Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VO2max) is a critical performance trait under positive selection in some high-altitude taxa, and several high-altitude natives have evolved to resist the depressive effects of hypoxia on VO2max. This is associated with enhanced flux capacity through the O2 transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O2 transport. Some highlanders exhibit elevated rates of carbohydrate oxidation during exercise, taking advantage of its high ATP yield per mole of O2. Certain highland native animals have also evolved more oxidative muscles and can sustain high rates of lipid oxidation to support thermogenesis. The underlying mechanisms include regulatory adjustments of metabolic pathways and to gene expression networks. Therefore, the evolution of hypoxia resistance in high-altitude natives involves integrated functional changes in the pathways for O2 and substrate delivery and utilization by mitochondria. Expected final online publication date for the Annual Review of Physiology Volume 81 is February 10, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BACKGROUND

The Magpie Trial compared magnesium sulfate with placebo for women with preeclampsia. The objective of this study was to explore women's views and experiences of participating in the Magpie Trial in the United Kingdom.

METHODS

Postal questionnaires were sent to 771 women participants in the Magpie Trial to assess long-term health of UK women and children. The questionnaire included three questions exploring women's experience of participating in the trial: (a) If time suddenly went backward, and you had to do it all over again, would you agree to participate in the Magpie Trial? (b) Please tell us if there was anything about the Magpie Trial that you think could have been done better; and (c) Please tell us if there was anything about the Magpie Trial, or your experience of joining the trial, that you think was particularly good.

RESULTS

Overall, 619 of the 771 women who were sent questionnaires returned them. In response to the three questions: (a) 58 percent (356) of women responded "definitely yes," 27 percent (169) "probably yes," 4 percent (23) "probably no," 5 percent (33) "definitely no," and 5 percent (34) "not sure." No clear evidence was shown of a relationship with allocated treatment, although women who responded "probably or definitely no" were more likely to have had side effects from trial treatment. (b) Although 44 percent of women stated that nothing could have been done better, free text suggestions related to content of recruitment information, and its timing, and wanting to know treatment allocation and trial results. c) Women were generally extremely positive about being followed up and receiving trial results.

CONCLUSIONS

Women were largely positive about participation in the trial and its follow-up, but still reported ways they believed the study could have been improved, such as more information, given earlier, which also has implications for clinical care.

Patient Blood Management is the timely application of evidence-based medical and surgical concepts designed to maintain hemoglobin concentration, optimize hemostasis, and minimize blood loss to improve patient outcomes. Conceptually similar to a "bundle" strategy, it is designed to improve clinical care using comprehensive evidence-based treatment strategies to manage patients with potential or ongoing critical bleeding, bleeding diathesis, critical anemia, and/ or a coagulopathy. Patient Blood Management includes multimodal strategies to screen, diagnose and properly treat anemia, coagulopathies and minimize bleeding, using goal-directed therapy and leverages a patient's physiologic ability to adapt to anemia while definitive treatment is undertaken. Allogeneic blood component transfusion is one traditional therapeutic modality out of many for managing blood loss and anemia and, while it may be the best choice in certain situations, other effective and more appropriate options are available and should be used in conjunction or alone. Therefore, comprehensive Patient Blood Management is the new standard of care to prevent and manage anemia and optimize hemostasis and has been recommended by the World Health Organization, the American Society of Anesthesiologists, the European Society of Anaesthesiology and the Australian National Blood Authority. While there is a plethora of expert consensus and good practice guidelines published for blood component transfusion from multiple professional organizations and societies, there remains a need for more comprehensive and broader standards of patient medical management to proactively reduce the risk of exposure to allogeneic transfusions. In 2010, the Society for Advancement of Blood Management published the first comprehensive standards to address the administrative and clinical components of an effective, patient-centered Patient Blood Management program. Recognizing the need to reduce inappropriate transfusions, some professional organizations have placed their emphasis on transfusion guidelines. In contrast, the focus of the Society for Advancement of Blood Management Standard is on the centrality of the patient and the full spectrum of therapeutic strategies needed to improve clinical outcomes in patients at risk for blood loss or anemia, thereby reducing avoidable transfusions as well. The Standards are meant not to replace, but to complement transfusion guidelines by more completely addressing the need for a multi-modal clinical approach with the goal to improve patient outcomes. Compared to adult programs, Pediatric Patient Blood Management programs are currently not commonly accepted as standard of care for pediatric patients. This is partly due to the fact that, until recently, there was a paucity of robust evidence-based literature and expert consensus guidelines on pediatric PBM. Managing pediatric bleeding and blood product transfusion presents a unique set of challenges. The main goal of transfusion is to correct or avoid imminent inadequate oxygen carrying capacity caused by inadequate red blood cell mass. Determining when, what, and how much to transfuse can be difficult. Neonates, infants, children, and adolescents each have specific considerations based on age, weight, physiology, and pharmacology. In this edition of Pediatric Anaesthesia we provide, in abbreviated format, the 4th edition of the Administrative and Clinical Standards for Patient Blood Management; Pediatric Version, first published in 2010 with the addition of a new Pediatric section in 2016. These Standards provide guidance for implementing a comprehensive Pediatric Patient Blood Management program at both pediatric and adult medical institutions. While every hospital may not be equipped to have a dedicated Pediatric Patient Blood Management program, this document highlights important universal clinical strategies that can be implemented to optimize pediatric bleeding management and minimize allogeneic blood product exposure through the use of multi-modal therapeutic strategies that have their central emphasis on the patient rather than the transfusion. Important strategies include: treatment of preoperative anemia, standardized transfusion algorithms, the use of restrictive transfusion thresholds, goal-directed therapy based on point of care and viscoelastic testing, antifibrinolytics, and avoidance of hemodilution and hypothermia as supported by evidence. For the full version, please go to https://www.sabm.org/publications.

Cooking is one of the basic activities in our lives. However, people frequently feel they fall short of time to cook when facing problems with the temporal organization of daily life. How people think about home cooking is considered to be important for the time they spend on preparing meals. It is assumed that the meaning of cooking differs for different people, depending on the temporal and social context. This contribution allows us to clarify how the meaning of cooking varies according to individual and household characteristics and the cooking occasion. By using the pooled time-diary data from the Flemish time-use surveys from 1999 and 2004 we can examine people's views on cooking in order to understand how people use time for food preparation. Although the results suggest that people consider cooking primarily as a household chore, preparing food can also be a way to please others, as well as themselves. It seems that feelings of time pressure and the family situation are clearly related to men's and women's cooking experiences. Furthermore, the meaning of cooking also tends to be clearly influenced by the meal situation and (the moment of) the day.

The nucleolus of mammalian cells contains hundreds of box C/D small nucleolar RNAs (SNORDs). Through their ability to base pair with ribosomal RNA precursors, most play important roles in the synthesis and/or activity of ribosomes, either by guiding sequence-specific 2'-O-methylations or by facilitating RNA folding and cleavages. A growing number of SNORD genes with elusive functions have been discovered recently. Intriguingly, the vast majority of them are located in two large, imprinted gene clusters at human chromosome region 15q11q13 (the SNURF-SNRPN domain) and at 14q32 (the DLK1-DIO3 domain) where they are expressed, respectively, only from the paternally and maternally inherited alleles. These placental mammal-specific SNORD genes have many features of the canonical SNORDs that guide 2'-O-methylations, yet they lack obvious complementarity with ribosomal RNAs and, surprisingly, they are processed from large, tandemly repeated genes expressed preferentially in the brain. This review summarizes our understanding of the biology of these peculiar SNORD genes, focusing particularly on SNORD115 and SNORD116 in the SNURF-SNRPN domain. It examines the growing evidence that altered levels of these SNORDs and/or their host-gene transcripts may be a primary cause of Prader-Willi syndrome (PWS; a rare disorder characterized by overeating and obesity) as well as abnormalities in signaling through the 5-HT2C serotonin receptor. Finally, the hypothesis that PWS may be a ribosomopathy (ribosomal disease) is also discussed. WIREs RNA 2017, 8:e1417. doi: 10.1002/wrna.1417 For further resources related to this article, please visit the WIREs website.

Mechanobiology, the study of the influence of mechanical loads on biological processes through signaling to cells, is fundamental to the inherent ability of bone tissue to adapt its structure in response to mechanical stimulation. The immense contribution of computational modeling to the nascent field of bone mechanobiology is indisputable, having aided in the interpretation of experimental findings and identified new avenues of inquiry. Indeed, advances in computational modeling have spurred the development of this field, shedding new light on problems ranging from the mechanical response to loading by individual cells to tissue differentiation during events such as fracture healing. To date, in silico bone mechanobiology has generally taken a reductive approach in attempting to answer discrete biological research questions, with research in the field broadly separated into two streams: (1) mechanoregulation algorithms for predicting mechanobiological changes to bone tissue and (2) models investigating cell mechanobiology. Future models will likely take advantage of advances in computational power and techniques, allowing multiscale and multiphysics modeling to tie the many separate but related biological responses to loading together as part of a larger systems biology approach to shed further light on bone mechanobiology. Finally, although the ever-increasing complexity of computational mechanobiology models will inevitably move the field toward patient-specific models in the clinic, the determination of the context in which they can be used safely for clinical purpose will still require an extensive combination of computational and experimental techniques applied to in vitro and in vivo applications. WIREs Syst Biol Med 2016, 8:485-505. doi: 10.1002/wsbm.1356 For further resources related to this article, please visit the WIREs website.

Although viruses comprise the most abundant genetic material in the biosphere, to date only several thousand virus species have been formally defined. Such a limited perspective on virus diversity has in part arisen because viruses were traditionally considered only as etiologic agents of overt disease in humans or economically important species and were often difficult to identify using cell culture. This view has dramatically changed with the rise of metagenomics, which is transforming virus discovery and revealing a remarkable diversity of viruses sampled from diverse cellular organisms. These newly discovered viruses help fill major gaps in the evolutionary history of viruses, revealing a near continuum of diversity among genera, families, and even orders of RNA viruses. Herein, we review some of the recent advances in our understanding of the RNA virosphere that have stemmed from metagenomics, note future directions, and highlight some of the remaining challenges to this rapidly developing field. Expected final online publication date for the Annual Review of Virology Volume 6 is September 30, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

There is need for a valid, sensitive and short instrument capable of detecting and quantifying behavioural changes in ALS, which can be utilized in clinical and research settings. This study aimed to 1) develop and validate such an instrument; 2) verify the most common behavioural symptoms; and 3) investigate longitudinal changes over a six-month period. Two hundred and nineteen patients were included. The development sample (n = 140) was used to determine the most appropriate items to include in the new tool, the Motor Neuron Disease Behavioural Instrument (MiND-B) * , via a data-driven approach. An independent sample (n = 79) validated the tool. A more comprehensive sample (n = 50, sub-classified into ALS and ALS plus) was utilized to verify if the MiND-B could detect ALS plus patients. Finally, 20 ALS patients completed the MiND-B after a six-month period. Apathy, disinhibition and stereotypical behaviour were all found to be very common symptoms in ALS occurring in 75%, 66% and 58%, respectively, of cases. Notably, the MiND-B could identify ALS plus patients without standard cognitive assessments. In conclusion, the MiND-B tool can detect patients with ALS plus reliably, by means of questions to the informant. This test could enable ALS centres to evaluate non-motor symptoms and adapt management and decision-making approaches as necessary. *only available in the online version of the journal. Please find this material with the following direct link to the article: http://www.informahealthcare.com/(DOI: 10.3109/21678421.2014.896927).

The quality of reporting clinical and preclinical research is not optimal. Reporting guidelines can help make reports of research more complete and transparent, thus increasing their value and making them more useful to all readers. Getting reporting guidelines into practice is complex and expensive, and involves several stakeholders, including prospective authors, peer reviewers, journal editors, guideline developers, and implementation scientists. Working together will help ensure their maximum uptake and penetration. We are all responsible for helping to ensure that all research is reported so completely that it is of value to everybody. Please see related article: http://dx.doi.org/10.1186/s12916-015-0266-y.

Microfluidic paper-based analytical devices (μPADs) are the newest generation of lab-on-a-chip devices and have made significant strides in both our understanding of fundamental behavior and performance characteristics and expanding their applications. μPADs have become useful analytical techniques for environmental analysis in addition to their more common application as medical point-of-care devices. Although the most common method for device fabrication is wax printing, numerous other techniques exist and have helped address factors ranging from solvent compatibility to improved device function. This review highlights recent reports of fabrication and design, modes of detection, and broad applications of μPADs. Such advances have enabled μPADs to be used in field and laboratory studies to address critical needs in fast, cheaper measurement technologies. Expected final online publication date for the Annual Review of Analytical Chemistry, Volume 13 is June 12, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

The genetic basis of sickle cell disease (SCD) was elucidated >60 years ago, yet current therapy does not rely on this knowledge. Recent advances raise prospects for improved, and perhaps curative, treatment. First, transcription factors, BCL11A and LRF/ZBTB7A, that mediate silencing of the β-like fetal (γ-) globin gene after birth have been identified and demonstrated to act at the γ-globin promoters, precisely at recognition sequences disrupted in rare individuals with hereditary persistence of fetal hemoglobin. Second, transformative advances in gene editing and progress in lentiviral gene therapy provide diverse opportunities for genetic strategies to cure SCD. Approaches include hematopoietic gene therapy by globin gene addition, gene editing to correct the SCD mutation, and genetic manipulations to enhance fetal hemoglobin production, a potent modifier of the clinical phenotype. Clinical trials may soon identify efficacious and safe genetic approaches to the ultimate goal of cure for SCD. Expected final online publication date for the Annual Review of Medicine Volume 70 is January 27, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Simulation plays a significant role in human cognition. This article reviews evidence for a simulational account of mind reading. Drawing on findings in developmental psychology and cognitive neuroscience, it shows that mind reading involves the imitation, copying, or reexperience of the mind reading target's mental processes. The article also introduces evidence for simulational accounts of episodic memory and prospection. It identifies relevant similarities between mind reading, memory, and prospection as well as independent evidence for a role for simulation in memory. Copyright © 2010 John Wiley & Sons, Ltd. For further resources related to this article, please visit the WIREs website.

Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor. The bulk of evidence from recent surveys of the types of RNA species that are affected in these disorders suggests a global deregulation of control rather than a very small number of RNA species, although why some groups of neurons are sensitive to these changes is not well understood. Overall, these data suggest that neurodegeneration can be initiated by mutations in RNA binding proteins and, as a corollary, that neurons are particularly sensitive to loss of control of gene expression at the post-transcriptional level. Such observations have implications not only for understanding the nature of neurodegenerative disorders but also how we might intervene therapeutically in these diseases. WIREs RNA 2017, 8:e1397. doi: 10.1002/wrna.1397 For further resources related to this article, please visit the WIREs website.

From the late 1970s until the early 1990s, there have been several reports of improved appendage muscle strength and athletic performance. Much of the criticism of using a mouthguard alone or in conjunction with a splint, such as a mandibular orthopedic repositioning appliance (MORA), to enhance athletic performance has been aimed at study designs, controls, periods of time, double blindness, and the placebo effect. Although it would appear that designing a study which pleases both clinician and researcher would be a difficult task, studies have been performed that do meet the "gold standard." The results favor the premise that jaw repositioning can enhance appendage muscular strength and athletic performance. Studies performed during the mid-1980s, and to which the scientific community refers to continually, on closer examination are flawed.

Transformation is a widespread mechanism of horizontal gene transfer in bacteria. DNA uptake to the periplasmic compartment requires a DNA-uptake pilus and the DNA-binding protein ComEA. In the gram-negative bacteria, DNA is first pulled toward the outer membrane by retraction of the pilus and then taken up by binding to periplasmic ComEA, acting as a Brownian ratchet to prevent backward diffusion. A similar mechanism probably operates in the gram-positive bacteria as well, but these systems have been less well characterized. Transport, defined as movement of a single strand of transforming DNA to the cytosol, requires the channel protein ComEC. Although less is understood about this process, it may be driven by proton symport. In this review we also describe various phenomena that are coordinated with the expression of competence for transformation, such as fratricide, the kin-discriminatory killing of neighboring cells, and competence-mediated growth arrest. Expected final online publication date for the Annual Review of Genetics, Volume 53 is November 23, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Differences in diet can explain resource partitioning in apparently similar, sympatric species. Here, we analyzed 1,252 fecal droppings from five species (Eptesicus nilssonii, Myotis brandtii, M. daubentonii, M. mystacinus, and Plecotus auritus) to reveal their dietary niches using fecal DNA metabarcoding. We identified nearly 550 prey species in 13 arthropod orders. Two main orders (Diptera and Lepidoptera) formed the majority of the diet for all species, constituting roughly 80%-90% of the diet. All five species had different dietary assemblages. We also found significant differences in the size of prey species between the bat species. Our results on diet composition remain mostly unchanged when using either read counts as a proxy for quantitative diet or presence-absence data, indicating a strong biological pattern. We conclude that although bats share major components in their ecology (nocturnal life style, insectivory, and echolocation), species differ in feeding behavior, suggesting bats may have distinctive evolutionary strategies. Diet analysis helps illuminate life history traits of various species, adding to sparse ecological knowledge, which can be utilized in conservation planning.

BACKGROUND

Shoulder pain is a common problem with an estimated prevalence of 4% to 26%. About 1% of adults aged over 45 years consult their GP with a new presentation of shoulder pain every year in the UK. The aetiology of shoulder pain is diverse and includes pathology originating from the neck, glenohumeral joint, acromioclavicular joint, rotator cuff, and other soft tissues around the shoulder girdle. The most common source of shoulder pain is the rotator cuff, accounting for over two-thirds of cases.

METHODS

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of oral drug treatment, topical drug treatment, local injections, non-drug treatment, and surgical treatment? We searched: Medline, Embase, The Cochrane Library, and other important databases up to August 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

RESULTS

We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

CONCLUSIONS

In this systematic review we present information relating to the effectiveness and safety of the following interventions: acupuncture, arthroscopic subacromial decompression, autologous whole blood injection, corticosteroids (oral, subacromial injection, or intra-articular injection), electrical stimulation, excision of distal clavicle, extracorporeal shock wave therapy, ice, laser treatment, manipulation under anaesthesia, suprascapular nerve block, non-steroidal anti-inflammatory drugs (oral, topical or intra-articular injection), opioid analgesics, paracetamol, physiotherapy (manual treatment, exercises), platelet-rich plasma injection, rotator cuff repair, shoulder arthroplasty, and ultrasound.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

BACKGROUND

Keloid is a fibrotic skin disease for which immune cell infiltration is a primary pathological hallmark. Meanwhile, in autoimmune diseases, triggering of the inflammation response can lead to tissue injury and subsequent organ fibrosis. When the skin is involved in autoimmune disease, skin fibrosis such as that seen in scleroderma can occur. In this study, we propose that keloid possesses features of autoimmune disease.

METHODS

To verify whether keloid possesses features of autoimmune disease, immune cell infiltration and immune complex deposits were detected with immunohistochemical staining and immunofluorescence, respectively, in keloid and normal skin tissues. A routine antinuclear antibody profile was tested in sera from 28 keloid patients and 28 healthy controls. Lastly, the anti-hnRNPA2B1 autoantibody in sera was evaluated by enzyme-linked immunosorbent assay.

RESULTS

The numbers of CD1α(+) Langerhans cells, CD3(+) T lymphocytes, CD68(+) macrophages, and CD20(+) B lymphocytes increased in keloid tissues compared to normal skin. IgA, IgM, C3, and C1q deposits were found in keloid tissues but not in normal skin, while anti-hnRNPA2B1 levels in sera from keloid patients were elevated.

CONCLUSIONS

The above findings suggest that keloids have some characteristics that are similar to autoimmune disease and might be mediated by autoimmune responses.

METHODS

This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Advances in nanotechnology have had profound impacts on therapeutic delivery, leading to the development of nanomaterials engineered with large carrying capabilities and targeting functionalities. Among the nanomaterials, dendrimers have garnered particular attention from researchers owing to their well-defined structure, near-monodispersity, and ease of multifunctionalization. As hyperbranched, three-dimensional macromolecules, dendrimers can be engineered to target and deliver a wide range of therapeutic agents, including small molecules, peptides, and genes, reducing their systemic toxicities and enhancing efficacies. In this review, we provide a comprehensive overview of the commonly employed dendrimer-based nanocarrier designs, including dendrimer conjugates, Janus dendrimers, and linear-dendritic block copolymers. The discussion will progress through the basic synthetic strategies of dendrimer-based nanocarriers, followed by the potential clinical applications related to their unique structural properties. Finally, the major challenges that these nanocarriers are currently facing in their clinical translation and possible solutions to address these issues will be discussed, with the aim to provide researchers in the drug delivery field a good understanding of the potential utilities of dendrimer-based nanocarriers. WIREs Nanomed Nanobiotechnol 2017, 9:e1409. doi: 10.1002/wnan.1409 For further resources related to this article, please visit the WIREs website.

The deployment of molecular to microscale carriers for intracellular delivery has tremendous potential for biology and medicine, especially for in vivo therapies. The field remains limited, however, by a poor understanding of how carriers gain access to the cell interior. In this review, we provide an overview of the different types of carriers, their speculated modes of entry, putative pathways of vesicular transport, and sites of endosomal escape. We compare this alongside pertinent examples from the cell biology of how viruses, bacteria, and their effectors enter cells and escape endosomal confinement. We anticipate insights into the mechanisms of cellular entry and endosomal escape will benefit future research efforts on effective carrier-mediated intracellular delivery. WIREs Nanomed Nanobiotechnol 2016, 8:465-478. doi: 10.1002/wnan.1377 For further resources related to this article, please visit the WIREs website.

The thalamus of the brain is far more than the simple sensory relay it was long thought to be. From its location at the top of the brain stem it interacts directly with nearly every part of the brain. Its dense loops into and out of cortex render it functionally a seventh cortical layer. Moreover, it receives and sends connections to most subcortical areas as well. Of course it does function as a very sophisticated sensory relay and thus is of vital importance to perception. But also it functions critically in all mental operations, including attention, memory, and consciousness, likely in different ways for different processes, as indicated by the consequences of damage to its various nuclei as well as by invasive studies in nonhuman animals. It plays a critical role also in the arousal system of the brain, in emotion, in movement, and in coordinating cortical computations. Given these important functional roles, and the dearth of knowledge about the details of its nonsensory nuclei, it is an attractive target for intensive study in the future, particularly in regard to its role in healthy and impaired cognitive functioning. WIREs Cogn Sci 2013, 4:523-545. doi: 10.1002/wcs.1256 CONFLICT OF INTEREST: The author has declared no conflicts of interest for this article. For further resources related to this article, please visit the WIREs website.