This is why the PA66/graphene film produced a more subtle secondary network with the addition of graphene, used as a charge capture site to increase its surface charge. Additionally, all the layered structures of TENGs were composed of breathable electrospun films and plain conductive cloth, with water vapor transmittance (WVT) of 9.6 Kgm−2d−1, reflecting excellent wearing comfort. The study showed that TENGs, based on all electrospinning, have great potential in the field of wearable energy supply devices.Triboelectric nanogenerators (TENGs) are considered to be the most promising energy supply equipment for wearable devices, due to their excellent portability and good mechanical properties. Nevertheless, low power generation efficiency, high fabrication difficulty, and poor wearability hinder their application in the wearable field. In this work, PA66/graphene fiber films with 0, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% graphene and PVDF films were prepared by electrospinning. Meanwhile, TENGs were prepared with PA66/graphene fiber films, PVDF films and plain weave conductive cloth, which were used as the positive friction layer, negative friction layer and the flexible substrate, respectively. The results demonstrated that TENGs prepared by PA66/graphene fiber films with 2 wt% grapheme showed the best performance, and that the maximum open circuit voltage and short circuit current of TENGs could reach 180 V and 7.8 μA, respectively, and that the power density was 2.67 W/m With the development of Internet of Things technology (IoT), portable, flexible wearable electronic devices with various functions have been widely considered. In the IoT society, various devices offer many possibilities through data transmission and processing ,2,3,4, s2 under hand patching. Incorporating functional materials into polymer nanofibers could improve electrical output performance. Currently, most research focuses on improving output performance, such as selection of friction materials [All electrospun nanofiber films are widely used in TENGs design. The electrospun fibrous films have remarkable properties, such as inherent rough structure, large specific surface area and hierarchical porous structure ,17, whicaterials ,23,24, saterials ,26,27 anaterials ,29,30. H2. Water vapor transmission rate could be up to 9.6 Kgm−2d−1. In addition, the TENGs prepared could be placed anywhere on the body, detecting various human movements, and the mechanical energy that is wasted in life could be obtained. This energy can instead be used to power wearable electronic devices in daily life.In this work, a method for all-electrospun fiber-based TENGs, consisting of two parts, including a PA66/graphene nanofiber-film-rubbed positive base layer and PVDF-rubbed negative electrode layer, was proposed. On the one hand, a PA66/graphene nanofiber film with multi-layer micro-nano structure could not only increase the effective friction area of contact, but also graphene dispersed in the PA66 fiber could be used as a charge capture site, which could increase the surface charge on the film surface, greatly improving its triboelectric properties . In addiPolyamide66 (PA66) was bought from Aladdin Pharmaceuticals . Graphene was sold by Shenzhen Turing Artificial Intelligence Black Technology Co., Ltd. . Polyvinylidene Difluoride  was produced by Arkema . Formic Acid and Polyethylene Oxide (PEO) were bought from Macklin . N, N-Dimethylformamide (DMF) and Acetone were produced by Sinopharm . Plain weave conductive fabric was produced by Saintyear Electronic .Firstly, 0.5 wt% PEO was added to 10 mL of Formic Acid and a magnetic stirrer was used to stir for 1 h to increase the viscosity of the solution, so that it could be well electrospun. Secondly, 15 wt% PA66 particles were put into Formic Acid/PEO solution, which were fully dissolved via a magnetic stirrer for 4 h to obtain 15 wt% PA66 solutions. Finally, different mass fractions of graphene  were put into the prepared PA66 solution, respectively, and stirred to fully mix. Further, ultrasonic dispersion was applied for 6 h to make the graphene evenly dispersed in the solution.The electrospinning process was performed with a supply voltage of 20 kV, a working distance between the spray nozzle and the substrate was 15 cm and the PA66/graphene solution was injected into a 10 mL syringe with a blunt needle (0.6 mm inner diameter). The injection rate of the syringe was 0.1 mL/h. PA66/graphene nanofiber films were collected on plain weave conductive cloth (Ni-Cu) fabric electrodes, which were prepared at 25 °C and relative humidity of 50 ± 5%. The thickness of PA66/graphene fiber film was 80 ± 10 μm, measured by Talysurf Profiler .Firstly, 3 mL Acetone was added into 7 mL DMF to obtain a DMF/Acetone solution in a 7-to-3 volume ratio. Secondly, 10 wt% PVDF powder was added into the mixed solution and magnetically stirred for 4 h under heating in a 60 °C water bath. Finally, the 10 wt% clear and transparent PVDF solution was obtained.The electrospinning process was performed with a supply voltage of 12 kV, while the working distance between the spray nozzle and the substrate was 10 cm. The advance rate of the syringe was 0.4 mL/h. The PVDF nanofiber membrane was collected on the conductive fabric electrode, which was also collected under the same conditions, mentioned in Based on the electrospinning process, the composite fabric of the two friction layers of TENGs was prepared. Firstly, the double-sided conductive tape was used as the electrode lead, which was tightly pasted on the back of the conductive fabric substrate where the different films were located. Then, the required size could be trimmed, such as 4 cm × 4 cm. Finally, these breathable films could be pasted on the corresponding positions of daily clothes, collecting the mechanical energy generated by wasted human movement.SC and VOC were measured by Keithley System Electrometer .The surface morphologies of PA66 films, PA66/graphene films and PVDF films were characterized by the Field Emission Scanning Electron Microscopy . X-ray Diffraction  was used to study the elements and material structure of the electrospun fiber films. The IThe main concept of the design in this work was to use common fabric materials as the basic building unit to construct a wearable TENGs platform, so as to achieve effective harvesting of low-frequency, ubiquitous and easily wasted human biomechanical energy, such as walking and running. The all-electrospinning-based power-generating textile had multiple secondary structures and it could be better integrated with personal clothing, powering wearable electronic devices. These power-generating fabrics with excellent mechanical properties exhibited excellent breathability and cutability. It was an ideal device to make energy harvesters and sensors of a flexible wearable electronic system integrated, which guaranteed the integration of TENGs and wearable electronic devices with clothing.A detailed preparation process for the PA66/graphene nanofiber film and PVDF film are schematically illustrated in The prepared TENGs were composed of three functional components, including a PA66/graphene fiber film and PVDF film with two tribological polarities for contact electrification, and a plain weave conductive cloth for charge conduction. Based on previous studies , construTo study the elements in the films, the XRD patterns of PA66/graphene thin-film layers with different mass fractions of graphene were observed, shown in To study the effect of graphene doping on the output performance, contact-separation-mode TENGs based on PA66/graphene and PVDF films were designed. The two films were glued to two 3D-printed slabs with bosses a,b. The C(x) was the capacitance between the two electrodes at different time-varying displacements x; ε0 was the vacuum dielectric constant; S was the surface area of the friction layer; d0 was the effective thickness of the dielectric layer; σ was the triboelectric surface charge density; SCQ(x) was the amount of short-circuit charge transfer at displacement x; and f was the frequency. Therefore, according to Equations (1) and (2), we could observe that the open-circuit voltage of TENGs was independent of frequency f and increased only with larger displacement between the two contact surfaces, and the short-circuit current was proportional to the frequency f, so the measured maximum short-circuit current increased with the frequency f, shown in SCI) and open-circuit voltage (OCV) of the TENGs and an external force exerted with a frequency of 4 Hz, a higher circuit signal and output power could be obtained.According to previous studies ,34,35, wOCV and SCI were both increased by about four-times. Therefore, the TENGs made of PA66/graphene fiber film with 2 wt% graphene content were the most suitable experimental sample. Further, the piezoelectric properties of PVDF films were tested by the method reported by Yin [With the increase in graphene, the dielectric constant of the electrospun film also had an effect on the output performance. The enhanced dielectric constant of the triboelectric layer could improve the ability to transfer charge density and the surface potential also had a large impact on the performance of TENGs. A higher dielectric constant could use the electrospun PA66/graphene film as a friction layer to store more charge. However, an excessively large dielectric constant would generate a larger dielectric loss, which leads to the leakage of charge. Due to the changes in frequency and external strain during human motion, it was necessary to explore their effects on the output performance of wearable devices. As shown in d by Yin , so the P = I2R, the power of TENGs could be calculated. At 113 MΩ resistance, the maximum power density could reach 2.67 W/m2. The generated output power was sufficient to drive some low-energy electronic devices, solving the problem of sustainable power supply for wearable systems in a stable and reliable manner effectively.To study the effects of load resistance on output of the voltage and current, the output performance of nanofiber-film-based TENGs was researched, shown in m1 was the test cup mass before the test; m2 was the test cup mass after the test; S was the test cup mouth area; and the obtained WVT rate was 9.6 Kgm−2d−1, which could confirm that the all-electrospun textile film had excellent air permeability. In other words, electrospun nanofibers had excellent wearing comfort, ensuring human thermal comfort and wide personal practical applications after their integration into wearable electronic devices.Due to the striking features of the porous structure, the fabricated power generation fabric had excellent water vapor permeability, which can be visually seen in To explore the durability and stability of TENGs, the fabric current outputted after bending the two friction layers for 1000 cycles was tested and compared. It could be clearly seen that there was no significant mechanical damage to the surface, shown in To accurately evaluate the practical application of TENGs, a series of tests was carried out and the combined light chain composed of 110 LEDs in series could be lit by using the TENGs a, which To demonstrate the charging capability of TENGs, a circuit composed of a commercial capacitor and bridge rectifier was designed to test its charging efficiency. The charge in the capacitors  to 1.2V with 4 s, 36 s, 180 s, respectively, is shown in To further demonstrate the application of TENGs based on all-electrospun nanofilms, they could be easily combined with textiles to harvest the mechanical energy generated from the human body, As shown in 2, respectively. In addition, TENGs maintained excellent performance after 1000 cycles under cyclic pressure, keeping its advantages in durability and stability. TENGs with good comfort and high flexibility could obtain biomechanical energy from various human motions. There are great prospects in the system integration of wearable electronic devices.In this work, an electrospun PA66/graphene nanofiber film with a secondary nano-network structure, as a tribo-cathode layer, was fabricated, and it was assembled with the electrospun PVDF film as the tribo-anode layer to form all-electrospun film-based TENGs. The rough surface of the two friction layers not only increased the effective contact area, but also improved the breathability. Furthermore, the porous fiber network in each functional layer guaranteed the air permeability of the TENGs. Compared with the pure PA66 fiber film, the introduced graphene increased the effective contact area of the PA66 nanofiber film and graphene could act as a charge trapping site, enhancing the electrical properties of the TENGs. The fabricated TENGs exhibited high Voc, Isc and peak power density of 180 V, 7.8 µA and 2.67 W/m


The vulnerability of chromosome 22q11.2 region to rearrangement is due to several low copy repeat (LCR) sequences. These rearrangements are involved in syndromes that share similar phenotypic features. The rearrangements of the 22q11.2 chromosomal region are common, specifically, duplications and deletions associated with congenital anomalies and developmental disabilities disorders. However, the features associated with this chromosomal rearrangement remain largely unknown. We present, to the best of our knowledge, the third patient affected by triplication of the 22q11.2 chromosome region, who presents with Peters anomaly, global developmental delay, patent ductus arteriosus, and subaortic stenosis. This case highlights a new phenotypic feature associated with triplication of this genomic region. The 22q11.2 deletion syndrome is due to the 22q11.2 chromosomal region, including phenotype previously known as DiGeorge/Velocardiofacial syndrome (DGS/VCFS), which has a prevalence estimated between 1:2000-1:17000 live births .Deletions are largely undetected. However, researchers suggested that the prevalence of duplications is about half of the deletions. Lately, 22q11.2 microduplication syndrome has been reported as a new genomic duplication syndrome. Additionally, it is phenotypically highly variable in appearance ranging from a normal or a mild learning disability to multiple congenital defects such as velopharyngeal insufficiency with and without cleft palate, heart defects, growth delay, and mild dysmorphic features .Triplication (four copies) is a rare mutation; however, exploring the related phenotype may explain the dosage sensitivity of the genes in this chromosomal interval. We describe a patient with 646 Kb triplication of 22q11.2 (LCR22B-D) of the DiGeorge region. The triplication of the 22q11.2 region has been reported only twice earlier ,4. This We present a case of a 28-month-old female child who was born to a 34-year-old multipara and 32-year-old father. The mother's pregnancy was uneventful except for gestational hypertension, for which she took antihypertensives. She had routine prenatal care, including obstetric ultrasounds. The patient was born at term via spontaneous vaginal delivery. Her birth weight was 3.8 kg (75th percentile), length was 52.3 cm (80th percentile). The child had an uneventful postnatal course; corneal opacities were noted bilaterally at birth, and the patient was appropriately referred for ophthalmologic evaluation. The mother said no murmur was auscultated at birth, and the child was discharged on the second day of life. She reportedly passed the newborn hearing screen.At two weeks of life, on the first visit with her primary care pediatrician, the child was noted to have widely spaced eyes, internal epicanthus, long palpebral fissures, down slanting palpebral fissures, low set posteriorly rotated auricles, flat nasal bridge, long philtrum, thin, cupid bow-shaped upper lip, and a cardiac murmur; therefore, she was sent to be evaluated by a pediatric geneticist and cardiologist. However, she missed all the genetic appointments until the age of nine months. During the first cardiology visit, a harsh 3/6 continuous machine-like murmur was noted in the left infraclavicular region with radiation throughout the precordium and back along with palpable thrill. Echocardiography performed showed subaortic stenosis with the subaortic membrane Figure . There wThe child was seen by an ophthalmologist at two months, and the exam was significant for bilateral opacified cornea, possible media changes as well as damage from glaucoma. The patient was diagnosed with type-1 bilateral Peters Anomaly. Family history was ascertained. This is a non-consanguineous family of African American (mother) and African American/Native American/Caucasian (father) ancestry. The mother is nearly 35 years old, 164 cm tall, and has a recent diagnosis of hypertension. Dad is 32 years old, 179 cm tall, and healthy. The mother has a 17-year-old daughter and a ten-year-old daughter from a previous union, both healthy and did not have spontaneous pregnancy losses. The father has a 12-year-old son, an 11-year-old son, and an eight-year-old daughter from previous unions. The maternal grandmother has diabetes. The mother has a healthy older sister, the mother of two healthy daughters. The paternal grandmother has diabetes, and the grandfather is well. The father has a healthy brother and a sister, none with children yet. The patient is the first affected in the family. The family pedigree is represented in Figure At six months of age, the patient was having tachypnea and since the echocardiographic findings suggested left ventricular failure; she was started on furosemide daily therapy and underwent cardiac catheterization. A peak-to-peak invasive systolic gradient of 45mmHg was detected at the level of the membrane in the presence of the large PDA shunt (left-to-right). A 4 mm Amplatzer Piccolo™ Occluder  was used to close the PDA with a 50% reduction in the peak-to-peak systolic pressure difference across the membrane. Discharge echocardiography showed no residual PDA and subaortic membrane with a peak systolic gradient of 65 and mean of 42mmHg with mild to moderate left ventricular hypertrophy (LVH) as in Figures On genetic evaluation at nine months of age, the significant physical findings were as follows: widely spaced eyes, internal epicanthus, long palpebral fissures, everted lower eyelids, down slanting palpebral fissures, bilateral dense corneal opacities, eye malalignment, low-set posteriorly rotated auricles, flat nasal bridge, long philtrum, thin, cupid bow-shaped upper lip, hypodontia, widely spaced nipples, 3/6 systolic murmur, small reducible umbilical hernia, mild rhizomelia of the upper limbs, tapered fingers, single palmar crease on the left, mild 2-3 soft tissue syndactyly, and simple sacral dimple. The child had normal tone, strength, and reflexes in all extremities.B3GLCT gene analysis through a diagnostic genetic laboratory was recommended, the result of which came back negative. This significantly decreased the likelihood of Peters plus syndrome as her unifying diagnosis. On the additional panel of ocular genes through the laboratory, the performing lab reported a variant of uncertain significance in the PAX6 gene c.580G>A p.Gly194Arg. However, PAX6 genes were shown to cause variable ocular phenotypes, including anterior segment dysgenesis, Peters anomaly, aniridia, and glaucoma [PAX6 variant was paternally inherited (the same variant of uncertain significance in the PAX6 gene was noted in the father). High-resolution chromosomal microarray by using array comparative genomic hybridization (aCGH) to examine the DNA extracted from the patient showed a likely pathogenic A copy number gain of 646.6 kb on chromosome 22q11.21(LCR22B-D) of the DiGeorge region (based on coverage in the Database of Genomic Variants) [PI4KA, SERPIND1 (HCF2), SNAP29, and LZTR1). Overlapping gains may be associated with developmental gains and congenital anomalies, including cardiovascular anomalies. This finding was confirmed by fluorescence in situ hybridization (FISH) using a bacterial artificial chromosomes (BAC) probe that hybridized to the chromosome 22q11.21 region  and a control probe specific to the subtelomeric region of chromosome 22q . Parental genetic testing and chromosomal and microarray analysis were recommended; we offered parental testing for the triplication, and the parents didn't come for the test.Genetic testing for Peters plus syndrome with On her most recent follow-up, the patient was 27 months old, and she had undergone uncomplicated cardiac surgery for the subaortic membrane three months earlier. The patient had a history of cough, cold, and wheezing for a day, so she was admitted to the inpatient unit on account of acute asthma exacerbation. She improved with albuterol nebulization first at two hours intervals and later three hours intervals. She was eventually discharged on albuterol every four hours as needed. Her anthropometric measurements at the time of admission were as follows: weight: 15.5 kg (96th percentile), length: 87 cm (40th percentile), and head circumference: 56 cm (>99th percentile). She had normal tone, strength, and reflexes in all extremities. On the latest developmental evaluation, she was found to have a global developmental delay as in Table In summary, this is a rare case of Peters Anomaly, congenital heart disease including PDA status post (s/p) closure, aortic stenosis pertaining to subaortic membrane s/p repair, macrocephaly, abnormal facial features, and global developmental delay with triplication of 22q11.2 of DiGeorge region and a variant of uncertain significance on genetic evaluation. To the best of our knowledge, we are presenting the third reported case of triplication of the 22q11.2 chromosomal region. This triplication has a broad range of phenotypes affecting phenotypic and cognitive development, comparable to the two reported cases in the literature. The first patient presented with speech delay, learning disabilities, and dysmorphic features . The secCentral corneal opacification can lead to delayed visual development progression caused by defects in the Descemet membrane and the posterior stroma . Our patWe thus present Peters anomaly as a new characteristic of triplication of the 22q11.2 chromosome region. This was noted in our patient with a 646 Kb triplication of 22q11.2 (LCR22B-D) of the DiGeorge region with a different eye anomaly, consistent with a phenotypic expansion that has not been detected been reported in the literature. Although it is rare, we reaffirm that medical practitioners should take heed to the similarities between 22q11.2 triplication, microduplication, and deletion syndromes to prevent misdiagnosis. in addition, these syndromes should be taken into account in a patient presenting with a dysmorphic face associated with heart defects, developmental delay, and other malformations.Increased dosage of this region remains unclear whether it causes a recognizable phenotype. A clinically significant phenotype has been theorized that could be a benign polymorphism or risk variant requiring a "second hit." Furthermore, a second hit could be an additional copy of the same region, assuming that one or more involved genes are dosage sensitive. It is suggested that an increased dosage of these genes might increase the risk for cardiac abnormalities .We described in depth the phenotypic features of a female with triplication of the 22q11.2 DiGeorge region to highlight the consequence of increased dosage number of the 22q11.2chromosomal region. Moreover, this patient's phenotypic appearance may support a new feature and characteristic of triplication of this genomic region, which includes phenotype influencing cardiovascular development, facial appearance, cognition, and developmental. We present Peters anomaly as a new characteristic of triplication of the 22q11.2 chromosome region.


The interactions between cells and molecules in the tumor microenvironment can give insight into the initiation and progression of tumors and their optimal treatment options. In this paper, we developed an ordinary differential equation (ODE) mathematical model of the interaction network of key players in the clear cell renal cell carcinoma (ccRCC) microenvironment. We then performed a global gradient-based sensitivity analysis to investigate the effects of the most sensitive parameters of the model on the number of cancer cells. The results indicate that parameters related to IL-6 have high a impact on cancer cell growth, such that decreasing the level of IL-6 can remarkably slow the tumor’s growth. Clear cell renal cell carcinoma (ccRCC) is a type of kidney cancer that makes up 80% of kidney cancer cases . SurgeryMathematical models can provide valuable information about the complex interactions in biological systems, such as cancer ,11,12,13reatment . Since vreatment . In addireatment ,17,18.The tumor microenvironment, including its cytotoxicity, plays an essential role in inhibiting cancer proliferation . Many cland IL-2 ,21,22. Hand IL-2 . More reand IL-2  by increand IL-2 ,26,27. Pand IL-2 ,26,27. Oand IL-2 . IFN-γ iferation . When tuferation ,30,31,32feration ,34. Althferation .The ccRCC microenvironment has the highest levels of immune cell infiltration among all epithelial cancer types, making it a pro-inflammatory environment . InfiltrThis paper investigates the dynamics of tumors based on their immune patterns by developing an ODE model that considers the interaction network of key players that we mentioned above see . We clusAs mentioned in the introduction, ccRCC has the highest infiltration of cytotoxic cells, dendritic cells, Th1, and macrophages among all of the other epithelial cancers, and low levels of regulatory T-cells and Th2 ; the resHelper T-cells, interleukin-12 (IL-12), and interleukin-2 (IL-2) help the proliferation of cytotoxic cells, but regulatory T-cells (T-reg cells) inhibit both helper T-cells and cytotoxic cells ,41,42,43In addition, both cancer and necrotic cells release relatively large portions of HMGB1 that helps promote dendritic cells and helper T-cells ,31,33,51We derived an ordinary differential equation (ODE) for each variable in the model using Helper T-cells :Macrophages d[M]Naive macrophages :Dendritic cells :Cancer cells :Necrotic cells d[NIFN- Interferon-ic cells ,29,57.(H):HMGB1  along with the immune classification by Su et al.  where thP byWe determined the actual cell population based on the intermediate tumor size described in the TCGA clinical data of renal cell carcinoma patients . We chosironment ,17,18,75We let the cells and cytokines of the smallest tumor in each cluster be the initial conditions of the system and nondimensionalized the variables by dividing them by their steady state values. The nondimensional initial conditions are given in X and We have 15 ODEs and 67 parameters, but there is not enough biological information to estimate all of the parameter values specific to ccRCC. However, we collected and derived some of the decay rates, such as alf-life ,17,18. Wly 7 min  and the ly 7 min , so we tted from ,18 or caWe estimate the remaining parameters of the model by assuming the large tumors are at a steady state and utilize their data. The ODEs in F with respect to Since there is not enough biological evidence to estimate all of the parameter values of the ccRCC model, the limitations of unknown parameter estimations must be considered when using the result of the dynamics. We performed a global gradient-based sensitivity analysis to assess our estimations by scaling the 34 parameter assumptions in ct to X¯ . Then, wct to X¯ .The dynamics of the cells and molecules over 5000 days are presented in The helper T-cell population decreases at the beginning and eventually increases to reach a steady state in clusters 3 and 4. In cluster 2, it increases, and in cluster 1, it decreases to reach a steady state within the first few days. As a result, the helper T-cell populations in clusters 1 and 2 remain constant almost all of the time.Cytotoxic cells in all clusters decrease in the first few days but eventually increase in population to reach a steady state. Furthermore, cytotoxic cells in cluster 2 start with the highest population and achieve the highest saturation level. This is followed by cluster 4, with the second highest saturation level, where the cells grow faster and reach a steady state in around 1500 days. In cluster 3, cytotoxic cells reach the lowest saturation level, leaving cluster 1 with the second lowest saturation level. Overall, the steady state populations and the time points that each cluster reaches steady states are noticeably different in each cluster.T-reg cells in clusters 1, 2, and 4 increase quickly from their initial conditions and decrease to reach a steady state. T-reg cells in cluster 4 reach a steady state at around 1500 days and clusters 1 and 2 reach a steady state at around 3000 days. In cluster 3, T-reg cells decrease and reach a steady state faster than in any other cluster. Furthermore, the slow increase in cytotoxic cells in clusters 1 and 2 could be due to regulations by T-reg cells that slowly decrease in these clusters. Similarly, the faster growth in cluster 4 of cytotoxic cells could be related to the fast decrease of T-reg cells in cluster 4.Naive T-cells in cluster 1 attain the highest steady state population, followed by 3, 2, and 4, respectively. In clusters 1 and 2, naive T-cells increase slowly and reach a steady state of around 2000 days, whereas clusters 3 and 4 stabilize before and after 1000 days.Macrophages . Cluster 2 has the slowest growth despite having the highest initial population. Clusters 2, 3, and 4 all achieve a similar steady state population sooner or later within 5000 days. The slow growth in cluster 2 can also be attributed to the significantly high cytotoxic levels. Overall, we can see a clear correlation between cancer progression and cytotoxicity levels.Interferon-Since we assume that the concentrations of The sensitivity analysis reveals that the parameters directly involved in the cancer ODE are the most sensitive parameters for cancer cells and total cells. Additionally, macrophage-related parameters, such as We could say that a quantity is positively sensitive to a parameter when an increase in the parameter causes the quantity to become larger. A quantity is negatively sensitive to a parameter when an increase in the parameter causes a decrease in the quantity. According to the sensitivity plot in In addition, The sensitivity analyses of the parameters show that the direct and indirect interactions between the variables impact cancer or total cell growth in the cancer microenvironment. For instance, the inhibition of cancer cells by cytotoxic T-cells, IFN-rophages  and posirophages . This isThese three scalings cause significant changes in the parameters as illustrated in umptions  and 22)ADN, δDC,sumption . What isAlthough the parameters er cells . Since αAs a result, the term involving The figure indicates that the dynamic of the cancer cell population remains unchanged after varying the term Cancer is a diverse and complex disease that cannot be understood with a unified approach. Each cancer patient is unique in his/her immune infiltration profile and cancer type. In this paper, we proposed a model describing the critical interactions in the ccRCC tumor microenvironment. The model was inspired by the emerging clinical model of targeted therapy efficacy within distinct ccRCC subgroups. These models consider the infiltrating immune cells, such as cytotoxic, helper, and regulatory T-cells, macrophages, and dendritic cells . TherefDespite the limitations of the model, we could infer interesting pathways in ccRCC and its microenvironment development. For instance, pathways that directly or indirectly affect the cytotoxicity of the microenvironment seemed to affect the cancer dynamics. We saw that a higher population of cytotoxic cells in cluster 2 is correlated to slower cancer cell growth. This could indicate that environments with initially higher cytotoxicity have a better shot at controlling ccRCC. Furthermore, the slow cancer growth in cluster 1 at the beginning can be related to naive dendritic cell growth patterns. More naive dendritic cells result in more mature dendritic cells that promote helper T-cells, aiding in more cytotoxicity in the environment . AlthougWe performed a global sensitivity analysis on the parameters of the model to see their impacts on cancer and total cell growth. We saw that the most sensitive parameters were the production/promotion and decay/inhibition rates directly involved in cancer ODE, which was expected. In addition, we noticed a lot of macrophage-related production and inhibition rates as the second most sensitive parameters. Specifically, the sensitivity values hinted that more macrophages lead to worse prognoses. It has been shown that macrophage polarization into anti- and pro-tumor subtypes can have different implications for cancer progression and prognosis ,78. The of ccRCC ,80,81,82As with all the other mathematical models, our model is not without limitations. Many assumptions were used here, even though biologically feasible, but they were of mere mathematical nature. Some examples of such assumptions are: (1) the estimation of initial conditions by the small tumors in each cluster and assuming the largest tumors to give us the steady state values, and (2) the specific scales used to enforce the dominant activator or inhibitor of certain cells or cytokines. We tried our best to assess the sensitivity of our model to these assumptions and justify their robustness. However, none of these attempts can replace a direct validation using time-course data, and we acknowledge this limitation of the study. Moreover, for simplicity, we ignored important factors, such as angiogenesis and metabolites. We acknowledge this as another limitation of our model. However, this model provides a basis for future computational models of the ccRCC tumor microenvironment and can be extended to include new biological and biomedical discoveries and find optimal treatment options for ccRCC patients.


Background: Pituitary apoplexy (PA) can be symptomatic, namely acute apoplexy (APA), or asymptomatic or subclinical (SPA). Objective: To describe the clinical characteristics and evolution of the patients with APA compared to SPA Patients and methods: Retrospective, longitudinal database analysis. Results: We identified 58 patients with PA, and 37 accomplished the inclusion criteria . A total of 29 (78.4%) had APA , and 8 (21.6%) had SPA. The presence of non-functioning pituitary adenoma (NFPA) odds ratio (OR): 29.36 : 1.86–462.36) and the largest size OR 1.10 (95% CI: 1.01–1.2) elevated the risk of having surgery. Hypopituitarism developed in 35.1% without significant differences between APA and SPA. In non-surgical patients, adenoma volume shrunk spontaneously at one year magnetic resonance imaging (MRI), without statistical differences between the conservatively treated and SPA group. Conclusions: APA is more frequent in larger NFPAs, and this subset of patients has a higher risk of surgery. Hypopituitarism is quite frequent even in patients with SPA, and, therefore, long-term follow-up is mandatory. In the non-surgical group, the pituitary tumour shrinkage is clinically relevant after one year of PA. Consequently, surgery indication in NFPA should be delayed and reassessed if patients remain asymptomatic. Pituitary apoplexy (PA) is a rare, sometimes life-threatening clinical syndrome as a result of acute/subacute haemorrhage and/or infarction of a pituitary tumour, and a severe sudden onset headache is one of its main symptoms ,2. NeverTraditionally, PA has been described as more frequent in non-functioning pituitary adenomas (NFPAs) ,5,6. ThiIn less than 50% of cases, there are some precipitating factors reported in the literature, such as prior major surgery (mainly orthopaedic and cardiac surgery), brain traumatism, endocrinological dynamic test, and cerebral angiographic procedures, as well as some drugs . In addition, PA is less frequent and has a more favourable prognosis in the setting of microadenoma . MoreoveRegarding treatment, traditionally, PA has been universally considered a neurosurgical emergency . In factFinally, little is known regarding pituitary function and tumour volume evolution after apoplexy.In summary, pituitary apoplexy remains a poorly understood condition . PotentiWe analysed our database searching for patients diagnosed with PA from 2010 to 2021. This registry is annually updated in compliance with CSUR ) and Endo-ERN (Endocrine European Reference Network) designation. Records are obtained based on electronic codes regarding the following items: (1) Emergency room’ or ICU diagnostic; (2) Ward admission diagnosis; (3) Surgical diagnosis; (4) Pathology diagnosis; (5) Medical consultation diagnosis. We followed the Strengthening the reporting of observational studies in epidemiology (STROBE) Statement for observational studies Definitions:Subclinical PA (SPA): presence of radiological evidence of haemorrhage or necrosis in the pituitary gland incidentally discovered (absence of symptoms).Acute apoplexy (APA): patient consulting for symptoms consistent with PA  with radiological confirmation of PA.Conservative management: When patients did not require surgery, or surgery was delayed and scheduled after one month. By protocol, we used a bolus of hydrocortisone (100 mg intravenous) followed by 50 mg every 6 h iv. in any patient with PA suspicion while waiting for an ophthalmologist and neurosurgery evaluation.Surgical management: It was considered when the patient required surgery within 1 week after PA diagnosis. All the patients had an endonasal endoscopic transsphenoidal surgical approach for tumour removal, and the sample was sent for histopathological examination.Fail to conservative management: Patients who required surgery after 1 week of conservative approach and before one month from the APA due to the absence of clinical improvement.The study was conducted according to the mandates in the Declaration of Helsinki, and the Ethics Committees of the Vall d’Hebron University Hospital approved all procedures. All neuroimages were reviewed by two neuroradiologist (SS and YKN).Inclusion criteriaInclusions criteria were: (1) patients older than 18 years at apoplexy diagnosis with a follow-up conducted in our Hospital; (2) imaging confirmation (MRI scanning of the pituitary with haemorrhage or necrosis); (3) at least one MRI at one year of follow-up, except in case of death.Variables and measurementsClinical characteristics: age, gender, body mass index, history of diabetes, hypertension, dyslipidaemia, smoking habit, cardiovascular disease, hypopituitarism, haematological disease, cancer, general surgery, pregnancy, and dynamic endocrinological tests. Drug abuse and medications, including contraceptives, antiplatelets, or anticoagulants, were also recorded. In the group of APA: signs, symptoms, number of days with symptoms, treatment options, date of surgery and eventual complications, corticosteroid doses, and pathology results were recorded. In all patients, the following outcomes from the first day of PA to the end of follow-up were recorded: hyponatremia, neurological and hormonal status, tumour changes, and death.Tumour characteristics: Size, parasellar tumour involvement by Knosp grading , apoplexPituitary MRI: The standard MRI  protocol included non-enhanced and contrast-enhanced coronal and sagittal 2D T1 weighted image (T1-WI), and coronal 2D T2 weighted image (T2-WI) (slice thickness 3 mm). The maximum tumour diameter was measured and used to classify pituitary adenoma as microadenoma (<10 mm) or macroadenomas (≥10 mm). The percentage of tumour shrinkage was calculated using the two largest diameters in sagittal view as previously reported [(%) =  × 100/Basal DI × D2] .Statistical analysis2 test or with Fisher’s exact test when at least one of the expected frequencies was less than 5. Continuous variables are expressed as the median and interquartile range (IQR), and comparison between two groups was performed using Student’s t-test or the nonparametric Mann–Whitney U-test accordingly to variable distribution.Categorical variables are expressed as a percentage and compared using the χp < 0.20 were included in multiple logistic regression, and a stepwise backward selection approach was used to identify the best predictive model for surgery. The model fit and calibration were assessed by Akaike’s and Bayesian information criterion, the Hosmer–Lemeshow goodness-of-fit test, and the discrimination power by calculating the area under the receiver operating characteristic (ROC) curves (AUC). Results were expressed as odds ratio (OR) and 95% CI. A p-value of <0.05 was considered significant. Statistical analyses were performed using the STATA16 statistical package  for Windows.We used Spearman’s rank test to investigate which variables among demographic variables, past history, or tumour characteristics influenced to have surgery. Predictors with From February 2010 to August 2021, we identified 58 patients with PA of a total of 529 patients with pituitary lesions . Of this, 37 accomplished the inclusion criteria. A total of 21 were excluded for the following reasons: eleven because the first 2–3 days were managed in other hospitals, thus impeding our full access to data ; eight SPA because a second MRI was lacking and/or the follow-up, was not conducted in our Hospital and two cases because after a careful evaluation by the radiologists the lesion was defined as a Rathke cleft cyst . Overallp < 0.04, and 34% vs. 0%; p < 0.05, respectively).The clinical features of the total included patients, patients with SPA, and APA are summarised in . The majRegarding tumour characteristics: 13 (35.1%) were previously diagnosed with pituitary adenoma , of which only 3 were microadenomas (2 NFPAs and 1 prolactinoma). The median time from the diagnosis of pituitary adenoma to PA was 27.3 (IQR 59.3) months. Of the remaining 24 patients without prior know adenoma, the majority were non-functional macroadenomas , followed by prolactinomas  and GH-secreting tumours . As a whole, there were 24 (64.9%) NFPAs, 10 (27.0%) prolactinomas, and 3 (8.1%) GH-secreting adenomas. The prevalence of apoplexy in each tumour type in our series was , for NFPA),  for prolactinomas) and (3/74 (4.1%) for acromegaly). We did not find any PA in patients with Cushing disease.p < 0.01) and less invasive tumours  than those patients who suffered APA, and all of them were hyperintense in T1-WI  cases, 6 (85.7%) had adrenal insufficiency, and 1 (14.3%) presented a SIADH, all of them belonging to the APA group.p < 0.03). The surgery group had larger tumours , with more frequent suprasellar extension and optic chiasm compression  than the group treated with conservative measures.Clinical presentation and tumour characteristics and the type of treatment  are displayed in All patients with APA received glucocorticoid treatment without statistical differences in the doses employed in the first 24 h between those treated with conservative measures and those requiring surgery.All the patients under conservative management improved clinical signs and symptoms except three patients who required surgery. The development of hypopituitarism during follow-up considering the presence of SPA vs. APA and the type of treatment is shown in The baseline and changes in pituitary tumour volume at 12 months of follow-up after PA in patients in whom surgery was not required are displayed in In the follow-up, four patients died, but only one was related to PA. A new apoplexy episode was observed in two cases.In 3 out of 17 surgical cases, the pathology evaluation was not possible due to massive haemorrhage or necrosis. In the remaining 14 cases, we did not find any specific characteristic that could identify a more aggressive behaviour of these tumours. Only in one case was the Ki67 near 10%, but there was no tumour regrowth or relapse after five years of follow-up.We used Spearman’s rank test and stepwise backward selection approach to identify the best predictive model for surgery. The included variables were maximum diameter of the pituitary tumour, age, gender, body mass index, hyper T1 and T2 signalling, presence of T2DM, dyslipidaemia, smoking habit, cranial nerve involvement, chiasma compression, and presence of NFPA (extrasellar and sinus invasion were excluded due to co-linearity). The reduced and parsimonious model that best explained the probability of required surgery included: having a NFPA, hyperintensity on T1-WI, and maximum diameter on MRI. The model was well-fitted according to Akaike’s and Bayesian information criteria, and the likelihood ratio compared with the null model was <0.01. The binomial area under the receiver operating characteristic curve (AUC) was 0.89 CI (0.73–0.98). The Youden index was 0.70  .In our series, patients with APA had more frequent larger and invasive NFPAs, as well as T2DM and dyslipidemia. Conversely, in SPA, the tumours were smaller and less invasive, and characteristically all of them had hyperintense in T1-WI. Despite these differences, it is remarkable that in the follow-up, the hypopituitarism, as well as a clinically relevant tumour volume reduction at one year of the follow-up, was similar in both groups.Our results are in line with the proposed grading apoplexy scale by Jho DH et al. , in whicIn our series, up to 38% of the patients with APA had T2DM, and none of the patients with SPA. Diabetic microangiopathy, haemodynamic changes, and the pro-thrombotic state that occurs in patients with uncontrolled diabetes could favour pituitary apoplexy ,23,24. HSimilarly to the results observed in the present study, Singh et al.  found thThe most common tumour in our PA series was NFPA. These results are consistent with other series ,4,25. ThIn the clinical setting, Semple et al.  showed aTo our knowledge, this is the first study to assess and compare the clinical course and long-term outcomes of apoplexy in SPA vs. APA. Liu et al.  evaluateIn addition, we found that in non-surgical patients, the tumour volume shrunk after apoplexy in 65% of the patients, and none of them re-grew. On the other hand, two patients with NFPA in the APA group had new apoplexy in the follow-up, thus re-enforcing the concept that a predisposition to bleeding could be present in NFPA.Regarding the treatment of choice in APA, the modalities of treatment and times of intervention have been largely debated. The risk–benefit ratio of conservative treatment vs. surgery should be carefully evaluated. Singh et al.  describeFinally, in our series, only three patients failed conservatory treatment and required surgery, but one of them, in fact, had clinical criteria for acute surgery but was delayed due to active oncological treatment.The prediction model for undergoing surgery confirmed that the risk of having a PA and requiring surgery was many times higher in NFPA and larger tumours.Our study has some limitations, such as the retrospective design in a single centre. The sample size did not allow the analysis of events with low frequency. In addition, being a referral hospital could imply a potential bias towards more APA than SPA. The main strengths were the rigorous selection and good characterisation of the patients included in the study.In conclusion, these data suggest that larger NFPA adenomas have a higher risk of APA and could require surgery. Hypopituitarism is quite frequent even in patients with SPA, and therefore, long-term follow-up is mandatory. In the non-surgical group, the pituitary tumour shrinkage is clinically relevant after one year of PA, and consequently, surgical options should be delayed and reassessed if the patients remain asymptomatic.


Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of paratuberculosis (PTB), chronic enteritis of ruminants spread worldwide. PTB is, by now, considered a conditioned disease, depending on both environmental and genomic factors. PTB susceptibility seems to be related to some genes coding for immune regulators involved in the cell-mediated response during infection: genetic markers, particularly single nucleotide polymorphisms (SNPs), have been investigated in several studies, and different candidate genes have been highlighted as associated with PTB resistance/susceptibility. The aim of this preliminary study was to verify, for the first time in a local beef cattle breed, known as Marchigiana, an association between MAP infection status and SNPs in candidate immune-genes. Specifically, in a MAP-infected herd, IFN-γ tests, ELISA, qPCR, and cultures were performed, for a follow-up range of 3–6 years, on 112 bovines to evaluate the state of MAP infection. Animals with positive results for at least one test were considered infected. DNA samples of bovines with a known MAP status were analyzed to assess the presence and the genotypic frequency of SNPs in genes encoding for gamma-interferon (BoIFNG), interleukin receptor 10 (IL10RA), interleukin receptor 12 (IL12RB2), and toll-like receptors . For the IL10RA and IL12RB2 genes, relevant differences in genotypic frequencies among the considered cattle groups were observed. For all the investigated candidate genes, SNP genotypes that have been associated with PTB resistance in the literature, were found more frequently, suggesting potential genetic resistance traits in the Marchigiana breed.Mycobacterium avium ssp. paratuberculosis (MAP) is the causative agent of paratuberculosis (PTB), a widespread chronic enteritis of ruminants. The progression of the infection depends on the containment action of innate and cell-mediated immunity (CMI), and it is related to environmental and genetic factors. In particular, PTB susceptibility seems to be associated with specific genes coding for immune regulators involved in the cell-mediated response during the infection. The aim of this preliminary study was to verify, in Italian beef cattle, an association between MAP infectious status and the presence of single nucleotide polymorphisms (SNPs) in candidate genes. To the best of our knowledge, this is the first investigation conducted on a native beef cattle breed, known as Marchigiana, reared in Central Italy. The present research, based on a longitudinal study, aimed to identify and correlate phenotypic and genetic profiles characteristic of the subjects potentially able to contrast or contain PTB. In a MAP-infected herd, ELISA, IFN-γ tests, qPCR, and cultures were performed at a follow-up, occurring within a period ranging from three to six years, to evaluate the individual state of infection. Animals testing positive for at least one test were considered infected. DNA samples of 112 bovines, with known MAP statuses, were analyzed to verify an association with SNPs in the genes encoding gamma-interferon (BoIFNG), interleukin receptor 10 (IL10RA), interleukin receptor 12 (IL12RB2), and toll-like receptors . Regarding statistical analysis, the differences among target genes and pairs of alleles in the analyzed groups of animals, were evaluated at a significance level of p < 0.05. For IL10RA and for IL12RB2 genes, relevant differences in genotypic frequencies among the considered cattle groups were observed. For all candidate genes studied in this investigation, SNP genotypes already associated with PTB resistance were found more frequently in our population, suggesting potential resistance traits in the Marchigiana breed.  Mycobacterium avium subsp. paratuberculosis (MAP) and is characterized by a chronic granulomatous enteritis affecting farmed ruminants and wild species [Paratuberculosis (PTB), or Johne’s disease (JD), is an infectious disease of ruminants caused by  species ,2. Clini species ,4. Infec species ,6,7 repr species ,9. In pa species ,11,12. R species ,16,17,18 species ,20, and  species . Concerning animal husbandry, PTB infection can result in substantial economic losses, as it causes a decline in milk production ,23, weigDifferent factors can influence the progression of infection, such as the host’s age, nutritional status, infection pressure, and the virulence of the pathogen. However, these factors alone cannot explain the extreme variations in disease outcomes . TherefoTLR genes, particularly single nucleotide polymorphisms (SNPs), are the primary cause of reduced pathogen recognition, contributing to increased susceptibility to some infections, and interfering with the immune response [TLR2 and TLR4 genes can cause increased susceptibility to infections such as tuberculosis, malaria, acute rheumatic fever, urinary tract infections, and CD [TLR1 and TLR4 genes have been documented in the literature to cause a decreased response against bacterial cell wall components, such as lipopeptides and lipopolysaccharides, that are highly present in mycobacteria [Several studies also suggest the existence of host genetic components in susceptibility or resistance to PTB, and investigations have focused on a set of genes encoding for immune-regulators involved in the cell-mediated response ,38. In presponse . In huma, and CD ,45. Indebacteria .IFN-γ, IL10RA, and IL12RB2 [In cattle, 10 different types of TLRs ,7,8,9,10 IL12RB2 ,41,42.intra vitam diagnosis of PTB is based on methods that assess the humoral immune response through serological testing, and direct detection of MAP from feces is carried out using cultures and PCR [Marchigiana. As widely known, during the latent stage of JD, infected animals spread MAP in feces before showing any clinical signs, representing an important source of infection for other animals in the herd ,5,6. The and PCR ,53. Unfo and PCR . The ini and PCR . This st and PCR ,37,54. I and PCR ,56,57; h and PCR , in part and PCR . In the Bos taurus taurus, some Italian beef breeds such as Chianina, Romagnola, and Marchigiana, belonging to the so called “Podolian group” [B. t. taurus and B. t. indicus ancestries [Marchigiana breed, the object of the present study, is a beef breed derived from the more ancient breeds Chianina and Romagnola [In this regard, literature has further documented, also through whole-genome sequencing, different susceptibility levels among breeds of sheep , goats , deer 6, and catn group”  and showcestries ,70,71. Iomagnola ,69,71. Iomagnola . In thisomagnola .Marchigiana cattle breed, a typical local beef breed reared in Central Italy, in order to assess PTB resistance genetic traits, and verify the presence of SNPs in candidate genes encoding for target cytokines and their receptors, that are involved in the disease. The ultimate goal of the research, based on a longitudinal study, was the identification and correlation of phenotypic and genetic profiles characteristic of those individuals potentially able to contrast or contain MAP infection.On this basis, our preliminary study was conducted on the Marchigiana cattle from a bTB officially free (OF) herd, who had previous PTB positivity, were enrolled in the trial. At first, various farms were screened and monitored, however, the investigation was then focused only on a Marchigiana cow-calf beef farm, with breeding cows of high genetic value, that were older than 36 months. In this herd, farmer collaboration was guaranteed and the cows could be followed for a long time. Furthermore, in the herd, there were two bulls, used for natural mating, that were screened with a six-year follow-up. Additionally, the remaining animals in the farm, consisting of calves destined to be sold as breeding stock, were followed for at least 3 years.No ethical approval was required because sampling was carried out concurrently with the periodic tests required by the Italian National Health Programs ,73,74 anMarchigiana cattle herd, with previous serological positivity for PTB, 112 animals (aged from 2 to 10 years) were tested at least once per year and at a follow-up ranging from three to six years. Particularly, the animals were subjected to: -®-Grabels, France; IDEXX®-Westbrook, ME, USA) in accordance with the manufacturer’s instructions;a serological assay, ELISA test for PTB from blood serum  were considered to be PTB-positive subjects.-“Phosphate Buffered Saline” (PBS) without specific antigens;-Bovine PPD and Italian Avian PPD (produced at IZSUM);-Johnin PPD (produced at IZSUM); and-® Pokeweed Mitogen-Thermofisher Scientific, Waltham, MA, USA) for the lymphocyte viability check.Mitogen .After 18–22 h of incubation, plasma was collected and IFN-γ was detected with ELISA kit (BOVIGAM® kit (if PPDA or PPDJ—PBS > 0.1 = MAP infection), as described by Corneli et al., 2021 [Gamma interferon assay outcomes were interpreted by considering the difference between the optical density (OD) values of PPDs(obtained after lymphocyte stimulation) and the basal OD value, using the cut-off value provided by the Bovigaml., 2021 .-group 1: healthy, uninfected cattle, which were always negative for the ELISA, qPCR, and IFN-γ assays;-group 2: healthy but MAP-infected cattle, with positivity for the IFN-γ test but always negative for the ELISA and qPCR assays; and-group 3: PTB affected cattle, with positivity for at least the ELISA and/or qPCR from feces and/or the MAP culture, regardless of the IFN-γ test results.Based on the results obtained from the traditional methods, the animals were classified into three phenotypic groups: The within-herd PTB prevalence was estimated at around 1.8%. Out of 112 analyzed subjects, 50 of them had negative results for the ELISA, IFN-γ test, and qPCR from feces (group 1). A total of 57 subjects were healthy but infected, with negative outcomes for the ELISA and qPCR from feces but positive outcomes for the IFN-γ assay (group 2). Finally, five animals (group 3) were PTB positive; in particular, five tested positive on the ELISA, and one of them also tested positive on the qPCR from feces and the MAP culture. Genomic DNA was extracted from whole blood using the High Pure PCR Template Preparation Kit , following the manufacturer’s instructions. TLR4 gene sequence (446 bp), about 100 ng of extracted DNA was used as a template in PCR amplification and the optimal reaction concentration of the primer forward and reverse set of Mucha et al. [Target genes and polymorphic sites were accurately selected from the literature . For thea et al.  was 400 TLR4 amplicons were controlled on 1.5% agarose gel electrophoresis containing Midori Green Advanced DNA Stain  and PCR products were purified with QIAquick® PCR Purification Kit , according to the manufacturer’s instructions. The quality and quantity of PCR products were assessed using a Biophotometer, , measuring the absorbance at 260, 280, and 230 nm and the relative ratio.Bos taurus TLR4 mRNA, (GeneBank accession number: NM_174198.6) Electropherograms were checked at each investigated mutation point to locate and discriminate heterozygous peaks. SNPs presence was assessed with BioEdit v7.2.5 software [Sequencing reactions were performed, in both directions, using BrilliantDye™ Terminator Cycle Sequencing Kit v3.1  according to the manufacturer’s instructions. Sequencing reactions were run in a 3500 Genetic Analyzer (Thermo Fisher Scientific). All sequences in the FASTA format were aligned to software , using tsoftware , to deteThe other target genes were analyzed in service by LGC Biosearch Technologies  with KASP™  SNP genotyping technology. p < 0.05. The analysis was performed using Stata software v.11.2 .In order to evaluate whether there were statistically significant differences between the most represented phenotypic groups, a comparison among animals presenting the polymorphisms of interest for each investigated gene was carried out using Pearson’s chi-square, and considering the different allelic pairs of group 1  versus those of group 2 . Z-tests were performed for all target genes to compare the number of animals with genotypes related to each SNP by comparing the proportions of the two groups. The differences were considered significant at In our investigation, 50 animals, although exposed to MAP infection, were followed for a long period of time (from three years up to six years), and were always negative for the IFN-γ test, the ELISA, and the qPCR from feces (group 1). On the other hand, 57 animals only showed reactivity to the IFN-γ test against Avian PPD and Johnin, thus representing animals that have an acquired “immunological memory” against MAP (group 2). In addition, the remaining 5 animals of the herd, tested positive on the ELISA with one of them having positive results for the qPCR and MAP culture; still, they never showed clinical signs. For this reason, animals from group 3 were considered affected but not diseased, which is in accordance with the Whittington “JD case-definition” . Thus, tBoIFNG, IL10RA, IL12RB2, TLR1, TLR 2 and TLR4 genes found in the group of healthy subjects (group 1) and the group of infected ones (group 2). For IL10RA, there were four SNP variants  considered by Verschoor [Regarding the candidate genes investigated in our preliminary study, erschoor ; howeverBoIFNG, IL12RB2, and all TLRs genes  [As reported in  status) ,39,40,42IL10RA gene, which is associated with a high probability that the carrier animal is MAP infected and/or affected [It is relevant to highlight that the wild-type G/G genotype of the affected , occurreConversely, the mutated A/A genotype of the same gene (44% for group 1 and 58% for group 2) and the heterozygous ones (46% for group 1 and 40% for group 2), which are associated with PTB resistance in literature , are mosIL12RB2 gene (A/A p = 0.03), which despite being present in each group, had a higher frequency in group 2 (54% for group 1 and 74% for group 2).Regarding the phenotypic groups, it has to be considered that the specificity and sensitivity of diagnostic assays are influenced by the stage of MAP infection and by the individual host response. For instance, ELISA has lower sensitivity in the early stages than in the late stages of PTB. On the other hand, fecal cultures and qPCR from feces are strictly dependent on the intermittent and transient fecal MAP shedding of cattle . These fFurthermore, as already known, there is a substantial difference between PTB-affected animals and healthy animals but MAP infected animals , as highTLR1, 2, and 4 genes can affect the efficiency of the bovine immune system in containing MAP infection [TLR2 haplotype, the clinical phase of PTB was more severe and started earlier as a consequence of inadequate innate and CMI responses. It has to be considered that the comprehension of the mechanisms and genetic loci of resistance and disease tolerance to infectious agents in asymptomatic individuals is currently very limited . Howevernfection ,39,45. Lnfection ,41,42. Anfection , provideBoIFNG gene,  plans, allowing for the valorization of a native or ancient breed. On this basis, and considering the genetic profiles found in this investigation, our preliminary results are promising. Thus, we are planning to utilize a more large-scale approach through a genome-wide association study (GWAS), on the


Most of the existing chest X-ray datasets include labels from a list of findings without specifying their locations on the radiographs. This limits the development of machine learning algorithms for the detection and localization of chest abnormalities. In this work, we describe a dataset of more than 100,000 chest X-ray scans that were retrospectively collected from two major hospitals in Vietnam. Out of this raw data, we release 18,000 images that were manually annotated by a total of 17 experienced radiologists with 22 local labels of rectangles surrounding abnormalities and 6 global labels of suspected diseases. The released dataset is divided into a training set of 15,000 and a test set of 3,000. Each scan in the training set was independently labeled by 3 radiologists, while each scan in the test set was labeled by the consensus of 5 radiologists. We designed and built a labeling platform for DICOM images to facilitate these annotation procedures. All images are made publicly available in DICOM format along with the labels of both the training set and the test set.  Leveraging deep convolutional neural networks (CNN)6, these systems can reach the expert-level performance in classifying common lung diseases and related findings. Training a CNN heavily relies on high quality datasets of annotated images. However, it is costly and time-consuming to build such datasets due to several constraints: (1) medical data are hard to retrieve from hospitals or medical centers; (2) manual annotation by physicians is expensive; (3) the annotation of medical images requires a consensus of several expert readers to overcome human bias7; and (4) it lacks an efficient labeling framework to manage and annotate large-scale medical datasets.Computer-aided diagnosis (CAD) systems for chest radiographs  have recently achieved great success thanks to the availability of large labeled datasets and the recent advances of high-performance supervised learning algorithms8, Padchest9, CheXpert2, and MIMIC-CXR10. ChestX-ray14, an extended version of ChestX-ray8, was released by the US National Institutes of Health (NIH), containing over 112,000 CXR scans from more than 30,000 patients. Without being manually annotated, this dataset poses significant issues related to the quality of its labels11. Padchest consists of more than 160,000 CXR images, 27% of which were hand-labeled by radiologists with 174 different findings and 19 diagnoses. The rest of the dataset were labeled using a Natural Language Processing (NLP) tool. Recently released CheXpert provides more than 200,000 CXRs of 65,240 patients, which were labeled for the presence of 14 observations using an automated rule-based labeler that extracts keywords from medical reports. Adopting the same labeling mechanism, MIMIC-CXR contains 377,110 images in DICOM format along with free-text radiology reports. Table 12, Indiana13, MC14, and SH14.Notable public datasets of CXR include ChestX-ray8, ChestX-ray142 and NIH labelers8) or an NLP model to extract disease labels from free-text radiology reports. These tools can produce labels on a large scale but, at the same time, introduce a high rate of inconsistency, uncertainty, and errors15. These noisy labels may lead to the deviation of deep learning-based algorithms from reported performances when evaluated in a real-world setting16. Furthermore, the report-based approaches only associate a CXR image with one or several labels in a predefined list of findings and diagnoses without identifying their locations. There are a few CXR datasets that include annotated locations of abnormalities but they are either too small for training deep learning models (JSRT) or not detailed enough (PadChest). The interpretation of a CXR is not all about image-level classification; it is even more important, from the perspective of a radiologist, to localize the abnormalities on the image. This partly explains why the applications of CAD systems for CXR in clinical practice are still very limited.Most existing CXR datasets depend on automated rule-based labelers that either use keyword matching . All DICOM images and the labels of both the training set and the test set are released. A slightly modified version of this dataset was used to organize the VinBigData Chest Xray Abnormalities Detection Challenge on the Kaggle platform .In an effort to provide a large CXR dataset with high-quality labels for the research community, we have built the VinDr-CXR dataset from more than 100,000 raw images in DICOM format that were retrospectively collected from the Hospital 108 (H108) and the Hanoi Medical University Hospital (HMUH), two of the largest hospitals in Vietnam. The published dataset consists of 18,000 postero-anterior (PA) view CXR scans that come with both the localization of critical findings and the classification of common thoracic diseases. These images were annotated by a group of 17 radiologists with at least 8 years of experience for the presence of 22 critical findings  and 6 diagnoses ; each finding is localized with a bounding box. The local and global labels correspond to the “Findings” and “Impressions” sections, respectively, of a standard radiology report. We divide the dataset into two parts: the training set of 15,000 scans and the test set of 3,000 scans. Each image in the training set was independently labeled by 3 radiologists, while the annotation of each image in the test set was even more carefully treated and obtained from the consensus of 5 radiologists. The labeling process was performed via an in-house system called VinDr LabVinDr-CXR, to the best of our knowledge, is currently the largest public CXR dataset with radiologist-generated annotations in both training and test sets. We believe the dataset will accelerate the development and evaluation of new machine learning models for both localization and classification of thoracic lesions and diseases on CXR scans.The building of VinDr-CXR dataset, as visualized in Fig. 18, all personally identifiable information associated with the images has been removed or replaced with random values. Specifically, we ran a Python script that removes all DICOM tags of protected health information (PHI)19 such as: patient’s name, patient’s date of birth, patient ID, or acquisition time and date, etc. We only retained a limited number of DICOM attributes that are necessary for processing raw images. The entire list of retained attributes is shown in Table 1 . Next, a simple algorithm was implemented to automatically remove textual information appearing on the image data (i.e. pixel annotations that could include patient’s identifiable information). The resulting images were then manually verified to make sure all texts were removed before they were digitally sent out of the hospitals’ systems.To protect patient’s privacyadult PA-view CXRs, but also included a significant amount of outliers such as images of body parts other than chest (due to mismatched DICOM tags), pediatric scans, low-quality images, or lateral CXRs. Examples of these images are shown in Fig. The collected raw data was mostly of The VinDr-CXR dataset was labeled for a total of 28 findings and diagnoses in adult cases: (1) Aortic enlargement, (2) Atelectasis, 3) Cardiomegaly, (4) Calcification, (5) Clavicle fracture, (6) Consolidation, (7) Edema, (8) Emphysema, (9) Enlarged PA, (10) Interstitial lung disease (ILD), (11) Infiltration, (12) Lung cavity, (13) Lung cyst, (14) Lung opacity, (15) Mediastinal shift, (16) Nodule/Mass, (17) Pulmonary fibrosis, (18) Pneumothorax, (19) Pleural thickening, (20) Pleural effusion, (21) Rib fracture, (22) Other lesion, (23) Lung tumor, (24) Pneumonia, (25) Tuberculosis, (26) Other diseases, (27) Chronic obstructive pulmonary disease (COPD), and (28) No finding. These labels were divided into 2 categories: local labels (1–22) and global labels (23–28). The local labels should be marked with bounding boxes that localize the findings, while the global labels should reflect the diagnostic impression of the radiologist. The definition of each label is detailed in Table 2 . This list of labels was suggested by a committee of the most experienced radiologists from the two hospitals. The selection of these labels took into account two factors: first, they are prevalent and second, they can be differentiated on CXRs. Figure  CardiomeTo facilitate the labeling process, we designed and built a web-based framework called VinDr Lab and had a team of 17 experienced radiologists remotely annotate the data. All the radiologists participating in the labeling process were certified in diagnostic radiology and received healthcare profession certificates from the Vietnamese Ministry of Health. A set of 18,000 CXRs were randomly chosen from the filtered data, of which 15,000 scans  serve as the training set and the remaining 3,000 form the test set. Each sample in the training set was assigned to 3 radiologists for annotating in a blind fashion. Additionally, all of the participating radiologists were blinded to relevant clinical information. For the test set, 5 radiologists were involved in a two-stage labeling process. During the first stage, each image was independently annotated by 3 radiologists. In the second stage, 2 other radiologists, who have a higher level of experience, reviewed the annotations of the 3 previous annotators and communicated with each other in order to decide the final labels. The disagreements among initial annotators, as shown in Fig. 3 , were carefully discussed and resolved by the 2 reviewers. Finally, the consensus of their opinions will serve as reference ground-truth.Once the labeling was completed, the labels of 18,000 CXRs were exported in JavaScript Object Notation (JSON) format. We then parsed their contents and organized the annotations in the form of a single comma-separated values (CSV) file. As a result, we provided a single CSV file that contains labels, bounding box coordinates, and their corresponding image IDs. For the training set, each sample comes with the annotations of three different radiologists. For the test set, we only provide the consensus labels of the five radiologists. The data characteristics, including patient demographic and the prevalence of each finding or pathology, are summarized in Table 20. We provide all imaging data and the corresponding ground truth labels for both the training and test sets. The images were organized into two folders, one for training and the other one for testing. Each image has a unique, anonymous identifier which was encoded from the value of the SOP Instance UID provided by the DICOM tag . The encoding process was supported by the Python hashlib module (see [sec:code]Code Availability). The radiologists’ local annotations of the training set were provided in a CSV file, annotations_train.csv. Each row of the table represents a bounding box with the following attributes: image ID (image_id), radiologist ID (rad_id), label’s name (class_name), and bounding box coordinates . Here, rad_id encodes the identities of the 17 radiologists,  are the coordinates of the box’s upper left corner, and  are the coordinates of the lower-right corner. Meanwhile, the image-level labels of the training set were stored in different CSV file, image_labels_train.csv, with the following fields: Image ID (image_id), radiologist ID (rad_ID), and labels (labels) for both the findings and diagnoses. Specifically, each image ID goes with vector of multiple labels corresponding to different pathologies, in which positive ones were encoded with “1” and negative ones were encoded with “0”. Similarly, the bounding-box annotations and the image-level labels of the test set were recorded in annotations_test.csv and image_labels_test.csv, respectively. The only difference is that each row in the CSV files of the test set was not associated with a radiologist ID.The VinDr-CXR dataset has been submitted to PhysioNet for public downloadhttps://www.hhs.gov/hipaa/for-professionals/privacy/laws-regulations/index.html), the European GDPR (https://gdpr-info.eu/), as well as the local privacy laws. Pixel values of all CXR scans were also carefully examined. All images were manually reviewed case-by-case by a team of 10 human readers. During this review process, a small number of images containing private textual information that had not been removed by our algorithm was excluded from the dataset. The manual review process also helped identify and discard outlier samples that the CNN-based classifier was not able to detect. To control the quality of the labeling process, we developed a set of rules underlying VinDr Lab for automatic verification of radiologist-generated labels. These rules prevent annotators from mechanical mistakes like forgetting to choose global labels or marking lesions on the image while choosing “No finding” as the global label. To ensure the complete blindness among annotators, the images were randomly shuffled before being assigned to each of them.The data de-identification was controlled. In particular, all DICOM meta-data was parsed and manually reviewed to ensure that all individually identifiable health information of the patients has been removed to meet the U.S. HIPAA (https://physionet.org/content/vindr-cxr/view-license/1.0.0/). By accepting the DUA, users agree that they will not share the data and that the dataset can be used for scientific research and educational purposes only and will not attempt to re-identify any patients, institutions or hospitals. For any publication that explores this resource, the authors must cite this original paper. We also encourage such authors to release their code and models, which will help the community to reproduce experiments and to boost the research in the field of medical imaging.To download the dataset, users are required to accept a Date Usage Agreement (DUA) called PhysioNet Credentialed Health Data License 1.5.0


High cancer-related psychological distress levels have been observed in BC patients, with a potentially relevant impact on disease management, compliance with disease treatments, and everyday life activities and relationships. This work evaluated the effectiveness of three individual cognitive–behavioral therapy psychoeducational sessions versus a self-managed informative guide with individual counseling sessions without specific psychological treatment. (2) Methods: the intervention group received three individual 50-min sessions of psychoeducational training, and the control group received a self-managed informative guide with individual counseling sessions without any kind of psychological treatment. The Hospital Anxiety Depression Scale (HADS), the Distress Thermometer (DT), and the EORTC (European Organization for Research and Treatment of Cancer) QLQ-C30 were administered at baseline and two months after study inclusion. (3) Results: A total of 60 participants were included in the study . Significant improvements were observed in both groups after two months ( Breast cancer accounts for 12% of all new annual cancer cases worldwide , althougFurthermore, providing information to patients and their family members or caregivers at all stages of the disease is one of the most critical elements of supportive care in oncology because adequate information helps patients reduce uncertainty and strengthen a sense of control, allowing them to make appropriate decisions . In a syIn the field of psycho-oncology, four macro-categories of intervention are possible: counseling, behavioral methods, bodily methods, and psychotherapies , among wThis work aimed to evaluate the effect of two psychological approaches in increasing the quality of life level and reducing depression, anxiety, and distress in two groups of women with breast cancer who underwent two different approaches: three CBT individual psychoeducational sessions versus a self-managed informative guide with individual counseling sessions without any specific psychological treatment.A monocentric prospective randomized clinical study was carried out at the U.O. of Medical Oncology of the P.O. “Giovanni Paolo II” of Sciacca  from October 2020 to March 2021. The Ethical Committee of Palermo approved the study .Adult women who have breast cancer, treated with chemo- or radiotherapy and who had already undergone surgery, afferent to the U.O. of Medical Oncology of the P.O. “Giovanni Paolo II” of Sciacca, were selected to participate in the study. The medical staff consisted of an oncologist and a psychotherapist. Patients were enrolled according to the following inclusion criteria: (1) aged between 35–70 years; (2) patients with breast cancer undergoing treatment  and undergoing surgery . The exclusion criteria were: (1) patients with psychiatric pathologies as detected through the Symptom Checklist-90 Scale (SCL-90-R) and/or medical records; (2) patients suffering from secondary metastases or neoplastic pathologies ; (3) patients suffering from blood cancers and sarcomas. Sixty patients were enrolled and assigned to the intervention or control group, respectively. All the participants signed informed consent forms.The intervention group received three individual 50-min session of psychoeducational training, and the control group received a self-managed informative guide with individual counseling sessions without any kind of psychological treatment.According to a 1:1 randomization process, the participants were randomized into two groups. The clinicians randomly generated the treatment allocations using sealed opaque envelopes and assigned these to the patients accordingly. The researchers and clinicians knew to which of both of the groups the individuals belonged. Only the patients were blinded.The Hospital Anxiety Depression Scale (HADS) , the Disα = 0.05, 1 − β = 0.8, and d = 0.74 . As a result, the required sample size was determined to be 60 .The sample size was evaluated according to two previous studies . The samThe theoretical model of reference was the cognitive–behavioral approach: an active treatment focused on the problems presented by the patient at the time of the interview and limited in time. It is based on cooperation and transparency. The patient’s expertise regarding their living condition is as necessary as the therapist’s expertise regarding the disease and the cognitive–behavioral approach .In the present study, psychoeducational techniques were used to develop correct information on the disease, favoring both the acceptance and processing of the diagnosis itself and the recognition, understanding, and management of the pathology .The CBT psychoeducational intervention consisted of three individual meetings lasting 50 min, aiming to deepen the following topics: (1) breast cancer types, symptoms, risk factors, diagnosis, and importance of prevention; (2) surgical treatment and chemo-radiotherapy; and (3) the emotional and psychological impact of the course of care and the use of functional strategies.https://www.aimac.it, accessed on 10 November 2020), ESMO , and AIRC  guides. The main aim of this guide was to accompany patients and their caregivers in the care path by providing adequate information. The first part of the guide contained topics concerning breast cancer, breast cancer histotypes, the staging and evolution of the disease, symptoms, diagnosis, and risk factors . The following section included information on the various forms of treatment for breast cancer, such as surgery, radiotherapy, hormone therapy, molecular target therapy, and chemotherapy. In addition, there were indications and precautions to help reduce chemotherapy side effects to improve the patients’ quality of life after breast cancer surgery. The last part of the guide contained aspects related to the follow-up after the treatment, lifestyles after surgery, secondary prevention, and preventive diets. In addition, this section included helpful links, support groups, and information on the patients’ rights. Finally, a glossary containing 26 terms from the medical and psychological fields was used to help patients understand some terms often used by oncologists during a specialist medical interview. Given the complexity of the disease and the breast cancer impact on the patient’s psychological sphere, patients in the control group received individual counseling and psychological listening meetings without specific treatments.Patients received an informative guide containing clinical information, psychological aspects, and indications related to breast cancer. This guide was developed using information reported by the AIMAC (p < 0.05).After HADS, DIS, and EORTC QLQ-C30 data collection , statistical analyses were performed using STATA17 . Quantitative variables were reported as mean ± standard deviation, while frequencies and percentages were used for qualitative variables. Fisher’s exact test, the Mann–Whitney U test, and the Wilcoxon test on paired samples were used for group and intra-group comparisons. Significance was set at 5% . All the enrolled patients completed the study and were included in the analysis as reported by the CONSORT flow chart .n = 26) of the women were aged between 51 and 65 years, 38.3% (n = 23) over 65 years old, and 18.3% (n = 11) between 36 and 50 years old. More than 73% (n = 44) of the women had received a BC diagnosis two to three years before enrollment. Many participants  had received neoadjuvant chemotherapy before surgery; 31.7% (n = 19) had received postmenopausal hormone treatment; 31.7% (n = 19) had received radiotherapy, and a similar percentage had been treated with biological therapy; while 30% (n = 18) of the participants had received molecular target therapy. At baseline, no statistically significant differences emerged. The participants’ characteristics are reported in About 43% (p > 0.05) for HADS and EORT QLQ-C30. Instead, many improvements were registered in both groups between baseline and T1. Specifically, in HADS, statistically significant differences between baseline and T1 emerged for depression , anxiety , and stress   .T0 = 47.50 ± 18.07, treatmentT1 = 86.67 ± 12.87, p < 0.001; controlT0 = 46.39 ± 12.70, controlT1 = 88.89 ± 13.37, p < 0.001), physical functioning , role functioning , emotional functioning , cognitive functioning , and social functioning   .T0 = 35.56 ± 24.13, treatmentT1 = 12.59 ± 12.29, p < 0.001; controlT0 = 46.30 ± 22.81, controlT1 = 14.44 ± 11.36, p < 0.001), nausea and vomiting , pain , dyspnea , and insomnia . Moreover, in the control group, significant improvement was observed for appetite loss .According to the QLQ-C30 EORTC symptom scales , signifiSupporting patients and their families or caregivers to cope with and adapt to the difficulties associated with BC plays an overarching role in managing the disease and the treatment-related side effects. Therefore, this study aimed to evaluate the effectiveness of cognitive–behavioral therapeutic intervention, specifically psychoeducation, to improve the quality-of-life levels and to reduce depression, anxiety, and stress.Being informed is reported as a key element in managing breast cancer, but, to date, it is mistakenly believed that patients prefer not to know (a culture of “non-disclosure”). A recent survey found that, contrary to what one might expect, the average number of questions asked during the first visit with the oncologist by Italian women with BC was higher as compared with the number of questions asked by patients in other countries .In our work, all the participants reported a significant improvement in the pre–post comparisons without statistically significant differences between groups. Overall, 65% of the women at baseline showed an elevated anxiety level (≥11), while only 8.33% of the participants continued to report the same high anxiety level after two months. A similar trend emerged for depression: while 18% of the participants reported severe depression symptoms at enrollment, only 3.33% of the women continued to report severe depressive symptoms in the follow-up phase. Finally, encouraging results emerged for distress: 36.6% of the participants showed a high degree of distress (DT > 7) at enrollment, but none showed distress in any form after two months.TM program, University of Nebraska Medical Center, Omaha NE, USA) with that achieved through the usual care after 12 weeks of treatment: a reduction in distress and the avoidance of negative thoughts without reporting significant differences in the overall effects between the two groups was observed in both groups [p = 0.042) and yoga  [These findings for distress reduction confirm the positive results that have already emerged about a strong association between psychological interventions and the reduction of distress ,31,32, ah groups . For imph groups . Conflich groups , while ah groups . The posh groups . AnotherAll the patients in our study reported significant improvements in quality of life and symptom reduction in relation to quality of life. Still, no statistically significant differences emerged between the two groups. These effects show how informative guides and psychological supports have benefited both groups, allowing them to achieve a general psychological, social, and relational wellbeing. These findings are in line with those that emerged in similar studies in which, for ethical considerations, the control group was treated with a form of external support. A recent study analyzing the role of psychoeducational programs focused on psychological stresses and management skills in a sample of 290 BC patients during radiotherapy did not only report statistically significant differences between the intervention and control group, as also emerged in our work, but the control group, who received a 15-min educational course on basic knowledge of breast cancer and radiotherapy, also showed an increase in anxiety and depression levels . For CBTMoreover, it is necessary to consider the environmental context in which this study was conducted (October 2020 to March 2021). In Italy, during the last two years, the prevalence of the COVID-19 pandemic could have determined a different sense of the quality of life and distress, especially in oncologic patients, who, even owing to few external supports, such as an informative and complete guide, could have achieved an optimal quality of life perception. Furthermore, the individual counseling meetings, during which participants could have had the opportunity to discuss some topics reported in the informative guide, and the lack of group therapy for the intervention group, which was not allowed given the stringent regulations about COVID-19 containment, could have further reduced the differences between the two groups. Indeed, as emerged in previous studies, group therapy represents a fundamental factor in creating affective–relational and informative interrelations that facilitate the perception of the disease as an opportunity for a significant existential improvement and provide a psychological sense of belonging to the group, a possible way to manage stress and overcome the sense of isolation ,38. CipoAs with other trials, this work has several limitations. First, although we used validated tools to assess anxiety, distress, depression, and quality of life, few studies have discussed the diagnostic role of these tools. As already emerged in other works, conclusions of no statistically significant differences between the two groups should not be considered conclusive. Second, this study was conducted during the largest pandemic in the last 100 years in Europe; this means that participants’ perception could have been modified because of a different approach: a significant threat from the COVID-19 pandemic and less attention to one’s own distress level. Third, we enrolled patients with various comorbidities and times of diagnosis. Fourth, the observation time and the number of CBT sessions could have been too short or too few. Five, a Hawthorne effect could have changed the patients’ behavior and responses. Finally, we did not consider a control group without psychological intervention.In conclusion, our understanding of the different impacts of CBT and psychoeducation could be deepened in future studies. However, from this work, we can affirm that both psychoeducational intervention and CBT can help patients with BC to overcome the fear of the disease and to achieve an optimal distress level management and a good quality of life because these psychological supports provide a source of information about their condition and reduce the sense of isolation.