bluuebunny/crossref_metadata_2025 huggingface dataset:
Altered intrinsic connectivity distribution in internet gaming disorder and its associations with psychotherapy treatment outcomes
Authors: Liu Lu , Potenza Marc N. , Lacadie Cheryl M. , Zhang Jin‐Tao , Yip Sarah W. , Xia Cui‐Cui , Lan Jing , Yao Yuan‐Wei , Deng Lin‐Yuan , Park Soyoung Q. , Fang Xiao‐Yi
Published: May 2020

Alterations in brain connectivity have been implicated in internet gaming disorder (IGD). However, little is known about alterations in whole‐brain connectivity and their associations with long‐term treatment outcomes. Here, we used a relatively new analytic approach, intrinsic connectivity distribution (ICD) analysis, to examine brain connectivity in 74 IGD participants and 41 matched healthy controls (HCs) and conducted post hoc seed‐based resting‐state functional connectivity (rsFC) analyses based on the ICD findings. We also examined how these findings related to outcomes involving a craving behavioral intervention (CBI) for IGD. IGD participants showed less whole‐brain connectivity in the left angular gyrus and ventromedial prefrontal cortex (vmPFC) compared with HC participants. Seed‐based rsFC analyses revealed that the left angular gyrus in the IGD group showed less connectivity with areas involved in the default‐mode network and greater connectivity with areas in the salience and executive control networks. CBI was associated with improved connectivity within regions in the default‐mode network and regions across the default‐mode and salience networks. ICD‐identified connectivity differences in the left angular gyrus and vmPFC were related to changes in craving and severity of addiction 6 months after the intervention. The findings suggest that IGD is associated with alterations in brain connectivity that may be sensitive to interventions. Thus, the findings have implications for understanding mechanisms underlying CBI effects and for further treatment development.
Tracheal tube size in adults undergoing elective surgery – a narrative review
Authors: Karmali S. , Rose P.
Published: May 2020

Tracheal tubes are routinely used in adults undergoing elective surgery. The size of the tracheal tube, defined by its internal diameter, is often generically selected according to sex, with 7–7.5 mm and 8–8.5 mm tubes recommended in women and men, respectively. Tracheal diameter in adults is highly variable, being narrowest at the subglottis, and is affected by height and sex. The outer diameter of routinely used tracheal tubes may exceed these dimensions, traumatise the airway and increase the risk of postoperative sore throat and hoarseness. These complications disproportionately affect women and may be mitigated by using smaller tracheal tubes (6–6.5 mm). Patient safety concerns about using small tracheal tubes are based on critical care populations undergoing prolonged periods of tracheal intubation and not patients undergoing elective surgery. The internal diameter of the tube corresponds to its clinical utility. Tracheal tubes as small as 6.0 mm will accommodate routinely used intubation aids, suction devices and slim‐line fibreoptic bronchoscopes. Positive pressure ventilation may be performed without increasing the risk of ventilator‐induced lung injury or air trapping, even when high minute volumes are required. There is also no demonstrable increased risk of aspiration or cuff pressure damage when using smaller tracheal tubes. Small tracheal tubes may not be safe in all patients, such as those with high secretion loads and airflow limitation. A balanced view of risks and benefits should be taken appropriate to the clinical context, to select the smallest tracheal tube that permits safe peri‐operative management.
A comparative analysis of human adult testicular cells expressing stem Leydig cell markers in the interstitium, vasculature, and peritubular layer
Authors: Eliveld Jitske , van Daalen Saskia K. M. , de Winter‐Korver Cindy M. , van der Veen Fulco , Repping Sjoerd , Teerds Katja , van Pelt Ans M. M.
Published: May 2020

Background

Origin of human adult Leydig cells (ALCs) is not well understood. This might be partly due to limited data available on the identification and location of human precursor and stem Leydig cells (SLCs) which hampers the study on the development of ALCs.

Objectives

The aim of the present study was to investigate whether described human (PDGFRα, NGFR) and rodent (NES, PDGFRα, THY1, NR2F2) SLC markers are expressed by a common cell population within human adult testicular interstitial cells in vivo and before and after in vitro propagation.

Materials and methods

Immunohistochemical analyses were used to identify localization of human adult testicular interstitial cells expressing described SLC markers. Next, interstitial cells were isolated and cultured. The percentage of cells expressing one or more SLC markers was determined before and after culture using flow cytometry.

Results

NR2F2 and PDGFRα were present in peritubular, perivascular, and Leydig cells, while THY1 was expressed in peritubular and perivascular cells. Although NES and NGFR were expressed in endothelial cells, co‐localization with PDGFRα was found for both in vitro, although for NGFR only after culture. All marker positive cells were able to undergo propagation in vitro.

Discussion

The partly overlap in localization and overlap in expression in human testicular cells indicate that PDGFRα, NR2F2, and THY1 are expressed within the same ALC developmental lineage from SLCs. Based on the in vitro results, this is also true for NES and after in vitro propagation for NGFR.

Conclusion

Our results that earlier described SLC markers are expressed in overlapping human interstitial cell population opens up further research strategies aiming for a better insight in the Leydig cell lineage and will be helpful for development of strategies to cure ALC dysfunction.
Effect of serum 25‐hydroxyvitamin D levels on sperm quality and assisted reproductive technology outcomes for men of infertile Chinese couples
Authors: Chen Yilu , Liu Defeng , Zeng Lin , Xu Huiyu , Jiang Hui , Yang Rui , Wang Haining , Yan Liying , Li Rong , Qiao Jie , Zhi Xu
Published: May 2020

Introduction

Vitamin D insufficiency/deficiency is highly prevalent in China, but its effect on sperm quality and outcomes of assisted reproductive technology (ART) in men from infertile couples is not clear. This study aimed to explore the association of serum 25‐hydroxyvitamin D (25OHD) levels and semen parameters, as well as ART outcomes for men from infertile couples.

Materials and methods

This study recruited 1308 men from infertile couples who attended the Reproductive Medicine Center of Peking University Third Hospital for first time from February to August 2019 (NCT03804294). Reproductive hormones levels, semen parameters, and clinical outcomes of ART were compared between vitamin D‐deficient group (serum 25OHD ≤ 10 ng/mL), insufficient group (serum 25OHD 10‐20 ng/mL), and sufficient group (serum 25OHD ≥ 20 ng/mL).

Results

We found 27.7% of participants were vitamin D sufficient, suggesting high prevalence of vitamin D insufficiency/deficiency in China. Reproductive hormone levels were similar between the three groups. The total number of morphologically normal spermatozoa was significantly different between the three groups in all participants, impaired semen quality subgroup, and normozoospermia subgroup (P < .05) with the adjustment of confounders (age, BMI, alcohol consumption, cigarette smoking, and physical exercise). The percentage of normal sperm morphology significantly increased with elevated serum 25OHD levels in all participants and the participants with impaired semen quality (P < .05), and the total sperm count showed significant difference in participants with impaired semen quality (P = .026). For routine in vitro fertilization and intracytoplasmic sperm injection cycles, there were no differences in fertilization rate, top‐quality embryo rate, biochemical pregnancy rate, and clinical pregnancy rate between serum 25OHD < 20 ng/mL and serum 25OHD ≥ 20 ng/mL groups.

Conclusions

Males of infertile couples with higher serum 25OHD levels exhibit better results in sperm morphology, and serum 25OHD levels may contribute to total sperm number in participants with impaired semen quality, but show no effects on the ART outcomes.
Blood pressure and hypertension during pregnancy in women with polycystic ovary syndrome: Odense Child Cohort
Authors: Nielsen Julie Hougård , Birukov Anna , Jensen Richard Christian , Kyhl Henriette Boye , Jørgensen Jan Stener , Andersen Marianne Skovsager , Glintborg Dorte
Published: May 2020

Introduction

The aim of this study was to compare blood pressure and prevalence of pregnancy‐induced hypertension in women with polycystic ovary syndrome and the reference group throughout pregnancy.

Material and methods

This retrospective study was part of the prospective study Odense Child Cohort. Pregnant women were recruited from January 2010 to December 2012. Blood pressure was measured in 200 women with polycystic ovary syndrome and in 2197 in the reference group. Main outcome measures were blood pressure and pregnancy‐induced hypertension. Pregnancy‐induced hypertension was defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg occurring after gestational week 20 at two separate visits. Mann‐Whitney U test and Chi‐square test were used to test differences between women with polycystic ovary syndrome and the reference group. Associations between polycystic ovary syndrome status (PCOS; the reference group) and blood pressure were tested using random mixed‐effect linear regression analyses with subjects as random effect to comply with repeated blood pressure measurements.

Results

Median blood pressure was comparable in women with polycystic ovary syndrome and the reference group throughout pregnancy: systolic blood pressure 116 (111‐123) vs 119 (112‐124) (P = .06), diastolic blood pressure 72 (69‐77) vs 73 (69‐78) (P = .23) and mean arterial pressure 87 (83‐93) vs 88 (84‐92) (P = .13). In first trimester where systolic blood pressure was lower in polycystic ovary syndrome, median systolic blood pressure was 116 (111‐123) vs 119 (112‐124) mmHg (P = .04). The prevalence of pregnancy‐induced hypertension was similar in polycystic ovary syndrome and the reference group: 17/200 (8.5%) vs 178/1997 (8.9%) (P = .84). Regression analyses showed no significant associations between polycystic ovary syndrome and blood pressure.

Conclusions

Blood pressure and prevalence of pregnancy‐induced hypertension were comparable in pregnant women with polycystic ovary syndrome and the reference group.
Maternal intentions towards infant sleeping practices in Ireland
Authors: O’ Brien Niamh , McGarvey Cliona , Hamilton Karina , Hayes Breda
Published: May 2020

Aim

Mortality from Sudden Infant Death Syndrome (SIDS) has reduced by 50%‐85% globally. Despite improvements from 1990 to 2009, the Irish SIDS rate has plateaued. Reasons for this are unclear, but may be related to a reduced parental SIDS awareness. Our study aimed to assess intentions regarding infant sleeping practices in mothers in Ireland.

Methods

A cross‐sectional survey of post‐partum mothers was performed in the Rotunda Hospital over a four month period. Mothers with a history of SIDS, miscarriage or neonatal admissions were excluded.

Results

Of 451 participants, unsafe sleeping positions were intended by 15.4%, reduced by Irish ethnicity [AOR = 0.52, 95% CI = 0.277‐0.959, P = .036]. Safe sleep locations were intended by 66%, increased by Irish ethnicity [AOR = 2.6, 95% CI = 1.617‐4.191, P < .001], and reduced by young maternal age [AOR = 0.15, 95% CI = 0.03‐0.713, P = .02]. Maternal smoking was more likely in mothers with lower educational level [AOR = 3.51, 95% CI = 1.169‐10.56, P = .03]. Soft bedding use was intended by 34.8%, increased in younger mothers [AOR = 2.28, 95% CI = 1.04‐4.98, P = .04]. Breastfeeding was intended by 72.2%, decreased by Irish ethnicity [AOR = 0.14, 95% CI = 0.067‐0.271, P < .001], and low maternal education [AOR = 0.22, 95% CI = 0.117‐0.406, P < .001].

Conclusion

Educational campaigns on safe sleep for infants in Ireland need to address modifiable SIDS risks factors, focusing on younger, non‐Irish mothers, with lower educational attainment.
Slc26a3 deletion alters pH‐microclimate, mucin biosynthesis, microbiome composition and increases the TNFα expression in murine colon
Authors: Kini Archana , Singh Anurag K. , Riederer Brigitte , Yang Ines , Tan Xinjie , di Stefano Gabriella , Tan Qinghai , Xiao Fang , Xia Weiliang , Suerbaum Sebastian , Seidler Ursula
Published: May 2020

Aim

SLC26A3 (DRA) mediates the absorption of luminal Cl− in exchange for HCO3− in the distal intestine. Its expression is lost in congenital chloride diarrhoea (CLD) and strongly decreased in the presence of intestinal inflammation. To characterize the consequences of a loss of Slc26a3 beyond disturbed electrolyte transport, colonic mucus synthesis, surface accumulation and composition, pH microclimate, microbiome composition and development of inflammation was studied in slc26a3−/− mice.

Methods

The epithelial surface pH microclimate and the surface mucus accumulation in vivo was assessed by two photon microscopy in exteriorized mid colon of anaesthetized slc26a3−/− and wt littermates. Mucus synthesis, composition and inflammatory markers were studied by qPCR and immunohistochemistry and microbiome composition by 16S rRNA sequencing.

Results

Colonic pH microclimate was significantly more acidic in slc26a3−/− and to a lesser extent in cftr−/− than in wt mice. Goblet cell thecae per crypt were decreased in slc26a3−/− and increased in cftr−/− colon. Mucus accumulation in vivo was reduced, but much less so than in cftr−/− colon, which is possibly related to the different colonic fluid balance. Slc26a3−/− colonic luminal microbiome displayed strong decrease in diversity. These alterations preceded and maybe causally related to increased mucosal TNFα mRNA expression levels and leucocyte infiltration in the mid‐distal colon of slc26a3−/− but not of cftr−/− mice.

Conclusions

These findings may explain the strong increase in the susceptibility of slc26a3−/− mice to DSS damage, and offer insight into the mechanisms leading to an increased incidence of intestinal inflammation in CLD patients.
Inflammatory bowel disease and pancreatic cancer: a Scandinavian register‐based cohort study 1969‐2017
Authors: Everhov Åsa H. , Erichsen Rune , Sachs Michael C. , Pedersen Lars , Halfvarson Jonas , Askling Johan , Ekbom Anders , Ludvigsson Jonas F. , Sørensen Henrik Toft , Olén Ola
Published: May 2020

Background

Patients with inflammatory bowel disease (IBD) have an increased risk of cancer.

Aim

To assess the risk of pancreatic cancer in IBD compared to the general population.

Methods

Patients with incident IBD 1969‐2017 were identified in Danish and Swedish National Patient Registers and through biopsy data, and were matched to IBD‐free reference individuals by sex, age, place of residence and year of IBD diagnosis. We linked data to Cancer and Causes of Death Registers and examined the absolute and relative risks of pancreatic cancer and pancreatic cancer death.

Results

Among 161 926 patients followed for 2 000 951 person years, 442 (0.27%) were diagnosed with pancreatic cancer compared to 3386 (0.21%) of the 1 599 024 reference individuals. The 20‐year cumulative incidence was 0.34% (95% confidence interval 0.30‐0.38) vs 0.29% (0.28‐0.30). The incidence rate was 22.1 (20.1‐24.2)/100 000 person years in the patients (excluding the first year of follow‐up: 20.8 [18.8‐23.0]), and 16.6 (16.0‐17.2) in the reference individuals. The hazard ratio (HR) for pancreatic cancer was increased overall: 1.43 (1.30‐1.58), in subtypes (Crohn's disease: 1.44 [1.18‐1.74]; ulcerative colitis: 1.35 [1.19‐1.53]; IBD unclassified: 1.99 [1.50‐2.64]) and especially in IBD patients with primary sclerosing cholangitis: 7.55 (4.94‐11.5). Patients and reference individuals with pancreatic cancer did not differ in cancer stage (P = 0.17) or pancreatic cancer mortality (HR 1.07 [0.95‐1.21]).

Conclusions

Patients with IBD had an excess risk of pancreatic cancer, in particular patients with primary sclerosing cholangitis. However, the cumulative incidence difference after 20 years was small: 0.05%, that is, one extra pancreatic cancer per 2000 IBD patients.
Duodenal bacterial load as determined by quantitative polymerase chain reaction in asymptomatic controls, functional gastrointestinal disorders and inflammatory bowel disease
Authors: Shah Ayesha , Talley Nicholas J. , Koloski Natasha , Macdonald Graeme A. , Kendall Bradley J. , Shanahan Erin R. , Walker Marjorie M. , Keely Simon , Jones Michael P. , Morrison Mark , Holtmann Gerald J.
Published: May 2020

Background

Small intestinal bacterial overgrowth may play a role in gastrointestinal and non‐gastrointestinal diseases.

Aims

To use quantitative polymerase chain reaction (qPCR) to determine and compare bacterial loads of duodenal biopsies in asymptomatic controls, and patients with functional gastrointestinal disorders (FGIDs) and inflammatory bowel disease (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD). To define effects of gastric acid inhibition on bacterial load, explore links of bacterial load and gastrointestinal symptoms in response to a standardised nutrient challenge and compare bacterial load with glucose breath test results.

Methods

In 237 patients (63 controls, 84 FGID and 90 IBD), we collected mucosal samples under aseptic conditions during endoscopy extracted and total DNA. Bacterial load metric was calculated utilising qPCR measurements of the bacterial 16S rRNA gene, normalised to human beta‐actin expression. Standard glucose breath test and nutrient challenge test were performed.

Results

The duodenal microbial load was higher in patients with FGID (0.22 ± 0.03) than controls (0.07 ± 0.05; P = 0.007) and patients with UC (0.01 ± 0.05) or CD (0.02 ± 0.09), (P = 0.0001). While patients treated with proton pump inhibitors (PPI) had significantly higher bacterial loads than non‐users (P < 0.05), this did not explain differences between patient groups and controls. Bacterial load was significantly (r = 0.21, P < 0.016) associated with the symptom response to standardised nutrient challenge test. Methane, but not hydrogen values on glucose breath test were associated with bacterial load measured utilising qPCR.

Conclusions

Utilising qPCR, a diagnosis of FGID and treatment with PPI were independently associated with increased bacterial loads. Increased bacterial loads are associated with an augmented symptom response to a standardised nutrient challenge.
Alternative education spaces and pathways: Insights from an international Christian school in China
Authors: De Silva Menusha , Woods Orlando , Kong Lily
Published: May 2020

The nascent scholarship on geographies of alternative education focuses on alternative education spaces, mostly located in the UK, that resist and/or negotiate neoliberal restructuring of education, some of which cater to socially marginalised groups. In contrast, through an ethnographic focus on an underground Christian international school in China, we examine an alternative education space that responds to parents' aspirations for their children to be inculcated with global cultural capital, Chinese values, and Christian beliefs. These aspirations are not fulfilled in mainstream state schools or international schools in China, but are demanded by parents looking for a “superior” set of skills for their children to navigate the increasingly neoliberal, and global, higher education and employment landscapes. The discussion reveals the incongruities in the school's claim to simultaneously instil global, local, and spiritual forms of cultural capital, which leads to two visions of the pathway to higher education. The paper expands the geographies of alternative education in three ways. First, it shows how international and faith‐based schools can provide alternative schooling. Second, it shows how the departure of alternative education spaces from their mainstream counterparts can reveal the inadequacies of the latter. Third, it draws attention to how the cultural capital inculcated through alternative education can lead to alternative international higher education pathways within and beyond China.
Transferability of vegetation recovery models based on remote sensing across different fire regimes
Authors: Fernández‐Guisuraga José Manuel , Suárez‐Seoane Susana , Calvo Leonor
Published: May 2020

Aim

To evaluate the transferability between fire recurrence scenarios of post‐fire vegetation cover models calibrated with satellite imagery data at different spatial resolutions within two Mediterranean pine forest sites affected by large wildfires in 2012.

Location

The northwest and east of the Iberian Peninsula.

Methods

In each study site, we defined three fire recurrence scenarios for a reference period of 35 years. We used image texture derived from the surface reflectance channels of WorldView‐2 and Sentinel‐2 (at a spatial resolution of 2 m × 2 m and 20 m × 20 m, respectively) as predictors of post‐fire vegetation cover in Random Forest regression analysies. Percentage vegetation cover was sampled in two sets of field plots with a size roughly equivalent to the spatial resolution of the imagery. The plots were distributed following a stratified design according to fire recurrence scenarios. Model transferability was assessed within each study site by applying the vegetation cover model developed for a given fire recurrence scenario to predict vegetation cover in other scenarios, iteratively.

Results

For both wildfires, the highest model transferability between fire recurrence scenarios was achieved for those holding the most similar vegetation community composition regarding the balance of species abundance according to their plant‐regenerative traits (root mean square error [RMSE] around or lower than 15%). Model transferability performance was highly improved by fine‐grained remote‐sensing data.

Conclusions

Fire recurrence is a major driver of community structure and composition so the framework proposed in this study would allow land managers to reduce efforts in the context of post‐fire decision‐making to assess vegetation recovery within large burned landscapes with fire regime variability.
Prospective validation of a model‐informed precision dosing tool for vancomycin in intensive care patients
Authors: ter Heine Rob , Keizer Ron J. , van Steeg Krista , Smolders Elise J. , van Luin Matthijs , Derijks Hieronymus J. , de Jager Cornelis P.C. , Frenzel Tim , Brüggemann Roger
Published: May 2020

Aims

Vancomycin is an important antibiotic for critically ill patients with Gram‐positive bacterial infections. Critically ill patients typically have severely altered pathophysiology, which leads to inefficacy or toxicity. Model‐informed precision dosing may aid in optimizing the dose, but prospectively validated tools are not available for this drug in these patients. We aimed to prospectively validate a population pharmacokinetic model for purpose model‐informed precision dosing of vancomycin in critically ill patients.

Methods

We first performed a systematic evaluation of various models on retrospectively collected pharmacokinetic data in critically ill patients and then selected the best performing model. This model was implemented in the Insight Rx clinical decision support tool and prospectively validated in a multicentre study in critically ill patients. The predictive performance was obtained as mean prediction error and relative root mean squared error.

Results

We identified 5 suitable population pharmacokinetic models. The most suitable model was carried forward to a prospective validation. We found in a prospective multicentre study that the selected model could accurately and precisely predict the vancomycin pharmacokinetics based on a previous measurement, with a mean prediction error and relative root mean squared error of respectively 8.84% (95% confidence interval 5.72–11.96%) and 19.8% (95% confidence interval 17.47–22.13%).

Conclusion

Using a systematic approach, with a retrospective evaluation and prospective verification we showed the suitability of a model to predict vancomycin pharmacokinetics for purposes of model‐informed precision dosing in clinical practice. The presented methodology may serve a generic approach for evaluation of pharmacometric models for the use of model‐informed precision dosing in the clinic.
Major bleeding risk associated with oral anticoagulant in real clinical practice. A multicentre 3‐year period population‐based prospective cohort study
Authors: Bouget Jacques , Balusson Frédéric , Maignan Maxime , Pavageau Laure , Roy Pierre‐Marie , Lacut Karine , Scailteux Lucie‐Marie , Nowak Emmanuel , Oger Emmanuel
Published: May 2020

Aims

The objective was to compare major bleeding risk of direct oral anticoagulants (DOACs; per type and dose) with vitamin K antagonists (VKAs), irrespective of indication, using real‐world data.

Methods

A population‐based prospective cohort study, using the French national health data system (SNIIRAM), identified 47 469 adults living within 5 well‐defined geographical areas, who were new users of oral anticoagulants in the period 2013–2015: 20 205 VKA users, 19 579 rivaroxaban users, 4225 dabigatran users and 3460 apixaban users. From all emergency departments within these areas, clinical data for all adults referred for bleeding was collected and medically validated. The databases were linked for common key variables. The main outcome measure was major bleeding: intracranial haemorrhage, major gastrointestinal bleeding and other major bleeding events. Hazard ratios were derived from adjusted Cox proportional hazard models. We used propensity score weighting as a sensitivity analysis, with separate analyses according to indications (atrial fibrillation or venous thromboembolism).

Results

Compared to VKAs, high and low‐dose DOACs were associated with a reduced risk of intracranial haemorrhage (adjusted hazard ratio 0.55, 95% confidence interval 0.37–0.82 and 0.54, 0.26–1.12 respectively), and a reduced risk of other major bleeding events (0.41, 0.29–0.58 and 0.41, 0.22–0.79 respectively), irrespective of duration and indication. Neither DOAC dose evidenced any significant difference from VKAs in terms of risk of major gastrointestinal bleeding.

Conclusion

There is a clear benefit of using DOACs with regard to intracranial haemorrhage. The study provides new insight into major gastrointestinal and other major bleeding events.
Modelling of the relationship between infliximab exposure, faecal calprotectin and endoscopic remission in patients with Crohn's disease
Authors: Dreesen Erwin , Berends Sophie , Laharie David , D'Haens Geert , Vermeire Séverine , Gils Ann , Mathôt Ron
Published: May 2020

Aims

Evidence for the benefits of pharmacokinetic (PK) and pharmacodynamic (PD) monitoring of infliximab in patients with Crohn's disease (CD) remains scarce. We aimed to develop a population (pop)PK/PD model to characterise the infliximab dose–exposure–biomarker–response (faecal calprotectin [fCal] and endoscopic remission [ER]) relationship.

Methods

Data were obtained from 116 patients with CD in a phase 4 dose‐escalation study. Three sequential models were developed: a 2‐compartment popPK model linking infliximab dose to exposure; an indirect response popPK/PD model describing the inhibitory effect of infliximab exposure on fCal; and a first‐order Markov popPD model linking fCal to transitions between states of ER, no ER and dropout.

Results

Infliximab clearance increased with increasing fCal, decreasing albumin, increasing CD activity index and presence of anti‐drug antibodies. Baseline fCal increased with increasing C‐reactive protein and decreasing platelet count. Lower fCal increased the probability of attaining ER and decreased the probability of losing ER. Probability of dropping out given an earlier state of absence of ER increased with time. Large interpatient PK and PD variability resulted in a flat dose–response curve. Predicted fraction of patients achieving ER was 45% [30–61] (median [interquartile range], n = 50 000) when on 5 mg/kg infliximab (~46% observed in data). Simulations with 10 mg/kg induction doses predicted an increase to 48% [32–63]. This minor benefit at the population level argues against systematic 10 mg/kg induction dosing in all patients.

Conclusion

Model‐informed infliximab dose optimisation towards a predefined fCal concentration (while accounting for PK and PD variability) may improve effectiveness of infliximab therapy.
Development of AITC‐induced dermal blood flow as a translational in vivo biomarker of TRPA1 activity in human and rodent skin
Authors: Joseph Victory , Yang Xiaoying , Gao Simon S. , Elstrott Justin , Weimer Robby M. , Theess Wiebke , Thrasher Cory , Singh Nand , Lin Joseph , Bauer Rebecca N.
Published: May 2020

Background and Purpose

Develop a translational assay of Transient Receptor Potential Ankyrin 1 (TRPA1) activity for use as a preclinical and clinical biomarker.

Experimental Approach

Allyl isothiocyanate (AITC), capsaicin or citric acid were applied to ears of wildtype and Trpa1‐knock out (Trpa1 KO) rats, and changes in dermal blood flow (DBF) were measured by laser speckle contrast imaging. In humans, the DBF, pain and itch responses to 5‐20% AITC applied to the forearm were measured and safety was evaluated. Reproducibility of the DBF, pain and itch responses to topically applied 10% and 15% AITC were assessed at two visits separated by 13‐15 days. DBF changes were summarized at 5‐minute intervals as areas under the curve (AUC) and maxima. Intraclass correlation coefficient (ICC) was calculated to assess arm‐arm and period‐period reproducibility.

Key Results

AITC‐ and citric acid‐induced DBF were significantly reduced in Trpa1 KO rats compared to wildtype (90 ± 2% and 65 ± 11% reduction, respectively), whereas capsaicin response did not differ. In humans, each AITC concentration significantly increased DBF compared to vehicle with the maximal increase occurring 5 minutes post application. Ten percent and 15% AITC were selected as safe and effective stimuli. AUC from 0 to 5 minutes was the most reproducible metric of AITC‐induced DBF across arms (ICC = 0.92) and periods (ICC = 0.85). Subject‐reported pain was more reproducible than itch across visits (ICC = 0.76 vs 0.17, respectively).

Conclusion and Implications

AITC‐induced DBF is a suitable target engagement biomarker of TRPA1 activity for preclinical and clinical studies of TRPA1 antagonists.
Allostatic load, emotional hyper‐reactivity, and functioning in individuals with bipolar disorder
Authors: Dargél Aroldo A. , Volant Stevenn , Brietzke Elisa , Etain Bruno , Olié Emilie , Azorin Jean‐Michel , Gard Sebastian , Bellivier Frank , Bougerol Thierry , Kahn Jean‐Pierre , Roux Paul , Aubin Valerie , Courtet Philippe , Leboyer Marion , Henry Chantal ,   The FACE‐BD collaborators
Published: May 2020

Objectives

Diagnosis and management of bipolar disorder (BD) are limited by the absence of available biomarkers. Allostatic load (AL) represents the strain that stress, including the effects of acute phases and inter‐episode chronic mood instability, exerts on interconnected biological systems. This study aimed to operationalize an AL index and explore whether it could be relevant to better characterize BD patients with and without emotional hyper‐reactivity particularly those at higher risk of immune‐cardiometabolic dysregulation and functional impairment.

Methods

Levels of biomarkers of chronic inflammation (hsCRP and albumin), cardiovascular (systolic/diastolic blood pressure) and metabolic functions (fasting glucose, glycosylated hemoglobin, total cholesterol, LDL, HDL, and triglycerides) were measured in 1072 adult BD outpatients. Patients were classified in two groups (with/without emotional hyper‐reactivity) assessed by the Multidimensional Assessment of Thymic States scale. An Allostatic Load Index for BD (BALLI), comprising six biomarkers, was constructed using data‐driven biomarker selection.

Results

BALLI showed 81.1% accuracy with good sensitivity (81%) and specificity (81.2%) for characterizing BD patients presenting emotional hyper‐reactivity, elevated risk of inflammation (increased hsCRP, hypoalbuminemia) and cardiometabolic disturbances (hypertension, hyperglycemia, and hypertriglyceridemia). Patients classified by the BALLI as presenting emotional hyper‐reactivity had significantly lower global and cognitive functioning than those without emotional hyper‐reactivity (P < .0001).

Conclusions

A multidimensional approach based on a simple AL score (eg, BALLI) and dimensions of behavior (eg, emotional hyper‐reactivity) alongside mood is clinically relevant. AL index could be a useful tool to detect multisystemic physiological dysregulations in BD patients with/without emotional hyper‐reactivity particularly those at higher risk of immune‐cardiometabolic disturbances and functional impairment.
Cross‐sector alliances in the global refugee crisis: An institutional theory approach
Authors: Yang Aimei , Liu Wenlin , Wang Rong
Published: May 2020

The global refugee crisis has posed severe challenges to social stability and sustainable development around the world. While the business sector is expected to shoulder social responsibility in crisis relief efforts, our initial assessment shows that refugee‐related corporate social responsibility (CSR) significantly diverged across the Global Fortune 500 corporations. To advance scholars and managers' understanding of this complex CSR issue, this study draws upon National Business System Theory to explore how country‐level factors influence the multinational corporations' CSR communication about the refugee issue. Specifically, the study focuses on the strategic cross‐sector alliances between corporations, NGOs, and IGOs. The analysis shows that in this controversial global crisis, the following factors of corporations' countries‐of‐origin can significantly affect the level of cross‐sector CSR alliances: democracy levels, economic inequality levels, and unemployment rates. Findings of this study provide practical guidelines that can help managers to anticipate societal expectations when dealing with controversial social issues in an international setting. Our findings could also assist policymakers, NGOs, and IGOs to better design strategies to mobilize the corporate resources.
Iterated multisource exchangeability models for individualized inference with an application to mobile sensor data
Authors: Brown Roland , Fan Yingling , Das Kirti , Wolfson Julian
Published: May 2020

Researchers are increasingly interested in using sensor technology to collect accurate activity information and make individualized inference about treatments, exposures, and policies. How to optimally combine population data with data from an individual remains an open question. Multisource exchangeability models (MEMs) are a Bayesian approach for increasing precision by combining potentially heterogeneous supplemental data sources into analysis of a primary source. MEMs are a potentially powerful tool for individualized inference but can integrate only a few sources; their model space grows exponentially, making them intractable for high‐dimensional applications. We propose iterated MEMs (iMEMs), which identify a subset of the most exchangeable sources prior to fitting a MEM model. iMEM complexity scales linearly with the number of sources, and iMEMs greatly increase precision while maintaining desirable asymptotic and small sample properties. We apply iMEMs to individual‐level behavior and emotion data from a smartphone app and show that they achieve individualized inference with up to 99% efficiency gain relative to standard analyses that do not borrow information.
Estimating and inferring the maximum degree of stimulus‐locked time‐varying brain connectivity networks
Authors: Tan Kean Ming , Lu Junwei , Zhang Tong , Liu Han
Published: May 2020

Neuroscientists have enjoyed much success in understanding brain functions by constructing brain connectivity networks using data collected under highly controlled experimental settings. However, these experimental settings bear little resemblance to our real‐life experience in day‐to‐day interactions with the surroundings. To address this issue, neuroscientists have been measuring brain activity under natural viewing experiments in which the subjects are given continuous stimuli, such as watching a movie or listening to a story. The main challenge with this approach is that the measured signal consists of both the stimulus‐induced signal, as well as intrinsic‐neural and nonneuronal signals. By exploiting the experimental design, we propose to estimate stimulus‐locked brain networks by treating nonstimulus‐induced signals as nuisance parameters. In many neuroscience applications, it is often important to identify brain regions that are connected to many other brain regions during cognitive process. We propose an inferential method to test whether the maximum degree of the estimated network is larger than a prespecific number. We prove that the type I error can be controlled and that the power increases to one asymptotically. Simulation studies are conducted to assess the performance of our method. Finally, we analyze a functional magnetic resonance imaging dataset obtained under the Sherlock Holmes movie stimuli.
The revised Psychosis Attachment Measure: Measuring disorganized attachment
Authors: Pollard Catherine , Bucci Sandra , MacBeth Angus , Berry Katherine
Published: May 2020

Objectives

The Psychosis Attachment Measure (PAM) is currently the most widely used and validated measure of attachment in psychosis. However, the PAM does not assess disorganized attachment, the type of attachment that has been most closely linked with vulnerability to psychosis. This study aimed to expand the PAM to capture the concept of disorganized attachment and to examine its psychometric properties in a psychosis sample.

Methods

Clinical and academic experts in the field of psychosis and service user representatives were asked to assess the comprehensiveness and comprehensibility of the pool of disorganized items. This process resulted in 12 items hypothesized to capture disorganized attachment that were included with the original items of the PAM. A sample of 144 individuals with either a self‐reported diagnosis of, or treatment for, a psychosis‐related condition completed a battery of online measures comprising the revised PAM, existing measures of adult disorganized attachment and constructs hypothesized to be conceptually related to disorganized attachment.

Results

An exploratory factor analysis was conducted with three factors retained; these were labelled anxious, avoidant and disorganized attachment. The factors displayed good internal consistency and test–retest reliability and the disorganized factor displayed good construct validity with related measures and constructs.

Conclusions

These results provide preliminary evidence that the revised PAM captures the concept of disorganized attachment. However, confirmatory psychometric evaluation of the revised PAM is required, within a separate psychosis sample, to confirm its factor structure. The relationship between these results and the current literature, in addition to the clinical and research implications, are discussed.

Practitioner points

We present an expanded version of the Psychosis Attachment Measure (PAM), revised to capture the concept of disorganised attachment in adulthood. This expanded measure showed good reliability and the new disorganized subscale demonstrated construct validity.

These results provide preliminary evidence that disorganized attachment can be measured using a simple self‐report measure with individuals with psychosis.

Further research is required to confirm the structural dimensionality of the revised PAM within a new sample using confirmatory factor analysis.

Following further psychometric validation the use of this measure has the potential to be expanded to other mental health conditions in which disorganized attachment has been implicated in the development and maintenance of difficulties, for example, trauma‐related conditions and borderline personality disorder.
Low educational level of head of household, as a proxy for poverty, is associated with severe anaemia among children with sickle cell disease living in a low‐resource setting: evidence from the SPRING trial
Authors: Bello‐Manga Halima , Galadanci Aisha A. , Abdullahi Shehu , Ali Shehi , Jibir Binta , Gambo Safiya , Haliru Lawal , Jordan Lori C. , Aliyu Muktar H. , Rodeghier Mark , Kassim Adetola A. , DeBaun Michael R. , Galadanci Najibah A.
Published: May 2020

Severe anaemia, defined as haemoglobin level < 6·0 g/dl, is an independent risk factor for death in individuals with sickle cell disease living in resource‐limited settings. We conducted a cross‐sectional study of 941 children with sickle cell anaemia, who had been defined as phenotype HbSS or HbSβ0 thalassaemia, aged five to 12 years, and were screened for enrollment into a large primary stroke prevention trial in Nigeria (SPRING; NCT02560935). The main aim of the study was to determine the prevalence and risk factors for severe anaemia. We found severe anaemia to be present in 3·9% (37 of 941) of the SPRING study participants. Severe anaemia was significantly associated with the lower educational level of the head of the household (P = 0·003), as a proxy for poverty, and a greater number of children per room in the household (P = 0·004). Body mass index was not associated with severe anaemia. The etiology of severe anaemia in children living with sickle cell anaemia in Nigeria is likely to be multifactorial with an interplay between an individual's disease severity and other socio‐economic factors related to poverty.
Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
Authors: Hughes Dyfrig A.
Published: May 2020

Background and Purpose

Resurgence in the use of chloroquine as a potential treatment for COVID‐19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity.

Experimental Approach

In vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine alone or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone‐anaesthetised rats and rabbits. Randomised, controlled treatment studies in rats assessed diazepam, clonazepam and Ro5‐4864 administered: (i) prior, (ii) during and (iii) after chloroquine and the effects of diazepam: (iv) at high dose, (v) in urethane‐anaesthetised rats and (vi) co‐administered with adrenaline.

Key Results

Chloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose‐dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between treatments and control. Diazepam increased heart rate in study (iv) and as with clonazepam also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia.

Conclusion and Implications

Neither diazepam nor other ligands for benzodiazepine binding sites protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity.

Linked Articles

This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc
Potential role of transforming growth factor‐beta 1/Smad signaling in secondary lymphedema after cancer surgery
Authors: Sano Masaki , Hirakawa Satoshi , Suzuki Minoru , Sakabe Jun‐ichi , Ogawa Mikako , Yamamoto Seiji , Hiraide Takanori , Sasaki Takeshi , Yamamoto Naoto , Inuzuka Kazunori , Tanaka Hiroki , Saito Takaaki , Sugisawa Ryota , Katahashi Kazuto , Yata Tatsuro , Kayama Takafumi , Urano Tetsumei , Tokura Yoshiki , Sato Kohji , Setou Mitsutoshi , Takeuchi Hiroya , Konno Hiroyuki , Unno Naoki
Published: May 2020

Secondary lymphedema often develops after cancer surgery, and over 250 million patients suffer from this complication. A major symptom of secondary lymphedema is swelling with fibrosis, which lowers the patient's quality of life, even if cancer does not recur. Nonetheless, the pathophysiology of secondary lymphedema remains unclear, with therapeutic approaches limited to physical or surgical therapy. There is no effective pharmacological therapy for secondary lymphedema. Notably, the lack of animal models that accurately mimic human secondary lymphedema has hindered pathophysiological investigations of the disease. Here, we developed a novel rat hindlimb model of secondary lymphedema and showed that our rat model mimics human secondary lymphedema from early to late stages in terms of cell proliferation, lymphatic fluid accumulation, and skin fibrosis. Using our animal model, we investigated the disease progression and found that transforming growth factor‐beta 1 (TGFB1) was produced by macrophages in the acute phase and by fibroblasts in the chronic phase of the disease. TGFB1 promoted the transition of fibroblasts into myofibroblasts and accelerated collagen synthesis, resulting in fibrosis, which further indicates that myofibroblasts and TGFB1/Smad signaling play key roles in fibrotic diseases. Furthermore, the presence of myofibroblasts in skin samples from lymphedema patients after cancer surgery emphasizes the role of these cells in promoting fibrosis. Suppression of myofibroblast‐dependent TGFB1 production may therefore represent an effective pharmacological treatment for inhibiting skin fibrosis in human secondary lymphedema after cancer surgery.
Associations of Japanese food intake with survival of stomach and colorectal cancer: A prospective patient cohort study
Authors: Minami Yuko , Kanemura Seiki , Oikawa Tomoyuki , Suzuki Shinichi , Hasegawa Yasuhiro , Nishino Yoshikazu , Fujiya Tsuneaki , Miura Koh
Published: May 2020

Dietary factors may affect the prognosis of digestive tract cancer, but evidence has been sparse. We investigated the association between pretreatment intake of 6 Japanese foods (including soy food, miso [soybean paste] soup and seaweed) and the risk of death among patients with histologically confirmed major digestive tract cancers (stomach, 1931; colon, 793; rectum, 510) diagnosed during 1997‐2013 at a single institution in Japan. Pretreatment dietary intake was assessed using a food frequency questionnaire, and the patients were followed until December 2016. The Cox proportional hazards model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). Among the patients with stomach cancer, frequent intake of soy food was inversely associated with the risk of all‐cause (Ptrend for four frequency groups = 0.01; HR = 0.72, 95% CI: 0.50‐1.04 for highest vs lowest group) and stomach cancer (Ptrend = 0.03; HR = 0.63, 95% CI: 0.40‐0.99) death. A similar inverse association was also found for intake of miso soup. In contrast, frequent seaweed intake was inversely associated with the risk of all‐cause death among the patients with colon cancer (Ptrend = 0.03). Rectal cancer patients who had frequently consumed seaweed tended to have a lower risk of rectal cancer death (Ptrend = 0.02). These findings indicate that pretreatment intake of Japanese foods such as soybean products and seaweed may have favorable effects on patient survival of stomach and colorectal cancer, although this needs to be confirmed by further research.