Flexible Unipolar IGZO Transistor-Based Integrate and Fire Neurons for Spiking Neuromorphic Applications.

In this article, three different implementations of an Axon-Hillock circuit are presented, one of the basic building blocks of spiking neural networks. In this work, we explored the design of such circuits using a unipolar thin-film transistor technology based on amorphous InGaZnO, often used for large-area electronics. All the designed circuits are fabricated by direct material deposition and patterning on top of a flexible polyimide substrate. Axon-Hillock circuits presented in this article consistently show great adaptability of the basic properties of a spiking neuron such as output spike frequency adaptation and output spike width adaptation. Additional degrees of adaptability are demonstrated with each of the Axon-Hillock circuit varieties: neuron circuit threshold voltage adaptation, differentiation between input signal importance, and refractory period modulation. The proposed neuron can change its firing frequency up to three orders of magnitude by varying a single voltage brought to a circuit terminal. This allows the neuron to function, and potentially learn, at vastly different timescales that coincide with the biologically meaningful timescales, going from milliseconds to seconds, relevant for circuits meant for interaction with the environment. Thanks to careful design choices, the average measured power consumption is kept in the nW range, realistically allowing upscaling towards the spiking neural networks in the future. The spiking neuron with refractory period modulation presented in this work has an area of 607.3 µm × 492.2 µm, it experimentally demonstrated firing rates as low as 11.926 mHz, and its energy consumption per spike is ≈ 700 pJ at 30 Hz.

A Thin-Film Pinned-Photodiode Imager Pixel with Fully Monolithic Fabrication and beyond 1Me- Full Well Capacity.

Thin-film photodiodes (TFPD) monolithically integrated on the Si Read-Out Integrated Circuitry (ROIC) are promising imaging platforms when beyond-silicon optoelectronic properties are required. Although TFPD device performance has improved significantly, the pixel development has been limited in terms of noise characteristics compared to the Si-based image sensors. Here, a thin-film-based pinned photodiode (TF-PPD) structure is presented, showing reduced kTC noise and dark current, accompanied with a high conversion gain (CG). Indium-gallium-zinc oxide (IGZO) thin-film transistors and quantum dot photodiodes are integrated sequentially on the Si ROIC in a fully monolithic scheme with the introduction of photogate (PG) to achieve PPD operation. This PG brings not only a low noise performance, but also a high full well capacity (FWC) coming from the large capacitance of its metal-oxide-semiconductor (MOS). Hence, the FWC of the pixel is boosted up to 1.37 Me- with a 5 µm pixel pitch, which is 8.3 times larger than the FWC that the TFPD junction capacitor can store. This large FWC, along with the inherent low noise characteristics of the TF-PPD, leads to the three-digit dynamic range (DR) of 100.2 dB. Unlike a Si-based PG pixel, dark current contribution from the depleted semiconductor interfaces is limited, thanks to the wide energy band gap of the IGZO channel material used in this work. We expect that this novel 4 T pixel architecture can accelerate the deployment of monolithic TFPD imaging technology, as it has worked for CMOS Image sensors (CIS).

Image sensors using thin-film absorbers.

Image sensors are must-have components of most consumer electronics devices. They enable portable camera systems, which find their way into billions of devices annually. Such high volumes are possible thanks to the complementary metal-oxide semiconductor (CMOS) platform, leveraging wafer-scale manufacturing. Silicon photodiodes, at the core of CMOS image sensors, are perfectly suited to replicate human vision. Thin-film absorbers are an alternative family of photoactive materials, distinguished by the layer thickness comparable with or smaller than the wavelength of interest. They allow design of imagers with functionalities beyond Si-based sensors, such as transparency or detectivity at wavelengths above Si cutoff (e.g., short-wave infrared). Thin-film image sensors are an emerging device category. While intensive research is ongoing to achieve sufficient performance of thin-film photodetectors, to our best knowledge, there have been few complete studies on their integration into advanced systems. In this paper, we will describe several types of image sensors being developed at imec, based on organic, quantum dot, and perovskite photodiode and show their figures of merit. We also discuss the methodology for selecting the most appropriate sensor architecture (integration with thin-film transistor or CMOS). Application examples based on imec proof-of-concept sensors are demonstrated to showcase emerging use cases.

Respiratory virus type to guide predictive enrichment approaches in the management of the first episode of bronchiolitis: A systematic review.

It has become clear that severe bronchiolitis is a heterogeneous disease; even so, current bronchiolitis management guidelines rely on the one-size-fits-all approach regarding achieving both short-term and chronic outcomes. It has been speculated that the use of molecular markers could guide more effective pharmacological management and achieve the prevention of chronic respiratory sequelae. Existing data suggest that asthma-like treatment (systemic corticosteroids and beta2-agonists) in infants with rhinovirus-induced bronchiolitis is associated with improved short-term and chronic outcomes, but robust data is still lacking. We performed a systematic search of PubMed, Embase, Web of Science, and the Cochrane's Library to identify eligible randomized controlled trials to determine the efficacy of a personalized, virus-dependent application of systemic corticosteroids in children with severe bronchiolitis. Twelve studies with heterogeneous methodology were included. The analysis of the available results comparing the respiratory syncytial virus (RSV)-positive and RSV-negative children did not reveal significant differences in the associatons between systemic corticosteroid use in acute episode and duration of hospitalization (short-term outcome). However, this systematic review identified a trend of the positive association between the use of systematic corticosteroids and duration of hospitalization in RSV-negative infants hospitalized with the first episode of bronchiolitis (two studies). This evidence is not conclusive. Taken together, we suggest the design for future studies to assess the respiratory virus type in guiding predictive enrichment approaches in infants presenting with the first episode of bronchiolitis. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42020173686.

Machine Learning Method for Functional Assessment of Retinal Models.

Challenges in the field of retinal prostheses motivate the development of retinal models to accurately simulate Retinal Ganglion Cells (RGCs) responses. The goal of retinal prostheses is to enable blind individuals to solve complex, reallife visual tasks. In this paper, we introduce the functional assessment (FA) of retinal models, which describes the concept of evaluating the performance of retinal models on visual understanding tasks. We present a machine learning method for FA: we feed traditional machine learning classifiers with RGC responses generated by retinal models, to solve object and digit recognition tasks (CIFAR-10, MNIST, Fashion MNIST, Imagenette). We examined critical FA aspects, including how the performance of FA depends on the task, how to optimally feed RGC responses to the classifiers and how the number of output neurons correlates with the model's accuracy. To increase the number of output neurons, we manipulated input images - by splitting and then feeding them to the retinal model and we found that image splitting does not significantly improve the model's accuracy. We also show that differences in the structure of datasets result in largely divergent performance of the retinal model (MNIST and Fashion MNIST exceeded 80% accuracy, while CIFAR-10 and Imagenette achieved ∼40%). Furthermore, retinal models which perform better in standard evaluation, i.e. more accurately predict RGC response, perform better in FA as well. However, unlike standard evaluation, FA results can be straightforwardly interpreted in the context of comparing the quality of visual perception.

Increased apoptotic activity on inflammatory human placentas in spontaneous abortions during the first and second trimester of gestation: a histochemical and immunohistochemical study.

The aim of this study was to investigate the role of apoptotic markers on inflammatory human placentas from spontaneous abortions during the first and second trimester of gestation and compare them to those without inflammation. Paraffin-embedded specimens from 76 placentas were investigated by conventional histology and immunohistochemistry using monoclonal antibodies against M30, Caspase 3, Caspase 8 and Caspase 9, as well as the terminal deoxynucleotidyl tranferase-mediated deoxyuridine triphosphate nick end labeling method. A higher prevalence of expression of apoptotic markers (94.4%) was observed in placentas associated with chorioamnionitis in comparison with those without inflammation. Our observations confirm that apoptosis is strikingly prevalent in placentas diagnosed with histologic chorioamnionitis, while the inflammation induces cell death.

Inactivating germ-line and somatic mutations in polypeptide N-acetylgalactosaminyltransferase 12 in human colon cancers.

Aberrant glycosylation is a pathological alteration that is widespread in colon cancer, and usually accompanies the onset and progression of the disease. To date, the molecular mechanisms underlying aberrant glycosylation remain largely unknown. In this study, we identify somatic and germ-line mutations in the gene encoding for polypeptide N-acetylgalactosaminyltransferase 12 (GALNT12) in individuals with colon cancer. Biochemical analyses demonstrate that each of the 8 GALNT12 mutations identified inactivates the normal function of the GALNT enzyme in initiating mucin type O-linked protein glycosylation. Two of these inactivating GALNT12 mutations were identified as acquired somatic mutations in a set of 30 microsatellite stable colon tumors. Relative to background gene mutation rates, finding these somatic GALNT12 mutations was statistically significant at P < 0.001. Six additional inactivating GALNT12 mutations were detected as germ-line changes carried by patients with colon cancer; however, no inactivating variants were detected among cancer-free controls (P = 0.005). Notably, in 3 of the 6 individuals harboring inactivating germ-line GALNT12 mutations, both a colon cancer and a second independent epithelial cancer had developed. These findings suggest that genetic defects in the O-glycosylation pathway in part underlie aberrant glycosylation in colon cancers, and they contribute to the development of a subset of these malignancies.

CD30 (Ber-H2) expression by thymocytes and thymic epithelial cells during the late first and second trimester of gestation: an immunohistochemical and in situ hybridization (ISH) study.

BACKGROUND: The exact biological function of CD30 in the thymus during development has been only partially elucidated, although data indicate it may be involved in negative selection. This study was prompted by the observation of a positive reaction of thymic epithelial cells (TECs), Hassall's corpuscles, and thymocytes with the monoclonal antibody CD30 during the late first and second trimester. MATERIAL/METHODS: Twenty paraffin-embedded fetal thymus specimens at the late first and second trimester were investigated by conventional histology and immunohistology for CD30 expression. To provide additional information on the nature and localization of CD30+ thymocytes and CD30+ TECs, in situ hybridization (ISH) was performed on the specimens. RESULTS: 1) In the medulla, a statistically significant difference between CD30+ thymocytes from the late first trimester and those from the second trimester (p<0.0001, t-test) was demonstrated. No significant difference was found concerning CD30+ thymocytes in the cortex. 2) Many medullary TECs and Hassall's corpuscles showed high expression of CD30 during the second trimester, whereas small numbers of CD30+ TECs were found during the late first trimester. No statistically significant difference was found concerning CD30+ TECs in the cortex. CD30 was expressed by ISH in many cells in the medulla and along the septa, whereas the cortex showed little if any expression. Accordingly, a higher CD30 expression was found in medullary than in cortical thymocytes. CONCLUSIONS: Comparison of CD30 expression by TECs and thymocytes during the late first trimester and second trimester suggests an important role for CD30 in thymic selection.

Cytoplasmic expression of c-erb-B2 in endometrial carcinomas.

BACKGROUND: The aim of this study was to investigate the expression of c-erb-B2 in endometrial cancer with attention to both membranous and cytoplasmic staining, and to elucidate the significance of cytoplasmic signaling. MATERIALS AND METHODS: c-erb-B2 reactivity was assessed by immunohistochemistry in 110 patients using a polyclonal antibody, and evaluated semiquantitatively according to the percentage of cells demonstrating membranous or diffuse cytoplasmic staining. Correlation was made with tumor stage, grade, myometrial invasion, histologic type, and disease outcome. RESULTS: c-erb-B2 overexpression, indicated by membranous and cytoplasmic staining of at least 10% of the tumor cells, was found in 47 (42.7%) cases. Cytoplasmic expression of c-erb-B2 was observed more frequently than membranous (69.1 vs. 5.5%). Synchronous cytoplasmic and membranous signaling was noticed in 7.9% of cases. Interestingly, patients with cytoplasmic c-erb-B2-positive tumors had a significantly shorter survival (p = 0.047). CONCLUSIONS: These results indicate that c-erb-B2 is a specific marker of endometrial cancer. It is also an independent prognostic indicator of poor outcome. Cytoplasmic staining is as important as membranous staining, and is also a specific finding.

An unusual case of posttransplant peritoneal primary effusion lymphoma with T-cell phenotype in a HIV-negative female, not associated with HHV-8.

Primary effusion lymphoma (PEL) is a recently individualized form of non-Hodgkin's lymphoma (WHO classification) that mainly develops in HIV infected males, more frequently in homosexuals and advanced stages of the disease (total CD4+ lymphocyte count below 100-200/microL). Occasionally, it appears in other immunodepressive states (such as solid organs transplant period) and even, although very rarely, in immunocompetent patients. From a pathogenetic point of view, PEL has been related to Kaposi's sarcoma associated herpes virus (also named human herpesvirus 8, HHV-8), an etiological factor of Kaposi's sarcoma. The relative infrequency of this disease, the absence of wide casuistics allowing a better characterization, and its unfavorable outcome support the need of a deeper knowledge. We present here the clinical-biological findings of a patient, HIV seronegative, who was diagnosed with peritoneal PEL of T-cell origin, and not HHV-8-associated, five years after renal transplantation.

Fine needle aspiration cytology diagnosis of gastrointestinal stromal tumors utilizing scanning electron microscopy.

BACKGROUND: Digestive stromal neoplasms are the most frequent undifferentiated mesenchymal tumors. The outcome of these malignancies is difficult to predict and the histogenesis is still controversial. However, the frequent and specific expression of CD117 (c-kit) by these tumors could imply an origin from interstitial cells of Cajal. Our objective was to analyze the role of fine needle aspiration cytology, cell block preparation, and immunocytochemistry in the interpretation of gastrointestinal stromal tumors, and to establish scanning electron microscopy as a useful research aid for pathologic changes of the surface cells of gastrointestinal stromal tumors, not totally appreciated by light microscopy. MATERIAL AND METHODS: Twelve cases of gastrointestinal stromal tumors were included in this study, in which fine needle aspiration cytology was performed. RESULTS: On aspirated material, the tumor cells formed closely packed cohesive tissue fragments with high cellular density often in bloody background, or fascicles with parallel side-by-side arrangements of the nuclei. On cell block biopsy material, gastrointestinal stromal tumors were highly cellular spindle or epithelioid tumors with basophilic appearance. Immunocytochemically, they were CD117 positive in all twelve cases, CD34 positive in nine, weakly smooth muscle actin-positive in five, and S-100 and GFAP-negative in all cases. The scanning electron microscopy study showed a strong correlation with the cytomorphological profile. CONCLUSIONS: Gastrointestinal stromal tumors show a broad morphologic variety, but nuclear pleomorphism by cytology alone, rarely correlates with malignant potential. In the appropriate clinical and radiological setting, a confident diagnosis of gastrointestinal stromal tumors can be documented by fine needle aspiration cytology, cell block, immunocytochemical, and scanning electron microscopy results.

Human embryonal epithelial cells of the developing small intestinal crypts can express the Hodgkin-cell associated antigen Ki-1 (CD30) in spontaneous abortions during the first trimester of gestation.

BACKGROUND: Ki-1 (CD30) antigen expression is not found on peripheral blood cells but its expression can be induced in vitro on T and B lymphocytes by viruses and lectins. Expression of CD30 in normal tissues is very limited, being restricted mainly to a subpopulation of large lymphoid cells; in particular, cells of the recently described anaplastic large cell lymphoma (ALCL), the Reed-Sternberg (RS) cells of Hodgkin's lymphoma and scattered large parafollicular cells in normal lymphoid tissues. More recent reports have described CD30 expression in non-hematopoietic and malignant cells such as cultured human macrophages, human decidual cells, histiocytic neoplastic cells, mesothelioma cells, embryonal carcinoma and seminoma cells. RESULTS: We investigated the immunohistochemical expression of CD30 antigen in 15 paraffin-embedded tissue samples representing small intestines from fetuses after spontaneous abortion in the 8th, 10th and 12th weeks using the monoclonal antibody Ki-1. Hormones had been administered to all our pregnant women to support gestation. In addition, a panel of monoclonal antibodies was used to identify leukocytes (CD45/LCA), B-lymphocytes (CD20/L-26) and T-lymphocytes (CD3). Our findings were correlated with those obtained simultaneously from intestinal tissue samples obtained from 15 fetuses after therapeutic or voluntary abortions. CONCLUSIONS: The results showed that: (1) epithelial cells in the developing intestinal crypts express the CD30 (Ki-1) antigen; (2) CD30 expression in these epithelial cells is higher in cases of hormonal administration than in normal gestation. In the former cases (hormonal support of gestation) a mild mononuclear intraepithelial infiltrate composed of CD3 (T-marker)-positive cells accompanies the CD30-positive cells.

Human decidual cells activity in women with spontaneous abortions of probable CMV aetiology during the first trimester of gestation. An immunohistochemical study with CMV-associated antigen.

AIM: To determine the expression of CMV-associated antigen in the human decidual endometrial stromal cells in spontaneous abortions with no evidence of maternal relapse during the first trimester of gestation. EXPERIMENTAL DESIGN: We examined 15 placentas resulting from intrauterine fetal death after spontaneous abortion during the 8th, 10th, and 12th week of gestation respectively, and in which CMV reactivation was ruled out from serological evaluation of the pregnant women at admission, versus equal controls after voluntary abortion following well-documented maternal viral recurrence. In addition, a panel of monoclonal antibodies for the identification of leukocytes (CD45/LCA), B-lymphocytes (CD20/L-26), and T-lymphocytes (CD45RO/UCHL1), was performed. All women received hormonal medication to support gestation, in the cases of spontaneous abortions. RESULTS: Immunohistochemical examination using a specific antibody against cytomegalovirus showed large multinucleated infected cells with intranuclear inclusions, located primarily in the decidual stroma within a lymphoplasmacytic infiltrate in the cases of spontaneous abortions. No evidence of infection was observed in the chorionic villi. In the cases of voluntary abortions same findings were observed in the relevant areas, and a strong evidence of infection was observed in the chorionic villi. CONCLUSION: This study demonstrates 1) that the decidual endometrial stromal cells can express the CMV-associated antigen prior to serological manifestation of the viral replication, 2) the expression of the antigen is higher in cases of hormonal administration to support gestation. In these cases a mild mononuclear infiltrate of UCHL1 (T marker) positive cells, accompanies the CMV-associated antigen positive cells.

Does neoplastic cholecystokinin expression reflect the embryonal pattern of the protein? A study in human pancreas.

AIM: To determine the immunoreactivity of cholecystokinin (CCK) during the development of the human fetal pancreas and pancreatic adenocarcinoma, given that, CCK positive cells were demonstrated either in its embryonic anlage or in pancreatic cancer. In order to obtain possible parallels in the expression pattern of neoplastic cells in adults (well--moderately--poorly differentiated), we investigated the pattern of CCK expression in the pancreatic tissue during the various stages of development and compared these with the proliferation of tissue assessed by proliferating cell nuclear antigen (PCNA) immunohistochemistry. EXPERIMENTAL DESIGN: Tissue sections from 15 pancreatic fetal specimens, and equal number of ductal adenocarcinoma specimens, were assessed using immunohistochemical methods for CCK. RESULTS: The density of positive cells in the primitive exocrine ductal walls and outgrowing buds was significantly higher than the relevant density in the neoplastic pancreatic tissue of mixed (ductal-endocrine) and pure ductal type (p1=0.004, p2 < 0.0005, p3 < 0.0005 and p4=0.023 respectively). The above values were estimated from 20th to 22nd weeks of gestation. There was no significant difference in the density of positive cells in the islet cell epithelium from 25-30 weeks, and the neoplastic tissue of mixed (p5=0.10) and pure ductal type (p6=0.15). CONCLUSIONS: The immunostaining for CCK identifies a sub-group of pancreatic ductal adenocarcinomas with a neuroendocrine component (initially considered as pure ductal tumors), and mixed ductal-endocrine tumors. This pattern of expression in neoplasms recapitulates the normal pattern during the embryonal development of the organ, and may be important for the development of new therapeutic approaches with eventual clinical utility.

Altered intrahepatic hematopoiesis in neonates from women with pregnancy induced hypertension/pre-eclampsia.

AIM: To detect whether preeclampsia influences neonatal intrahepatic hematopoiesis, given that an activation of fetal neutrophils and monocytes during the course of this disorder occurs. EXPERIMENTAL DESIGN: We examined liver samples from 10 neonates of hypertensive/preeclamptic women at 27 to 28 weeks of gestation delivered by a cessarian section. All neonates were placed in incubators but they all died within 24 hours due to immaturity. The control group comprised 10 fetuses of the same gestational age, after voluntary abortion due to a neural defect. Specific antibodies against CD34, glycophorin C, hemoglobins A and F, myeloperoxidase, CD61, CD68, terminal desoxynucleotidyl transferase and the pax-5/B-cell specific activator protein, were used in each sample. RESULTS: Neonates from hypertensive/preeclamptic women, in comparison with controls, showed: a statistically significant reduction of erythropoiesis by 25% (p=0.015); a statistically significant increase of granulopoiesis (p=0.019); a statistically significant increase in the expression of CD68 positive cells of the monocytic lineage (p=0.017); a statistically significant increase in the expression of CD34 progenitor/stem positive cells (p=0.021). No statistically significant differences were observed in both examined groups, concerning megakaryopoiesis and B lymphopoiesis. CONCLUSIONS: Preeclampsia of pregnancy has an impact on neonatal intrahepatic hematopoiesis by increasing granulopoiesis, reducing erythropoiesis and triggering endothelial and stem cell activation. We suggest that these findings reflect a state of persistent inflammation and a loss of red blood cell production possibly contributing to the neonatal morbidity related to this disorder.

Gains and losses of HLA class II (DR) and CD4 in atypical hyperplasia, carcinoma in situ and infiltrating ductal carcinoma of the breast.

AIM: Breast cancer is a frequent cause of death among women with gynaecologic malignancies despite the introduction of combination chemotherapy. There is therefore a need for new therapeutic strategies for patients with breast cancer, such as cellular immunotherapy. In this immunohistochemical study we analyzed the epithelial expression of major histocompatibility complex (MHC) class II (HLA-DR) on atypical and malignant primary mammary epithelial cells, as well as the magnitude of the stromal T lymphocytes (T4 subset) at the tumor site. EXPERIMENTAL DESIGN: The study was carried out retrospectively in tumor tissue from 82 patients with mammary lesions (31 cases of atypical ductal hyperplasia -ADH-, 12 cases of ductal carcinoma in situ -DCIS- and 39 cases of infiltrating ductal carcinoma not otherwise specified -IDC-NOS). Medullary carcinomas were not included in our investigation. Material used had been formalin fixed and paraffin embedded. RESULTS: HLA class II (DR) was expressed in 20 of 31 ADHs (64.5%), in 4 of 12 DCISs (33.3%), and in 10 of 39 IDC-NOSs (25.6%). CD4 was expressed in 9 of 31 ADHs (29%), in 5 of 12 DCISs (42%), and in 26 of 39 IDC-NOSs (67%). CONCLUSIONS: The results showed decreased epithelial expression of HLA class II (DR) and increased stromal expression of CD4, as the lesion progressed to malignancy. Gradual loss of epithelial HLA class II expression might be a manifestation of cellular differentiation from the atypical form versus the malignant one, signaling simultaneously a selective effect on the response capacity of the immune system.

Malignant mucoepidermoid tumor arising in the accessory parotid gland: a case report.

PURPOSE: The head and neck surgeon's fascination with parotid surgery arises from the gland's spectrum of histopathological presentations, as well as the diversity of its morphological features. A mass arising in the mid-cheek region may often be overlooked as a rare accessory lobe parotid neoplasm. This report serves to revisit the topic of accessory parotid gland neoplasms to emphasize proper management, particularly the surgical aspects, so that consequences of salivary fistula, facial nerve paralysis, and recurrence are avoided. CASE REPORT: We report a case of mucoepidermoid carcinoma which was assessed pre-operatively as arising from the accessory parotid gland of a 11-year-old female. She had complained of a painless and round mass of the left cheek for a duration of 12 months. Sialography, ultrasonography, CT scan and MRI were performed preoperatively. Sialography revealed a small duct separating from the Stensen's duct. CT and MRI showed that the tumor with smooth outline was lying on the masseter muscle and detached from the main parotid gland. The preoperative diagnosis was an accessory parotid gland tumor. The tumor was removed without facial nerve injury via standard parotidectomy incision. The tumor was composed of mucous, intermediate and epidermoid cells. The pathological diagnosis was low-grade mucoepidermoid carcinoma. CONCLUSIONS: Accessory parotid gland neoplasms are rare and may present as innocuous extraparotid mid-cheek masses. A high index of suspicion, prudent diagnostic skills (including fine-needle aspiration [FNA] biopsy followed by computed tomography [CT] imaging), and scrupulous surgical approach (extended parotidectomy-style incision and limited peripheral nerve dissection when possible) are the keys to successful management of these lesions.