bluuebunny/crossref_metadata_2025 huggingface dataset:
Systematic review on the current knowledge and use of single‐cell RNA sequencing in head and neck cancer
Authors: Stampe Helene , Jakobsen Kathrine Kronberg , Bendtsen Simone Kloch , Grønhøj Christian , von Buchwald Christian
Published: September 2021

Single‐cell RNA sequencing (scRNA‐seq) is a novel method enabling genetic characterization of tumor tissue at a single‐cell level. This study systematically reviewed the literature on studies using scRNA‐seq to characterize head and neck squamous cell carcinomas (HNSCCs). Seven studies were included, of which two studies performed scRNA‐seq on 20 patients in total, and five studies used scRNA‐seq data in a subsequent clinical study. The former mentioned two studies found intra‐tumoral genetic heterogeneity among malignant cells but genetic uniformity among non‐malignant cells. The five latter studies used scRNA‐seq data in various ways. Three studies identified biomarkers related to predicting whether a patient would benefit from immunotherapeutic treatment. One study characterized genes related to the perineural invasion. One study identified genes to be used in diagnostics. Further studies performing scRNA‐seq on HNSCC are required to continue the ongoing development and use of scRNA‐seq.
Loss of response to anti‐TNFα agents depends on treatment duration in patients with inflammatory bowel disease
Authors: Schultheiss Johannes P. D. , Mahmoud Remi , Louwers Jonas M. , van der Kaaij Michiel T. , van Hellemondt Boris P. , van Boeckel Petra G. , Mahmmod Nofel , Jharap Bindia , Fidder Herma H. , Oldenburg Bas
Published: September 2021

Background

Inflammatory bowel disease (IBD) is often managed with anti‐tumour necrosis factor‐α therapy (anti‐TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%‐21% per patient‐year).

Aims

To assess whether the incidence of loss of response decreases with longer treatment duration

Methods

This was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti‐TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti‐TNFα discontinuation and dose escalation.

Results

We included 844 anti‐TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti‐drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three‐fold higher than after four years of treatment (17.2% vs 4.8% per patient‐year, P < 0.001). The incidence of anti‐TNFα discontinuation (28.6% vs 14.0% per patient‐year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient‐year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10‐2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15‐2.46) and male sex (aHR 0.55, 95% CI 0.38‐0.78). Immunomodulators were protective against loss of response with anti‐drug antibodies (aHR 0.42, 95% CI 0.24‐0.74).

Conclusions

Patients with sustained benefit to anti‐TNFα after 2 years are at low risk of subsequent loss of response.
On restricted mean time in favor of treatment
Authors: Mao Lu
Published: September 2021

The restricted mean time in favor (RMT‐IF) of treatment is a nonparametric effect size for complex life history data. It is defined as the net average time the treated spend in a more favorable state than the untreated over a prespecified time window. It generalizes the familiar restricted mean survival time (RMST) from the two‐state life–death model to account for intermediate stages in disease progression. The overall estimand can be additively decomposed into stage‐wise effects, with the standard RMST as a component. Alternate expressions of the overall and stage‐wise estimands as integrals of the marginal survival functions for a sequence of landmark transitioning events allow them to be easily estimated by plug‐in Kaplan–Meier estimators. The dynamic profile of the estimated treatment effects as a function of follow‐up time can be visualized using a multilayer, cone‐shaped “bouquet plot.” Simulation studies under realistic settings show that the RMT‐IF meaningfully and accurately quantifies the treatment effect and outperforms traditional tests on time to the first event in statistical efficiency thanks to its fuller utilization of patient data. The new methods are illustrated on a colon cancer trial with relapse and death as outcomes and a cardiovascular trial with recurrent hospitalizations and death as outcomes. The R‐package rmt implements the proposed methodology and is publicly available from the Comprehensive R Archive Network (CRAN).
Iron parameters in pregnant women with beta‐thalassaemia minor combined with iron deficiency anaemia compared to pregnant women with iron deficiency anaemia alone demonstrate the safety of iron supplementation in beta‐thalassaemia minor during pregnancy
Authors: Chen Niankun , Li Zhongjun , Huang Yingying , Xiao Chaoqun , Shen Xinyang , Pan Shumin , Su Qiongqiong , Wang Zhijian
Published: September 2021

In patients with beta‐thalassaemia intermedia or major, hepcidin induces iron overload by continuously promoting iron absorption. There have been no studies in pregnant women with beta‐thalassaemia minor combined with iron deficiency anaemia (IDA), examining whether hepcidin is inhibited by GDF15, as may occur in patients with beta‐thalassaemia intermedia or major, or whether the iron metabolism characteristics and the effect of iron supplementation are consistent with simple IDA in pregnancy. We compared and analysed routine blood parameters, iron metabolism parameters, the GDF15 levels, and the hepcidin levels among four groups, namely the beta‐thalassaemia (β) + IDA, β, IDA, and normal groups. In addition, the β + IDA and IDA groups received iron supplementation for four weeks. We found no statistically significant correlation between hepcidin and GDF15 in any group, but a positive correlation was observed between hepcidin and ferritin. After iron supplementation, the routine blood parameters and iron metabolism parameters in the β + IDA group were improved, and the hepcidin content was significantly increased. These results suggest that in pregnant women with beta‐thalassaemia minor, hepcidin functions normally to maintain iron homeostasis, and that iron supplementation is effective and safe.
A new pancreatic adenocarcinoma‐derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms
Authors: Hadj Bachir Elsa , Poiraud Charles , Paget Sonia , Stoup Nicolas , El Moghrabi Soumaya , Duchêne Belinda , Jouy Nathalie , Bongiovanni Antonino , Tardivel Meryem , Weiswald Louis‐Bastien , Vandepeutte Marie , Beugniez César , Escande Fabienne , Leteurtre Emmanuelle ,   OrgaRES consortium, Poulain Laurent , Lagadec Chann , Pigny Pascal , Jonckheere Nicolas , Renaud Florence , Truant Stephanie , Van Seuningen Isabelle , Vincent Audrey
Published: September 2021

Background Information

Although improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5‐year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5‐fluorouracil, irinotecan (SN‐38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long‐term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient‐derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.

Results

We first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi‐compartmental elimination models of oxaliplatin and SN‐38. We then treated PaTa‐1818x naive PDAC organoids with six cycles of 72 h‐FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa‐1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.

Conclusions

We reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa‐1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.

Significance

To our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.
Alpha‐arrestins Aly1/Art6 and Aly2/Art3 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis
Authors: Robinson Benjamin P. , Hawbaker Sarah , Chiang Annette , Jordahl Eric M. , Anaokar Sanket , Nikiforov Alexiy , Bowman Ray W. , Ziegler Philip , McAtee Ceara K. , Patton‐Vogt Jana , O'Donnell Allyson F.
Published: September 2021

Background information

Phosphatidylinositol (PI) is an essential phospholipid, critical to membrane bilayers. The complete deacylation of PI by B‐type phospholipases produces intracellular and extracellular glycerophosphoinositol (GPI). Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters at the yeast plasma membrane. Internalized GPI is degraded to produce inositol, phosphate and glycerol, thereby contributing to these pools. GIT1 gene expression is controlled by nutrient balance, with phosphate or inositol starvation increasing GIT1 expression to stimulate GPI uptake. However, less is known about control of Git1 protein levels or localization.

Results

We find that the α‐arrestins, an important class of protein trafficking adaptor, regulate Git1 localization and this is dependent upon their interaction with the ubiquitin ligase Rsp5. Specifically, α‐arrestin Aly2 stimulates Git1 trafficking to the vacuole under basal conditions, but in response to GPI‐treatment, either Aly1 or Aly2 promote Git1 vacuole trafficking. Cell surface retention of Git1, as occurs in aly1∆ aly2∆ cells, is linked to impaired growth in the presence of exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of GPI somehow causes cellular toxicity. Regulation of α‐arrestin Aly1 by the protein phosphatase calcineurin improves steady‐state and substrate‐induced trafficking of Git1, however, calcineurin plays a larger role in Git1 trafficking beyond regulation of α‐arrestins. Interestingly, loss of Aly1 and Aly2 increased phosphatidylinositol‐3‐phosphate on the limiting membrane of the vacuole, and this was further exacerbated by GPI addition, suggesting that the effect is partially linked to Git1. Loss of Aly1 and Aly2 leads to increased incorporation of inositol label from [3H]‐inositol‐labelled GPI into PI, confirming that internalized GPI influences PI balance and indicating a role for the a‐arrestins in this regulation.

Conclusions

The α‐arrestins Aly1 and Aly2 are novel regulators of Git1 trafficking with previously unanticipated roles in controlling phospholipid distribution and balance.

Significance

To our knowledge, this is the first example of α‐arrestin regulation of phosphatidyliniositol‐3‐phosphate levels. In future studies it will be exciting to determine if other α‐arrestins similarly alter PI and PIPs to change the cellular landscape.
Variations in tephra stratigraphy created by small‐scale surface features in sub‐polar landscapes
Authors: Thompson Polly I. J. , Dugmore Andrew J. , Newton Anthony J. , Streeter Richard T. , Cutler Nick A.
Published: September 2021

We explore the effect small‐scale surface features have on influencing the morphology and grain‐size distribution (GSD) of tephra layers within the Quaternary stratigraphy of sub‐polar landscapes. Icelandic thúfur, small cryogenic earth mounds, are used to assess how and why the morphology and GSD of tephra layers vary over such formations. Through measurement of tephra layer thickness and GSD, Hekla 1947 and Grímsvötn 2011 tephra layers are analysed. Results indicate that such microtopographic features do indeed alter the form of tephra deposits and therefore the tephra layer that is preserved in the stratigraphy. Tephra thickness is significantly greater in hollows than on the thúfur crests. There is greater variation in tephra thickness measurements from thúfur in comparison to control measurements from a surface where thúfur are absent. Thúfur crests contain larger grain sizes than hollows, for both H1947 and G2011 tephras; however this was only statistically significant for the G2011 tephra. Such morphological patterns are thought to arise from an interplay of tephra characteristics, altered topography from the thúfur formations and earth surface processes operating at the sites. This study provides insight into the potential of tephra layer morphology and internal structures as indicators of Quaternary landforms and processes. Additionally, it provides important context for the appropriate sampling of tephra layers to infer volcanological processes, as the characteristics of preserved layers do not necessarily reflect those of the original fall‐out.
Effect of oral health literacy on self‐reported tooth loss: A multiple mediation analysis
Authors: Ju Xiangqun , Jamieson Lisa M. , Mejia Gloria C. , Mittinty Murthy N.
Published: September 2021

Background

This study aims to investigate the mediating pathways of oral health literacy (OHL) and oral health‐related behaviours on the relationship between education and self‐reported tooth loss among Australian adults.

Methods

Data used for studying the effects of mediating pathways are from the National Dental Telephone Interview Survey 2013, a random sample survey of Australian adults aged 18+ years. To study the mediating effects, we use counterfactual‐based analysis. To decompose the effect of multiple mediator’s alternate, to natural effect, methods such as interventional effects have been proposed. In this paper, we use these approaches to decompose the effect between education, OHL and oral health‐related behaviours on self‐reported tooth loss. Sensitivity analysis was performed for unmeasured confounding with multiple mediators.

Results

Data were available for 2936 Australian adults. The prevalence of persons with ≥12 self‐reported tooth loss was approximately 15%. The average total causal effect from the low education group was nearly 150%, and the interventional indirect effect through OHL and the dependence of oral health‐related behaviours on OHL to more than 12 missing teeth were 20% and 120%, respectively, higher than in the high education group. Sensitivity analysis indicated if the difference in the prevalence of unmeasured confounder is as big as 6% the direct effect and the indirect effect remains as observed.

Conclusions

An additional two‐fifths reduction on having more than 12 missing teeth for Australian adults with lower education level could be achieved if the proportion of lower OHL was decreased and optimal dental behaviours were increased.
Down-regulation of PR/SET domain 10 underlies natural killer cell dysfunction in hepatocellular carcinoma
Authors: Han Jiantao , Ke Chao , Jiang Bin , Zhou Hongjian , Xu Hanbin , Xie Xingwang
Published: September 2021

Hepatocellular carcinoma (HCC) is the world's leading cause of tumor-related mortalities. Natural killer (NK) cells play a critical role at the first immunological defense line against HCC initiation and progression. NK cell dysfunction is therefore an important mechanism for immune evasion of HCC cells. In the present study using a murine HCC model, we revealed the down-regulation of PR/SET Domain 10 (PRDM10) in hepatic NK cells that were phenotypically and functionally exhausted. PRDM10 silencing diminished the expression of natural killer group 2 member D (NKG2D) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), augmented T cell immunoglobulin and ITIM domain (TIGIT) expression, and decreased the expression of interferon (IFN)-γ, perforin and granzyme B in normal hepatic NK cells in vitro. Consistently, PRDM10-deficient NK cells exhibited impaired cytotoxicity on target cells. In contrast, PRDM10 over-expression promoted NKG2D and Fas ligand (FasL) expression, reduced CD96 expression and enhanced transcripts of IFN-γ, perforin and granzyme B in NK cells in vivo. Moreover, PRDM10 silencing and PRDM10 over-expression down-regulated and up-regulated Eomesodermin (Eomes) expression, respectively. In summary, this study reveals PRDM10 down-regulation as a novel mechanism underlying NK cell dysfunction and identifies PRDM10 as a supporting factor of NK cell function.
Identification of embolic stroke in patients with large vessel occlusion: The Chinese embolic stroke score, CHESS
Authors: Hong Lan , Lin Longting , Li Gang , Yang Jianhong , Geng Yu , Lou Min , Parsons Mark , Cheng Xin , Dong Qiang
Published: September 2021

Aims

The aim of the study was to develop a simple and objective score using clinical variables and quantified perfusion measures to identify embolic stroke with large vessel occlusions.

Methods

Eligible patients from five centers participating in the International Stroke Perfusion Imaging Registry were included in this study. Patients were split into a derivation cohort (n = 213) and a validation cohort (n = 116). A score was developed according to the coefficients of independent predictors of embolic stroke from stepwise logistic regression model in the derivation cohort. The performance of the score was validated by assessing its discrimination and calibration.

Results

The independent predictors of embolic stroke made up the Chinese Embolic Stroke Score (CHESS). There were: history of atrial fibrillation (3 points), non‐hypertension history (2 points), and delay time>6 s volume/delay time>3 s volume on perfusion imaging ≥0.23 (2 points). The AUC of CHESS in the derivation cohort and validation cohort were 0.87 and 0.79, respectively. Patients with a CHESS of 0 could be identified as low‐risk of embolic stroke, with a CHESS of 2–4 could be identified as medium‐risk and with a CHESS of 5–7 could be regarded as high‐risk. The observed rate of embolic stroke of each risk group was well‐calibrated with the predicted rate.

Conclusion

CHESS could reliably and independently identify embolic stroke as the cause of large vessel occlusion.
Morinda officinalis oligosaccharides alleviate depressive‐like behaviors in post‐stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation
Authors: Li Zhifang , Xu Hexiang , Xu Yi , Lu Guanfeng , Peng Qiwei , Chen Jiefang , Bi Rentang , Li Jianzhuang , Chen Shengcai , Li Hongkai , Jin Huijuan , Hu Bo
Published: September 2021

Aims

Morinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive‐like behaviors in post‐stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation.

Methods

Behavioral tests were performed to evaluate the effect of MOOs on depressive‐like behaviors in PSD rats. The effects of MOOs on the expression of IL‐18, IL‐1β, and nucleotide‐binding domain leucine‐rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT‐PCR), immunofluorescence and Western blot analysis. Adeno‐associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence.

Results

MOOs can alleviate depressive‐like behaviors in PSD rats. PSD rats showed increased expression of IL‐18, IL‐1β, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive‐like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive‐like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL‐18, IL‐1β, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF‐κB p65 signaling pathway.

Conclusion

Overall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.
Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development
Authors: Liu Xiao , Dai Shang‐Kun , Liu Pei‐Pei , Liu Chang‐Mei
Published: September 2021

Objective

Neurodevelopmental diseases are common disorders caused by the disruption of essential neurodevelopmental processes. Recent human exome sequencing and genome‐wide association studies have shown that mutations in the subunits of the SWI/SNF (BAF) complex are risk factors for neurodevelopmental diseases. Clinical studies have found that ARID1A (BAF250a) is the most frequently mutated SWI/SNF gene and its mutations lead to mental retardation and microcephaly. However, the function of ARID1A in brain development and its underlying mechanisms still remain elusive.

Methods

The present study used Cre/loxP system to generate an Arid1a conditional knockout mouse line. Cell proliferation, cell apoptosis and cell differentiation of NSPCs were studied by immunofluorescence staining. In addition, RNA‐seq and RT‐PCR were performed to dissect the molecular mechanisms of Arid1a underlying cortical neurogenesis. Finally, rescue experiments were conducted to evaluate the effects of Neurod1 or Fezf2 overexpression on the differentiation of NSPCs in vitro.

Results

Conditional knockout of Arid1a reduces cortical thickness in the developing cortex. Arid1a loss of function inhibits the proliferation of radial glial cells, and increases cell death during late cortical development, and leads to dysregulated expression of genes associated with proliferation and differentiation. Overexpression of Neurod1 or Fezf2 in Arid1a cKO NSPCs rescues their neural differentiation defect in vitro.

Conclusions

This study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of NSPCs during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations.
Examining stakeholder perceptions of oyster ecosystem services using fuzzy cognitive mapping
Authors: Drew Joshua , Kahn Beryl , Locatelli Nicolas , Airey Montana , Humphries Austin
Published: September 2021

Nature provides numerous ecosystem services to people, yet the prioritization of these services often depends on the goals of various stakeholder groups. The eastern oyster (Crassostrea virginica) is an ecologically important species along the Gulf and Atlantic coasts of the United States, where it provides essential fish habitat and may mitigate against climatic variations in urban areas. The eastern oyster also supports a multimillion dollar aquaculture industry in coastal communities. Recent declines in eastern oyster populations, however, have spurred widespread restoration activities. Here, we look at three expert stakeholder groups (academics, nongovernmental organizations, and governmental agencies) in Rhode Island (United States) to understand how stakeholder perceptions of oyster ecosystem services differ. Stakeholders' mental models showed differences among the groups' topologies and components, although the terms “Water Quality” and “Habitat/Structural Complexity” were prioritized in all the groups. Our results suggest that there is substantial intergroup variation, but that there are common threads around which future oyster restoration and management programs can be designed. By making these mental models of ecosystem services explicit, we illuminate tacit assumptions held by different stakeholders of the oyster stakeholder community in Rhode Island. In doing so, we highlight opportunities for more efficient collaboration around commonly shared goals for sustainable social and ecological management.
Evaluation of the safety, tolerability, and pharmacokinetics of RO7049389 in healthy Chinese volunteers
Authors: Wu Xiaojie , Feng Sheng , Zhang Jing , Zhang Wenhong , Zhang Yuchen , Zhu Mingfen , Triyatni Miriam , Zhao Na , Bo Qingyan , Jin Yuyan
Published: September 2021

The objectives of this phase I study are to assess the safety, tolerability, and pharmacokinetics (PKs) of RO7049389 in healthy Chinese volunteers (HVs) and evaluate potential ethnic differences in the safety and PKs using data from this study and the first‐in‐human study (in which most of the HVs were non‐Asian). HVs randomly received a single dose of 200–600 mg of RO7049389 or a placebo in a single ascending dose (n = 28) or multiple doses of 200–400 mg of RO7049389 or a placebo in multiple ascending doses (n = 24). Safety and tolerability were monitored throughout the study. Serial blood samples were collected for PK analysis. RO7049389 was safe and well‐tolerated in the HVs. The time to maximum concentration ranged from 1.5 to 3.0 h, and terminal half‐life ranged from 3.66 to 14.6 h. A single dose of 200–600 mg and multiple doses of 200–400 mg exhibited nonlinear PKs. In general, the safety profiles were comparable between non‐Asian and Asian HVs, but the plasma exposure of RO7049389 in Chinese HVs was higher than that in non‐Asian HVs. The data generated from this study will provide guidance for future clinical studies on RO7049389 in Chinese/Asian patients with hepatitis B virus.
Multisite evaluation of institutional processes and implementation determinants for pharmacogenetic testing to guide antidepressant therapy
Authors: Tuteja Sony , Salloum Ramzi G. , Elchynski Amanda L. , Smith D. Max , Rowe Elizabeth , Blake Kathryn V. , Limdi Nita A. , Aquilante Christina L. , Bates Jill , Beitelshees Amber L. , Cipriani Amber , Duong Benjamin Q. , Empey Philip E. , Formea Christine M. , Hicks J. Kevin , Mroz Pawel , Oslin David , Pasternak Amy L. , Petry Natasha , Ramsey Laura B. , Schlichte Allyson , Swain Sandra M. , Ward Kristen M. , Wiisanen Kristin , Skaar Todd C. , Van Driest Sara L. , Cavallari Larisa H. , Bishop Jeffrey R. ,   for the IGNITE Pharmacogenetics Working Group
Published: September 2021

There is growing interest in utilizing pharmacogenetic (PGx) testing to guide antidepressant use, but there is lack of clarity on how to implement testing into clinical practice. We administered two surveys at 17 sites that had implemented or were in the process of implementing PGx testing for antidepressants. Survey 1 collected data on the process and logistics of testing. Survey 2 asked sites to rank the importance of Consolidated Framework for Implementation Research (CFIR) constructs using best‐worst scaling choice experiments. Of the 17 sites, 13 had implemented testing and four were in the planning stage. Thirteen offered testing in the outpatient setting, and nine in both outpatient/inpatient settings. PGx tests were mainly ordered by psychiatry (92%) and primary care (69%) providers. CYP2C19 and CYP2D6 were the most commonly tested genes. The justification for antidepressants selected for PGx guidance was based on Clinical Pharmacogenetics Implementation Consortium guidelines (94%) and US Food and Drug Administration (FDA; 75.6%) guidance. Both institutional (53%) and commercial laboratories (53%) were used for testing. Sites varied on the methods for returning results to providers and patients. Sites were consistent in ranking CFIR constructs and identified patient needs/resources, leadership engagement, intervention knowledge/beliefs, evidence strength and quality, and the identification of champions as most important for implementation. Sites deployed similar implementation strategies and measured similar outcomes. The process of implementing PGx testing to guide antidepressant therapy varied across sites, but key drivers for successful implementation were similar and may help guide other institutions interested in providing PGx‐guided pharmacotherapy for antidepressant management.
Neurological outcome in WDR62 primary microcephaly
Authors: Ruaud Lyse , Drunat Séverine , Elmaleh‐Bergès Monique , Ernault Anais , Guilmin Crepon Sophie ,   The MCPH Consortium, El Ghouzzi Vincent , Auvin Stéphane , Verloes Alain , Passemard Sandrine
Published: September 2021

Aim

To characterize the cortical structure, developmental, and cognitive profiles of patients with WD repeat domain 62 (WDR62)‐related primary microcephaly.

Method

In this observational study, we describe the developmental, neurological, cognitive, and brain imaging characteristics of 17 patients (six males, 11 females; mean age 12y 3mo standard deviation [SD] 5y 8mo, range 5y–24y 6mo) and identify 14 new variants of WDR62. We similarly analyse the phenotypes and genotypes of the 59 previously reported families.

Results

Brain malformations, including pachygyria, neuronal heterotopia, schizencephaly, and microlissencephaly, were present in 11 out of 15 patients. The mean full‐scale IQ of the 11 assessed patients was 51.8 (standard deviation [SD] 12.6, range 40–70). Intellectual disability was severe in four patients, moderate in four, and mild in three. Scores on the Vineland Adaptive Behavior Scales obtained from 10 patients were low for communication and motor skills (mean 38.29, SD 7.74, and 37.71, SD 5.74 respectively). The socialization score was higher (mean 47.14, SD 12.39). We found a significant difference between scores for communication and daily living skills (mean 54.43, SD 11.6; p=0.001, one‐way analysis of variance). One patient displayed progressive ataxia.

Interpretation

WDR62‐related cognitive consequences may be less severe than expected because 3 out of 11 of the assessed patients had only mild intellectual disability and relatively preserved abilities of autonomy in daily life. We identified progressive ataxia in the second decade of life in one patient, which should encourage clinicians to follow up patients in the long term.
Inequities in quality and safety outcomes for hospitalized children with intellectual disability
Authors: Mimmo Laurel , Harrison Reema , Travaglia Joanne , Hu Nan , Woolfenden Susan
Published: September 2021

Aim

To investigate if there are inequities in quality and safety outcomes for children with intellectual disability admitted to two tertiary paediatric hospitals.

Method

A cross‐sectional study of 1367 admissions for 1018 randomly selected patients admitted for more than 23 hours to one of two tertiary children’s hospitals in Sydney, Australia (1st January–31st December 2017). Electronic medical records were manually interrogated to identify children with intellectual disability (including developmental delay). Data extracted included patient demographics, length of stay, number of admissions, and reported clinical incidents.

Results

In total, 12.3% (n=125) of children admitted during the study period had intellectual disability, which represented 13.9% (n=190) of admissions. Sex and age at admission in children with and without intellectual disability were similar: 83 (43.7%) vs 507 (43.1%) females and 107 (56.3%) vs 670 (56.9%) males, p=0.875; median age 3 years (0–18y) vs 4 years (0–18y), p=0.122. Children with intellectual disability had significantly greater median length of stay (100.5h vs 79h, p<0.001) and cost of admission (A$11 596.38 vs A$8497.96) than their peers (p=0.001). Children with intellectual disability had more admissions with at least one incident compared to children without intellectual disability (14.7% vs 9.7%); this was not statistically significant (p=0.06).

Interpretation

Children with intellectual disability experience inequitable quality and safety outcomes in hospital. Engaging children and families in clinical incident reporting may enhance understanding of safety risks for children with intellectual disability in hospital.
Sources of divergence in income in Indian states, 2001–2015
Authors: Misra Biswa Swarup , Nazlioglu Saban , Kucukkaplan Ilhan
Published: September 2021

Motivation

Empirical studies on income convergence for India indicate that Indian states exhibit divergence in income. The literature, however, has neglected the convergence dynamics of the main sources of output. A pertinent question is whether divergence in income is due to divergence in factor inputs (capital and labour) and/or in total factor productivity (TFP) in India, a low middle‐income country with high dispersion of per capita income across its states.

Purpose

This article examines the sources of income divergence in Indian states by analysing convergence in TFP, labour, and capital.

Methods and approach

We test for stochastic convergence hypothesis by employing state‐level data for 19 Indian states during the period 2001–2015. Given the small sample dimension of the Indian state‐level income data, we benefit from the recent developments in non‐stationary panel data literature; and conduct novel panel stationarity and unit root tests with a fixed time dimension. We further carry out a robustness analysis to account for cross‐section dependency across the states.

Findings

TFP as well as the factor inputs (labour and capital) exhibit divergence, implying persistence in income inequality across Indian states. Divergence in labour across the states reflects the fact that migration is primarily an intra‐district phenomenon. Poor investment climate in low‐income states acts as a barrier for convergence in capital. TFP and capital stock are found to be correlated, and thereby lower investment in poorer states may be responsible for divergence in TFP across the states.

Policy implications

Migration in India is primarily an intra‐district phenomenon. There is a need to study the reasons which are discouraging inter‐district and inter‐state migration for better utilization of the labour resource. Government intervention has not been adequate to improve the infrastructure position and encourage capital inflows to low‐income states. Low‐income states should improve their business climate and create support infrastructure to earn the confidence of investors. Increasing investment in low‐income states would help to increase their TFP and catch up with the high‐income states.
Pull factors for migration: The impact of migrant integration policies
Authors: Beverelli Cosimo
Published: September 2021

This paper investigates the impact of migrant integration policies set by destination countries on migration from 202 origins to 27 destinations during the period 2010–2018. Employing a structural gravity methodology which features international and domestic (i.e., intra‐national) migration flows, it shows that migrant integration policies, on average, positively affect cross‐border migration relative to domestic migration. Moving from the 25th percentile to the median of the variable summarizing migrant integration policies increases cross‐border relative to domestic migration by one third. Such impact is largely driven by policies on family reunion and permanent residence.
Nanosystems and exosomes as future approaches in treating multiple sclerosis
Authors: Sidoryk‐Węgrzynowicz Marta , Dąbrowska‐Bouta Beata , Sulkowski Grzegorz , Strużyńska Lidia
Published: September 2021

Multiple sclerosis (MS) is an immune‐mediated demyelinating disease of the central nervous system which leads to neurological dysfunctions and severe disabilities. MS pathology is characterised by damage of the blood‐brain barrier and infiltration of autoreactive T cells that overactivate glial cells, thereby initiating neuroinflammation accompanied by the formation of demyelinating plaques and neurodegeneration. Clinical deficits in this multifactorial disease depend on the progression of myelin loss, the stage of inflammation, the status of axons and the activity of oligodendrocyte precursor cells (OPCs). Despite significant progress in the treatment of MS, current therapies remain limited and new approaches are highly desirable. Nanosystems based on liposomes and nanoparticles are among some of the more noteworthy therapeutic strategies being investigated. Applications of nanosystems alone or as drug carriers in animal models of MS have been found to successfully alleviate the symptoms of the disease and exert anti‐inflammatory potential. Exosomes are a specific type of nanosystem based on nanometre‐sized extracellular vesicles released by different cells which exhibit important healing features. Exosomes contain an array of anti‐inflammatory and neuroprotective agents which may contribute to modulation of the immune system as well as promoting remyelination and tissue repair. In this review, opportunities to use nanosystems against progression of MS will be discussed in context of cell‐specific pathologies associated with MS.
Potential of combined neutron and X‐ray imaging to quantify local carbon contents in soil
Authors: Koestel John , Fukumasu Jumpei , Larsbo Mats , Herrmann Anke M. , Ariyathilaka Pawala , Magdysyuk Oxana V. , Burca Genoveva
Published: September 2021

In this study, we investigated the potential and limitations of using joint X‐ray and time‐of‐flight (TOF) neutron imaging for mapping the 3‐dimensional organic carbon distribution in soil. This approach is viable because neutron and X‐ray beams have complementary attenuation properties. Soil minerals consist to a large part of silicon and aluminium, and elements that are relatively translucent to neutrons but attenuate X‐rays. In contrast, attenuation of neutrons is strong for hydrogen, which is abundant in soil organic matter (SOM), while hydrogen barely attenuates X‐rays. In theory, TOF neutron imaging does further more allow the imaging of Bragg edges, which correspond to d‐spacings in minerals. This could help to distinguish between SOM and clay minerals, the mineral group in soil that is most strongly associated with hydrogen atoms. We collected TOF neutron image data at the IMAT beamline at the ISIS facility and synchrotron X‐ray image data at the I12 beamline at the Diamond Light source, both located within the Rutherford Appleton Laboratory, Harwell, UK. The white beam (the full energy spectrum) neutron image clearly showed variations in neutron attenuation within soil aggregates at approximately constant X‐ray attenuations. This indicates a constant bulk density with varying organic matter and/or clay content. Unfortunately, the combination of TOF neutron and X‐ray imaging was not suited to allow for a distinction between SOM and clay minerals at the voxel scale. While such a distinction is possible in theory, it is prevented by technical limitations. One of the main reasons is that the neutron frequencies available at modern neutron sources are too large to capture the main d‐spacings of clay minerals. As a result, inference to voxel scale SOM concentrations is presently not feasible. Future improved neutron sources and advanced detector designs will eventually overcome the technical problems encountered here. On the positive side, combined X‐ray and TOF neutron imaging demonstrated abilities to identify quartz grains and to distinguish between plastics and plant seeds.

Highlights

Full understanding of biogeochemical processes requires three‐dimensional (3‐D) maps of organic matter in soil (SOM).

This study investigates a novel method to map voxel‐scale SOM contents with 3‐D resolution.

The method is based a combination of X‐ray and time‐of‐flight neutron tomography.

At present, technical limitations prevent distinguishing between SOM and clay mineral contents.

More advanced neutron sources are required to overcome the encountered technical obstacles.
Recurrent febrile seizures alter intrahippocampal temporal coordination but do not cause spatial learning impairments
Authors: Kloc Michelle L. , Daglian Jennifer M. , Holmes Gregory L. , Baram Tallie Z. , Barry Jeremy M.
Published: September 2021

Objective

Febrile seizures (FSs) are the most common form of seizures in children. Single short FSs are benign, but FSs lasting longer than 30 min, termed febrile status epilepticus, may result in neurological sequelae. However, there is little information about an intermediary condition, brief recurrent FSs (RFSs). The goal of this study was to determine the role of RFSs on spatial learning and memory and the properties of spontaneous hippocampal signals.

Methods

A hippocampus‐dependent active avoidance task was used to assess spatial learning and memory in adult rats that underwent experimental RFSs (eRFSs) in early life compared with their littermate controls. Following completion of the task, we utilized high‐density laminar probes to measure spontaneous hippocampal CA1 circuit activity under urethane anesthesia, which allowed for the simultaneous recording of input regions in CA1 associated with both CA3 and entorhinal cortex.

Results

RFSs did not result in deficits in the active avoidance spatial test, a hippocampus‐dependent test of spatial learning and memory. However, in vivo high‐density laminar electrode recordings from eRFS rats had significantly altered power and frequency expression of theta and gamma bandwidths as well as signaling efficacy along the CA1 somatodendritic axis. Thus, although eRFS modified CA1 neuronal input/output dynamics, these alterations were not sufficient to impair active avoidance spatial behavior.

Significance

These findings indicate that although eRFSs do not result in spatial cognitive deficits in the active avoidance task, recurrent seizures do alter the brain and result in longstanding changes in the temporal organization of the hippocampus.
Chaos during the COVID‐19 outbreak: Predictors of household chaos among low‐income families during a pandemic
Authors: Johnson Anna D. , Martin Anne , Partika Anne , Phillips Deborah A. , Castle Sherri ,   The Tulsa SEED Study Team*
Published: September 2021

Objective

The objective of this study was to explore whether household chaos measured during the COVID‐19 pandemic is predicted by prepandemic parental and household characteristics.

Background

The COVID‐19 pandemic has dramatically altered children's home environments and routines due to stay‐at‐home orders, school closures, and economic shocks. These disruptions have been especially challenging for low‐income families who have limited resources and have been disproportionately affected by the pandemic. Household chaos, which captures routines, organization, stability, noise, and crowding in the home, is a documented threat to parent functioning and positive child development. The pandemic has likely exacerbated household chaos, especially for low‐income families.

Method

Data come from a larger, ongoing study of low‐income children and their parents in Tulsa, Oklahoma; this analysis relies on data from the subset of low‐income parents who responded to surveys when their children were in kindergarten (in 2018–2019) and during the pandemic, when their children were in first grade (n = 335). We use multivariate ordinary least squares regression models to test whether household chaos measured during the pandemic is predicted by prepandemic parental and household characteristics.

Results

Prepandemic parental depression and household chaos were significantly predictive of chaos during the pandemic, even after accounting for household demographics.

Implications

The current study highlights pandemic‐induced elevations in parental distress and household chaos among low‐income families. Results will provide valuable direction to policymakers, educators, and parents on how best to offset negative impacts of the COVID‐19 pandemic on family functioning and child development.
Using the Range of Research Evidence to Help Inform Clinical Decision Making and Treatment for Family Court‐Involved Children and Families
Authors: Davis Frank , Sexton Thomas
Published: September 2021

Over the past 20 years, a number of evidence‐based and evidence‐informed mental health treatment models, interventions, and best practices have emerged for use with a wide range of client populations, with many different mental health conditions and diagnoses. Unfortunately, many family court‐involved children and families do not have access to mental health programs and services that have been identified as evidence‐based or evidence‐informed. The reasons for this disparity are complex and multi‐layered. The primary aim of this paper is to identify the challenges and possibilities of adopting evidence‐based or evidence‐informed practices when working in the family court arena. To achieve this, the authors will describe a potential decision‐making model to help practitioners determine what is evidence‐based and evidence‐informed and what model or interventions may fit the context. This model has been referred to as a “levels‐of‐evidence” approach for evaluating family‐focused mental treatment interventions and programs and making informed clinical decisions to better serve children and families. As an example, the authors illustrate how a levels‐of‐evidence approach could be used to identify how evidence‐based practices such as Functional Family Therapy (FFT), designed for use in the juvenile justice setting, could be adapted for use in child custody cases. The authors hope this paper serves as a catalyst to further build a bridge between the family law and evidence‐based mental health research communities.