subjects. Caffeine and its major metabolite, paraxanthine, were measured in saliva samples collected before and 4 h after the oral intake of caffeine (100 mg). We measured caffeine absorption as the normalized increase in caffeine levels, and caffeine metabolism as the paraxanthine/caffeine ratio. The Movement Disorder Society Unified Parkinson's Disease Rating Scale part III, the Hoehn & Yahr, the presence of motor complications, and levodopa equivalent dose (LED) were assessed and correlated with caffeine levels, absorption, and metabolism. The effects of demographic and environmental features possibly influencing caffeine levels were also investigated. Caffeine levels were decreased in patients with moderate/advanced PD, while caffeine levels were normal in patients with early and de-novo PD, unrelated to caffeine intake. Caffeine absorption and metabolism were normal in PD. Decreased salivary caffeine levels in PD were associated with higher disease severity, longer duration, and the presence of motor complications, no significant association was found with LED. Salivary caffeine decrease correlates with PD progression.