bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I randomized, double‐blind, single subcutaneous dose escalation study to determine the safety, tolerability, and pharmacokinetics of rezafungin in healthy adult subjects
Authors: Gu Kenan , Ruff Dennis , Key Cassandra , Thompson Marissa , Jiang Shoshanna , Sandison Taylor , Flanagan Shawn
Published: April 2022

Rezafungin is a novel echinocandin being developed for the treatment and prevention of invasive fungal infections. The objectives of this randomized, double‐blind study in healthy adults were to determine the safety, tolerability, and pharmacokinetics of rezafungin after subcutaneous (s.c.) administration. The study design consisted of six sequential cohorts of eight subjects, except for the first cohort with four subjects. The subjects were randomized in a 3:1 ratio of rezafungin to placebo and were to receive a single dose of 1, 10, 30, 60, 100, or 200 mg. The most common adverse events (AEs) were increased alanine aminotransferase and sinus bradycardia (unsolicited) and erythema at the injection site (solicited). Unsolicited AEs were generally mild to moderate and not rezafungin‐related. Although the study was terminated after the 10 mg dose cohort due to concerns of potential increased severity of injection site reactions, no predetermined dose escalation halting criteria were met. Following the 10 mg single s.c. dose of rezafungin (n = 6), the geometric mean (GM) maximum concentration (Cmax) was 105.0 ng/ml and the median time to Cmax was 144 h. The GM area under the concentration‐time curve was 32,770 ng*h/ml. The median estimated terminal half‐life was 193 h. The GM apparent oral clearance was 0.255 L/h and the GM apparent volume of distribution was 68.5 L. This study demonstrates that a single s.c. dose of rezafungin in healthy adult subjects: (1) did not result in serious AEs, death, or withdrawal from the study due to an AE; and (2) produced a pharmacokinetic profile with long exposure period postadministration. In an effort to reduce the occurrence of injection site reactions, a re‐evaluation of the rezafungin s.c. formulation could be considered in the future.
Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension
Authors: Wilding John P. H. , Batterham Rachel L. , Davies Melanie , Van Gaal Luc F. , Kandler Kristian , Konakli Katerina , Lingvay Ildiko , McGowan Barbara M. , Oral Tugce Kalayci , Rosenstock Julio , Wadden Thomas A. , Wharton Sean , Yokote Koutaro , Kushner Robert F. ,   STEP 1 Study Group
Published: April 2022

Aim

To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension.

Materials and Methods

STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m2 (or ≥ 27 kg/m2 with ≥ 1 weight‐related co‐morbidity) without diabetes to 68 weeks of once‐weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off‐treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory.

Results

Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables.

Conclusions

One year after withdrawal of once‐weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two‐thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.
The irony of sectarianism: Sectarianizing by desectarianizing in Syria
Authors: Menshawy Mustafa
Published: April 2022

The study seeks to resolve a conundrum in Syrian politics: the ruling regime has always claimed and celebrated a harmonious social fabric, national unity, and a long‐standing tradition of coexistence despite the prevalence of an opposite grim reality marked by sectarian divisions and factionalism which the regime itself mainly created or sustained. I explore the process of acting “as if not” by analyzing the speeches of Syria's President Bashar al‐Assad since the eruption of the conflict in 2011, a period when the country has been buffeted by extreme sectarian waves. The process shows how Assad has constructed a process of desectarianization based on repetition, frequency, and resonance of specific frames in his speeches, and also based on building an image of an idealized present of internal unity and integration. The process includes externalizing sectarianization as a “western” import and emphasizing the regime's ideologies of pan‐Arab nationalism and secularism as bulwarks against it. Furthermore, the Assad regime has taken credit as a “desectarianization guardian” in different ways including maintaining the status quo and consolidating the impression of his active positive leadership drawn on taking the country down the path of unity and solidarity. However, ironically, desectarianization has also entrenched the very sectarian practices which it claimed its mission to stand against. Sectarianisation and desectarianization are both sides of the same coin in Syria's politics of authoritarianism.
Solidifying identity discourse through the politicized monumentation of struggle
Authors: Panossian Vicky
Published: April 2022

This article investigates contemporary examples of monumentation and the extent to which they solidify and reproduce a politicized discourse on identities. Focusing predominantly on the representation of refugees and migrants, the article is broken down into four sections, the first of which looks into the challenges of monumentation and the discourse it represents. The second part includes three case studies, each representing a different vestige of the struggle with the discourse propagated by certain monuments. The core of the argument concerns the parameters of social representation of the suffering subject, be it the refugee, the asylum seeker, their mother, or the colonial subject. I propose an adaptation of Fairclough's model of language and power to include monuments as replicas of texts which can be analyzed at word, discursive and social levels.
Green vehicle routing problem: Metaheuristic solution with time window
Authors: Prakash Ravi , Pushkar Shashank
Published: April 2022

The aim of a Green Vehicle Routing Problem is to find an optimal route for alternative fuel vehicles to minimize the overall travelling distances while reducing energy consumption and CO2emissions. In this problem each vehicle handles a subset of customers/orders, leaving from and returning to the depot, with respect to maximum distance travelled, while minimizing energy consumptions. We proposed a time window‐based GVRP solution (GVRP‐TW) with exact routing approach. Wherein, each route serves a subset of customers/orders with minimum intermediate refuelling/recharges. To test our method, we conducted experiments using MATLAB software on a set of three reference problem specimens (C‐101, R‐101 and RC‐11). Our approach, evaluated on these benchmark problems, par exceeds in performance in relation to the existing VRP methods (like tabu search, variable neighbourhood search, and GRASP). Moreover, the proposed GVRP‐TW can be further optimized to solve other VRP problems with energy minimisations and less intermediate stops.
“It brought my family more together”: Mixed‐methods study of low‐income U.S. mothers during the pandemic
Authors: Haskett Mary E. , Hall Jodi K. , Finster Heather P. , Owens Caitlyn , Buccelli Alexandra R.
Published: April 2022

Objective

We sought to understand challenges and positive experiences of low‐income families during the pandemic.

Background

Strength‐based perspectives of economically disadvantaged mothers are missing from literature on the impact of the COVID‐19 pandemic. Although it is imperative to recognize disparities that were highlighted by the pandemic, strengths‐based approaches and a resilience framework can help professionals build upon and learn from ways families manage during those times.

Method

We used a mixed‐method approach to gain understanding of the unique experiences of 15 low‐income mothers at the height of the pandemic. We administered a brief COVID‐19 stress screener, the Five‐Minute Speech Sample measure, and an open‐ended question about potential positive experiences during the pandemic.

Results

We learned that strength and resilience supersede the liabilities brought on by COVID‐19 that are so often focused on. We found highly divergent experiences across mothers in terms of stress; even mothers with high levels of stress readily identified positive aspects of life during the pandemic. Mothers' responses were indicative of greater feelings of warmth and tenderness than negativity about their children.

Conclusion and Implications

We discuss findings in terms of strengths‐based practices and policies for mothers receiving public assistance and provide suggestions for continued research on resilience of mothers during the pandemic.
Cohesive analysis of a 3D benchmark for delamination growth under quasi‐static and fatigue loading conditions
Authors: Raimondo Antonio , Dávila Carlos G. , Bisagni Chiara
Published: April 2022

This paper evaluates the capabilities of the recently developed CF20 cohesive fatigue model, which can predict crack initiation as well as the rates of crack propagation by relying on intrinsic relationships between a stress‐life diagram and its corresponding Paris law. The model is validated here using a partially reinforced double cantilever beam (R‐DCB) benchmark proposed in literature. The two parameters needed for the CF20 cohesive fatigue model were obtained by performing preliminary analyses of a conventional DCB. The analysis results indicate that the CF20 cohesive fatigue model can accurately reproduce the complex evolution of the delamination observed in the R‐DCB.
Hydrodynamic connectivity and dispersal patterns of a transboundary species (Pagellus bogaraveo) in the Strait of Gibraltar and adjacent basins
Authors: Nadal Irene , Sammartino Simone , García‐Lafuente Jesús , Sánchez Garrido José C. , Gil‐Herrera Juan , Hidalgo Manuel , Hernández Pilar
Published: April 2022

The blackspot seabream (Pagellus bogaraveo) is a benthopelagic fish species highly appreciated by consumers and an important target of the Spanish and Moroccan fisheries in the transcontinental waters of the Strait of Gibraltar area. It is also one of the most exploited resources of the region, which has led to a situation of overexploitation and a notable drop of catches. To gain insight into the sustainability of this resource and certain patterns of the spatial adaptation of the species, a high‐resolution circulation model coupled to a Lagrangian tracking module has been employed to investigate the dispersal pathways of blackspot seabream, using eggs and larvae (early‐life‐stages, ELS) as purely passive particles advected by currents. Several spawning scenarios consisting of different spatial (depths and sites) and temporal (tidal phase and strength) initial conditions have been analyzed to identify the most likely pathways of ELS dispersion. Eastward transport by the Atlantic Jet exiting the Strait of Gibraltar is the most influencing process in that dispersion. Regarding temporal fluctuations, fortnightly tidal modulation is the prevailing factor to determine the horizontal paths of the ELS, spring tides being the cause of the greatest scattering of propagules. Spawning depth in the Strait of Gibraltar is a critical condition, as revealed by the model sensitivity tests. Potential implications of the results of the study to improve the assessment and management of this species are discussed.
Winter conditions structure extratropical patterns of species richness of amphibians, birds and mammals globally
Authors: Gudex‐Cross David , Zhu Likai , Keyser Spencer R. , Zuckerberg Benjamin , Pauli Jonathan N. , Radeloff Volker C.
Published: April 2022

Aim

The aim was to derive global indices of winter conditions and examine their relationships with species richness patterns outside of the tropics.

Location

All extratropical areas (>25° N and 25° S latitudes), excluding islands.

Time period

2000–2018.

Major taxa studied

Amphibians, birds and mammals.

Methods

We mapped three global indices of winter conditions [number of days of frozen ground (length of frozen ground winter); snow cover variability; and lack of subnivium (below‐snow refuge)] from satellite data, then used generalized additive models to examine their relationships with species richness patterns derived from range data.

Results

Length of frozen ground winter was the strongest predictor of species richness, with a consistent cross‐taxonomic decline in species richness occurring beyond 3 months of winter. It also often outperformed other environmental predictors of species richness patterns commonly used in biodiversity studies, including climate variables, primary productivity and elevation. In areas with ≥3 months of winter conditions, all three winter indices explained much of the deviance in amphibian, mammal and resident bird species richness. Mammals exhibited a stronger relationship with snow cover variability and lack of subnivium than the other taxa. Species richness of fully migratory species of birds peaked at c. 5.5 months of winter, coinciding with low species richness of residents.

Main conclusions

Our study demonstrates that winter structures latitudinal and elevational gradients of extratropical terrestrial species richness. In a rapidly warming world, tracking the seasonal dynamics of frozen ground and snow cover will be essential for predicting the consequences of climate change on species, communities and ecosystems. The indices of winter conditions we developed from satellite imagery provide an effective means of monitoring these dynamics into the future.
Morphological spectrum and molecular features of somatic malignant transformation in germ cell tumours
Authors: Lobo João , Rodrigues Ângelo , Henrique Rui , Christiansen Ailsa , Beyer Jörg , Moch Holger , Bode Peter Karl
Published: April 2022

Aims

Somatic malignant transformation (SMT) arising in germ cell tumours (GCTs) is an infrequent, but clinically relevant event. There is only limited knowledge on the morphological spectrum of SMT, and the therapeutic management of these patients is poorly defined. In this work we revisit two consecutive case series (n = 756) of GCTs. Clinicopathological data of SMTs arising in GCTs were determined, with a focus on the histopathological spectrum, and molecular aspects were obtained by Fluorescence in situ Hybridization (FISH) and Next Generation Sequencing (NGS).

Methods and Results

Thirty male patients (28 primary testicular, two primary extragonadal) were included. These patients represent 4% of GCT patients diagnosed at two institutes (University Hospital Zurich and IPO Porto). The most common SMTs were adenocarcinoma (n = 8), embryonic‐type neuroectodermal tumours (ENETs, n = 8), and rhabdomyosarcoma (n = 6), but a wide range of challenging morphologies were depicted, including low‐grade neuroglial tumour, adenosquamous carcinoma, neuroblastoma, and neuroendocrine carcinoma. SMT was found in 15 primary tumour samples and in 27 metastatic samples of these 30 patients, the latter showing poorer overall survival. Adenocarcinoma occurred only in metastasis postchemotherapy and in one primary retroperitoneal GCT with SMT, but not in GCT of the testis. The 12p gains were identified by FISH in all cases. NGS results were available in six patients. Clinical trials and/or targeted treatments based on the molecular profile of SMT were recommended in four patients.

Conclusions

SMT arising in GCTs represent a diagnostic challenge and should be confirmed by a specialized uropathologist. NGS‐based treatment recommendations may improve the outcome of these patients.
Exploring perceived challenges of self‐management in low‐income older people with hypertension: A qualitative study
Authors: Zhang Meng , Liu Yu , Zhang Wen‐Yan , Yang Jiang‐Guo , Yang Wei‐Mei , Zhou Jing , Mao Zhong‐Min
Published: April 2022

Background

Hypertension is a public health problem globally. Understanding the perceived challenges of low‐income older people populations with chronic disease is an obstacle the world is facing today.

Aim

To explore perceived challenges of self‐management in low‐income older people with hypertension.

Methods

Data were collected in three communities from September 2019 to October 2019 by semi‐structured interviews. Interviews were audio‐taped by digital voice recorder and analysed according to Colaizzi's seven steps.

Results

Participants demonstrated perceived challenges concerning hypertension self‐management. Six themes were identified: hypertension belief bias, family dysfunction, deep‐rooted habit, elder self‐neglect, medical informatization and supportive health policy. Each theme was identified with several subthemes.

Conclusions

Findings implied that most of the low‐income older people lacked self‐management behaviours. Future research is needed to address perceived challenges related to self‐management behaviour for patients with hypertension worldwide.
One ‘welfare recipient’ stereotype or many? Using the stereotype content model to examine the stereotypes of different categories of benefit recipients
Authors: Schofield Timothy , Suomi Aino , Butterworth Peter
Published: April 2022

The stereotype content model (SCM) provides a basis to investigate stereotypes of different social groups. Previous SCM research has shown that the “welfare recipients” are stereotyped negatively, with low warmth and low competence. However, prior research has not considered different categories of income support recipients who may be stereotyped differently. Using the SCM, we investigated the stereotypes held by the Australian general population (n = 807) towards five key social groups (unemployed, people with a mental disability, people with a physical disability, single parents, elderly). People with a mental or physical disability and the elderly were similar regardless of whether they were described as receiving income support payments or not. In contrast, the unemployed and single parents were stereotyped with significantly lower levels of warmth and competence when they were receiving payments. This research shows that the needs and circumstances of different groups may be reflected in different levels of community support.
A nomogram for predicting post‐operative wound complications after open reduction and internal fixation for calcaneal fractures
Authors: Hu Wei , Huang Chengbin , Zhang Yingying , Wang Xingyu , Jiang Yanshu
Published: April 2022

The purpose of our study was to determine the risk factors for post‐operative wound complications (PWCs) after open reduction and internal fixation (ORIF) for calcaneal fracture and establish a nomogram prediction model. We retrospectively analysed the clinical data of patients who suffered from calcaneal fractures and had been surgically treated for ORIF in our institution between January 2010 and January 2020. Perioperative information was obtained through the electronic medical record system, univariate and multivariate analyses were performed to determine the risk factors of PWCs, and a nomogram model was constructed to predict the risk of PWCs. The predictive performance and consistency of the model were evaluated by the Hosmer –Lemeshow (H‐L) test and the calibration curve. In total, 444 patients were enrolled in our study. Multivariate analysis results showed that smoking, limb swelling, angle of incision, and CRP were independent risk factors for skin necrosis. The AUC value for skin necrosis risk was 0.982 (95%CI 0.97‐0.99). The H‐L test revealed that the normogram prediction model had good calibration ability (P = .957). Finally, we found a correlation between PWCs and smoking, limb swelling, angle of incision, and CRP after ORIF for calcaneal fracture patients. Our nomogram prediction model might be helpful for clinicians to identify high‐risk patients, as interventions could be taken early to reduce the incidence of PWCs.
Dispersal and habitat dynamics shape the genetic structure of the Northern chamois in the Alps
Authors: Leugger Flurin , Broquet Thomas , Karger Dirk Nikolaus , Rioux Delphine , Buzan Elena , Corlatti Luca , Crestanello Barbara , Curt‐Grand‐Gaudin Nadine , Hauffe Heidi Christine , Rolečková Barbora , Šprem Nikica , Tissot Nathalie , Tissot Sophie , Valterová Radka , Yannic Glenn , Pellissier Loïc
Published: April 2022

Aim

Understanding the drivers of species distribution ranges and population genetic structure can help predict species' responses to global change, while mitigating threats to biodiversity through effective conservation measures. Here, we combined species habitat suitability through time with process‐based models and genomic data to investigate the role of landscape features and functional connectivity in shaping the population genetic structure of Northern chamois.

Location

European Alps.

Taxon

Northern chamois (Rupicapra rupicapra).

Methods

Using a model that simulates dispersal and tracks the functional connectivity of populations over dynamic landscapes, we modelled the response of the chamois to climate change from the last glaciation (20,000 years ago) to the present. We reconstructed species habitat suitability and landscape connectivity over time and simulated cumulative divergence of populations as a proxy for genetic differentiation. We then compared simulated divergence with the actual population structure of 449 chamois (with >20 k SNPs) sampled across the Alps.

Results

We found that Alpine populations of chamois are structured into two main clades, located in the south‐western and the eastern Alps. The contact zone between the two lineages is located near the Rhone valley in Switzerland. Simulations reproduced the geographic differentiation of populations observed in the genomic data, and limited dispersal ability and landscape connectivity co‐determined the fit of the simulations to data.

Main conclusions

The contemporary genetic structure of the chamois across the Alps is explained by limited functional connectivity in combination with large rivers or valleys acting as dispersal barriers. The results of our analysis combining simulations with population genomics highlight how biological characteristics, habitat preference and landscapes shape population genetic structure over time and in responses to climate change. We conclude that spatial simulations could be used to improve our understanding of how landscape dynamics, shaped by geological or climatic forces, impact intra‐ and interspecific diversity.
The impact of hospital case volume on the outcomes after catheter ablation for atrial fibrillation according to the ablation technology
Authors: Kanaoka Koshiro , Nishida Taku , Nishioka Yuichi , Myojin Tomoya , Kubo Shinichiro , Soeda Tsunenari , Okada Katsuki , Noda Tatsuya , Iwanaga Yoshitaka , Miyamoto Yoshihiro , Sakata Yasushi , Imamura Tomoaki , Saito Yoshihiko
Published: April 2022

Introduction

The appropriate hospital case volume for catheter ablation (CA) in patients with atrial fibrillation (AF) according to the ablation technology has not been fully examined. This study aimed to investigate the association between the hospital case volume for AF and periprocedural complications and AF recurrence.

Methods

In this retrospective cohort study, we used data from the National Database of Health Insurance Claims and Specific Health Checkups, which covers almost all healthcare insurance claims data in Japan. We included patients with AF who underwent first‐time CA from April 2014 to March 2020. Using mixed‐effect logistic regression, we analyzed the effect of the annual case volume for AF ablation on acute periprocedural complications and 1‐year success rate off antiarrhythmic drugs according to the ablation technology (radiofrequency ablation or cryoballoon ablation).

Results

Among 270 116 patients, 207 839 (77%) patients underwent radiofrequency ablation and 56 648 (21%) patients underwent cryoballoon ablation. Of all patients, acute complications occurred in 5411 (2.0%) patients, and the recurrence at 1 year was 71 511 (27%). In the radiofrequency ablation group, acute complications and 1‐year AF recurrence according to case volume decreased as the annual case volume increased to up to 150−200 cases/year. However, in the cryoballoon ablation group, these outcomes were similar regardless of the case volumes.

Conclusion

The case‐volume effect was noted in the radiofrequency ablation group, but not in the cryoballoon ablation group. Our results may affect the selection of ablation technology, especially in smaller case‐volume hospitals.
Insurance lesions: Does a second lesion make a difference?
Authors: Toloczko Alexandra , Buchan Skylar , John Mathews , Post Allison , Razavi Mehdi
Published: April 2022

Introduction

In radiofrequency ablation procedures for cardiac arrhythmia, the efficacy of creating repeated lesions at the same location (“insurance lesions”) remains poorly studied. We assessed the effect of type of tissue, power, and time on the resulting lesion geometry during such multiple ablation procedures.

Methods

A custom ex vivo ablation model was used to assess lesion formation. An ablation catheter was oriented perpendicular to the tissue and used to create lesions that varied by type of tissue (atrial or ventricular free wall), power (30 or 50 W), and time (30, 40, or 50 s for standard ablations and 5, 10, or 15 s for high‐power, short‐duration [HPSD] ablations). Lesion dimensions were recorded and then analyzed. Radiofrequency ablations were performed on 57 atrial tissue samples (28 HPSD, 29 standard) and 28 ventricular tissue samples (all standard).

Results

With ablation parameters held constant, performing multiple ablations significantly increased lesion depth in ventricular tissue when ablations were performed at 30 W for 50 s. No other set of ablation parameters was shown to affect the width or depth of the resulting lesions in either tissue type.

Conclusion

Multiple ablations created with the same power and time, delivered within 30 s of each other at the same exact location, offer no meaningful benefit in lesion depth or width over single ablations, with the exception of ventricular ablation at 30 W for 50 s. Given the risks associated with excessive ablation, our results suggest that this practice should be re‐evaluated by clinical electrophysiologists.
Alexithymia in individuals maltreated as children and adolescents: a meta‐analysis
Authors: Khan Anika N. , Jaffee Sara R.
Published: April 2022

Background

Children who are maltreated show deficits in emotion recognition, expression, and understanding. The goal of the current meta‐analysis was to determine the degree to which maltreatment is associated with deficits in the ability to recognize one’s own emotions – a phenomenon known as alexithymia. Alexithymia may be a mechanism explaining the association between childhood maltreatment and various psychological disorders.

Methods

This meta‐analytic review (88 studies, n = 43,076) examined the association between the experience of childhood maltreatment and alexithymia, mainly in adulthood. Additional meta‐analyses were run to examine if the strength of the association between maltreatment as a child and alexithymia varied as a function of the type of maltreatment individuals reported and other moderators.

Results

We found significant small effect sizes for all models, indicating higher levels of maltreatment in childhood or adolescence were associated with higher levels of alexithymia. Alexithymia was more strongly associated with forms of neglect than with physical or sexual abuse. The effect sizes also increased as the percentages of females in the sample increased.

Conclusions

Results suggest that researchers should examine whether alexithymia is a transdiagnostic mechanism in the association between childhood maltreatment and psychopathology and whether targeting alexithymia in treatment could reduce a wide range of symptoms.
Carbon‐film‐based Zernike phase plates with smooth thickness gradient for phase‐contrast transmission electron microscopy with reduced fringing artefacts
Authors: Obermair M. , Hettler S. , Dries M. , Hugenschmidt M. , Spiecker R. , Gerthsen D.
Published: April 2022

Phase plates (PPs) in transmission electron microscopy (TEM) improve the contrast of weakly scattering objects under in‐focus imaging conditions. A well‐established PP type is the Zernike (Z)PP, which consists of a thin amorphous carbon (aC) film with a microscaled hole in the centre. The mean inner potential of the aC film is exploited to shift the phase of the scattered electrons while the unscattered electrons in the zero‐order beam propagate through the hole and remain unaffected. However, the abrupt thickness increase at the hole edge induces an abrupt change of the phase‐shift distribution and leads to fringing, that is, intensity oscillations around imaged objects, in TEM images. In this work, we have used focused‐ion‐beam milling to fabricate ZPPs with abrupt and graded thickness profiles around the centre hole. Depending on the thickness gradient and inner hole radius, graded‐ZPP‐TEM images of an aC/vacuum interface and bundles of carbon nanotubes (CNTs) show strongly reduced fringing. Image simulations were performed with ZPP‐phase‐shift distributions derived from measured thickness profiles of graded ZPPs, which show good agreement with the experimental images.

Fringing artefacts, that is, intensity oscillations around imaged objects, are strongly reduced for Zernike phase plates with a graded thickness profile around the centre hole.

Focused‐ion‐beam milling is used to fabricate graded Zernike phase plates with specific inner hole radius and thickness gradients.

The phase‐shift distribution is obtained from measured thickness profiles around the centre hole.

Image simulations based on experimentally measured thickness/phase‐shift distributions show good agreement with experimental Zernike phase‐plate TEM images.
Hedgehog signaling plays a crucial role in hyperalgesia associated with neuropathic pain in mice
Authors: Okuda Hiroaki , Ishikawa Tatsuya , Hori Kiyomi , Kwankaew Nichakarn , Ozaki Noriyuki
Published: April 2022

Neuropathic pain is a debilitating chronic syndrome of the nervous system caused by nerve injury. InDrosophila, the Hedgehog (Hh) signaling pathway is related to increased pain sensitivity (hyperalgesia) but does not affect the baseline nociceptive threshold. In general, the contribution of the Hh signaling pathway to neuropathic pain in vertebrates is a highly debated issue. Alternatively, we investigated the potential role of Hh signaling in mechanical allodynia using a mouse model of neuropathic pain. Seven days after spinal nerve‐transection (SNT) surgery, microglial activation increased in the ipsilateral spinal dorsal horn compared with that in the sham group; however, 21 days after surgery, microglial activation decreased. Contrastingly, astrocyte activation in the spinal cord did not differ between the groups. On day 21 of postsurgery, the SNT group showed marked upregulation of sonic hedgehog expression in peripheral glial cells but not in dorsal root ganglion (DRG) neurons. Intrathecal administration of the Hh signaling inhibitor vismodegib attenuated the mechanical allodynia observed on day 21 postsurgery. Conversely, intrathecal treatment with the Hh signaling activator smoothened agonist in naive mice induced mechanical allodynia, which was abolished by the ATP transporter inhibitor clodronate. Moreover, inhibition of Hh signaling by pretreatment with vismodegib significantly reduced ATP secretion and the frequency/number of spontaneous elevations of intracellular calcium ion levels in cultured DRG cells. Thus, the Hh signaling pathway appears to modulate the neural activity of DRG neurons via ATP release, and it plays an important role in sustaining mechanical allodynia and hypersensitivity in a mouse model of neuropathic pain.

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Machine learning prediction models for postpartum depression: A multicenter study in Japan
Authors: Matsuo Seiko , Ushida Takafumi , Emoto Ryo , Moriyama Yoshinori , Iitani Yukako , Nakamura Noriyuki , Imai Kenji , Nakano‐Kobayashi Tomoko , Yoshida Shigeru , Yamashita Mamoru , Matsui Shigeyuki , Kajiyama Hiroaki , Kotani Tomomi
Published: April 2022

Aim

Postpartum depression (PPD) and perinatal mental health care are of growing importance worldwide. Here we aimed to develop and validate machine learning models for the prediction of PPD, and to evaluate the usefulness of the recently adopted 2‐week postpartum checkup in some parts of Japan for the identification of women at high risk of PPD.

Methods

A multicenter retrospective study was conducted using the clinical data of 10 013 women who delivered at ≥35 weeks of gestation at 12 maternity care hospitals in Japan. PPD was defined as an Edinburgh Postnatal Depression Scale score of ≥9 points at 4 weeks postpartum. We developed prediction models using conventional logistic regression and four machine learning algorithms based on the information that can be routinely collected in daily clinical practice. The model performance was evaluated using the area under the receiver operating characteristic curve (AUROC).

Results

In the machine learning models developed using clinical data before discharge, the AUROCs were similar to those in the conventional logistic regression models (AUROC, 0.569–0.630 vs. 0.626). The incorporation of additional 2‐week postpartum checkup data into the model significantly improved the predictive performance for PPD compared to that without in the Ridge regression and Elastic net (AUROC, 0.702 vs. 0.630 [p < 0.01] and 0.701 vs. 0.628 [p < 0.01], respectively).

Conclusions

Our machine learning models did not achieve better predictive performance for PPD than conventional logistic regression models. However, we demonstrated the usefulness of the 2‐week postpartum checkup for the identification of women at high risk of PPD.
Where did it hit harder? Understanding the geography of excess mortality during the COVID‐19 pandemic
Authors: Díaz Ramírez Marcos , Veneri Paolo , Lembcke Alexander C.
Published: April 2022

The health impact of the COVID‐19 pandemic across OECD (Organisation for Economic Co‐operation and Development) and European regions has been strikingly uneven. In 2020, excess mortality rates in the hardest‐hit regions were, on average, 17 percentage points higher than those in the least affected regions of the same country. This paper shows that low health system capacity, followed by population density, air pollution, the share of elderly people, and low institutional quality were associated with higher excess mortality during the first year of the pandemic. Finally, reduced home‐to‐work mobility, following governments' COVID‐19 responses, was associated with lower excess mortality 2 months after implementation of the measures.
Expert recommendations for prevention and management of Candida auris transmission
Authors: Aldejohann Alexander Maximilian , Wiese‐Posselt Miriam , Gastmeier Petra , Kurzai Oliver
Published: April 2022

Candida auris was first described as a yeast pathogen in 2009. Since then, the species has emerged worldwide. In contrast to most other Candida spp., C. auris frequently exhibits multi‐drug resistance and is readily transmitted in hospital settings. While most detections so far are from colonised patients, C. auris does cause superficial and life‐threatening invasive infections. During management of the first documented C. auris transmission in a German hospital, experts from the National Reference Centers for Invasive Fungal Infections (NRZMyk) and the National Reference Center for Surveillance of Nosocomial Infections screened available literature and integrated available knowledge on infection prevention and C. auris epidemiology and biology to enable optimal containment. Relevant recommendations developed during this process are summarised in this guidance document, intended to assist in management of C. auris transmission and potential outbreak situations. Rapid and effective measures to contain C. auris spread require a multi‐disciplinary approach that includes clinical specialists of the affected unit, nursing staff, hospital hygiene, diagnostic microbiology, cleaning staff, hospital management and experts in diagnostic mycology / fungal infections. Action should be initiated in a step‐wise process and relevant interventions differ between management of singular C. auris colonised / infected patients and detection of potential C. auris transmission or nosocomial outbreaks.
Interstate Arbitration: “… Settling Disputes Which Diplomacy Has Failed to Settle”
Authors: Salacuse Jeswald W.
Published: April 2022

The subject of interstate arbitration has been largely neglected in the field of international relations, often dismissed as merely an obscure legal process. Drawing on numerous cases, this article argues that interstate arbitration has been a significant strategic factor in settling important international disputes and that its merit as a dispute resolution method should be evaluated not only on the basis of arbitrators’ decisions alone but also on its impact on the underlying diplomatic process between disputants. The author examines the nature of interstate arbitration, traces its historical development, outlines its contemporary processes, and proposes a framework explaining how and when it may be applied to international conflicts between states.
COVID‐19 death and kidney disease in a multiracial Asian country
Authors: Goh Bak Leong , Shanmuganathan Malini , Peariasamy Kalaiarasu , Misnan Nor Arisah , Chidambaram Suresh Kumar , Wong Eddie Fook Sem , Pathmanathan Mohan Dass , Ang Kim Liong , Wong Hin Seng , Yeap Lena Lay Ling
Published: April 2022

Introduction

COVID‐19 infection and kidney disease (KD) carry a considerable risk of mortality. Understanding predictors of death and KD may help improve management and patient outcome.

Methods

This is a prospective multicentre observational study conducted in a multiracial Asian country to identify predictors of death and acute kidney injury (AKI) in hospitalized COVID‐19 patients from January to June 2020.

Results

A total of 6078 patients were included in this study. Mean age was 37.3 (±16.8) years, 71% were male, 59.4% Malay, 6.7% Chinese, 2.3% Indian and 31.7% other ethnicities. AKI was seen in 3.5% of patients while 1.6% had pre‐existing chronic kidney disease (CKD). Overall case fatality rate (CFR) was 1.3%. Patients with KD (AKI and CKD) had CFR of 20%. Many factors were associated with increased risk of death and AKI. However, significant predictors of death after adjustment for covariates were age (>70 years), Chinese ethnicity, diabetes mellitus (DM) and KD. Adjusted predictors of AKI were age (>51 years), DM and severity at presentation. Chinese were 2.58 times more likely to die (p = .036) compared to Malay. Centre capacity to manage, ventilate and dialyze patients significantly influenced death. Among those with AKI, the most common symptoms were fever, cough, and dyspnea. They had lower absolute lymphocyte count, were more likely to be admitted to ICU, required more ventilation and longer hospitalization.

Conclusion

Patient and centre factors influence death and AKI among COVID‐19 patients. This study also demonstrates death disparities across different racial groups and centre capacities in this multiracial Asian country.
Preliminary experience of permanent left bundle branch area pacing using stylet‐directed pacing lead without delivery sheath
Authors: Sun Yaxun , Yao Xiaofeng , Zhou Xiang , Jiang Chenyang , Zhang Jiefang , Sheng Xia , Wang Min , Yang Ying , Pan Yiwen , Su Lan , Chen Xueying , Fu Guosheng
Published: April 2022

Background

Left bundle branch area pacing (LBBAP) aims to capture the cardiac conduction system in area of the left bundle branch. Currently, LBBAP is mainly performed using lumen‐less pacing leads (LLLs) with preshaped sheath. However, the data on LBBAP with stylet‐driven leads (SDLs) without sheath is limited.

Objective

This study presents the feasibility, safety, and pacing characteristics of LBBAP using SDLs without the support of sheath.

Methods

A total of 25 patients with bradycardia indications who received LBBAP implantation with an attempt of SDL (FINELINE II 4471 lead, Boston Scientific, MA, US) between August 2020 and April 2021 at Sir Run Run Shaw Hospital were included in this retrospective cohort study. Twenty of them finally were paced with SDL in priority (SDL‐LBBAP group). Twenty propensity score matching patients who underwent LBBAP with LLL (Select Secure 3830 lead, Medtronic, MN, US) and 20 right ventricular septal pacing (RVSP) with regular active fixation lead respectively in the same period (the LLL‐LBBAP group and RVSP group) were compared using ECG characteristics, pacing parameters and complications during 6‐month follow‐up.

Results

LBBAP was successful with SDL in 23 of 25 patients (92%) and 20 of them were paced with SDL first. In the SDL‐LBBAP group, the average age was 70.4 ± 8.2 years, and 55% of patients were male. Paced QRS duration and the stimulus to peak left ventricular activation time (Sti‐LVAT) in SDL‐LBBAP group were similar with those in LLL‐LBBAP group and significantly shorter than those in RVSP group (126.1±14.1 ms vs. 124.8±10.9 ms, p = 1.00; 77.7 ± 11.2 ms vs. 73.5 ± 9.3 ms, P = .75; 126.1 ± 14.1 ms vs. 147.7 ± 22.5 ms, P<.001; 77.7 ± 11.2 ms vs. 97.0 ± 13.2 ms, P<.001). The pacing threshold and R‐wave amplitude of SDL‐LBBAP group were 0.53 ± 0.18V and 11.53 ± 3.63 mV at baseline respectively, which were comparable with the other two groups. During the 6‐month follow‐up, the pacing parameters remained stable and no lead‐related complications were recorded.

Conclusion

It is feasible and safe to use stylet‐directed pacing lead for permanent LBBAP without a delivery sheath. Similar to LLL, LBBAP using SDL showed stable parameters and narrower paced QRS duration compared with RVSP, which could be an alternative to LLL in LBBAP.
Imagination in science
Authors: Murphy Alice
Published: April 2022

While discussions of the imagination have been limited in philosophy of science, this is beginning to change. In recent years, a vast literature on imagination in science has emerged. This paper surveys the current field, including the changing attitudes towards the scientific imagination, the fiction view of models, how the imagination can lead to knowledge and understanding, and the value of different types of imagination. It ends with a discussion of the gaps in the current literature, indicating avenues for future research.
Maternal periconceptional alcohol consumption and gastroschisis in the National Birth Defects Prevention Study, 1997–2011
Authors: Fisher Sarah C. , Howley Meredith M. , Romitti Paul A. , Desrosiers Tania A. , Jabs Ethylin Wang , Browne Marilyn L. ,   the National Birth Defects Prevention Study
Published: April 2022

Background

Gastroschisis is particularly prevalent among offspring of young women and has increased over recent decades. Although previous studies suggest that maternal alcohol consumption is associated with increased gastroschisis risk, none have explored whether maternal age modifies that association.

Objective

The objective of the study was to evaluate associations between self‐reported maternal periconceptional alcohol consumption (1 month prior through the third month after conception) and risk of gastroschisis among offspring, by maternal age.

Methods

We used data from the National Birth Defects Prevention Study (NBDPS), a multi‐site population‐based case‐control study. The analysis included 1450 gastroschisis cases and 11,829 unaffected liveborn controls delivered during 1997–2011 in ten US states. We estimated adjusted odds ratios (aOR) and 95% confidence intervals (CI) for the individual and joint effects of alcohol consumption and young maternal age at delivery (<25 years vs ≥25 years) on gastroschisis risk. We estimated the relative excess risk due to interaction (RERI) to quantify additive interaction.

Results

Periconceptional alcohol consumption was common regardless of maternal age (women <25 years: cases 38.8%, controls 29.3%; women ≥25: cases 43.5%, controls 39.5%). Compared with women ≥25 years who did not consume alcohol, we observed increased risk of gastroschisis among women <25 years, with higher estimates among those who consumed alcohol (women <25 years who did not consume alcohol. aOR 5.90, 95% CI 4.89, 7.11; women <25 years who did consume alcohol: aOR 8.21, 95% CI 6.69, 10.07). Alcohol consumption among women ≥25 years was not associated with gastroschisis (aOR 1.12, 95% CI 0.88, 1.42). This suggests super‐additive interaction between alcohol consumption and maternal age (RERI −2.19, 95% CI 1.02, 3.36).

Conclusions

Periconceptional alcohol consumption may disproportionately increase risk of gastroschisis among young mothers. Our findings support public health recommendations to abstain from alcohol consumption during pregnancy.
Molecular characterization of wheat floret development‐related F‐box protein (TaF‐box2): Possible involvement in regulation of Arabidopsis flowering
Authors: Kim Jae Ho , Jung Woo Joo , Kim Moon Seok , Ko Chan Seop , Yoon Jin Seok , Hong Min Jeong , Shin Hyo Jeong , Seo Yong Weon
Published: April 2022

In wheat (Triticum aestivum L.), the floret development stage is an important step in determining grain yield per spike; however, the molecular mechanisms underlying floret development remain unclear. In this study, we elucidated the role of TaF‐box2, a member of the F‐box‐containing E3 ubiquitin protein ligases, which is involved in floret development and anthesis of wheat. TaF‐box2 was transiently expressed in the plasma membrane and cytoplasm of both tobacco and wheat. We also found that the SCFF‐box2(Skp1‐Cul1‐Rbx1‐TaF‐box2) ubiquitin ligase complex mediated self‐ubiquitination activity. Transgenic Arabidopsis plants that constitutively overexpressed TaF‐box2 showed markedly greater hypocotyl and root length than wild‐type plants, and produced early flowering phenotypes. Flowering‐related genes were significantly upregulated in TaF‐box2‐overexpressing Arabidopsis plants. Further protein interaction analyses such as yeast two‐hybrid, in vitro pull‐down, and bimolecular fluorescence complementation assays confirmed that TaF‐box2 physically interacted with TaCYCL1 (Triticum aestivum cyclin‐L1‐1). Ubiquitination and degradation assays demonstrated that TaCYCL1 was ubiquitinated by SCFF‐box2 and degraded through the 26S proteasome complex. The physiological functions of the TaF‐box2 protein remain unclear; however, we discuss several potential routes of involvement in various physiological mechanisms which counteract flowering in transgenic Arabidopsis plants.