Table Table1 Research Articles

Multidisciplinary Management of Locoregional Recurrent Breast Cancer.

Locoregional recurrence (LRR) from breast cancer represents a heterogeneous class of disease that has significant variation in its prognosis and preferred treatments. Therefore, the optimal management of LRR disease requires multidisciplinary assessment and integration of input from all disciplines involved in breast cancer management. In this review, we identify prognostic variables associated with the treatment outcome of LRR disease; discuss the roles of surgery, radiation, and systemic treatments; and define reasonable treatment algorithms to aid in the evaluation and management of patients. Unfortunately, there are few prospective clinical trials to provide high-level evidence regarding the optimal therapeutic strategy for patients with LRR disease. Such trials are difficult to design and execute because of the heterogeneity of prognostic factors and previous treatments of patients. In addition, LRR is becoming much less common with improvements in diagnostic and therapeutic management of primary disease. For example, the risk of development of LRR in patients with early-stage disease treated with breast-conserving surgery, whole-breast radiation, and appropriate systemic treatments is approximately 0.5% per year.1 This rate is almost half that seen in the first generation of breast-conserving therapy (BCT) trials conducted several decades ago, which averaged LRR rates of approximately 1% per year.2 A number of reasons have contributed to these improved outcomes, including better diagnostic imaging and tumor localization, improved pathologic techniques and attention to surgical margins, more optimal localization of radiation to intended targets, and increased use of effective systemic therapies. These therapeutic advances have also significantly decreased the rates of LRR in patients treated with mastectomy. In one study that focused on LRR for patients with 1-3 positive lymph nodes treated with mastectomy, the LRR rate in a more contemporary cohort who did not receive postmastectomy radiation was 2.8% compared with a rate of 9.5% in a similar staged cohort that was treated approximately 15 years earlier.3 In this study, the era in which the patient was treated was the most significant predictor of the risk of LRR for the cohort of patients who did not receive initial radiation, with an adjusted hazard ratio (HR) of 0.35 for the more recent era (P < .001). Table ​Table11 highlights many of the important prognostic factors for patients with LRR. One of the first considerations for patients with isolated LRR is to determine whether the disease represents a true recurrence versus a new primary, particularly for those with an in-breast recurrence. The following factors suggest a new primary: change in the biomarker profile and/or histopathology of the disease, recurrence is in a different quadrant of the breast compared with the primary tumor, and changes in gene-expression profiles. Investigators from MD Anderson Cancer Center evaluated 397 patients with an in-breast recurrence and classified approximately half as having a new primary and half as having a true recurrence (based on tumor location, histologic subtype, and biomarker profile). The new primary cohort had a better 10-year survival and developed metastatic disease less commonly than patients classified as true recurrence but were more likely to develop contralateral breast carcinoma.4 A similar study from Yale University compared 70 patients classified as having a new primary, with 60 patients classified as having a true recurrence. Again, those with a new primary had a better overall 10-year overall survival (75% v 55%; P < .0001) and distant disease-free survival (DFS; 85% v 41%; P < .0001).5 TABLE 1. Prognostic Factors for Patients With LRR Disease

The 2019 WHO classification of tumours of the digestive system.

The WHO classification of digestive system tumours presented in the first volume of the WHO classification of tumours series, 5th edition, reflects important advancements in our understanding of tumours of the digestive system (Table ​(Table1).1). For the first time, certain tumour types are defined as much by their molecular phenotype as their histological characteristics; however, in most instances histopathological classification remains the gold standard for diagnosis. The WHO classification of tumours series is designed to be used worldwide, including those settings where a lack of tissue samples or of specific technical facilities limits the pathologist's ability to rely on molecular testing. Table 1 Selected changes within the new classification of tumours of the digestive system

Protocol for a systematic review of interventions addressing health literacy to improve asthma self-management

Supported self-management for asthma (written action plans and regular review) is highly effective at improving control and reducing acute attacks;1–3 however, globally this is challenging to implement both in adults and children.4–7 One particular challenge is the need to tailor support for people with limited health literacy. Limited health literacy is a universal problem, especially (but not only) in low-and-middle-income countries (LMICs).8–10 For example, nearly 90% of adults with type 2 diabetes attending primary care clinics in Malaysia11 and a third of teachers in Sri Lanka12 were assessed as having limited health literacy compared to about half the general population in a European survey.9 Use of different assessment techniques and sampling of different populations make it difficult to compare these results, though it is clear that this is a problem in all countries. Derived from a systematic content analyses of 19 papers, Sorensen et al.13 describes health literacy as people’s knowledge, motivation and competence to assess, understand, appraise and apply health information (see Table ​Table11 for definitions). These processes are vital to enable people to make considered judgments and decisions about healthcare and health promotion, which can improve quality of life and health outcomes such as reducing morbidity.13,14 Table 1 Definition of terms

Interprofessional pain education-with, from, and about competent, collaborative practice teams to transform pain care.

Pain is a complex experience that impacts health, productivity, and well-being. It requires a collaborative team approach with a common language and clear understanding of roles and responsibilities. With few exceptions, a minimum amount of pain content has been documented in health sciences curricula, and much of that has been fragmented by profession and delivered within a crowded agenda of conventional course topics such as anatomy and physiology.21 Most health professionals learn pain management on the job and are often ill-prepared to function as a team member in the real world. Despite documentation of the need for improved education on pain of all types, consistent professional training in pain is not widespread and innovation is warranted. The 2018 IASP Global Year for Excellence in Pain Education is a call to action on multiple levels. The purpose of this report is to describe opportunities for mutual learning through interprofessional (IP) pain education. Interprofessional education (IPE) is a growing trend across health professions and has been defined (Table ​(Table1)1) as when 2 or more professions learn with, from, and about each other to improve collaboration and the quality of care.16 For IP learning to occur, all 3 “with, from, and about” must be present.11 Table 1 Operational definitions.

Considering Cell Therapy Product "Good Manufacturing Practice" Status.

The promise of cell therapies is beginning to be recognized internationally. Cell therapy products (CTPs) are different from other drug products because many aim to be curative, and they are less comprehensively characterizable and more variable, sometimes being manufactured one lot at a time. They have complex mechanisms of action that remain incompletely understood. These unique features have led some regulators to take different approaches to cell therapy regulation in the form of special guidance for navigating regulatory frameworks that were originally intended for pharmaceutical drugs. A consideration for CTP developers is where to manufacture them, and under what circumstances. With few regulators developing manufacturing requirements specifically for CTPs, highly harmonized regulatory principles of Good Manufacturing Practice (GMP) for pharmaceuticals and biologics apply. However, what people mean when they say they make “GMP grade” CTPs remains ambiguous, and this confusion is exacerbated because most CTPs in early stage development are processed in whole or in part in academic hospital-based settings instead of industrial facilities. Since GMP guidelines were not originally written with CTPs in mind, the regulatory landscape has been influenced by “multi-level model of practice-driven institutional change” (1). That is to say that, in the absence of prescriptive regulations, the regulated party improvises to meet what they think the regulator expects, and then reorient approaches based on what others can be seen doing. The resulting practices evolve into basic standards of practice that regulators expect the field to follow. This situation compounds confusion about “GMP grade” CTPs because it presents a moving target and creates uncertainty for manufacturing CTPs emerging at the investigational stage of development. To inject some clarity, stating that GMP is a grade of material is overly simplistic. Instead, GMP should be considered a product-specific assertion based on what is known about a product’s relevant characteristics and a system of ensuring its quality and must be determined on a case-by-case, product-specific basis. This assertion can be substantiated, which may or may not include direct or indirect evidence of third party (e.g., regulator) review. Others have identified the need for CTP GMP and noted jurisdictional and study phase differences (2–5). From a review of regulatory documents, here we take a basic look at approaches taken in three full ICH member jurisdictions (Canada, the United States, and the European Union) to briefly summarize in (Table ​(Table1)1) similar but different approaches to assessing GMP throughout clinical trial development, and to suggest potential strategies for cell therapy clinical trial product manufacturers. Table 1 Summary table.

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus on arrhythmias and cognitive function: What is the best practice?

Keywords: European Heart Rhythm Association, Heart Rhythm Society, Asia Pacific Heart Rhythm Society, Latin American Heart Rhythm Society, Cognitive, Arrythmias, Dementia Table of Contents Introduction 1400 Evidence review 1400 Relationships with industry and other conflicts 1400a Decline of cognitive function: terminology and epidemiology 1400a Terminology: cognitive decline, mild cognitive impairment, and dementia 1400a Epidemiology of dementia 1400a Methods for assessment of cognitive function 1400b Role of imaging 1400c Atrial fibrillation and cognitive function 1400c Atrial fibrillation, overt stroke, and cognitive function 1400c Atrial fibrillation, silent stroke, and cognitive function 1400e Atrial fibrillation and cognitive function in the absence of stroke 1400g Assessment of cognitive function in atrial fibrillation patients in clinical practice 1400g Prevention of cognitive dysfunction in atrial fibrillation patients 1400h Other arrhythmias and cognitive dysfunction 1400j Cognitive dysfunction in patients with regular supraventricular tachycardias 1400j Cognitive impairment after cardiac arrest 1400j Cardiac implantable electronic devices and cognitive dysfunction 1400k Catheter ablation 1400k Implications for electrophysiological procedures and cognitive function 1400l Current knowledge gaps, future directions, and areas for research 1400m Recommendations 1400m Introduction This expert consensus statement of the European Heart Rhythm Association (EHRA), Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and the Latin American Heart Rhythm Society (LAHRS) summarizes the consensus of the international writing group and is based on a thorough review of the medical literature regarding cognitive function in arrhythmias. The document is intended to describe the impact of different types of arrhythmias on cognitive function, to highlight possible risk markers for cognitive decline and to formulate implications for clinical practice regarding follow-up methods, prevention and treatment strategies. Our objective is to raise awareness of cognitive function among physicians treating patients with arrhythmias and to provide them with practical proposals that may lead to improvement of patient care in this regard. This document reviews terminology and the epidemiology of cognitive dysfunction, methods for assessment of cognitive function and the role of imaging. Recent studies have suggested possible associations between cognitive decline and atrial fibrillation (AF). We review the reported literature on AF and cognitive function, including the scenarios of AF with overt stroke, silent stroke, or no stroke, and then make recommendations for assessment of cognitive function and prevention of cognitive decline in patients with AF in clinical practice. The document also reviews the association of other arrhythmias and cognitive dysfunction, including settings such as post-cardiac arrest, cardiac implantable devices, such as implantable cardioverter-defibrillators (ICDs) and pacemakers, or ablation procedures. Implications for electrophysiological procedures and cognitive function are discussed. Long QT syndrome and cognitive function is not addressed in the document. For quick reference, sub-chapters are followed by a short section on consensus recommendations. The document concludes with a summary of consensus statements, current knowledge gaps, and future directions of research. Evidence review Members of the Task Force were asked to perform a detailed literature review, weigh the strength of evidence for or against a particular treatment or procedure, and include estimates of expected health outcomes for which data exist. Patient-specific modifiers, co-morbidities, and issues of patient preference that might influence the choice of particular tests or therapies are considered, as are frequency of follow-up and cost-effectiveness. In controversial areas, or with regard to issues without evidence other than usual clinical practice, a consensus was achieved by agreement of the expert panel after thorough deliberations. This document was prepared by the Task Force with representation from EHRA, HRS, APHRS, and LAHRS. The document was peer-reviewed by official external reviewers representing EHRA, HRS, APHRS, and LAHRS. Consensus statements are evidence-based and derived primarily from published data or determined through consensus opinion if data are not available. Current systems of ranking level of evidence are becoming complicated in a way that their practical utility might be compromised.1 In contrast to guidelines, we opted for an easier and user-friendly system of ranking using ‘coloured hearts’ that should allow physicians to easily assess the current status of the evidence and consequent guidance (Table ​Table11). This EHRA grading of consensus statements does not have separate definitions of the level of evidence. This categorization, used for consensus statements, must not be considered as directly similar to that used for official society guideline recommendations, which apply a classification (Class I–III) and level of evidence (A, B, and C) to recommendations used in official guidelines. Table 1 Scientific rationale of recommendations*

Fontan-associated liver disease: Monitoring progression of liver fibrosis.

FALD continues to attract much research interest as complications affecting patient morbidity and mortality become increasingly apparent. Currently, there are still no official guidelines for monitoring this population, and multicenter cohort studies have only been published within the past year.1 Guidelines are institution dependent (Fig. ​(Fig.2,2, Table ​Table11).1, 3, 7, 10, 12 Future research will continue to focus on risk stratification of patients for severe sequelae of liver disease and on understanding the role of elastography and noninvasive markers in this population while trying to learn more about the pathophysiological etiology of FALD.

Eradicating gastric cancer.

Gastric cancer develops in a stepwise manner along the inflammation–metaplasia–dysplasia–carcinoma pathway. Similar to several infection‐associated cancers, such as liver cancer (associated with viral hepatitis B and C) and cervical cancer (associated with human papilloma virus), Helicobacter pylori infection is the main trigger of this carcinogenic cascade. Observational studies with baseline serological testing and more than 10 years of follow up have found that chronic H. pylori infection is related to about 90% of gastric cancers and thus removal of this bacterium from a population has been postulated to eradicate the occurrence of gastric cancer.1 This hypothesis has stimulated numerous investigations indicating not only the magnitude of benefit obtained from a short‐course antibiotic treatment but also the principles to help policymakers design preventive services that maximize the effectiveness of using this strategy. The application of this antibiotic‐based approach for gastric cancer prevention has been hindered by a lack of answers to four important questions (Table ​(Table1).1). There are now satisfactory answers to these questions. Table 1 Questions about the elimination of gastric cancer through H. pylori eradication.

Pazopanib in Patients with Clear-Cell Renal Cell Carcinoma: Seeking the Right Patient.

Since its early development, the vascular endothelial growth factors (VEGFRs) inhibitor pazopanib showed both activity and tolerability in patients with metastatic RCC (mRCC) (Hurwitz et al., 2009), results which were subsequently confirmed in the following studies. A phase II study was at first designed as a randomized discontinuation study, but lately revised to an open-label study based on week 12 response rate (RR) of 38% in the first 60 patients. Thus, the primary end-point was changed from progressive disease rate at 16 weeks post-randomization to RR (Hutson et al., 2010). Overall RR was 35%, median duration of response was 68 weeks, and median progression-free survival (PFS) was 52 weeks (Hutson et al., 2010). Pazopanib was registered based on a global randomized, placebo-controlled, phase III trial. Of the 435 patients enrolled, 233 (54%) were treatment-naive, while 202 (46%) were pre-treated with cytokines. Pazopanib significantly prolonged PFS in overall study population [median PFS: 9.2 vs. 4.2 months, hazard ratio (HR): 0.46, 95% CI: 0.34–0.62, p < 0.0001], in the cytokine-pretreated subpopulation, as well as in the treatment-naive subpopulation (median PFS: 11.1 vs. 2.8 months, HR: 0.40, 95% CI: 0.27–0.60, p < 0.0001), compared to placebo (Sternberg et al., 2010). Furthermore, the objective response rate (ORR) was 30% with pazopanib with a median duration of response longer than 1 year. None clinically important difference in quality of life for pazopanib vs. placebo was observed in the safety analysis (Sternberg et al., 2010). More recently, the phase III COMPARZ study directly compared pazopanib with sunitinib in a non-inferiority study (Escudier et al., 2014). Pazopanib was non-inferior to sunitinib in terms of PFS (HR: 1.05, 95% CI: 0.90–1.22—predefined upper bound of the 95% CI < 1.25), and similar in OS (HR: 0.91, 95% CI: 0.76–1.08; Motzer et al., 2013); ORR was higher for pazopanib, as compared to sunitinib (31 vs. 25%, p = 0.03; Motzer et al., 2013). In terms of safety, pazopanib-treated patients experienced less fatigue, fewer side effects, including soreness of hand/foot and mouth/throat, and were more satisfied with treatment than those who received sunitinib (Motzer et al., 2013; Table ​Table1).1). Less fatigue and better overall quality of life were the most common reasons that justified the preference of pazopanib vs. sunitinib (70 vs. 22%, p < 0.01) in the PISCES study, a cross-over, double blind trial which specifically assessed the innovative endpoint of patients' preference (Escudier et al., 2014). Table 1 Comparison of baseline characteristics, clinical outcomes and adverse events in pivotal studies.

Where Are We Now with the Role of Steroids in the Management of Bronchopulmonary Dysplasia in Extremely Premature Babies?

Where Are We Now with the Role of Steroids in the Management of Bronchopulmonary Dysplasia in Extremely Premature Babies?

Pesticide regulatory risk assessment, monitoring, and fate studies in the northern zone: recommendations from a Nordic-Baltic workshop.

The recent revision of the legal framework for authorization of use of plant protection products and pesticides within the European Union/European Economic Area (EU/EEA; Regulation EC 1107/2009, Directive 2009/128/EC) imposes a need for close collaboration across country borders within the three pesticide authorization zones (designated the north, central, and south zones) in Europe. The principles of zonal evaluation and mutual recognition embedded in Regulation EC 1107/2009 concerning marketing of plant protection products are intended to reduce the approval times for pesticides. However, the three authorization zones represent a very simplified view compared to the 16 climatic zones/scenarios that have been outlined for pesticide modeling in Europe (Blenkinsop et al. 2008; Fig. 1). Pedoclimatic or agricultural constraints could entitle the individual states to adopt restrictions on the use of pesticides approved within their zone or even to refuse approval. Fig. 1 Zones for pesticide authorization overlaid on climatic zones for pesticide modeling (reprinted from Blenkinsop et al. 2008 with permission from Elsevier) in Europe To achieve a sound scientific basis for zonal evaluation and collaboration on a regulatory level, it is also necessary to increase research collaboration and knowledge exchange within the scientific community. Here, we report the main conclusions and recommendations from a Nordic-Baltic workshop on the environmental fate of pesticides, which was conducted in As, Norway, in September 2014 with the aim of promoting knowledge exchange, network building, and a common agenda for future research within the northern zone. Pesticide regulatory risk assessment in the northern zone Zonal evaluation and mutual recognition The “Guidance document on work sharing in the Northern zone in the authorization of plant protection products” (Anonymous 2015) states that the northern zone cooperation includes the EU member states Denmark, Sweden, Finland, Estonia, Latvia, and Lithuania, as well as the European Economic Community/European Free Trade Association (EEC/EFTA) members Norway and Iceland. The guidance document was implemented in all countries within the zone from January 2015. Climatic zones for pesticide modeling (Blenkinsop et al. 2008) reflect the complexity of the different authorization zones within Europe (Fig. 1). According to this classification, the northern zone countries cover seven of the 16 climatic zones (Table ​(Table1).1). The variation within the northern zone is further illustrated by the 13 environmental zones representing an aggregation of the environmental stratification of Europe (Metzger et al. 2005; Jongman et al. 2006), five of which are covered by the northern zone countries (Table ​(Table2).2). The duration of the growing season and the sum of active temperatures are doubled when moving southward from the alpine north to the Atlantic north. This will inevitably affect the possibility of harmonizing risk assessment procedures and/or requirements between the countries within the northern zone, and it will also influence the commercial viability of the pesticide industry. Table 1 Climate zones for pesticide modeling (Blenkinsop et al. 2008) in the northern zone countries Table 2 Growing season characteristics in the northern zone based on the environmental stratification of Europe (Metzger et al. 2005; Jongman et al. 2006) Due to the strict limits of the timeline for the zonal evaluation (SANCO/13169/2010 rev. 9), there must be good agreement between the countries in the northern zone to ensure a satisfactory risk assessment. The time frame during which the member states are to appraise specific national concerns comprises a period of 6 weeks for commenting on the draft regulatory report and 120 days for assessment after the initial zonal evaluation.

Not Only Clinical Efficacy in Psychological Treatments: Clinical Psychology Must Promote Cost-Benefit, Cost-Effectiveness, and Cost-Utility Analysis.

Not Only Clinical Efficacy in Psychological Treatments: Clinical Psychology Must Promote Cost-Benefit, Cost-Effectiveness, and Cost-Utility Analysis.

Commentary: Memory CD8(+) T cells colocalize with IL-7(+) stromal cells in bone marrow and rest in terms of proliferation and transcription.

Commentary: Memory CD8(+) T cells colocalize with IL-7(+) stromal cells in bone marrow and rest in terms of proliferation and transcription.

Biomolecular Relationships Discovered from Biological Labyrinth and Lost in Ocean of Literature: Community Efforts Can Rescue Until Automated Artificial Intelligence Takes Over

Many brilliant minds are at work to decipher the biological labyrinth and as a result immense amount of information about biological entities and their relationships is getting accumulated in the form of published literature (Hunter and Cohen, 2006). To cater the needs of a researcher, many tools are designed to perform tasks of Named Entity Recognition (NER), Information Retrieval (IR), and Information Extraction (IE) viz. A Combined Clinical Concept Annotator (Kang et al., 2012), BANNER (Leaman and Gonzalez, 2008), Biblio-MetReS (Usie et al., 2014), BioTextQuest+ (Papanikolaou et al., 2014), BIOSMILE Web Search (Dai et al., 2008), E3Miner (Lee et al., 2008), EBIMed (Rebholz-Schuhmann et al., 2007), eFIP (Arighi et al., 2011), FACTA+ (Tsuruoka et al., 2008), GNSuite1, iHOP (Hoffmann and Valencia, 2004), MyMiner (Salgado et al., 2012), RLIMS-P(Hu et al., 2005), Anni (Jelier et al., 2008), CoPub (Frijters et al., 2008), MedScan (Novichkova et al., 2003), PPInterFinder (Raja et al., 2012), pGenN (Ding et al., 2015), SciMiner (Hur et al., 2009), BIGNER (Li et al., 2009), hybrid named entity tagger (Raja et al., 2014), and more such tools can be obtained from BIONLP resource2 and in detail analysis of many NLP tools is given by Krallinger et al. (2008) and Fleuren and Alkema (2015). Table ​Table11 gives an informational and statistical insight into some of these literature mining tools, shedding light on their efficiency translated by statistical parameters viz. F-score, recall, and precision. Many tools are domain specific like kinase family specific but still calls for human intervention for exactitude and thus limit their usage. Moreover, the data output formats are sometimes too vague as name highlighting; to be put to use for bigger literature searches. Table 1 Informational (viz. data used, parameters for evaluation and working platform) and statistical (viz. f-value, recall and precision) insights for a few literature mining tools with their brief description and links to the tools' home page. The naming ambiguity in scientific literature is one of the major concerns for NER and sentence structure for IR and IE. Presently, NER tools need to maintain a comprehensive dictionary of all names, aliases and web-repository specific IDs or have their AI (Artificial Intelligence) defined algorithms trained on many test data sets. Many such dictionaries are available but the list is ever-increasing and so is the training data set. This results into investing more money, time and effort in obtaining a comprehensive list of names, aliases and IDs. A very comprehensive work on NLP can be found on BioNLP3. The availability of manpower or intellect is huge but there is acute scarcity of funds (Bourne et al., 2015), so we have to device optimized approaches to take care of the issues discussed in subsequent section.

The Evolutionary Concept of "Preadaptation" Applied to Cognitive Neurosciences.

The Evolutionary Concept of "Preadaptation" Applied to Cognitive Neurosciences.

Stone Throwing in the Glass House.

A small girl with a unique genetic syndrome lies in bed since birth. Her brain does not work. She is in a persistent vegetative state. Recurrent seizures punctuate her intractable epilepsy. She shows no meaningful interaction. Her breathing is insufficient. Upper airway obstruction, repeated aspiration events, chronic lung disease, and scoliosis make her struggle to breathe. Her parents never wanted her to suffer. Two years ago, they agreed to a Physician Orders for Life-Sustaining Treatment (POLST). Their daughter would not undergo resuscitation. Death did not come, however. With meticulous medical care, her body grew. Her breathing worsened. Offered either palliation or a tracheostomy tube, her parents chose “trach.” With easier breathing, the girl expended fewer calories. She continued gastrostomy tube feeds and gained 10 pounds in 3 months. Now she is rehospitalized with respiratory distress. Her weight rises another 2 pounds. We put off calorie reduction for the outpatient setting. For the first time, we discharge the family home with a mechanical ventilator. Our collective health-care efforts have set up a protracted course whose likely end will come in overwhelming sepsis or ARDS, rather than allowing natural death with palliative care. How many ethical issues were raised by this case? I count more than 40 (Table ​(Table11).

Astrocytes Modulate Local Field Potential Rhythm?

Astrocytes Modulate Local Field Potential Rhythm?

Atlas of the Postnatal Rat Brain in Stereotaxic Coordinates.

The series of atlases of the developing rat brain in stereotaxic coordinates that we propose here1,2 has been conceived as a tool for the exploration of the rat brain in vivo during the postnatal period, offering a choice of bregma and lambda as the reference points. We suggest to use this atlas, which provides stereotaxic coordinates, in combination with other histological atlases, where brain structures and boundaries between them were assessed using histochemistry or quantative magnetic resonance techniques, but where stereotaxic coordinates are not available (Ramachandra and Subramanian, 2011; Calabrese et al., 2013; Ashwell and Paxinos, 2015) or provided (at P10, P21, and P39) but not within the bregma-lambda metrics (Sherwood and Timiras, 1970). The neonatal rat is a powerful model for the study of the early stages of central nervous system development. Comparative developmental studies suggest that the first two postnatal weeks in the rat roughly correspond to the second half of gestation and the early postnatal period in humans, with the electrical brain activity patterns expressed during this period and their developmental trajectories matching the patterns observed in premature human neonates (Clancy et al., 2001, 2007; Khazipov and Luhmann, 2006; Colonnese et al., 2010; Workman et al., 2013) (see also http://www.translatingtime.net/). Recent advances in the understanding of the developing brain functions largely came from the use of techniques to record brain activity from neonatal and adolescent rats in vivo, notably in head restrained animals (Leinekugel et al., 2002; Khazipov et al., 2004; Minlebaev et al., 2011; Tiriac et al., 2012; Yang et al., 2013). However, the rat brain grows rapidly and non-proportionally during the postnatal period and brain structures change their position in relation to the conventional skull marks such as bregma and lambda, making difficult to perform targeted recordings, stimulations, lesions, or local drug injections in precise anatomical locations. Hence the importance of a developmental atlas of the rat brain in stereotaxic coordinates. Several examples of histology atlases series of the developing rat brain have been published (Table ​(Table1).1). The Atlas by Sherwood and Timiras “A Stereotaxic Atlas of the Developing Rat Brain” atlas includes three postnatal time points: postnatal days P10, P21, and P39 (Sherwood and Timiras, 1970). Ashwell and Paxinos' “Atlas of the Developing Rat Nervous System” provides photographs and accompanying diagrams of coronal and sagittal sections of rats aged E12, E13, E14, E16, E17, E19, and P0 (Ashwell and Paxinos, 2015). “Atlas of the Neonatal Rat Brain” by Ramachandra and Subramanian describes rat brains at P1, P7, and P14 (Ramachandra and Subramanian, 2011). More recently, Calabrese, Badea, Watson, and Johnson published their “Quantitative magnetic resonance histology atlas of postnatal rat brain development with regional estimates of growth and variability” based on the study of P0, P2, P4, P8, P12, P18, P24, P40, and P80 rats (Calabrese et al., 2013). Among these atlases, only the atlas by Sherwood and Timiras (1970) provides stereotaxic coordinates and yet for only three postnatal days P10, 21, and P39. Stereotaxic atlases for the early postnatal period are not available, however. Table 1 Atlases of the developing rat brain. The series of atlases of the developing rat brain in stereotaxic coordinates that we propose here has been conceived as a tool for the exploration of the rat brain in vivo during the postnatal period, offering a choice of bregma and lambda as the reference points. Each atlas contains a series of microphotographs of wet, non-stained 200 micron coronal brain sections in oblique light, obtained from postnatal days P0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 14, and 21 rats, with an indication of the main brain structures. Wet non-stained sections were used to avoid deformation, shrinkage and lessening associated with staining and mounting procedures, particularly when manipulating immature tissue. Because we did not stain sections, the images do not provide cellular resolution and not all brain structures and boundaries between them can be easily identified. Therefore, only certain brain structures are labeled without boundaries. Used in combination with the existing high image resolution atlases of the developing rat brain (Sherwood and Timiras, 1970; Ramachandra and Subramanian, 2011; Calabrese et al., 2013; Ashwell and Paxinos, 2015), this atlas may be useful for targeted recordings, stimulations, and drug injections in different brain structures at various postnatal ages. This atlas has been successfully used in several previous studies (Minlebaev et al., 2011; Petit et al., 2014; Tyzio et al., 2014).

Commentary: Attention to Eyes Is Present but in Decline in 2-6-Month-Old Infants Later Diagnosed with Autism.

A recent Nature article provided preliminary evidence that infants age 2–6 months old, who were later diagnosed with Autism Spectrum Disorder (ASD), fixated more on the mouth than eyes and more at objects than people when viewing videos of typical childhood social scenes (1). While the sample was small, a reliable pattern of decline in eye fixation accurately predicted their level and classification of symptoms at age three suggesting that – for the first time – an infant could be assessed within the first 6 months of life for their potential of developing ASD (see Table ​Table11 for studies that used eye-tracking with infants 12 months and younger). These eye-tracking devices, which are currently in clinical trials, could provide access to an affordable and objective tool with the potential for extremely early intervention. Detecting ASD risk during the first 6 months of life presents unprecedented opportunities to intervene, providing children opportunities to build critical skills before autistic characteristics fully emerge. Because the eye-tracking device allows for a non-invasive, portable assessment, the device could also enable pediatricians to provide comparable screening services globally. With such promise, a near future where infants are placed into an eye-tracking device at routine pediatric visits is compelling, if not guaranteed.

Numerical simulations in two-dimensional neural fields

We present and discuss a new numerical algorithm for solving the two-dimensional Neural Field Equation with space-dependent delays: c∂∂tV(x¯,t)=I(x¯,t)−V(x¯,t)+∫ΩK(|x¯−y¯|)S(V(y,t−τ(x¯,y¯))dy¯t∈[0,T], x¯∈Ω⊂ℝ2 used in Neuroscience to describe the evolution of a population of neurons and the interactions between them. A similar equation (without delays) was first introduced by Wilson and Cowan [1], and then by Amari [2]. Here V(x,t) represents the post-synaptic membrane potential at instant t and position x. The function I represents external sources of excitation and S describes the dependence between the firing rate of the neurons and their membrane potential (typically it is a function of sigmoidal type). The kernel function K(|x-y|) describes the connectivity between the neurons at positions × and y. The delay τ(x,y) takes into the consideration the time spent by an electrical signal to travel between these two positions. The new numerical method presented in this work is based on an implicit second order method for discretisation in time and uses Gaussian quadratures for space integration. We use low-rank methods to reduce the computational effort, which enables to reduce very significantly the dimensions of the involved matrices, without affecting the final accuracy of the method. This algorithm is targeted directly to the application in Neuroscience and Robotics. As an illustration of such applications, we consider a neural field described in [3], where the firing rate function has the form S(x)= 2/ (1+exp(- μ x)) (μ is a certain positive constant), and the connectivity function is given by K(x)= 1/(2 πξ12)1/2 exp(- ||x||2/ 2 ξ12) - A/(2 πξ22)1/2 exp(- ||x||2/ 2 ξ22), with A, ξ1, ξ2 given positive constants. It is known [3] that the stability of the trivial solution of this equation depends on the value of μ and on the parameters of the connectivity function. In particular, for each set of values of these parameters, it is possible to compute a bifurcation value μbif, such that if μ < μbif the zero solution is stable, and otherwise it is unstable. With the help of our algorithm, these bifurcation values can be efficiently computed. Some examples are displayed in Table ​Table11 . The presented values are for the case τ(x,y)=0. Table 1