The Cultivation of Creativity in the Classroom

Introduction

Conceptually, creativity is defined as the ability to produce a new work or idea based on imagination. Younger psychologists argue that creativity is not a special skill or ability of a few people, but rather is the result of special training and learning through specific processes, which enable each individual to activate inexhaustible forces of his mind [1]. Many view creativity as a tendency to activate or recognize alternative ideas or possibilities, which can prove useful in problem solving, in communicating with others, or even in the field of entertainment. Creativity according to others is to think outside the blueprints or frameworks, approaching new areas and achieving results, which are able to provide answers to problems that concern them [2]. In this process, a clear distinction is made between predetermined abilities. Of course, the first concerns creativity, learning ability and communication. The latter are directly related to production, economy, marketing, etc. Creativity therefore moves within an indefinite pattern and can be evaluated through different processes. Many also argue that creativity can be seen as a process by which new original and useful ideas are activated, which help to deal with everyday problems and challenges. But it is important to see human creativity as the art of the different in terms of thinking. But in order to formulate a definition that will be based on scientific data, it is important to do a historical review and to trace the way in which science used to deal with, and continues to deal with, the concept of creativity. But in order not to get lost in the vastness of the various sciences, we will approach it both as an object of psychological research and as an object of pedagogical practice [3].

It is a fact that creativity has preoccupied researchers and around the subject has developed a large bibliography that gives new dimensions to creative thinking and opens new perspectives. As a starting point for creativity, we refer to the discomfort Guilford posed to the American Psychological Society in 1950 over the way the scientific community approached creativity, which was listed in the international literature as an “American challenge.” This discomfort and Guilford’s concerns in general were the trigger for the development of a number of approaches to creative thinking [4]. The interest of scientists and researchers to deal with the creative thinking of man and the abandonment of the concept of the “divine gift”, gave a series of definitions which we present below in order to arrive at a more widely accepted definition, but also through management of the concept of creativity to be able to understand the nature of creative thinking and the structural principles that govern it. Guilford made a first attempt to define the concept, according to which “creativity covers the most characteristic abilities of creative individuals, which determine the probability for an individual to express a creative behavior, which is manifested by ingenuity, composition and design.” of course, this definition is simplistic, but some facts emerge that are then confirmed by researchers. This ability seems to be linked to certain personality traits.

These characteristics speculate if and how creativity will manifest. Creativity affects all individuals and is not a rare phenomenon only of gifted individuals [5]. “Differentiation between individuals is quantitative, a matter of classification, not qualitative.” Getzels and Jackson (1962) define creativity as the combination of those elements that are considered original and different [5]. They point out that creativity is one of the most valuable human possibilities, but it is difficult to examine it systematically. Lowenfeld and Brittain (1975) argue that creativity is directly related to who gives the definition. Thus, some psychologists distinguish as qualitative elements of creativity:
a. Flexibility of thought
b. The originality of the idea
c. The ability to think differently
d. How to solve problems.

Of course, here we have to contrast Einstein’s view, which argues that formulating a problem is more important than solving it. Piaget (1960) defines creativity as a process of problem solving, problem finding, exploration, experimentation, an intellectual energy that implies respect and thoughtful decision making. Torrance (1966) identifies creativity with the ability of the individual to face various problems, with sensitivity, originality but also with method and calm. Creativity according to Lee, Webberlen and Litt (1987) is a multifaceted phenomenon and every issue that arises is addressed through different processes. We must also cite the view of Bruner (1962) who defines creativity as an energy from which arises a special and effective surprise [3]. Freud (1972) defines creativity as an instinctive impulse that aims at creation but also correlates it with the impulse of destruction. Creativity can include shaping new systems, transferring familiar relationships to a different field, and shaping new correlations. Through the conceptual approach it follows that it is difficult to integrate creativity into a definition. We adopt what Davis (1992) states: “There are as many infinite definitions and ideas of creativity as there are people who have written their ideas on a piece of paper.” Of course, if we want to categorize the prevailing positions on creativity, we could mention:
a. The traditional view, which claims that there are a number of “intelligent”, “gifted” people, this category includes people with exceptional talent or some special skills that stand out from the rest and cite as examples personalities such as Mozart and Einstein and according to this creativity is not the same in all people, so it is not cultivated.
b. The modern view, which argues that talent is mainly the result of practice and hard work, and all individuals have the opportunity to reach a degree of creativity and the cognitive processes followed in the emergence of ideas are no different from every day and therefore creativity can be cultivated.

The nature of Creativity

Creativity is about observing known things, it is based on previous ideas - experiences and the search extends to something new or a different approach. Among the main reasons that drive creativity, we distinguish:
a) The need for an innate impulse inherent in the human mind for something new.
b) The communicative need for exchange of ideas.
c) The human need to solve problems and create new ideas.

The human brain is the one that plays an important role in every creation, whether it is associated with human survival and the construction of the first tools, with mental functions, with artistic creations or even with the confrontation of everyday human problems. Creativity does not start with zero states [6]. It can be built on pre-existing knowledge or experiences. In the nature of creativity, we must mention an important element that runs through the whole process. It is the element of imagination that enables people and much more children to successfully process everyday situations and develop their creative abilities [6]. Imagination and creativity could be said to move in parallel and are interconnected. Of course, we must emphasize that creativity does not start from scratch, like the imagination, in the sense that the pre-existing elements that are inscribed in the consciousness help to create new representations in the form of images or ideas. This begs the question, are the representations of memory the same as the representations that exist and are recorded in the imagination? Their difference is more in the form and not in the content. It is important to point out that there is a danger in childhood that the imaginary will become an extension of reality.

The Evaluation of Creativity

Evaluation is the stage at which an account of what has been produced is made. It is an important stage in the whole process through which the ideas produced are evaluated [7]. Without it, the process would be “incomplete”. Furthermore, every evaluation of ideas has basic principles, such as: “it is a continuous process, it must be done for all ideas, it must have the meaning of collectivity, it must be objective, and it must be a guide for further paths” [8]. It is suggested that the convergent thinking be evaluated separately from the divergent one in order to understand the differences. Evaluating creativity is important for the following reasons:
a) It contributes decisively for the younger generations to show their abilities and to take advantage of their inclinations and interests.
b) It is a determining factor and a steady step towards selfknowledge.
c) It prepares future generations to adapt to the rapid changes that are taking place” [8].

Creativity is not an objective feature, because we have the ability to use indicators to evaluate the creative possibilities through which objective determination is achieved. We should mention that there are no surefire ways to guarantee the reproduction of innovative ideas. Source inspiration does not fall into measurement scales. Of course, there have been references to specific brainstorming processes, but the issue remains open, as discussions persist in the qualitative dimension, which is not measurable [9].

Evaluation Methods

From the search in the foreign language literature regarding the methods of evaluation of the creative inclination and ability, we have distinguished numerous and flexible methods that enable the evaluation. Of course, we should point out the research controversy in the scientific community regarding the evaluation of creativity [10]. Hocevar in a thorough review of creativity presented key points - axes used in creativity studies:
a. Convergent thinking exercises.
b. Divergent thinking exercises.
c. Recording the behavior and interests of individuals.
d. Recording of special personality elements.
There are other ways to measure creativity, such as:
1. Plot titles: here the participants are given the plot of a story and asked to come up with original titles.
2. Quick reactions to word associations: this is where unusual answers are scored.
3. Conception of shapes and forms: here are presented simple drawings of people and objects and they are asked to find common properties and characteristics in two or more paintings. Scoring is again based on unusual answers.
4. Unusual uses: here are given everyday objects, e.g., a toothpick and unusual applications are required.
5. Remote correlations: here participants are asked to create a new word from two other simple ones.
6. Distant effects: this calls for the activation of a list of consequences of unexpected events.
7. Creativity can also be calculated based on the response to a variety of test scenarios, such as:
8. The expression of ideas: the ability to easily develop a variety of reasoning and correlations, when presented with a simple word or image.
9. The combination of ideas in a new way: the development of a wide range of innovative approaches and solutions, when we are asked to explore new possibilities for an ordinary simple object of our daily life (eg a brick).
The emergence of new benefits for existing ideas: the activation of original ideas or solutions based on pre-existing ideas. Investigation: the ability to process an idea in order to make it practically functional. Focus and distinction: identifying the most important elements of an idea and then approaching them in an effort to solve a problem while simultaneously evaluating the difficulties. Perspective exchange: the ability to suggest ways to view and solve a problem in the light of different perspectives.

Children and Creativity the Cultivation of Creativity in the Classroom

Teachers should review the teaching practices they apply in order to be able to judge the extent to which they have been able to instill in students a creative way of thinking. Some ways to boost creativity by teachers are:
Enhancing divergent thinking:
a) Allow the teacher to ask questions of the student.
b) Be educationally receptive and sensitive to the problems faced by students.
c) To make the children realize the maximum importance of the questions, but also not to be afraid to trust their senses.
d) Problems should not be presented simply but discovered.
e) Attempt to try a second Tuesday etc. to find a solution to each problem.
f) The taught subjects of the courses to be examined from different angles.
g) To convey to the students the message that they should not rest on the first correct answer they will give.
h) In general, is there anything going on in the school that could be part of the concept of divergent thinking?
i) In any case, Learning should not be a mechanical storage of knowledge from textbooks and teachers.
j) Existence of motivation and encouragement:
k) Students’ questions should be accepted by teachers so that they can then develop.
l) Children’s curiosity to be supported and additionally provoked.
m) Opportunities for self-directed learning should be provided.
n) The teacher appreciates and supports the personal interests of the student.
o) Unnecessary repetition of a theme should be avoided.
p) Receptivity to the new
q) The school should be not only a place of traditional teaching, but also of enjoyment, fun and challenge for spiritual adventures.
r) Teaching should convey the real world within the school.
s) As a place the school should be offered for the cultivation of imagination.
t) The school must be able to dispel stress and provide a sense of comfort and relaxation to the student.
u) The school must provide opportunities and opportunities for a subject to be examined in an experimental and at the same time pleasant way.
v) Finally, the uniqueness and individual personality of each student should be assessed, and a conservative attitude should not be imposed.
Cultivation of creativity must be an integral part of the educational process (Jullien, 2004). We emphasize that the cultivation of creative tendencies should not be pursued only within the framework of some ‘special hourly support programs that will be repeated at sparse intervals or at a predetermined time and place. The desire to cultivate such an important element must overcome all limitations and be systematically systematized, in every activity that accompanies school and extracurricular life.

Conclusions

Creativity is a multifaceted concept. Its special nature leads to the non-existence of a unified psychological theory that will explain and include all its dimensions. Many people still associate it with the arts and avoid associating it with other cognitive objects such as the sciences which are considered uncreative. They believe that creativity is a special feature of some people who are involved in the arts. The importance of creativity for art is very important but it is equally important in the sciences and in other cognitive areas that result from the composition of two areas. For example, the use of art in the natural sciences and vice versa. Today we have come to the conclusion that creativity is characteristic of every human being. All people can be creative as long as they are given the opportunity and find themselves in an environment where the conditions are right for them to develop and cultivate their creative skills. The development of creativity in the school context is important and there are specific ways to enhance and promote it that must be taken care of by teachers. The evaluation of creativity also plays an important role, which is a key factor in the course of children’s education at all levels of education.

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Rapid and Practical Screening Method for the Detection of Colistin-Resistant Bacteria in Food

Introduction

Colistin is recognized as one of the few remaining available antibiotics for the treatment of intractable infections caused by multidrug-resistant Gram-negative bacteria [1]. Recent studies have shown that bacteria carrying the mcr gene, which confers colistin resistance to most members of the Enterobacteriaceae, are widely disseminated, particularly in Asia [2,3]. Since colistin is widely used in animal husbandry [4], the spread of colistin-resistant (CR) bacteria in communities via livestock food is a potential risk factor. Moreover, CR bacteria are often found in animals and animalfood [5-7]; thus, monitoring CR bacteria in animal-food is essential. However, the conventional culture method [8] for detecting CR bacteria in food is laborious and time-consuming. Rapid detection of colistin resistance genes at the research level is now possible using the SYBR green method [9], but its widespread practicality is limited due to the need for complex steps and equipment involved in DNA extraction from samples and determination of result specificity. To overcome this limitation, we here report a simple, rapid, and practical detection method of Escherichia coli harboring mcr-1, as a representative CR bacterium, using a highspeed real-time polymerase chain reaction (PCR) kit. We further verified the utility of this method for detecting CR bacteria in retail meat samples. Although a real-time PCR assay for the detection of mcr genes from bacterial isolates has already been established, this newly proposed detection method holds practical relevance for widespread use, as the entire procedure, from food sample processing to the final result, can be completed within only 1 h.

Materials and Methods

A total of 27 retail meat samples, including pork and chicken, were collected from 10 markets (two supermarkets and eight local traditional markets) in Vietnam and five supermarkets in Japan during November and December 2019. None of the eight traditional markets in Vietnam maintained a refrigerator for meat preservation. In contrast, the two supermarkets in Vietnam and all five supermarkets in Japan had refrigerators for food storage. Each sample was collected from one meat type per market. Bacterial cultures and DNA extraction were performed on the collection day. Ten grams of each meat sample were placed in a stomacher bag (AS ONE, Osaka, Japan) containing 90 mL buffered peptone water. The samples were hand-homogenized for 2 min. The resulting homogenate was inoculated on CHROMagar COL-APSE (CHROMagar, Paris, France), a selective medium for CR Gram-negative bacteria, and cultured at 37 °C for 24 h. CR E. coli-like colonies were distinguished based on colony color (dark pink to reddish) after cultivation [8,10]. A representative colony was isolated by sub-culturing on MacConkey agar, and bacterial identification was performed. The colistin minimum inhibitory concentration (MIC) was estimated, and colistin resistance genes (mcr-1 to -5) were detected by multiplex PCR as described previously [6,11].
In parallel, DNA was extracted from 1 mL of the homogenate using the Kaneka Easy DNA Extraction Kit version 2 (Kaneka, Tokyo, Japan). The presence of E. coli and the colistin resistance gene mcr-1 in the DNA extracts was determined by real-time PCR using a mobile PCR device, PicoGene PCR1100 (Nippon Sheet Glass, Tokyo, Japan). PCR primers and TaqMan probes for realtime PCR detection of E. coli 16S rRNA and mcr-1 were prepared as described previously (Table 1) [12]. Details regarding the realtime PCR, including PCR mixtures and thermal cycling conditions, are provided in Tables 2 & 3, respectively. The DNA extract of the CR E. coli strain (E362) [6] carrying mcr-1 was utilized as a positive control in PCR. The entire 50 PCR cycles were completed within only 21 min. Moreover, the real-time PCR device could simultaneously measure fluorescence at three different wavelengths for the same sample. Two fluorescent dye-labeled TaqMan probes (Integrated DNA Technologies, Singapore), Cy5 for E. coli 16S rRNA and FAM for mcr-1, were used for each sample. The entire protocol is outlined in Figure 1. Figure 2 shows representative real-time PCR profiles of the samples.

Figure 1: Outline of the screening protocol using mobile real-time PCR PicoGene® PCR1100. BPW, buffered peptone water.

Figure 2: Representative plots obtained from real-time PCR amplification of mcr-1 and E. coli 16S rRNA genes in meat samples.
a) Positive control, mcr-1 E. coli.
b) mcr-1–negative pork sample, H-A market pork.
c) mcr-1–positive chicken sample, H-E market chicken.

Results and Discussion

The detection sensitivity of the method was assessed using pork meat samples spiked with an mcr-1-positive E. coli strain culture. The lower limit of mcr-1-E. coli detection for the entire method, from DNA extraction to detection by real-time PCR, was 7 × 102 CFU/g; however, a minimum of 7 × 103 CFU/g was required for quantification using a linear correlation. In the validation study using retail meat samples, CR E. coli-like bacteria were detected using the culture-based method in eight out of ten chicken and in three out of seven pork samples purchased in Vietnam (Table 4). The semi-quantitative levels of CR bacteria in these samples were in the range 103‒108 CFU/g (Table 4). All representative CR E. coli isolates from each sample were confirmed to be resistant to colistin (MIC ≥ 4 μg/mL) and possessed mcr-1 but not mcr-2 to -5, except for the H-E market pork sample, which harbored mcr-3 in addition to mcr-1, as determined by multiplex PCR. No samples from the Japanese supermarkets were contaminated with CR bacteria. All samples, except for the H-E market pork sample, that were positive via the culture-based method were also positive by real-time PCR (Table 4). Some culture-negative samples such as H-B market pork, T-B market chicken, T-B market pork, and T-E market chicken were PCR-positive. Such contradictory results may be attributed to the features of the real-time PCR method and its ability to detect mcr-1 even in dead cells and/or non-E. coli cells. In contrast, a pork sample from the H-E market showed CR E. coli colonies after culturing but tested negative for mcr-1 by real-time PCR. Such discrepant cases could be due to a low level of mcr-1–positive bacteria below the detection limit of the real-time PCR method or the presence of bacteria expressing non-mcr CR determinants [13].

The new method presented herein detects the target gene and facilitates quantitative analysis. In addition, the method using TaqMan probes has high detection specificity, and is simple because it does not require specificity verification by melting curve analysis, even for one-step extracted DNA from food. The results output the ratio of bacteria carrying mcr-1 to the total number of E. coli cells, which may be mcr-1–positive or –negative bacteria (Figure 2). The detected quantitative mcr-1 levels were higher than the CR E. coli-like bacterial levels determined via the culture-based method because the real-time PCR method detects all mcr-1 regardless of bacterial species. The quantitative linear range detected via realtime PCR was between 103 and 106 CFU/g. Although the detected signal was below the quantitative linear range limit in some samples, they were still considered to have positive results via realtime PCR. The approach described in this study provides limited information regarding the degree of contamination; nevertheless, the developed method is reliable and practical owing to a short processing time, enabling the rapid screening of contaminating bacteria with mcr-1 in food.

Conclusion

A new rapid and practical screening method was developed for detecting CR E. coli in food samples. The developed method is advantageous because it is easy to perform, has a short processing time, and provides reliable results that are consistent with those obtained by traditional methods.

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Remote Monitoring of the Health Status of Pregnant Women in the COVID-19 Pandemic

The Role of Remote Technologies in the Quality Management System and Safety of Medical Care

On April 26, 2021, Deputy Chairman of the State Duma Irina Yarovaya at a meeting of the Presidium of the Council of Legislators of the Russian Federation under the Federal Assembly of the Russian Federation called for simplifying the exchange of data between medical institutions and patients. In the Sverdlovsk region, an automated information system of mobile notifications «AIST_SMART» for pregnant patients and doctors began to operate. Using a smartphone or, say, a tablet, pregnant patients in their personal account get the opportunity to keep an electronic diary of self-control of their health. The diary has the functions of automatic interpretation of the results and the formation of signal information for the obstetrician-gynecologist. Now pregnant women do not need to fill out paper diaries of self-control, call their doctor or the reception of the antenatal clinic or wait for a doctor’s call in order to report the results - the process is fully automated. The women’s consultation received an IT tool for remote interaction with pregnant women and women in child child. The introduction of «AIST_SMART» technologies made it possible to replace paper diaries with electronic ones. Medical data of the patient are collected in a single database and allow you to track the dynamics of the patient’s health around the clock. The results of electronic diaries are automatically processed by the system and if no abnormalities are detected, the data is simply recorded in the system and does not disturb the doctor (Figure 1).

In case of detection of deviations in the patient’s state of health, the system marks the identified deviations and sends a notification to the doctor about the current state (Figure 2). Mobile notifications instantly convey accurate and detailed information about the patient’s state of health and thus contribute to the timely decision on hospitalization in case of detection of criteria for weighting the course of NCVI. All notifications in case of deviations are automatically sent to the attending physician and the doctor in the Obstetric Remote Consultation Center (hereinafter referred to as the ADCC) for the routing of the patient 24/7. Remote health monitoring functions as follows.

Figure 1: The data of the expanded diary of self-control at the NKVI, all indicators are normal.

Figure 2: The data of the expanded diary of self-control at COVID-19 with deviations in the state of health.

Registration in the System «AIST_SMART»

To register the patient in the personal account at the initial appointment of a pregnant patient, a consent-instruction [1] is issued to connect to the mobile service «AIST_SMART» with an individual QR code. At home, the patient reads the QR code using the camera of her smartphone or tablet and, according to the instructions, undergoes the registration procedure, forming a digital four-digit PIN-code. From now on, it is guaranteed 24/7 technical support. The QR code serves as the patient’s identifier and the link between her electronic medical record (EHR) in the AIST «RAM» and the personal account in the «AIST_SMART» system. To register a doctor in your personal account, you must log in to the medical information system - AIST «RAM», in which all medical personnel of the obstetric service in the region work. Open the «Personal Account» tab and register by scanning an individual QR code. So, in order to access electronic self-control diaries, the doctor and the patient connect to the AIST_SMART service, and after registering in the system, notifications about the results of remote health monitoring will be received on their mobile device. The doctor does not need to call on the phone to find out how she feels, what her temperature is, the symptoms of SARS, etc.

How the Mobile Alert System Works

Formation of Notification of the Result of Self-Control Diaries

This process is fully automated. AIST_SMART performs the role of an intellectual assistant to the obstetrician-gynecologist/ midwife. The patient fills in the diary data, and the doctor receives ready-made results with automatic interpretation. Now the patient will not forget to call the antenatal clinic, and the doctor will be able to make decisions on the tactics of conducting comprehensively, taking into account the results of the patient’s home self-control and his obstetric status.

Patients with COVID-19 are Asymptomatic/Mild and Receiving Care on an Outpatient Basis (at home)

Upon receipt of the results of testing in a pregnant woman / maternity for COVID-19, the data are entered by medical personnel in the AIST «RAM». Notifications about the results are automatically generated in the personal account «AIST_SMART» (Figures 3 & 4). These notifications are automatically sent to both the patient and the doctors. With what there is control that the patient is also informed about the result (Figure 5). If a positive result is detected on the COVID-19, the patient receives notifications 2 times a day about the need to fill out a self-control diary, which is also informed by the doctor - full feedback (Figure 6). The doctor of the ADC, based on the results of the self-control diary (Figure 7) and obstetric status according to the data in the electronic medical record (hereinafter referred to as the EHR) in the AIST «RAM», where there is information about all the results of the examination, the course of pregnancy and diagnoses, decides on further management tactics: to continue outpatient treatment or hospitalization in a covid hospital. The ADCC doctor fixes his decision in the EHR, making out a remote consultation for the attending physician of the antenatal clinic or obstetric hospital (if the patient is in the hospital at the time of detection of the COVID-19).

Figure 3: Mobile NOTIFICATION of PCR result for COVID-19: not detected.

Figure 4: Mobile NOTIFICATION of PCR result for COVID-19: DETECTED.

Figure 5: Marking about the patient’s reading of the results of the examination.

Figure 6: Mobile notification that a reminder has been sent to the patient to complete a self-monitoring diary.

If a decision is made on the need for hospitalization, the doctor of the ADC through a confidential «working» chat in AIST_SMART can contact the patient and clarify her consent to hospitalization and the possibility of transportation by personal transport. If consent is obtained (Figure 8), the ADC doctor makes an additional referral for (re-) hospitalization to a particular covid hospital for pregnant women and women in childcare, taking into account available places. The patient receives a notification about the referred referral indicating the covid hospital, the date and time of hospitalization (Figure 9). If it is necessary to organize transportation, the doctor of the ADC has resources through communication with the medical organization where the patient is on the dispensary register and agreeing on the method and time of transportation by the NSR team in compliance with epidemiological rules (Figure 10).

Figure 7: Dynamics of the state of health according to the electronic diary of self-control.

Figure 8: Communication with the patient through confidential “working” chat in AIST_SMART.

You do not Need to Receive a Paper Direction

If necessary, you can print the direction at the place of treatment of the patient, using a single information space of the regional obstetric monitoring of AIST «RAM». All the directions that a woman received during pregnancy are reflected in her personal account in the «My directions» section. The patient can open any document, even if the connection with the internet has disappeared.

Figure 9: Notification of referral to a Covid hospital and labeling of reading by a patient.

Advantages of Remote Monitoring of Health

The transition to electronic diaries of self-control allows you to identify the weighting of the course of ARVI / ARI in the case of outpatient treatment (at home) with COVID-19, and timely send the patient to hospitalization to prevent adverse events, which is from the main directions of the quality management system and safety of medical care. AIST_SMART allows you to create constant feedback [2] with the patient and thereby form a patient-centric model of care as one of the priority areas for the development of modern medicine and healthcare in general. All of the above increases the compliance of doctor-patient interaction and directly affects the quality and safety of medical care in the difficult conditions of the NCVI pandemic, which meets the modern needs of society and solves the tasks set by the Government of the Russian Federation in the field of digitalization of healthcare [3-8].

Figure 10: Finding out the possibilities of transportation and hospitalization to the covid hospital through a confidential “working” chat in AIST_SMART.

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Neuronomodulation

Opinion

Neuronomodulation (NRM) is a proposition raised by one of us as the change in excitability state of a neuron facing the extrinsic modulatory actions of the chemical nature. Neuron lives in the extracellular fluid environment, it would face influences from chemical agents in “milieu interne” every time and everywhere. Since excitability is the most important and characteristic feature of the neuron, which is defined by the membrane polarization state, every external perturbance that could alter the polarization state of the neuron would have a modulatory effect. NRM is of great importance for the neuron functioning. According to the mode of action of modulators on the ion channel, NRM can be direct or indirect. The excitable neuron is the basis of brain function, the significance of NRM in brain function is obvious. Since NRM presents every time and everywhere for any given neuron, therefore, every act of neuronal conduction or chemical synaptic transmission can only be implemented under such conditions. NRM is as important as neuronal conduction and synaptic transmission for the implementation of neural circuit and brain function in normal and pathological conditions. In fact, we believe that NRM, together with neuronal conduction and synaptic transmission are the three underpinnings for the central nervous system functioning. It is not strange that NRM have very wide pathological and pharmacological implications in the clinic.

The idea of NRM is evolved from the modulatory action of neurotransmitters. Around 1980, the distinction between conventional synaptic action and the modulatory actions of neurotransmitter are first discussed in depth [1]. Clearly this modulatory action refers to the action of neurotransmitter acting through intracellular second messengers. In a 2016 presentation, the idea of ambient modulation of neuronal excitability was raised [2]. Ambient modulation acts by three ways:

(a) Spillover of neurotransmitters from nearby synapse

(b) Hormones from the blood stream and

(c) Paracrinal secretions (Figure 1) [2].

Conceptually, NRM covers even more broader area than ambient modulation. For direct NRM, the most outstanding case is the tonic inhibition mediated by extrasynaptic GABAa receptors [3], a relevant issue is the action of neurosteroids [4], the binding of animal venom toxins to the voltage-gated ion channels and its actions are further examples [5]. Up to present we know little of the existence of tonic excitation of the neuron. For indirect NRM, all slow potential changes implemented by metabotropic receptors, be it evoked by small molecule neurotransmitters or neuropeptides, are all typical examples. Furthermore, there are evidences that hormones, cytokines, and chemokines can act by means of indirect NRM [6-9].

Figure 1:Synaptic transmission, synaptic modulation and ambient modulation of neuronal excitability.

1. Synaptic transmission

2. Can be modulated by neuromodulators released by neighboring presynaptic terminals

3. Acting either presynaptically or postsynaptically. The ambient modulation of neuronal excitability Acts by three ways:

a) spillover of neurotransmitters from nearby synapse

b) Hormones from the blood stream

c) And paracrinal secretions. (Adapted from Chen, 2016).

The molecular target of NRM is the ion channels on neuronal membrane. The significance of allosteric modulation of receptor and non-receptor molecules should be emphasized. Much of the implementation of NRM is associated with allosterism and binding activity of non-receptor molecules. This issue has been made clearer due to the recent advancement of structural biology, especially the advent of cryoEM [10,11]. The real situation of NRM is akin to volume transmission, they may represent two sides of a coin, with the former emphasizes the information transfer between neurons and the latter emphasizes the alternation of excitability of neuron. Brain modulatory systems and neuromodulation maneuver in clinic are frequently used terms in neuroscience literature, but their foundation is relied on NRM.

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Machine Learning Analysis of a Chilean Breast Cancer Registry

Purpose

As occurs in several countries, breast cancer (BC) is one of the leading causes of cancer related death among Chilean women [1]. Like other malignancies, breast neoplasms are characterized by their heterogeneity. This not only applies to clinical features of patients but also, to molecular, genetic and histologic characteristics [2]. Similarly, incidence rates and associated risk factors display a marked geographic variability [1]. To date, several studies have reported BC incidence and prevalence rates in both Europe and North America. These studies have also reported clinical-genetic characteristics and prognosis. In sharp contrast, South American reports on these topics are scarce [3]. Indeed, only a few Latin American studies have included data on limited populations, these are mostly from Brazil and Mexico [4,5]. Unpublished data from our group suggest that differences in lifestyle along with a diverse racial background could explain particular characteristics observed in the Chilean population.

In recent decades, Artificial Intelligence (AI) has emerged as an innovative and valuable tool in medicine, providing assistance to achieve more accurate patient diagnoses and to support making medical decisions. Interestingly, certain studies demonstrate that AI-algorithms can compete or even outperform clinicians in specific tasks [6]. In lay terms, AI-algorithms can be easily ‘trained’ by using sample data. Thus, algorithms “learn” to do their job much like doctors learn by attending medical school for years, making right decisions and sometimes mistakes. Within this context, Machine Learning (a form of AI) seeks to apply algorithms and build models based on training data in order to make predictions in a variety of applications including medicine [7]. In 1997 our institution started a longitudinal BC registry that included invasive disease cases. In recent years, our group has generated several publications focused on BC incidence, clinical characteristics of patients and clinical data based on these analyses [8-10]. Herein we report preliminary analyses on data applying machine learning to analyze our local BC patient registry.

Patients and Methods

This study was part of a collaborative effort between Hospital Sotero del Rio and Cancer Center at Pontificia Universidad Católica de Chile, the former a public hospital and the later a university cancer center, both at Santiago, Chile. We sought to determine relevant clusters of BC patients associated with clinical characteristics and survival that allow us to evaluate and propose patient-adapted therapeutic schemes. The K-medoids clustering algorithm was used to define a patient profile based on demographic (sex, age, weight / height, cancer family history, comorbidities and BC risk factors) and clinical-pathological information (stage, BC subtype, surgery, type of systemic treatment). Once the groups were separated, survival rates were calculated using the Kaplan-Meier method. This analysis allows us to link patient profiles with the behavior of survival rates. Then, data analytics methods were applied to determine the most relevant variables for each of the clusters and their correlation with survival rates. Finally, we estimate the time evolution of the treatments carried out (trajectories). In this way, it is possible to describe treatment schemes for each of the defined clustering.

Results

Overall, a total of 4838 registered BC patients were included into our study. Our analyses divided patients into five clusters with marked differences in clinical characteristics and prognoses see Figure 1. The key variables that defined these clusters included: age at diagnosis, body mass index, family history of cancer (by a first-degree relative), comorbidities (mainly hypertension), compromised nodes, and BC relapse. Clusters were also associated with significant differences in overall and disease-free survival (Figure 2).

Figure 1: Graphical three-dimensional representation of the five clusters of patients generated by our model. Panels A, B and C show different angles.

Figure 2: Overall survival for the identified clusters of patients.

Conclusion

To our knowledge, this is the first Latin American report applying a machine learning approach to analyze BC registry data, including clinical features and survival outcomes. Our findings confirm the capacity of machine learning to differentiate BC clusters with specific clinical and prognostic outcomes. Currently, we are validating this approach and expanding our database.

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Pulmonary Neuroendocrine Tumor with Pancreatic Metastasis: A Case Report

Introduction

Neuroendocrine tumors are a group of tumors that share morphological, immunohistochemical and ultrastructural pathology and molecular features. The incidence of pulmonary neuroendocrine tumor is gradually increasing, leading to distant metastasis of liver, bone, brain, and adrenal gland [1]. However, pancreatic metastasis is rare, which accounted for about 0.7% [2]. In addition, majority of patients with metastatic pancreatic cancer had normal serum carbohydrate antigen 19-9 (CA19-9) levels [3]. We herein reported a case report of pancreatic metastases from pulmonary neuroendocrine tumor with abdominal symptoms and elevated serum CA19-9 levels. Previous studies were reviewed in order to provide some experiences regarding the diagnosis and treatment of such diseases.

Case Presentation

A 56-year-old male was admitted to the People’s Hospital of Suichang County on May 10, 2019 with epigastric dull pain radiating into the posterior back for more than 20 days and had no obvious aggravation and relief factors. There were no nausea or any change in bowel movement habits and weight, and no pulmonary and nerve system symptoms were observed. Some medications for gastritis were taken by him, but no effect was achieved. The patient denied previous medical history of cardiovascular disease, pulmonary disease, gastrointestinal disease, tuberculosis, and denied history of food and drug allergy. He has smoking history of 40 cigarettes/day for more than 30 years (smoking index > 1200). A 4cm*4cm mass was found in the left chest wall, with clear boundary, hard texture, and well activity. His abdomen was soft, with slight tenderness in the right upper abdomen. No enlarged systemic superficial lymph nodes were observed. No positive signs of cardiovascular system, pulmonary system and nervous system were found. Laboratory tests revealed elevated levels of carcinoembryonic antigen (CEA) 9.82ng/ml (reference range: 0-5ng/ml), and CA19-9 44.50U/ml(reference range: 0-37U/ml). Enhanced CT scan showed multiple pancreatic tumors with lymph node metastasis in the retroperitoneum. Pulmonary CT showed left lung tumor with multiple metastasis (of lung in the left chest wall and lymph nodes in the hilum, mediastinum, axilla). (Figure 1) Cranial MR suggested multiple abnormal signal nodules in both cerebellar hemispheres and considered it as metastatic.

Figure 1: Enhancement CT of the patient.

a. a&b: Irregularly lobulated uniform-density soft tissue mass was found in the lateral hilar region of the upper lobe of the left lung, with mild enhancement in enhanced scanning. Bronchial stenosis and occlusion of the upper lobe of the left lung ⬉.

b. c&d: Multiple low-density lesions in the body and tail of enlarged pancreas, with delayed enhancement in enhanced scanning. The distal pancreatic duct was slightly dilated. The local fat space was not clear, and no enlarged lymph node was observed ⇐.

A multidisciplinary discussion (MDT) was conducted and concluded that the patient had a short course of disease and was generally in good condition, while radiology results suggested multiple occupying lesions in lung and pancreas, and advanced malignant tumors with multiple metastases. Metastatic process and elevated CA19-9 levels revealed lung metastasis from pancreatic cancer. However, according to radiological images, an irregular lobulated uniform-density soft tissue mass in the left lung was observed and was tended to be primary. Pathological diagnosis is considered extremely important. It is difficult to obtain a biopsy of lung and pancreatic lesion, for the limitation of medical equipment (such as endoscopic ultrasonography) in county hospital, and the patient was reluctant to be transferred. So coarse needle puncture biopsy of left chest wall mass was performed. The pathological results suggested (left chest wall puncture biopsy) neuroendocrine tumor (poorly differentiated neuroendocrine carcinoma), confirming it to be the origin of small cell carcinoma of the lung. Immunohistochemical results showed CgA (+), Syn (+), CD56 (+), CK18 (±), CK(±), CA199 (+), P53 (-), P63(-), P40 (-), Ki-67 (50%), ERCC-1 (+), CK7 (-), TTF1 (+), and Napsin-A (-). (Figures 2 & 3) Thus, the final diagnosis revealed extensive-stage small cell lung cancer with multiple metastases of pancreas, intracranial and left chest wall. The patient currently underwent six courses of chemotherapy and one course of cranial radiotherapy (30Gy/10F). The chemotherapy regimen used was etoposide (100mg/m2, d1-3) combined with cisplatin (75mg/m2, d1), and each course lasted for 21 days, according to the NCCN guidelines. After the first-course chemotherapy, the patient’s symptoms were improved. Follow-up CT after four courses of chemotherapy showed that the lesions in the lung, pancreas and left chest wall were obviously shrunken. (Figure4) The patient was closely followed up. The patient’s lung lesions developed later and eventually died of respiratory failure. The total survival time is 9 months. Patient’s informed consent was obtained to publish this case report.

Figure 2: Pathological biopsy of the left chest wall.

a. HE, x2.

b. HE, x200.

c. HE, x400.

The cell layers were clustered and nested, and organ-like structures were seen. The cells were small with less cytoplasm, unclear nucleoli, partial vacuoles in the nucleus and chromatin. Karyokinesis was observed with local coagulation necrosis.

Figure 3: Immunohistochemistry of the patient

a. CgA(+);

b. Syn(+);

c. CD56(+);

d. TTF-1(+);

e. CK(±);

f. Ki67(50%)

Figure 4: Enhancement CT of the patient after treatment.

a. Mass in the left lung was shrunken after treatment ⬉.

b. Lesions in the body and tail of enlarged pancreas were shrunken after treatment ⇐.

Discussion

Barnard has first reported neuroendocrine tumors in 1926 [4], and occurred in all parts of the body, including gastrointestinal tract, pancreas, bile duct, liver, lung, etc. Gastrointestinal neuroendocrine tumors are the most common neoplasms, accounting for 55-70% of all neuroendocrine tumors [5]. Recently, the incidence and prevalence of lung neuroendocrine tumors have increased linearly, and previous literature has reported as 1.35~1.57/ 100,000 people [6-7], accounting for 25% of primary lung tumors and 20%~25% of all neuroendocrine tumors [8]. Lung neuroendocrine tumors were divided into four histological types: small cell lung cancer (SCLC) (20%), large cell neuroendocrine cancer (LCNEC) (3%), typical carcinoid (TC) (2%) and atypical carcinoid (AC) (0.2%) [9]. SCLC is associated with smoking, mainly occurs in middle-aged and elderly men, and most commonly occurs in the hilum of lung. The 5-year and 10-year survival rates are 10% and 5%, respectively [10]. This patient has a previous risk of long-term smoking, and the primary lesion is located in the left hilum of the lung, which was consistent with the previous report [11].

Primary pulmonary neuroendocrine tumors are more prone to distant metastases, and the most common tissues included liver, bone, brain, and adrenal [1,12,13]. But pancreatic metastasis is quite rare, which accounted for about 0.7% [2]. Most of the metastases are still dominated by pulmonary symptoms, which might be related to the fact that the tumor cells metastasize to the pancreas through hematogenous or lymphatic routes, but there was no infiltration of the biliopancreatic duct wall. In this case, abdominal symptoms (abdominal pain) were the first symptoms, which were relatively rare, and may be related to the tumor compression of biliopancreatic duct. In addition, different from primary pancreatic cancer, majority of the patients with metastatic pancreatic cancer had normal serum CA19-9 levels [3]. He [14] analyzed 25 patients with pancreatic metastases and found that the CA19-9 levels were significantly increased in only one case of gallbladder cancer and one case of colon cancer with pancreatic metastases. Lung neuroendocrine neoplasms with elevated serum CA19-9 levels are rarely reported in the literature. According to the images of abdominal CT and elevated tumor markers (CA19-9 and CEA), our patient was misdiagnosed with pancreatic cancer. However, according to CT, and combined with patient’s advanced malignant status and good general conditions, the possibilities of uncommon tumors should also be considered, suggesting a multidisciplinary discussion. Thus, wide range of tumor properties should be considered during pathological and immunohistochemical examination. In addition, we also needed to consider the possibility that both the pancreas and lungs are primary lesions.

While the evidence supporting pancreatic metastases is as follows:

1. Miltifocal pancreatic masses

2. Slightly elevated CA19-9

3. Good condition and

4. The imaging finding supported the lung lesion tended to be primary.

For the limitaion of medical equipment (especially the endoscopic ultrasonography) in county hospital, and the the patient was reluctant to be transferred to the superior hospital, it is difficult to obtain a biopsy of lung and pancreatic lesion. The differentiation points of SCLC and other neuroendocrine tumor types included the cell size, the ratio of nucleoli to cytoplasm and the presence of nucleoli. Immunohistochemical markers of pulmonary neuroendocrine tumors were CgA (chromogranin A), Syn (synaptophysin), CD56, thyroid transcription factor 1 (TTF1), ki-67, et al. TTF-1 is a specific molecular marker of lung tissue and thyroid gland [15-17]. Syn, CD56 and CgA were considered as neuroendocrine markers. Among these, CD56 is more sensitive, while CgA and Syn are more specific [18,19]. The expression rates of Syn, CgA and CD56 were 91%, 54% and 87% in carcinoid (including typical carcinoid and atypical carcinoid), 91%, 54% and 87% in SCLC, and 76%, 97% and 92% in LCNEC, respectively [20]. In this patient, CgA, Syn, CD56, TTF1 and other lung neuroendocrine tumor markers were all positive, while CK7 and other gland sources and exocrine differentiation markers like Napsin-A were negative, and so the pancreatic sources were not considered. The diagnosis of left upper lobe SCLC remained clear.

The staging of SCLC was according to the AJCC TNM method and Veterans Administration Cancer Study Group (VALG) phase II method [21,22]. Surgery (T1-2) and concurrent chemoradiotherapy was performed within a limited stage, and chemoradiotherapy was performed for extensive stage [21-24]. The chemotherapy regimen used was platinum combined with etoposide or irinotecan [25- 28]. Patients with brain metastases should be treated with wholebrain radiation therapy, while prophylactic brain radiotherapy should be used by considering the disease carefully [29,30]. The brain metastasis of the patient was in extensive stage and received partial remission after 6 courses of etoposide and cisplatin (EP) chemotherapy, followed by whole-brain radiotherapy. After the first-course chemotherapy, the patient’s symptoms were improved. Follow-up CT after four courses of chemotherapy showed that the lesions in the lung, pancreas and left chest wall were obviously shrunken. However, the patient’s lung lesions developed later and eventually died of respiratory failure. The total survival time is 9 months.

Conclusion

We herein reported a case of pancreatic metastases from small cell carcinoma of the lung with abdominal symptoms and slightly elevated serum CA19-9 levels. The possibility of other rare tumors should be considered in patients with multiple systemic metastases but were in good general condition. Pathology and immunohistochemistry should adequately used by considering such situations.

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