bluuebunny/crossref_metadata_2025 huggingface dataset:
The Neural Correlates of Computational Thinking: Collaboration of Distinct Cognitive Components Revealed by fMRI
Authors: Xu Shan , Li Yan , Liu Jia
Published: May 2021

Recent technical advance attracts great attention to the promotion of programming skills, in particular, and computational thinking (CT), in general, as a new intellectual competency. However, the understanding of its cognitive substrates is limited. The present study used functional magnetic resonance imaging to examine the neural correlates of programming to understand the cognitive substrates of CT. Specifically, magnetic resonance imaging signals were collected while the participants were mentally solving programming problems, and we found that CT recruited distributed cortical regions, including the posterior parietal cortex, the medial frontal cortex, and the left lateral frontal cortex. These regions showed extensive univariate and multivariate resemblance with arithmetic, reasoning, and spatial cognition tasks. Based on the resemblance, clustering analyses revealed that cortical regions involved in CT can be divided into Reasoning, Calculation, Visuospatial, and Shared components. Further, connectivity increased during programming within the CT network constructed by these four components and decreased between the CT network and other cortical regions. In sum, our study revealed the cognitive components underlying CT and their neural correlates and further suggests that CT is not a simple sum of parallel cognitive processes, but a composite cognitive process integrating a set of intellectual abilities, particularly those in the science, technology, engineering, and math domains.
The Autophagy Inducer Spermidine Protects Against Metabolic Dysfunction During Overnutrition
Authors: Liao Chen-Yu , Kummert Oona M P , Bair Amanda M , Alavi Nora , Alavi Josef , Miller Delana M , Bagga Isha , Schempf Anja M , Hsu Yueh-Mei , Woods Bruce D , Brown Mayfield Stephen M , Mitchell Angelina N , Tannady Gabriella , Talbot Aislinn R , Dueck Aaron M , Barrera Ovando Ricardo , Parker Heather D , Wang Junying , Schoeneweis Jane K , Kennedy Brian K
Published: June 2021

Autophagy, a process catabolizing intracellular components to maintain energy homeostasis, impacts aging and metabolism. Spermidine, a natural polyamine and autophagy activator, extends life span across a variety of species, including mice. In addition to protecting cardiac and liver tissue, spermidine also affects adipose tissue through unexplored mechanisms. Here, we examined spermidine in the links between autophagy and systemic metabolism. Consistently, daily injection of spermidine delivered even at late life is sufficient to cause a trend in life-span extension in wild-type mice. We further found that spermidine has minimal metabolic effects in young and old mice under normal nutrition. However, spermidine counteracts high-fat diet (HFD)-induced obesity by increasing lipolysis in visceral fat. Mechanistically, spermidine increases the hepatokine fibroblast growth factor 21 (FGF21) expression in liver without reducing food intake. Spermidine also modulates FGF21 in adipose tissues, elevating FGF21 expression in subcutaneous fat, but reducing it in visceral fat. Despite this, FGF21 is not required for spermidine action, since Fgf21−/− mice were still protected from HFD. Furthermore, the enhanced lipolysis by spermidine was also independent of autophagy in adipose tissue, given that adipose-specific autophagy-deficient (Beclin-1flox/+Fabp4-cre) mice remained spermidine-responsive under HFD. Our results suggest that the metabolic effects of spermidine occur through systemic changes in metabolism, involving multiple mechanistic pathways.
The Longitudinal Association of Vision Impairment With Transitions to Cognitive Impairment and Dementia: Findings From the Aging, Demographics and Memory Study
Authors: Ehrlich Joshua R , Swenor Bonnielin K , Zhou Yunshu , Langa Kenneth M
Published: June 2021

Background

Vision impairment (VI) is associated with incident cognitive decline and dementia. However, it is not known whether VI is associated only with the transition to cognitive impairment, or whether it is also associated with later transitions to dementia.

Methods

We used data from the population-based Aging, Demographics and Memory Study (ADAMS) to investigate the association of visual acuity impairment (VI; defined as binocular presenting visual acuity <20/40) with transitions from cognitively normal to cognitive impairment no dementia (CIND) and from CIND to dementia. Multivariable Cox proportional hazards models and logistic regression were used to model the association of VI with cognitive transitions, adjusted for covariates.

Results

There were 351 participants included in this study (weighted percentages: 45% male, 64% age 70–79 years) with a mean follow-up time of 4.1 years. In a multivariable model, the hazard of dementia was elevated among those with VI (hazard ratio = 1.63, 95% confidence interval = 1.04–2.58). Participants with VI had a greater hazard of transitioning from cognitively normal to CIND (hazard ratio = 1.86, 95% confidence interval = 1.09–3.18). However, among those with CIND and VI a similar percentage transitioned to dementia (48%) and remained CIND (52%); there was no significant association between VI and transitioning from CIND to dementia (hazard ratio = 0.94, 95% confidence interval = 0.56–1.55). Using logistic regression models, the same associations between VI and cognitive transitions were identified.

Conclusions

Poor vision is associated with the development of CIND. The association of VI and dementia appears to be due to the higher risk of dementia among individuals with CIND. Findings may inform the design of future interventional studies.
Effects of changes in glycan composition on glycoprotein dynamics: example ofN-glycans on insulin receptor
Authors: Rao Rajas M , Wong Hua , Dauchez Manuel , Baud Stéphanie
Published: May 2021

Glycosylation is among the most common post-translational modifications in proteins, although it is observed in only about 10% of all the protein structures in protein data bank (PDB). Modifications of sugar composition in glycoproteins profoundly impact the overall physiology of the organism. One such example is the development of insulin resistance, which has been attributed to the removal of sialic acid residues from N-glycans of insulin receptor (IR) from various experimental studies. How such modifications affect the glycan-glycoprotein dynamics, and ultimately their function is not clearly understood to date. In this study, we performed molecular dynamics simulations of glycans in different environments. We studied the effects of removal of sialic acid on the glycan, as well as on the dynamics of leucine-rich repeat L1 domain of the IR ectodomain. We observed perturbations in L1 domain dynamics as a result of the removal of sialic acid. The perturbations include an increase in the flexibility of insulin-binding residues, which may affect insulin binding with IR. These changes are accompanied by perturbations in glycan–protein interactions and perturbation of long-range allosteric dynamics. Our observations will further aid in understanding the role of sugars in maintaining homeostasis and how changes in glycan composition may lead to perturbations in homeostasis, ultimately leading to conditions such as insulin resistance.
Applied systems thinking: unlocking theory, evidence and practice for health policy and systems research
Authors: Kwamie Aku , Ha Solip , Ghaffar Abdul
Published: June 2021

While systems thinking has been generally acknowledged as important to the field of health policy and systems research (HPSR), it remains underutilized. In particular, systems thinking has been perceived as predominantly conceptual, with fewer applications of systems thinking documented. This commentary makes three key points, namely that (1) advances in applied systems thinking in HPSR have been hindered by an imprecision in terminology, conflating ‘[health] systems approaches’ with complex adaptive systems theory; (2) limited examples of applied systems thinking have been highlighted and recognized in research, but have not been fully and equally appreciated in policymaking and practice and (3) explicit use of theory, long-term research-policy collaborations and better documentation of evidence can increase the use and usefulness of applied systems thinking in HPSR. By addressing these matters, the potentials of systems thinking in HPSR can be truly unlocked.
Impact of the early phase of the COVID pandemic on cancer treatment delivery and the quality of cancer care: a scoping review and conceptual model
Authors: Powis Melanie , Milley-Daigle Carissa , Hack Saidah , Alibhai Shabbir , Singh Simron , Krzyzanowska Monika K
Published: May 2021

Background

The disruption of health services due to coronavirus disease (COVID) is expected to dramatically alter cancer care; however, the implications for care quality and outcomes remain poorly understood.

Objective

We undertook a scoping review to evaluate what is known in the literature about how cancer treatment has been modified as a result of the COVID pandemic in patients receiving treatment for solid tumours, and what domains of quality of care are most impacted.

Methods

Citations were retrieved from MEDLINE and EMBASE (from 1 January 2019 to 28 October 2020), utilizing search terms grouped by the key concept (oncology, treatment, treatment modifications and COVID). Articles were excluded if they dealt exclusively with management of COVID-positive patients, modifications to cancer screening, diagnosis or supportive care or were not in English. Articles reporting on guidelines, consensus statements, recommendations, literature reviews, simulations or predictive models, or opinions in the absence of accompanying information on experience with treatment modifications in practice were excluded. Treatment modifications derived from the literature were stratified by modality (surgery, systemic therapy (ST) and radiotherapy) and thematically grouped. To understand what areas of quality were most impacted, modifications were mapped against the Institute of Medicine’s quality domains. Where reported, barriers and facilitators were abstracted and thematically grouped to understand drivers of treatment modifications. Findings were synthesized into a logic model to conceptualize the inter-relationships between different modifications, as well as their downstream impacts on outcomes.

Results

In the 87 retained articles, reductions in outpatients visits (26.4%) and delays/deferrals were commonly reported across all treatment modalities (surgery: 50%; ST: 55.8% and radiotherapy: 56.7%), as were reductions in surgical capacity (57.1%), alternate systemic regimens with longer treatment intervals or use of oral agents (19.2%) and the use of hypofractionated radiotherapy regimens (40.0%). Delivery of effective, timely and equitable care was the quality domains found to be the most impacted. The most commonly reported facilitator of maintaining cancer care delivery levels was the shift to virtual models of care (62.1%), while patient-initiated deferrals and cancellations (34.8%), often due to fear of contracting COVID (60.9%), was a commonly reported barrier.

Conclusions

As it will take a considerable amount of time for the cancer system to resume capacity and adjust models of care in response to the pandemic, these treatment delays and modifications will likely be prolonged and will negatively impact the quality of care and patient outcomes.
A case for multiscale habitat selection studies of small mammals
Authors: Schweiger Brittany R , Frey Jennifer K , Cain James W
Published: June 2021

Habitat information for small mammals typically consists of anecdotal descriptions or infrequent analyses of habitat use, which often are reported erroneously as signifying habitat preference, requirements, or quality. Habitat preferences can be determined only by analysis of habitat selection, a behavioral process that results in the disproportionate use of one resource over other available resources and occurs in a hierarchical manner across different environmental scales. North American chipmunks (Neotamias and Tamias) are a prime example of the lack of studies on habitat selection for small mammal species. We used the Organ Mountains Colorado chipmunk (N. quadrivittatus australis) as a case study to determine whether previous descriptions of habitat in the literature were upheld in a multiscale habitat selection context. We tracked VHF radiocollared chipmunks and collected habitat information at used and available locations to analyze habitat selection at three scales: second order (i.e., home range), third order (i.e., within home range), and microhabitat scales. Mean home range was 2.55 ha ± 1.55 SD and did not differ between sexes. At the second and third order, N. q. australis avoided a coniferous forest land cover type and favored particular areas of arroyos (gullies) that were relatively steep-sided and greener and contained montane scrub land cover type. At the microhabitat scale, chipmunks selected areas that had greater woody plant diversity, rock ground cover, and ground cover of coarse woody debris. We concluded that habitat selection by N. q. australis fundamentally was different from descriptions of habitat in the literature that described N. quadrivittatus as primarily associated with coniferous forests. We suggest that arroyos, which are unique and rare on the landscape, function as climate refugia for these chipmunks because they create a cool, wet microclimate. Our findings demonstrate the importance of conducting multiscale habitat selection studies for small mammals to ensure that defensible and enduring habitat information is available to support appropriate conservation and management actions.
How to manage behavioral problems
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

Behavioral problems are among the most difficult ones you may face caring for your loved one with dementia. The good news is that there are many approaches you can use to reduce unwanted behaviors and encourage positive ones. Conquer apathy with routines. Sidestep willfulness with small steps. Use the ABCs of Behavior Change, 4Rs, and Three Time Principles to manage agitation, aggression, combativeness, and inappropriate/disinhibited behavior. Stay safe by giving away or securing guns, power tools, and knives. Remember to call for help or leave a dangerous situation when you need to. Know how to stay safe in the car when you’re driving, and stop your loved one from driving when necessary. Deal with sundowning and challenging interactions outside of the home. Manage jealousy and paranoia. Finally, consider helping your loved one to feel more comfortable with soothing and familiar music, pleasing scents, stuffed animals, and real or robotic pets.
Why is it important to sustain your relationship?
Authors: Budson Andrew E. , O’Connor Maureen K.
Published: June 2021

Despite the challenges of dementia, it is important to continue to have fun with your loved one and nurture your relationship. Engaging in pleasant activities is a great way to remain connected. These activities can also help to reduce behavioral problems, boost mood, and even improve functioning in your loved one. Engaging in activities with your loved one can also help reduce burden and stress on you. Although your loved one may have trouble doing some of the things they enjoyed before their dementia, there are a variety of activities that they can still participate in. Some activities may be variations on things they used to enjoy and others may be entirely new. We encourage you to take time to engage in pleasant activities with your loved one on a regular basis.
Veteran Health Care
Authors: Gross Michael L.
Published: June 2021

Afterwar, embattled countries often forget their veterans. The rule is simple: nations must offer wounded veterans the same medical care other citizens enjoy. Nevertheless, veterans have no special rights to preferential or priority care. Virtuous or villainous conduct is an unacceptable criterion of medical attention. Just as the innocent victim of a traffic accident enjoys no stronger right to health care than the inattentive driver who ran the light, soldiers enjoy no exclusive right to medical treatment. Nor can discharged veterans appeal to military necessity to afford them the privilege of priority care. Despite provisions in the United States, the United Kingdom, and Australia to carve out special rights for veterans, they are without a firm moral foundation. Instead, each nation may reward military service with public recognition and financial compensation, while providing every citizen with the high level of care that each deserves by right.
Developmental Neuropsychiatry
Authors: Taylor Eric
Published: June 2021

Neurodevelopmental disorders are a group of conditions involving alterations of behaviour, thinking, and emotions. They have onsets in early childhood, persistence into adult life, and high rates of altered cognitive and neurological function. They are frequent reasons for referral to psychiatry, paediatrics, and clinical psychology and often require team approaches to meet a variety of needs for service. This book includes accounts of the typical development and possible pathology of key functions whose alterations can underlie problems of mental development: motor function, attention, memory, executive function, communication, social understanding and empathy, reality testing, and emotional regulation. It goes on to descriptions of frequent clinical conditions: the spectra of attention deficit hyperactivity disorder (ADHD), autism, tic disorders, coordination and learning difficulties, intellectual disability, and the psychotic disorders of young people. There are descriptions of recognition, diagnosis, prevalence, pathophysiology, and consequences for later development. These conditions very often coexist and present as dimensions rather than categorical illnesses. The effects of brain disorders on mental life are then considered, with special attention to epilepsy, cerebral palsy, hydrocephalus, acquired traumatic injury to the head, localized structural lesions, and endocrine and genetic disorders. Widely used treatments, both psychological and physical, are described in the context of their value for meeting multiple, often overlapping needs. Consequences of the conditions for individuals’ psychosocial development are described: stigma; physical illness and injury; economic disadvantage; and family, peer, and school stresses. This book is aimed at clinicians of all disciplines, clinical students, and educators encountering neuropsychiatric problems in young people.
From Altered Function to Restriction of Life
Authors: Taylor Eric
Published: June 2021

This chapter traces the development of children and young people with neurodevelopmental disorders through their later childhood and teenage years. The pattern and severity of impairments in mental function influence their course over time. In addition, the courses fluctuate in response to a series of encounters with potentially harmful influences. Stigma is widespread in many cultures. Physical illness and injury and premature mortality are consequences of several psychiatric syndromes. Economic disadvantage is more frequent for families of disabled people and interacts with other family stresses. Transitions into school, peer cultures, puberty, work, and the virtual world of the internet all tend to take different forms for those whose brain functions are altered by comparison with the rest of the population. All these can be responsible for adverse outcomes of children and young people.
Nuclear cardiology (PET and SPECT)—basic principles
Authors: Neglia Danilo , Liga Riccardo , Nekolla Stephan G. , Bengel Frank M. , Rimoldi Ornella , Camici Paolo G.
Published: June 2021

Historically, radionuclide imaging has been the key to the success and widespread clinical application of non-invasive techniques for detection of myocardial ischaemia. Today, the use of myocardial perfusion single photon emission computed tomography (SPECT) for the diagnostic and prognostic workup of coronary artery disease is supported by a very large body of evidence. Positron emission tomography (PET) as an advanced, quantitative technique is increasingly penetrating the clinical arena. The field is responding to recent trends by adopting new technology and algorithms for reduction of radiation exposure and by developing a toolbox for targeted molecular imaging of key biologic mechanisms involved in heart disease and therapy response. By this, nuclear cardiology will continue to serve as a role model for the success of functional imaging in heart disease. This chapter gives an overview over the basic technology, including novel methodologic developments.
Cardiac CT—basic principles
Authors: Pontone Gianluca , Cademartiri Filippo
Published: June 2021

Computed tomography (CT) was introduced for clinical diagnostic radiology in 1971, and it was used as neuro and body scanner for about 20 years. Spatial and temporal resolution required to evaluate a dynamic structure such as the heart was not sufficient until 1998. Thanks to the technical developments in CT technology over the past 20 years cardiac CT (CCT) developed from an investigative tool into an established clinical tool primarily used as non-invasive clinical diagnostic test for coronary artery imaging. The key technical development occurred in the late 1990s with the introduction of multidetector CT (4 slices) scanners able to synchronize image acquisition and reconstruction with an electrocardiographic (ECG) track. However, 4-slice and also the following 16-slice CT technology had technical limitations, such as limited coverage and temporal resolution, but which allowed diagnostic image quality in selected patients with low and stable heart rate. Moreover, relatively high radiation exposure was required to obtain clinically valid image quality. For this reason, different technical strategies were developed in the following years and advances were also provided in the field of reconstruction algorithm with the introduction of iterative algorithms that allowed an image noise reduction and in the field of tissue characterization with the use of dual-energy CT. All these advances allowed CCT to become a pivotal tool in the cardiology daily practice to image the coronary arteries and beyond.
Tricuspid and pulmonary valve disease
Authors: Muraru Denisa , Sade Elif Leyla
Published: June 2021

Right heart valves have gained significant interest in the context of a plethora of new emerging percutaneous transcatheter interventions for treating tricuspid and pulmonary valve diseases. Multimodality imaging is pivotal for patient diagnosis, management, and prognosis, as well as for planning interventional and surgical valve procedures. Echocardiography is the primary imaging modality for initial diagnosis and longitudinal follow-up of patients with right-sided valvular heart disease. Cardiovascular magnetic resonance has emerged as a complementary or alternative modality for providing diagnostic information on the tricuspid and pulmonary valve anatomy, and particularly on the pulmonary artery and the consequences on the right ventricle. This chapter highlights the current use of various imaging modalities for the state-of-the-art assessment of right-sided valvular heart diseases, with emphasis on the main clinical indications, as well as on the strengths and limitations of each modality.
Multiple and mixed valvular heart disease
Authors: Unger Philippe , Garbi Madalina
Published: June 2021

Multiple and mixed valvular heart disease are highly prevalent. Multiple valvular heart disease is the combination of stenotic and/or regurgitant lesions occurring on two or more cardiac valves. Mixed valvular heart disease is the combination of stenotic and regurgitant lesions on the same valve. Several haemodynamic interactions may impact their clinical expression and may result in diagnostic pitfalls. Accurate quantification of the valve lesions requires the use of methods that are less dependent on loading conditions, such as planimetry for stenotic lesions, and assessment of the effective regurgitant orifice area and vena contracta for regurgitant lesions. The assessment should address the diagnosis and severity of each single valve lesion as well as the overall consequences resulting from the combination of all lesions. Clinical decision-making should be based on an integrative approach including echocardiography and other imaging modalities.
Evaluation of systolic LV function and LV mechanics
Authors: Hoffmann Rainer , Flachskampf Frank A.
Published: June 2021

Analysis of global and regional left ventricular (LV) function is the most frequent indication to perform echocardiography. While visual assessment based on 2D images is the basis for analysis of LV function, it may be supplemented by quantitative techniques to obtain parameters of global or regional function. 2D echocardiography tends to underestimate LV volumes compared to cardiac magnetic resonance (CMR), 3D echocardiography results in less volume underestimation and high accuracy in the analysis of ejection fraction. Visual analysis of regional function is limited by significant interobserver variability. Another approach to systolic LV function is the assessment of LV mechanics, typically by measuring global longitudinal deformation (strain) by speckle-tracking echocardiography. Alternatively, information on deformation can be obtained from CMR (currently, mostly by feature tracking). Deformation parameters detect early impairment of LV systolic function with higher sensitivity than ejection fraction. While echocardiography continues to be the first-choice modality for ejection fraction, CMR has become the gold standard for quantification of LV volumes and ejection fraction. Nuclear imaging should be applied to assess LV function only if simultaneous assessment of myocardial perfusion is requested.
Imaging of the right heart
Authors: Rudski Lawrence , Nihoyannopoulos Petros , Blissett Sarah
Published: June 2021

The right ventricle has lost its designation as the ‘forgotten ventricle’ over the past decade. Clinicians recognize its prognostic significance in a wide array of disease processes and imagers are now providing an assessment of right ventricular size and function in most studies. Despite this recognition, imaging the right heart presents numerous challenges to the imager. The shape of the chamber, the unique structure, and its coupling to the pulmonary circulation mandate a different approach to its evaluation as compared to the left ventricle. Imaging may be done by several modalities, each with their own strengths and limitations. Even more so than with the left ventricle, the findings must be interpreted in the context of loading conditions and clinical setting. This chapter will focus on the two main right heart imaging modalities—echocardiography and cardiac MRI.
Echocardiography evaluation in extracorporeal support
Authors: Price Susanna , Gambaro Alessia
Published: June 2021

Extracorporeal circuits are increasingly used to support critically ill patients with severe cardiac and/or respiratory failure. They may be used as a bridge to recovery, transplantation, decision for further intervention, or as destination therapy. When undertaking echocardiography for extracorporeal support, certain key principles apply. First, as extracorporeal support is not a treatment per se, but rather a supportive therapy while awaiting resolution of the underlying pathological process echocardiography has a vital role in diagnosing/excluding any potentially treatable underlying cause for cardiorespiratory failure. Second, echocardiography is required to determine the requirement for right and/or left ventricular support, the level of support required, and assessing the ability of the right and left ventricles to support the extracorporeal circuit. This demands that the practitioner understands the different types of circuit, and the load that each will place on the heart. Third, echocardiography is mandatory to exclude cardiovascular contraindications to initiation of support. Echocardiography subsequently has a vital role in its successful implementation, including confirming/guiding correct cannula placement, ensuring the goals of support are met, detecting complications, and assessing tolerance to assistance. Finally, in patients requiring extracorporeal cardiac support, various echocardiographic parameters have been proposed to be used in conjunction with clinical and haemodynamic assessment in order to attempt to predict those patients who can be successfully weaned.
Dilated cardiomyopathy
Authors: Tayal Upasana , Prasad Sanjay , Germans Tjeerd , van Rossum Albert C.
Published: June 2021

Dilated cardiomyopathy (DCM) is characterized by enlargement of the heart with associated reduced left ventricular function. From an imaging perspective, important requirements are to exclude other pathologies, assess disease severity, guide therapeutic management, and identify complications. Establishing the imaging diagnosis of DCM is key to guiding the management of DCM. In this chapter we discuss how to use imaging to make an accurate diagnosis of DCM, and review how to exclude coronary artery disease (CAD) and valvular disease as these are two important differentials with differing management strategies. We then review the diagnostic and prognostic capabilities of echocardiography, cardiovascular magnetic resonance imaging (CMR) and nuclear techniques including single-photon emission computed tomography (SPECT) and positron emission tomography (PET) in DCM, with a focus on where imaging can identify particular causes of DCM.
Aortic disease: Aneurysm and dissection—role of CMR
Authors: Rodriguez-Palomares Jose F. , Evangelista Arturo
Published: June 2021

Cardiovascular magnetic resonance (CMR) is a non-invasive imaging technique that permits the most comprehensive study of aortic diseases since it offers morphological, functional, and biochemical information. Technological advances which have implied faster gradients, newer sequences, and ultrafast angiography, have made CMR the modality of choice for imaging aortic diseases. CMR can be used to define the location and extent of aneurysms, dissections, and aortic wall ulceration. This is the best technique to demonstrate areas of wall thickening related to aortitis or intramural haematoma. Furthermore, CMR may be used as a tool to study aortic physiology by assessment of elastic aortic properties, stiffness, and aortic wall shear stress. This information is obtained without the use of ionizing radiation, and in some instances, without the need of contrast. Thus, CMR is particularly useful in patients with either contraindications to iodinated contrast or in those with aortic diseases that require sequential follow-up.
Correia, Diamond and the Chester Exception: Vindicating Patient Autonomy?
Authors: Austin Louise
Published: June 2021

In Chester v Afshar [2004], the House of Lords stated they were departing from the traditional rules of causation in order to vindicate the patient’s right of autonomy. Subsequent judgments in the Court of Appeal expressed concerns over the lack of clarity of the legal principles to be derived from that judgment. In Correia v University Hospital of North Staffordshire NHS Trust [2017] and Diamond v Royal Devon and Exeter NHS Foundation Trust [2019], however, the Court of Appeal sought to clarify the scope and limits of Chester. This commentary sets out the scope and limits of Chester in light of those judgments and considers the extent to which they can be said to be vindicating patient autonomy. Drawing upon Coggon’s typology of autonomy, it concludes that future judgments should utilise that typology to explicate which understanding of autonomy they are seeking to protect.
Single-round deoxyribozyme discovery
Authors: Streckerová Tereza , Kurfürst Jaroslav , Curtis Edward A
Published: May 2021

Artificial evolution experiments typically use libraries of ∼1015 sequences and require multiple rounds of selection to identify rare variants with a desired activity. Based on the simple structures of some aptamers and nucleic acid enzymes, we hypothesized that functional motifs could be isolated from significantly smaller libraries in a single round of selection followed by high-throughput sequencing. To test this idea, we investigated the catalytic potential of DNA architectures in which twelve or fifteen randomized positions were embedded in a scaffold present in all library members. After incubating in either the presence or absence of lead (which promotes the nonenzymatic cleavage of RNA), library members that cleaved themselves at an RNA linkage were purified by PAGE and characterized by high-throughput sequencing. These selections yielded deoxyribozymes with activities 8- to 30-fold lower than those previously isolated under similar conditions from libraries containing 1014 different sequences, indicating that the disadvantage of using a less diverse pool can be surprisingly small. It was also possible to elucidate the sequence requirements and secondary structures of deoxyribozymes without performing additional experiments. Due to its relative simplicity, we anticipate that this approach will accelerate the discovery of new catalytic DNA and RNA motifs.
ATRT-05. REPURPOSED ANTI-MALARIAL QUINACRINE ACTIVATES P53 AND INHIBITS ATRT TUMORIGENICITY
Authors: Kaur Harpreet , Parthasarathy Akhila , Guo Huizi , Green Peter C , Akhtarkhavari Sepehr , Eberhart Charles G , Raabe Eric H
Published: June 2021

Atypical teratoid rhabdoid tumors (ATRTs) are fatal pediatric brain tumors that warrant improved therapies urgently. ATRTs are characterized by loss of INI1, a subunit of the SWI/SNF chromatin-remodeling complex. ATRTs grow aggressively despite majority of primary tumors expressing p53, suggesting inactivation of this tumor suppressor pathway. Reactivation of p53 could be a potential therapeutic strategy for inhibiting ATRT growth. Our laboratory specializes in researching mechanisms contributing to ATRT pathogenesis and potential therapies. In line with this, we investigated an anti-malarial drug called quinacrine that has been safely used in children for decades and can induce p53 in renal cell carcinoma. We used 5 patient-derived ATRT cell lines (BT-37, BT-12, CHLA-06, CHLA-266, CHLA-05) for our studies. We show that ATRT cell lines treated with quinacrine for 6 hours show increased expression of p53, suggesting its activation. Treatment of ATRT cell lines with increasing doses of quinacrine for 24 hours showed dose-dependent decrease in cell growth and proliferation (assessed by MTS assay and BrdU incorporation, P<0.05) and increase in apoptotic cell death (CC-3 and cleaved PARP expression). Nude mice harboring flank tumors of ATRT cell lines and treated with quinacrine for 3 weeks showed significant reduction in tumor growth compared to control animals (P<0.05). Since quinacrine is a substrate for the drug-efflux proteins P-gp/BCRP, we used quinacrine in combination with elacridar (Pgp/BCRP inhibitor) in our intracranial xenograft experiments to increase quinacrine’s retention in the brain. Mice harboring intracranial xenografts of ATRT cells showed increased survival when treated with quinacrine and elacridar (median survival 46 days) compared to control animals (median survival 25 days). These results suggest that quinacrine inhibits ATRT growth, partly by activating p53. Our studies are the first to show quinacrine’s effect on ATRTs and our current experiments include further investigation of quinacrine’s mechanism.
LGG-02. PEDIATRIC LOW-GRADE GLIOMA RISK STRATIFICATION IN THE MOLECULAR ERA
Authors: Hata Jessica , Barbour Mustafa , Huang Michael Angelo
Published: June 2021

Background

Pediatric low-grade gliomas (LGG), in particular those not amenable to surgical resection, are a therapeutic challenge owing to their heterogeneity in clinical behavior. Identification of the RAS/MAPK pathway as a universal feature of these tumors has led to an improved understanding and the development of targeted therapeutics. We examined the impact of known biological and novel molecular risk factors on patient outcomes at our institution.

Methods

We retrospectively reviewed risk factors and clinical outcomes in 38 LGG cases diagnosed by histopathology at Norton Children’s Hospital in Louisville, KY, USA from March 2015 to Jan 2019. Progression free survival (PFS) rates were generated using the Kaplan-Meier method. Log-rank tests and hazard ratios were used to identify prognostic factors by univariable analysis.

Results

Among previously described biological risk factors, subtotal resection/biopsy only (HR 3.67, p=0.0257), non-WHO Grade I histology (HR 3.34, p=0.0101), and infant age (< 3 years) (HR 4.19, p=0.0031) were associated with shorter PFS. Brainstem location had no significant impact on PFS. (HR 0.86, p=0.8071). H3K27M mutant status was predictably associated with worse PFS (HR 5.86, p=0.0012). BRAF v600e mutant status, however, was not associated with inferior outcomes. On the contrary, in our study population, BRAF v600e mutant status had a suggested protective effect (HR 0.14, p=0.0247). Patients with 2 or more oncogenic driver mutations demonstrated worsened PFS (HR 4.78, p=0.0059). We utilized the following scoring system for risk stratification: 1 point was allocated for each of the above biological and molecular risk factors except for H3K27M, which was allocated 3 points. A score of < 3 was designated low risk. Non-low risk classification was associated with significantly inferior PFS (median PFS 13 vs. 62 mos, HR 4.26, p=0.0012).

Conclusion

We herein demonstrate the utility of a combined biological and molecular risk classification for pediatric LGG.
Comparing the acute effects of shiftwork on mothers and fathers
Authors: Tucker P , Leineweber C , Kecklund G
Published: May 2021

Background

Shift work may impact women more negatively than men due to the increased burden of coping with demanding work schedules while also undertaking more of the domestic chores, including childcare.

Aims

To examine whether the combination of shift working and caring for children affects the sleep, fatigue and work–family conflict experienced by women more than it affects men.

Methods

Using data from a survey of the Swedish working population, mixed linear regression models examined work schedule (daywork, shift work with nights, shift work without nights), gender and presence of children <13 years at home as predictors of sleep insufficiency, sleep disturbance, fatigue and work–family conflict, over up to three successive measurement occasions. Adjustments were made for age, education, full/part-time working and baseline year.

Results

In fully adjusted models (N = 8938), shift work was associated with insufficient sleep (P < 0.01), disturbed sleep (P < 0.01), fatigue (P < 0.05) and work–family conflict (P < 0.001). Interactions in the analyses of sleep disturbance (P < 0.001) and work–family interference (P < 0.05) indicated that among participants with no children, females reported more disturbed sleep and more work–family conflict than their male counterparts, irrespective of schedule; while among participants with children, female dayworkers reported more disturbed sleep than their male counterparts, and females working shifts without nights reported more work–family interference.

Conclusions

Having young children did not exacerbate negative effects of shift work, in either men or women. This may reflect high levels of gender equality and childcare provision in Sweden.
Rice Putative Pectin Methyltransferase Gene OsPMT10 Is Required for Maintaining the Cell Wall Properties of Pistil Transmitting Tissues via Pectin Modification
Authors: Hasegawa Kazuya , Kamada Shihomi , Takehara Shohei , Takeuchi Haruki , Nakamura Atsuko , Satoh Shinobu , Iwai Hiroaki
Published: May 2021

Precise directional control of pollen tube growth via mechanical guidance by pistil tissue is critical for the successful fertilization of flowering plants and requires active cell-to-cell communication and maintenance of softness in the transmitting tissue. However, the regulation of transmitting tissue softness as controlled by cell wall properties, especially pectin, has not been reported. Here we report that regulation of pectin methylesterification supports pollen elongation through pistil transmitting tissues in Oryza sativa. The rice pectin methylesterase gene OsPMT10 was strongly expressed in reproductive tissues, especially the pistil. The ospmt10 mutant did not have a significant effect on vegetative growth, but the fertility rate was reduced by approximately half. In the ospmt10 mutant, pollen tube elongation was observed in the transmitting tissue of the style, but approximately half of the pollen tubes did not extend all the way to the ovule. Tissue cross-sections of the upper ovary were prepared, and immunohistochemical staining using LM19 and LM20 showed that methylesterified pectin distribution was decreased in ospmt10 compared with the wild type. The decreased expression of methylesterified pectins in ospmt10 may have resulted in loss of fluidity in the apoplast space of the transmitting tissue, rendering it difficult for the pollen tube to elongate in the transmitting tissue and thereby preventing it from reaching the ovule.
Pandemic Policymaking in Presidential Federations: Explaining Subnational Responses to Covid-19 in Brazil, Mexico, and the United States
Authors: Bennouna Cyril , Giraudy Agustina , Moncada Eduardo , Rios Eva , Snyder Richard , Testa Paul
Published: June 2021

Why do COVID-19 social distancing policies vary so widely across states in federal countries? This mixed-methods study of Brazil, Mexico, and the United States finds that state-level variation in the stringency of social distancing policies is driven not by the epidemiological, demographic, or socioeconomic factors commonly emphasized in previous research, but largely by political factors. Introducing a novel framework for explaining pandemic policymaking, the study shows the central importance of political parties, presidential power, and governors’ coalitions in determining state-level policy stringency. In the United States and Mexico, statistical and qualitative evidence indicates that interstate collaboration among governors, combined with top-down pressures from national party elites and presidents, led to greater policy alignment among coordinated states. In Brazil, in contrast, where there is little evidence of either policy coordination or alignment, state-level policies resulted instead from intrastate factors and diffusion. Together, these findings highlight how a multilevel framework attuned to varied combinations of intra-unit, cross-unit, and cross-level causal factors strengthens our understanding of pandemic policymaking.
The Upper And Lower Central Series In Linear Groups
Authors: de Giovanni F , Trombetti M , Wehrfritz B A F
Published: June 2021

A classical theorem of Reinhold Baer shows that any group which is finite over its k-th centre has a finite (k + 1)-th term of its lower central series. Although the converse statement is false in general, Philip Hall proved that for any group G the finiteness of γk + 1(G) implies that the index $|G:\zeta_{2k}(G)|$ is finite. Similar situations have been investigated when finiteness is replaced by suitable weaker conditions. Moreover, it was proved by Yuri${\text{\u{\i}}}$ Merzljakov that Baer’s theorem and its potential converse do hold for linear groups. The aim of this paper is to obtain results of the latter type for several other finiteness conditions.

Finally, although a result of Baer type does not hold for the class of soluble-by-finite reduced minimax groups, we prove that for this class a theorem of Hall type is true in arbitrary groups.
Repair calvarial defect of osteoporotic rats by berberine functionalized porous calcium phosphate scaffold
Authors: Wang Dahao , Zhang Peng , Mei Xifan , Chen Zhenhua
Published: June 2021

In this article, we propose a simple scheme of using berberine (BBR) to modify porous calcium phosphate ceramics (named PCPC). These BBR molecules regulate the crystallization of hydroxyapatite nanorods on PCPC. We found that these nanorods and the adsorbed BBR changed the interface micro-environment of PCPC by SEM images. The microenvironment of PCPC surface is essential for promoting BMSCs’ proliferation and differentiation. These results demonstrated that PCPC/BBR markedly improved the bone regeneration of osteoporosis rats. Moreover, PCPC/BBR had significantly increased the expression levels of ALP, osteocalcin and bone morphogenetic protein2 and RUNX2 in BMSCs originated from osteoporosis rats.
COMPARISON OF ORGAN ABSORBED DOSES IN WHOLE-BODY COMPUTED TOMOGRAPHY SCANS OF PAEDIATRIC AND ADULT PATIENT MODELS ESTIMATED BY DIFFERENT METHODS
Authors: Chipiga Larisa , Golikov Vladislav , Vodovatov Aleksandr , Bernhardsson Christian
Published: June 2021

This study aimed to identify the uncertainty in estimations of organ absorbed dose using dedicated software by comparing with corresponding doses measured in physical phantoms. The comparison was performed for whole-body computed tomography (CT) obtained as part of positron emission tomography. Whole-body CT scans provide an advantage in terms of comparison because all organs are in the primary beam of the irradiated area. Organ doses estimated by the different software programs (CT-Expo, VirtualDose and NCICT) were compared by thermoluminescent detector measurements in anthropomorphic phantoms in 1-y-old, 5-y-old and adult patients. Differences were within ~15% in 12 major organs. However, differences of ~30% were observed in organs located at slightly different positions in the computational models compared to the physical phantoms. All investigated programs were deemed suitable for accurate estimation of organ absorbed dose.
Event-related potentials in insomnia reflect altered perception of sleep
Authors: Feige Bernd , Baglioni Chiara , Boehm Philipp , Heinrich Anna , Trumm Samuel , Benz Fee , Nissen Christoph , Domschke Katharina , Frase Lukas , Riemann Dieter
Published: June 2021

Study Objectives

Insomnia is defined by the subjective complaint of poor sleep as well as daytime impairments. Since polysomnography (PSG) typically shows only modest sleep impairment, some still unidentified property of sleep, not mirrored in PSG, may be modified in insomnia.

One possible mechanistic hypothesis is that insomnia patients may be more sensitive to inevitably occurring internal or external stimuli during the night, causing brief sleep disruptions then perceived as wake time.

Methods

Auditory event-related potentials (ERP) to low intensity (50 dB SPL) synthesized guitar tones played continuously throughout two nights of polysomnographically registered sleep were obtained in fifty patients with insomnia disorder (ID, without comorbidities) and 50 age- and sex-matched good sleeper controls (GSC) for each sleep stage and NREM/REM cycle. Phasic and tonic REM were treated as separate stages. Latencies and amplitudes of components P1, N1 and P2 were measured and analyzed by multivariate repeated-measures ANCOVA including effects of group, night, cycle, and age.

Results

ID showed reduced P2 amplitudes relative to GSC specifically in phasic REM sleep. The same reduction also correlated with the amount of sleep misperception across groups. Independent component analysis showed a frontal negativity to contribute most to this group difference.

Conclusions

The present finding can be interpreted as increased mismatch negativity (MMN) in ID, reflecting automated detection of change in the auditory system and a concomitant orienting response. Specifically phasic REM sleep appears to be vulnerable to sensory afferences in ID patients, possibly contributing to the perception of being awake.

Clinical Trial Information

Short name “PERSLEEP 2,” URL https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00008965, Registration DRKS00008965.