bluuebunny/crossref_metadata_2025 huggingface dataset:
Population pharmacokinetics, safety and dosing optimization of voriconazole in patients with liver dysfunction: A prospective observational study
Authors: Tang Dan , Yan Miao , Song Bai‐li , Zhao Yi‐chang , Xiao Yi‐wen , Wang Feng , Liang Wu , Zhang Bi‐kui , Chen Xi‐jing , Zou Jian‐jun , Tian Yi , Wang Wen‐long , Jiang Yong‐fang , Gong Guo‐zhong , Zhang Min , Xiang Da‐xiong
Published: October 2020

Aims

Voriconazole is a broad‐spectrum antifungal agent for the treatment of invasive fungal infections. There is limited information about the pharmacokinetics and appropriate dosage of voriconazole in patients with liver dysfunction. This study aimed to explore the relationship between voriconazole trough concentration (Ctrough) and toxicity, identify the factors significantly associated with voriconazole pharmacokinetic parameters and propose an optimised voriconazole dosing regimen for patients with liver dysfunction.

Methods

The study prospectively enrolled 51 patients with 272 voriconazole concentrations. Receiver operating characteristic curves were used to explore the relationship between voriconazole Ctrough and toxicity. The pharmacokinetic data was analysed with nonlinear mixed‐effects method. Dosing simulations stratified by total bilirubin (TBIL, TBIL‐1: TBIL < 51 μmol/L; TBIL‐2: 51 μmol/L ≤ TBIL < 171 μmol/L; TBIL‐3: TBIL ≥ 171 μmol/L) were performed.

Results

Receiver operating characteristic curve analysis revealed that voriconazole Ctrough of ≤ 5.1 mg/L were associated with significantly lower the incidence of adverse events. A 1‐compartment pharmacokinetic model with first‐order absorption and elimination was used to describe the data. Population pharmacokinetic parameters of clearance, volume of distribution and oral bioavailability were 0.88 L/h, 148.8 L and 88.4%, respectively. Voriconazole clearance was significantly associated with TBIL and platelet count. The volume of distribution increased with body weight. Patients with TBIL‐1 could be treated with a loading dose of 400 mg every 12 hours (q12h) for first day, followed by a maintenance dose of 100 mg q12h administered orally or intravenously. TBIL‐2 and TBIL‐3 patients could be treated with a loading dose of 200 mg q12h and maintenance doses of 50 mg q12h or 100 mg once daily and 50 mg once daily orally or intravenously, respectively.

Conclusions

Lower doses and longer dosing intervals should be considered for patients with liver dysfunction. TBIL‐based dosing regimens provide a practical strategy for achieving voriconazole therapeutic range and therefore maximizing treatment outcomes.
A case series of confusional states and other neurotoxic effects caused by ertapenem
Authors: Danés Immaculada , Pérez Eulàlia , Pigrau Carles , Gracia Rosa M. , Perelló Manel , Sueiras Maria , Aguilera Cristina , Agustí Antònia
Published: October 2020

Ten cases of ertapenem neurotoxicity, mainly confusional states, are described, some of them with fatal outcomes. The majority of patients (90%) had a creatinine clearance (CrCl) < 50 mL/min/1.73m2 at some point during treatment and hypoalbuminaemia was always present when ertapenem treatment was started. The pharmacokinetic and pharmacodynamic properties of this carbapenem could favour a different profile, and approved doses can be excessive in some patients with moderate renal failure (CrCl 31–59 mL/min/1.73 m2). It may be necessary to re‐evaluate renal function during treatment and adjust doses or reconsider the adequacy of treatment based on clinical judgement, especially if relevant changes in the CrCl occur (i.e. a reduction to ≤30 mL/min/1.73 m2) or unexplained behavioural disorders are detected. The onset of the symptoms of ertapenem neurotoxicity can be insidious and go unnoticed, and so a knowledge and early suspicion of confusional states are important to improve the patient prognosis.
Affordances of a mobile learner‐generated tool for pupils’ English as a second language vocabulary learning: An ecological perspective
Authors: Song Yanjie , Ma Qing
Published: October 2020

This paper reports on a case study of English as a second language (ESL) vocabulary learning that examined a group of Grade 4 students’ mobile learning experiences of bridging in‐class and real‐life vocabulary learning mediated by a mobile learner‐generated content (m‐LGC) tool. This study was premised on the proposed framework of mobile vocabulary learning from an ecological perspective using the concept of affordances, taking the topic of “Food” as an example. Data collection included learning logs created by students and a questionnaire about students’ perceptions of the m‐LGC tool for vocabulary learning. The results revealed four types of affordances of the m‐LGC tool that the learners perceived and acted on in real life outside the classroom, namely: vocabulary form‐meaning mapping, consolidating vocabulary by productive use, vocabulary revision and social affordance. The students’ perceptions of the m‐LGC tool for vocabulary learning were positive. This study shows that the various affordances helped students in applying newly learned words to real‐life contexts. Social affordance provided the social contexts for communication via peer interaction, vocabulary expansion as well as the creation of a learning community.
Social attention across borders: A cross‐cultural investigation of gaze cueing elicited by same‐ and other‐ethnicity faces
Authors: Zhang Xinyuan , Dalmaso Mario , Castelli Luigi , Fiorese Alberto , Lan Yonglong , Sun Bo , Fu Shimin , Galfano Giovanni
Published: October 2020

The gaze‐cueing effect is a robust phenomenon which illustrates how attention can be shaped by social factors. In four experiments, the present study explored the interaction between the ethnic membership of the participant and that of the face providing the gaze cue. Firstly, we aimed to further investigate the differential impact of White, Black, and Asian faces on the gaze‐cueing effect in White individuals. Secondly, we aimed to explore, for the first time, the impact of faces belonging to different ethnicities on gaze cueing in Chinese participants. The results allowed to rule out alternative accounts and showed that White participants exhibit a gaze‐cueing effect for White and Asian faces, but not for Black faces, consistent with previous studies. As regards Chinese participants, the overall findings suggested a stronger gaze‐cueing effect for White faces than for Asian faces. The results are discussed with reference to differences in the perceived social status of the various groups, pointing to the need of taking into account different cultural contexts.
Person‐centred respite supports: The perspectives of adults with intellectual disabilities in Ireland
Authors: Gadd Teresa
Published: October 2020

Accessible Summary

This study looks at the experiences of adults with intellectual disabilities using respite services in Ireland. Some adults stayed overnight in a respite house, and others were part of evening and weekend groups.

Overall, the adults were happy with their respite supports.

They suggested nine important ways that respite services can meet a person's needs and support them to do the things they want to do.

The adults said it was important to have fun, time and space, choice, and to be independent at respite. They should have a chance to build friendships and be in groups that work well together. It is important to get on well with staff too. Respite supports must meet different needs. Persons with disabilities should take part in the design and management of respite supports.

A national policy for respite in disability services is needed in Ireland. The views and suggestions of persons with disabilities should be considered if a policy is developed.

Background

Respite supports are highly valued by persons with disabilities and their families/carers. In Ireland, there has been regular commentary in relation to a lack of respite services, with users and other stakeholders reporting limited access, inequity of provision, and long waiting lists for support.

Materials and Methods

Much of the research on respite focuses on the views of carers, with little account of the experiences of persons with disabilities. This study examines the perspectives of twenty‐eight adults with intellectual disabilities; most are regular users of traditional and/or alternative respite services. Information was gathered through individual interviews and focus groups.

Findings

Participants identified nine key elements of a person‐centred respite service; fun, time and space, choice, independence, friendships, compatible groupings, positive relationships with staff, flexible supports, and user involvement in service design and delivery.

Conclusions

Person‐centred supports should enable individuals to achieve maximum well‐being and flourish in all aspects of their lives. This study found that at a personal level, respite services and the interactions that occur within them are person‐centred in that they support the individual to do the things they want to do, make everyday choices, try new activities, develop positive relationships, and have a good quality of life. However, at the level of service planning and decision‐making, there is less evidence of a person‐centred approach. Participants reported having little involvement in the design and delivery of respite services at local or national level. The development of a respite policy in Ireland, that considers the views of respite service users, would be welcome.
Accumulation of neurofibrillary tangles and activated microglia is associated with lower neuron densities in the aphasic variant of Alzheimer’s disease
Authors: Ohm Daniel T. , Fought Angela J. , Martersteck Adam , Coventry Christina , Sridhar Jaiashre , Gefen Tamar , Weintraub Sandra , Bigio Eileen , Mesulam M.‐Marsel , Rogalski Emily , Geula Changiz
Published: October 2020

The neurofibrillary tangles (NFT) and amyloid‐ß plaques (AP) that comprise Alzheimer’s disease (AD) neuropathology are associated with neurodegeneration and microglial activation. Activated microglia exist on a dynamic spectrum of morphologic subtypes that include resting, surveillant microglia capable of converting to activated, hypertrophic microglia closely linked to neuroinflammatory processes and AD neuropathology in amnestic AD. However, quantitative analyses of microglial subtypes and neurons are lacking in non‐amnestic clinical AD variants, including primary progressive aphasia (PPA‐AD). PPA‐AD is a language disorder characterized by cortical atrophy and NFT densities concentrated to the language‐dominant hemisphere. Here, a stereologic investigation of five PPA‐AD participants determined the densities and distributions of neurons and microglial subtypes to examine how cellular changes relate to AD neuropathology and may contribute to cortical atrophy. Adjacent series of sections were immunostained for neurons (NeuN) and microglia (HLA‐DR) from bilateral language and non‐language regions where in vivo cortical atrophy and Thioflavin‐S‐positive APs and NFTs were previously quantified. NeuN‐positive neurons and morphologic subtypes of HLA‐DR‐positive microglia (i.e., resting [ramified] microglia and activated [hypertrophic] microglia) were quantified using unbiased stereology. Relationships between neurons, microglia, AD neuropathology, and cortical atrophy were determined using linear mixed models. NFT densities were positively associated with hypertrophic microglia densities (P < 0.01) and inversely related to neuron densities (P = 0.01). Hypertrophic microglia densities were inversely related to densities of neurons (P < 0.01) and ramified microglia (P < 0.01). Ramified microglia densities were positively associated with neuron densities (P = 0.02) and inversely related to cortical atrophy (P = 0.03). Our findings provide converging evidence of divergent roles for microglial subtypes in patterns of neurodegeneration, which includes hypertrophic microglia likely driving a neuroinflammatory response more sensitive to NFTs than APs in PPA‐AD. Moreover, the accumulation of both NFTs and activated hypertrophic microglia in association with low neuron densities suggest they may collectively contribute to focal neurodegeneration characteristic of PPA‐AD.
Sedimentation and viscosity controls on forearc high growth
Authors: Fernández‐Blanco David , Mannu Utsav , Cassola Teodoro , Bertotti Giovanni , Willett Sean D.
Published: October 2020

Crustal rheology and surface processes strongly influence strain distribution and shape of orogenic wedges at their front but how they influence the wedge rear is still unclear. Here, we analyse the coupled control of viscosity and sedimentation on forearc high growth during advanced stages of subduction accretion. We use 2D thermo‐mechanical finite element models constrained with data of the south Anatolian margin. Our simulations show that forearc highs grow as a thermally‐activated viscosity drop in the lower crust induces ductile deformation and viscous flow. Initial viscosity and the amount of sediments in the forearc basin control non‐linearly the occurrence and timing of the thermally‐activated viscosity drop, and thus of the growth of the forearc high. High sedimentation rates result in thicker forearc basins that stabilise the subduction wedge and delay the onset of uplift in the forearc high. Low viscosities promote earlier onset of forearc high uplift and lead to larger morphological variability along the subduction margin. Increasing either the sedimentation rate or viscosity may prevent forearc high formation entirely. The thermo‐viscous forearc highs grow at an age set by wedge thermal state as a function of accretionary flux, wedge viscosity, and synorogenic sedimentation. Our models explain vertical motions in south Anatolia and potentially in other accretionary margins, like the Lesser Antilles or Cascadia, during the formation of their broad forearc highs.
Increased expression of CXCL2 in ACPA-positive rheumatoid arthritis and its role in osteoclastogenesis
Authors: Wang X , Sun L , He N , An Z , Yu R , Li C , Li Y , Li Y , Liu X , Fang X , Zhao J
Published: October 2020

Anti-citrullinated protein/peptide antibodies (ACPA) play important roles in the pathogenesis of rheumatoid arthritis (RA). ACPA-positive (ACPA+) and ACPA-negative (ACPA−) RA were suggested to be different disease subsets, with distinct differences in genetic variation and clinical outcomes. The aims of the present study were to compare gene expression profiles in ACPA+ and ACPA− RA, and to identify novel candidate gene signatures that might serve as therapeutic targets. Comprehensive transcriptome analysis of peripheral blood mononuclear cells (PBMCs) from ACPA+ and ACPA− RA patients and healthy controls was performed via RNA sequencing. A validation cohort was used to further investigate differentially expressed genes via polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA). Spearman's correlation test was used to evaluate the correlation of differentially expressed genes and the clinical and laboratory data of the patients. The role of differentially expressed genes in osteoclastogenesis was further investigated. Expression of C-X-C motif chemokine ligand 2 (CXCL2) was significantly increased in ACPA+ RA than in ACPA− RA, which was validated in PBMCs and serum. CXCL2 promoted the migration of CD14+ monocytes and increased osteoclastogenesis in RA patients. RAW264.7 macrophages were used to investigate specific mechanisms, and the results suggested that CXCL2 stimulated osteoclastogenesis via extracellular receptor kinase (ERK) mitogen-activated protein kinase (MAPK) and nuclear factor kappa B pathways. In conclusion, CXCL2 was highly expressed in ACPA+ RA than in ACPA− RA. CXCL2 promoted osteoclastogenesis and was related to bone erosion in RA, which suggests that the blockade of CXCL2 might be a novel strategy for the treatment of RA.
Heterozygous de novo variants in CSNK1G1 are associated with syndromic developmental delay and autism spectrum disorder
Authors: Gold Nina B. , Li Dong , Chassevent Anna , Kaiser Frank J. , Parenti Ilaria , Strom Tim M. , Ramos Feliciano J. , Puisac Beatriz , Pié Juan , McWalter Kirsty , Guillen Sacoto Maria J. , Cui Hong , Saadeh‐Haddad Reem , Smith‐Hicks Constance , Rodan Lance , Blair Edward , Bhoj Elizabeth
Published: October 2020

The gamma‐1 isoform of casein kinase 1, the protein encoded by CSNK1G1, is involved in the growth and morphogenesis of cells. This protein is expressed ubiquitously among many tissue types, including the brain, where it regulates the phosphorylation of N‐methyl‐D‐aspartate receptors and plays a role in synaptic transmission. One prior individual with a de novo variant in CSNK1G presenting with severe developmental delay and early‐onset epilepsy has been reported. Here we report an updated clinical history of this previously published case, as well as four additional individuals with de novo variants in CSNK1G1 identified via microarray‐based comparative genomic hybridization, exome, or genome sequencing. All individuals (n = 5) had developmental delay. At least three individuals had diagnoses of autism spectrum disorder. All participants were noted to have dysmorphic facial features, although the reported findings varied widely and therefore may not clearly be recognizable. None of the participants had additional major malformations. Taken together, our data suggest that CSNK1G1 may be a cause of syndromic developmental delay and possibly autism spectrum disorder.
Copy number alterations involving 59 ACMG‐recommended secondary findings genes
Authors: Yatsenko Svetlana A. , Aarabi Mahmoud , Hu Jie , Surti Urvashi , Ortiz Damara , Madan‐Khetarpal Suneeta , Saller Devereux N. , Bellissimo Daniel , Rajkovic Aleksandar
Published: October 2020

In clinical exome/genome sequencing, the American College of Medical Genetics and Genomics (ACMG) recommends reporting of secondary findings unrelated to a patient's phenotype when pathogenic single‐nucleotide variants (SNVs) are observed in one of 59 genes associated with a life‐threatening, medically actionable condition. Little is known about the incidence and sensitivity of chromosomal microarray analysis (CMA) for detection of pathogenic copy number variants (CNVs) comprising medically‐actionable genes. Clinical CMA has been performed on 8865 individuals referred for molecular cytogenetic testing. We retrospectively reviewed the CMA results to identify patients with CNVs comprising genes included in the 59‐ACMG list of secondary findings. We evaluated the clinical significance of these CNVs in respect to pathogenicity, phenotypic manifestations, and heritability. We identified 23 patients (0.26%) with relevant CNV either deletions comprising the entire gene or intragenic alterations involving one or more secondary findings genes. A number of patients and/or their family members with pathogenic CNVs manifest or expected to develop an anticipated clinical phenotype and would benefit from preventive management similar to the patients with pathogenic SNVs. To improve patients' care standardization should apply to reporting of both sequencing and CNVs obtained via clinical genome‐wide analysis, including chromosomal microarray and exome/genome sequencing.
Novel GZF1 pathogenic variants identified in two Chinese patients with Larsen syndrome
Authors: Zeng Lanlan , Li Zhibin , Pan Lijuan , Li Hongyan , Wu Jiayu , Yuan Xiying , Li Zhuo , Liang Desheng , Wu Lingqian
Published: October 2020

GZF1 was recently reported as a genetic factor associated with Larsen syndrome. Two patients presenting hip dislocation, scoliosis and severe myopia, as well as hearing loss and other abnormal features, were found to carry two novel compounds heterozygous variants in GZF1 (c.397400del, p. Leu133fs; and c.1474del, p. Met492fs) through whole‐exome sequencing. The mRNA expression level of L133fs‐GZF1 did not significantly differ from that of WT‐GZF1. However, no HA‐conjugated mutant protein was detected by western blotting, which was also confirmed by immunofluorescence staining. In addition, both mRNA transcription and protein expression levels of M492fs‐GZF1 were significantly lower than those of wild type, and HA‐tagged M492fs‐GZF1 was mainly distributed in the cytoplasm of HEK 293 T cells. These results suggested that the two variants could lead to loss of function of GZF1. Our study was the second to report the association between GZF1 variants and Larsen syndrome. We also provided functional evidence for the pathogenicity of GZF1 variants, which expands the mutation spectrum and offers a basis for functional research on the role of GZF1 in the development of Larsen syndrome.
Obesity and activity patterns before and during COVID‐19 lockdown among youths in China
Authors: Yang Shujuan , Guo Bing , Ao Linjun , Yang Chao , Zhang Lei , Zhou Junmin , Jia Peng
Published: October 2020

This study aim to assess changes in obesity and activity patterns among youths in China during the COVID‐19 lockdown. We used the COVID‐19 Impact on lifestyle change survey (COINLICS), a national retrospective survey distributed via social media platforms in early May 2020 where more than 10 000 youth participants in China have voluntarily reported their basic sociodemographic information, weight status, and routine lifestyles in the months before and during COVID‐19 lockdown. The extended IOTF and WHO standards were used to define overweight and obesity of the participants. We used paired t‐tests or χ2 tests and non‐parametric methods to evaluate the significance of differences in weight‐related outcomes and lifestyles across education levels, between sexes, and before and during COVID‐19 lockdown. The mean body mass index of all participating youths has significantly increased (21.8‐22.6) and in all education subgroups during COVID‐19 lockdown. Increases also occurred in the prevalence of overweight/obesity (21.3%‐25.1%, P < .001) and obesity (10.5% to 12.9%, P < .001) in overall youths, especially in high school and undergraduate students. Their activity patterns had also significantly changed, including the decreased frequency of engaging in active transport, moderate−/vigorous‐intensity housework, leisure‐time moderate−/vigorous‐intensity physical activity, and leisure‐time walking, and the increased sedentary, sleeping, and screen time. Our findings would inform policy‐makers and clinical practitioners of these changes in time, for better policy making and clinical practice. School administrators should also be informed of these changes, so in‐class and/or extracurricular physical activity programs could be designed to counteract them.
Metastasizing basal cell carcinoma: A clinicopathologic and immunohistochemical study of 22 cases
Authors: Mochel Mark C. , Liaquat Samia , Moore Johanna B. , Hoang Mai P.
Published: October 2020

Basal cell carcinomas metastasize rarely, and there have been limited studies of potential drivers for this metastasis. Epithelial‐mesenchymal transition (EMT) may play a role, although this has not been investigated in detail. We reviewed clinicopathologic features of 22 patients with metastasizing basal cell carcinoma (MBCC). Immunohistochemical markers of EMT, including CD44, E‐cadherin, claudin, smooth muscle actin, beta‐catenin, Twist1, and Oct 3/4, were evaluated on 10 MBCC (primary and metastases) and 18 non‐metastasizing BCC. Primary sites included the head and neck, trunk, and extremity, while metastatic sites included lymph nodes, lung, bone, and soft tissue. Of 19 cases with follow‐up, the range of follow‐up after diagnosis of metastasis was 5 to 248 months (median: 50 months). Two cases were of unknown primary, nine metastases were diagnosed concurrently with primary tumors, and remaining cases showed a median latency between diagnosis of primary and metastatic tumors of 27.5 months (range: 3‐81 months). Median survival was 66 months. Compared to non‐metastasizing BCC, MBCC demonstrated reduced CD44 expression (primary [P = .0036], metastatic [P = .011]) and increased Twist1 expression (primary, P = .0017). MBCC shows variably aggressive behavior, and reduced CD44 and increased Twist1 expression may indicate significant EMT in metastasizing tumors and signify a metastatic phenotype.
Comparison of Afirma Gene Expression Classifier with Gene Sequencing Classifier in indeterminate thyroid nodules: A single‐institutional experience
Authors: Geng Yipeng , Aguilar‐Jakthong Josephine S. , Moatamed Neda A.
Published: October 2020

Introduction

The Afirma test has been used in the diagnosis of cytologically indeterminate thyroid nodules to reduce diagnostic uncertainty and unnecessary surgeries. Gene Sequencing Classifier (GSC) was developed to improve the positive predictive value and overall test performance of Gene Expression Classifier (GEC). Here we present our experience comparing the performance of first‐generation assay of Afirma (GEC) with the new assay (GSC).

Methods

Retrospective analysis was performed on all Bethesda III and IV cytology thyroid nodules tested with GEC and GSC. Test performance was evaluated by surgical pathology outcomes.

Results

In total, 167 cases were tested with GEC, of which 49% were reported as benign. Fourteen cases had surgical follow‐up with 11 benign, one non‐invasive follicular thyroid neoplasm with papillary‐like nuclear features (NIFTP) and two malignant diagnoses. Of the 167 cases, 51% had suspicious GEC result. Fifty‐seven of these suspicious GEC cases had surgical follow‐up with 28 benign, nine NIFTP and 20 malignant histology. There 133 cases tested with GSC, of which 61% were reported as benign. Ten cases had surgical follow‐up, all of which showed benign results and 32% of the cases were tested as suspicious. Thirty‐six cases with suspicious GSC had surgical follow‐up. Fourteen of them had benign, five NIFTP, and 17 malignant surgical pathology. Based on molecular testing, surgical resection could have been be prevented 61% with GSC, compared to 49% with GEC test.

Conclusion

Our experience shows that GSC has a better test performance than GEC. Also, our data support that GSC identify more cases as benign and reduces the number of unnecessary surgeries compared to GEC.
Manifestations, clinical course and prognostic markers in cutaneous polyarteritis nodosa
Authors: Munera‐Campos Mónica , Bielsa Isabel , Martínez‐Morillo Melania , Aparicio Gloria , Olivé Alejandro , Ferrándiz Carlos
Published: October 2020

Background and objectives

Cutaneous polyarteritis nodosa (CPAN) is a comparatively rare form of vasculitis that affects small arteries and arterioles in the panniculus and dermo‐subcutaneous junction. Limited information is available regarding its course in the European population. The aim of this study is to characterize the manifestations and prognostic markers of recurrence in CPAN.

Patients and methods

We report a retrospective study of patients with clinical and histopathologic evidence of CPAN, which was treated at two tertiary referral centers in Spain between 1989 and 2019.

Results

31 patients were included. The most frequent manifestation was subcutaneous nodules (90.3 %); ulcers were frequent at diagnosis (35.5 %). Two thirds of the patients had at least one extracutaneous manifestation. Seventeen patients (54.8 %) experienced relapse. The strongest predictor of recurrence was ulceration in the initial episode (OR 18.6; 95 % CI 2.73–38; p < 0.01). The pre‐treatment results of laboratory parameters associated with inflammation (such as C‐reactive protein and neutrophil‐to‐lymphocyte ratio) were significantly higher in the relapsing group. There were no disease‐related deaths and none of the patients developed systemic PAN.

Conclusions

Although CPAN is a vasculitis limited to the skin, symptoms may involve adjacent skeletal muscle or peripheral nerves. While the condition is not life‐threatening, the presence of ulceration and elevation of certain laboratory parameters predicts a worse prognosis.
Patient preferences for treatment of advanced melanoma: impact of comorbidities
Authors: Weilandt Juliane , Diehl Katharina , Schaarschmidt Marthe‐Lisa , Kiecker Felix , Sasama Bianca , Pronk Melanie , Ohletz Jan , Könnecke Andreas , Müller Verena , Utikal Jochen , Hillen Uwe , Harth Wolfgang , Peitsch Wiebke K.
Published: October 2020

Background and objectives

Choice of treatment for advanced melanoma is crucially influenced by comorbidities and patient preferences. Our study aimed to investigate the impact of comorbidities on preferences.

Patients and methods

150 patients with melanoma stage IIC–IV completed a discrete choice experiment to determine preferences for outcome (overall response rate [ORR], 2‐year survival, progression‐free survival [PFS], time to response [TTR], kind of adverse events [AE], AE‐related treatment discontinuation) and process attributes (frequency and route of administration [RoA], frequency of consultations) of systemic melanoma treatments. The impact of comorbidities was assessed by analysis of variance and multivariate regression.

Results

Participants with hypertension and other cardiovascular diseases attached significantly greater importance to TTR and RoA than others. Respondents with arthropathy cared more about TTR (β = 0.179, P = 0.047) and RoA, but less about ORR (β = –0.209, P =  0.021). Individuals with diabetes considered AE (β = 0.185, P = 0.039) and frequency of consultations more essential, but ORR less relevant. Those with other malignancies were particularly worried about treatment discontinuation (β = 0.219, P =  0.008), but less about ORR (β = –0.202, P =  0.015). Participants with depression focused more on PFS (β = 0.201, P =  0.025) and less on TTR (β = –0.201, P =  0.023) and RoA (β = –0.167, P =  0.050).

Conclusions

Treatment preferences of melanoma patients vary significantly dependent on comorbidities.
Trends in the detection of aquatic non‐indigenous species across global marine, estuarine and freshwater ecosystems: A 50‐year perspective
Authors: Bailey Sarah A. , Brown Lyndsay , Campbell Marnie L. , Canning‐Clode João , Carlton James T. , Castro Nuno , Chainho Paula , Chan Farrah T. , Creed Joel C. , Curd Amelia , Darling John , Fofonoff Paul , Galil Bella S. , Hewitt Chad L. , Inglis Graeme J. , Keith Inti , Mandrak Nicholas E. , Marchini Agnese , McKenzie Cynthia H. , Occhipinti‐Ambrogi Anna , Ojaveer Henn , Pires‐Teixeira Larissa M. , Robinson Tamara B. , Ruiz Gregory M. , Seaward Kimberley , Schwindt Evangelina , Son Mikhail O. , Therriault Thomas W. , Zhan Aibin
Published: October 2020

Aim

The introduction of aquatic non‐indigenous species (ANS) has become a major driver for global changes in species biogeography. We examined spatial patterns and temporal trends of ANS detections since 1965 to inform conservation policy and management.

Location

Global.

Methods

We assembled an extensive dataset of first records of detection of ANS (1965–2015) across 49 aquatic ecosystems, including the (a) year of first collection, (b) population status and (c) potential pathway(s) of introduction. Data were analysed at global and regional levels to assess patterns of detection rate, richness and transport pathways.

Results

An annual mean of 43 (±16 SD) primary detections of ANS occurred—one new detection every 8.4 days for 50 years. The global rate of detections was relatively stable during 1965–1995, but increased rapidly after this time, peaking at roughly 66 primary detections per year during 2005–2010 and then declining marginally. Detection rates were variable within and across regions through time. Arthropods, molluscs and fishes were the most frequently reported ANS. Most ANS were likely introduced as stowaways in ships’ ballast water or biofouling, although direct evidence is typically absent.

Main conclusions

This synthesis highlights the magnitude of recent ANS detections, yet almost certainly represents an underestimate as many ANS go unreported due to limited search effort and diminishing taxonomic expertise. Temporal rates of detection are also confounded by reporting lags, likely contributing to the lower detection rate observed in recent years. There is a critical need to implement standardized, repeated methods across regions and taxa to improve the quality of global‐scale comparisons and sustain core measures over longer time‐scales. It will be fundamental to fill in knowledge gaps given that invasion data representing broad regions of the world's oceans are not yet readily available and to maintain knowledge pipelines for adaptive management.
Arthropod abundance modulates bird community responses to urbanization
Authors: Planillo Aimara , Kramer‐Schadt Stephanie , Buchholz Sascha , Gras Pierre , von der Lippe Moritz , Radchuk Viktoriia
Published: October 2020

Aim

We analysed the role of species interactions in wildlife community responses to urbanization. Specifically, we investigated non‐trophic associations within a bird community and the role of trophic interactions in the responses of bird species to the urbanization gradient.

Location

City‐state of Berlin, Central Europe.

Methods

Arthropod and bird abundances were sampled across the study area and analysed using hierarchical joint species distribution models (JSDMs). Urbanization gradient was defined by environmental predictors reflecting anthropogenic disturbances, for example noise level and human population density, as well as nature‐like features, for example tree cover and open green area. Relevant environmental predictors for each group and relevant spatial resolution were selected a priori using AICc. Arthropod abundances were modelled for the bird sampling transects and included as additional predictor variable in the bird community model. In this model, we used abundances and traits of 66 breeding bird species as response variables.

Results

Bird species responses to urbanization were captured by the interaction between invertebrate abundance and environmental predictors. We identified three groups of birds: the urban group (12 species) showed no decrease in abundance along the urbanization gradient and were not related to arthropods abundance; the woodland group (18 species) were positively related to tree cover and arthropod abundance, also in areas with high anthropogenic disturbance; and the nature group (36 species) were positively related to arthropod abundance, but the species abundance decreased sharply with increasing anthropogenic disturbance. All the non‐trophic associations found within the bird community were positive.

Main conclusions

Arthropod abundance clearly modulated birds’ responses to the urbanization gradient for most species. Especially at moderate levels of anthropogenic disturbance, the abundance of arthropods is key for the occurrence and abundance of bird species in urban areas. To maintain bird diversity in urban green areas, management measures should focus on maintaining and increasing invertebrate abundance.
Puberty and menarche in young females with cerebral palsy and intellectual disability: a qualitative study of caregivers’ experiences
Authors: Gray Susan H , Wylie Molly , Christensen Sinead , Khan Anqa , Williams David , Glader Laurie
Published: October 2020

Aim

To explore experiences of parents of young females with cerebral palsy (CP) and intellectual disability at the onset of puberty.

Method

This was a phenomenological qualitative study. We conducted phone interviews of parents of young females with CP and intellectual disability who had been seen in the CP center at a freestanding children's hospital within the prior 2 years. Inclusion criteria were English‐speaking parents of young females who had combined diagnoses of CP and intellectual disability. Interviews were coded and analyzed by the research team facilitated by Dedoose software.

Results

Nine interviews were conducted with parents of daughters aged 14 to 24 years. All daughters used wheelchairs for mobility and augmentative technology for communication. Despite homogeneity in functional ability, there was marked variation in parental perception of the significance of puberty for their daughters. Families often learned about reproductive health from informal social networks. Although families acknowledged the need for sexual abuse screening, there was little consensus about how to do it, and most denied that their own daughter could ever be abused.

Interpretation

Parents of young females with CP and intellectual disability have diverse reproductive health beliefs that health care providers must explore in order to provide appropriate recommendations for management of puberty.

What this paper adds

Parents of young females with cerebral palsy (CP) and intellectual disability have diverse reproductive health beliefs.

Approaches to menstrual management in this population must be individualized.

Families discounted the likelihood of abuse, despite acknowledging their daughters’ risk.
Graft‐versus‐mastocytosis effect after donor lymphocyte infusion: Proof of principle
Authors: Hägglund Hans , Yavuz Akif Selim , Dreimane Arta , Malm Claes , Sundin Anders , Sander Birgitta , Nilsson Gunnar
Published: October 2020

Advanced systemic mastocytosis is a relatively rare entity where allogeneic stem cell transplantation can lead to the cure of the disease in selected patients. Delayed incomplete responses with graft‐versus‐mastocytosis effect were published in a few cases. In this particular patient's report, we describe the direct evidence and potency of graft‐versus‐mastocytosis effect of donor lymphocyte infusions in a patient with systemic mastocytosis with associated hematological neoplasm (SM‐AHN). In a 53‐year‐old female patient, an allogeneic stem cell transplantation after conventional induction treatment was performed for transformed acute myeloid leukemia (AML) during the course of polycythemia vera. After 6 years of remission period of AML and PV, the patient developed aleukemic mast cell leukemia and JAK2‐positive myeloproliferative neoplasm (SM‐AHN). We were able to achieve a sustained complete remission of SM‐AHN lasting for 6 years with only donor lymphocyte infusions in a status of mixed chimerism. The patient is in a good clinical condition and remission. The potent graft‐versus‐mastocytosis effect in this patient resembles the favorable effect of donor lymphocyte infusions in relapsing chronic myeloid leukemia patients after transplantation. This patient is, to our knowledge, the first case showing the proof of principle of graft‐versus‐mastocytosis effect.
Constraint‐induced movement therapy promotes motor recovery after neonatal stroke in the absence of neural precursor activation
Authors: Adams Kelsey V. , Mahmud Neemat , Green‐Holland Madeline , Vonderwalde Ilan , Umebayashi Daisuke , Sachewsky Nadia , Coles Brenda L. , van der Kooy Derek , Morshead Cindi M.
Published: October 2020

Neonatal stroke is a leading cause of long‐term disability and currently available rehabilitation treatments are insufficient to promote recovery. Activating neural precursor cells (NPCs) in adult rodents, in combination with rehabilitation, can accelerate functional recovery following stroke. Here, we describe a novel method of constraint‐induced movement therapy (CIMT) in a rodent model of neonatal stroke that leads to improved functional outcomes, and we asked whether the recovery was correlated with expansion of NPCs. A hypoxia/ischemia (H/I) injury was induced on postnatal day 8 (PND8) via unilateral carotid artery ligation followed by systemic hypoxia. One week and two weeks post‐H/I, CIMT was administered in the form of 3 botulinum toxin (Botox) injections, which induced temporary paralysis in the unaffected limb. Functional recovery was assessed using the foot fault task. NPC proliferation was assessed using the neurosphere assay and EdU immunohistochemistry. We found that neonatal H/I injury alone expands the NPC pool by >2.5‐fold relative to controls. We determined that using Botox injections as a method to provide CIMT results in significant functional motor recovery after H/I. However, CIMT does not lead to enhanced NPC activation or migration into the injured parenchyma in vivo. At the time of functional recovery, increased numbers of proliferating inflammatory cells were found within the injured motor cortex. Together, these findings suggest that NPC activation following CIMT does not account for the observed functional improvement and suggests that CIMT‐mediated modification of the CNS inflammatory response may play a role in the motor recovery.
Transcriptional frontloading contributes to cross‐tolerance between stressors
Authors: Collins Michael , Clark Melody S. , Spicer John I. , Truebano Manuela
Published: October 2020

The adaptive value of phenotypic plasticity for performance under single stressors is well documented. However, plasticity may only truly be adaptive in the natural multifactorial environment if it confers resilience to stressors of a different nature, a phenomenon known as cross‐tolerance. An understanding of the mechanistic basis of cross‐tolerance is essential to aid prediction of species resilience to future environmental change. Here, we identified mechanisms underpinning cross‐tolerance between two stressors predicted to increasingly challenge aquatic ecosystems under climate change, chronic warming and hypoxia, in an ecologically‐important aquatic invertebrate. Warm acclimation improved hypoxic performance through an adaptive hypometabolic strategy and changes in the expression of hundreds of genes that are important in the response to hypoxia. These ‘frontloaded’ genes showed a reduced reaction to hypoxia in the warm acclimated compared to the cold acclimated group. Frontloaded genes included stress indicators, immune response and protein synthesis genes that are protective at the cellular level. We conclude that increased constitutive gene expression as a result of warm acclimation reduced the requirement for inducible stress responses to hypoxia. We propose that transcriptional frontloading contributes to cross‐tolerance between stressors and may promote fitness of organisms in environments increasingly challenged by multiple anthropogenic threats.
New frontiers in translational research: Touchscreens, open science, and the mouse translational research accelerator platform
Authors: Sullivan Jacqueline A. , Dumont Julie R. , Memar Sara , Skirzewski Miguel , Wan Jinxia , Mofrad Maryam H. , Ansari Hassam Zafar , Li Yulong , Muller Lyle , Prado Vania F. , Prado Marco A. M. , Saksida Lisa M. , Bussey Timothy J.
Published: October 2020

Many neurodegenerative and neuropsychiatric diseases and other brain disorders are accompanied by impairments in high‐level cognitive functions including memory, attention, motivation, and decision‐making. Despite several decades of extensive research, neuroscience is little closer to discovering new treatments. Key impediments include the absence of validated and robust cognitive assessment tools for facilitating translation from animal models to humans. In this review, we describe a state‐of‐the‐art platform poised to overcome these impediments and improve the success of translational research, the Mouse Translational Research Accelerator Platform (MouseTRAP), which is centered on the touchscreen cognitive testing system for rodents. It integrates touchscreen‐based tests of high‐level cognitive assessment with state‐of‐the art neurotechnology to record and manipulate molecular and circuit level activity in vivo in animal models during human‐relevant cognitive performance. The platform also is integrated with two Open Science platforms designed to facilitate knowledge and data‐sharing practices within the rodent touchscreen community, touchscreencognition.org and mousebytes.ca. Touchscreencognition.org includes the Wall, showcasing touchscreen news and publications, the Forum, for community discussion, and Training, which includes courses, videos, SOPs, and symposia. To get started, interested researchers simply create user accounts. We describe the origins of the touchscreen testing system, the novel lines of research it has facilitated, and its increasingly widespread use in translational research, which is attributable in part to knowledge‐sharing efforts over the past decade. We then identify the unique features of MouseTRAP that stand to potentially revolutionize translational research, and describe new initiatives to partner with similar platforms such as McGill's M3 platform (m3platform.org).
Addressing power and scale in resilience programming: A call to engage across funding, delivery and evaluation
Authors: Jones Lindsey , Kuhl Laura , Matthews Nathanial
Published: October 2020

Resilience has recently emerged as a conceptual and operational buzzword spanning every facet of the international development agenda. The rise of resilience provides renewed opportunities for geographers to critically engage with the policy sphere and shape ongoing discourse over the nature of resilience programming. Yet, while aspects of the political economy of resilience have long been acknowledged in both academic and practitioner literatures, scholarly inputs have had limited influence in addressing issues of power and scale as applied directly to resilience programming. In this commentary, we argue that enhanced uptake of geographic enquiry is contingent on geographers being more proactive in engaging with resilience practitioners. One way of doing so is to tailor scholarly inputs to three critical elements of the programmatic cycle, namely how resilience‐building activities are funded, delivered, and evaluated. Using these three facets, we highlight key practical and ethical considerations worthy of further geographic enquiry – focusing on issues of power and scale as concepts at the heart of geography.
Ethnic identity and local government responsiveness in Taiwan
Authors: Newland Sara A. , Liu John Chung‐En
Published: October 2020

Countless studies have shown that local officials are less responsive to ethnic minority citizens. Surprisingly, we find no similar pattern of discrimination by Taiwanese local officials. In an online contacting experiment, we send citizen service requests to the websites of 358 township and district chiefs, randomly varying the name of the putative citizen to reflect an indigenous or an ethnically Chinese identity and collecting data on officials' responses. We find that officials are equally responsive to both identities. Drawing on in‐depth interviews and nonparticipant observation in government service centers, we attribute this surprising finding to institutional elements of Taiwan's local bureaucracy that limit the impact of individual‐level bias. However, our research provides preliminary evidence that local governments are generally less responsive in indigenous areas. While clearly defined procedures may prevent discrimination against indigenous individuals, interregional differences in local state capacity can nonetheless produce unequal experiences with local governance.