Digital pathology implementation in a private laboratory: The CEDAP experience.

Introduction: The transition to digital pathology has been carried out by several laboratories across the globe, with some cases described in Portugal. In this article, we describe the transition to digital pathology in a high-volume private laboratory, considering the main challenges and opportunities. Material and methods: Our process started in 2020, with laboratory workflow adaptation and we are currently using a high-capacity scanner (Aperio GT450DX) to digitize slides at 20×. The visualization system, Aperio eSlide Manager WebViewer, is integrated into the Laboratory System. The validation process followed the Royal College of Pathologists Guidelines. Results: Regarding validation, the first phase detected an error rate of 6.8%, mostly due to digitization errors. Phase optimization and collaboration with technical services led to improvements in this process. In the second validation phase, most of the slides had the desired quality for evaluation, with only an error rate of 0.6%, corrected with a new scan. The interpathologist correlation had a total agreement rate of 96.87% and 3.13% partial agreement. Conclusion: The implementation and validation of digital pathology was a success, being ready for prime time. The total integration of all laboratory systems and the acquisition of new equipment will maximize their use, especially with the application of artificial intelligence algorithms.

Avaliação dos desfechos relatados pelo paciente com diabetes mellitus e seu impacto no controle glicêmico / Assessment of patient-reported outcomes with diabetes mellitus and its impact on glycemic control

Objetivos: Este trabalho tem como objetivo avaliar a qualidade de vida em pacientes adultos com Diabetes Mellitus (DM) e usuários de insulina e analisar se há associação entre os resultados obtidos e os níveis de hemoglobina glicada (HbA1c) nesses indivíduos. Métodos: É um projeto de estudo transversal e observacional através da aplicação da versão brasileira validada do questionário específico de medida da qualidade de vida em diabetes (DQOL-Brasil) e avaliação laboratorial de HbA1c. Um total de 105 pacientes foram incluídos no estudo, sendo caracterizados conforme gênero, idade, tipo de diabetes, tempo de diagnóstico e tipo de insulina utilizada. Para análise comparativa, quanto aos valores de HbA1c, os pacientes foram divididos em grupos: HbA1c < 7% (bom controle glicêmico), 7 ­ 8,5% (intermediário) e > 8,5% (ruim). Resultados: Observou-se que a média do impacto do DM na qualidade de vida variou de forma crescente entre os grupos, sendo que, quanto mais pontos, pior a qualidade de vida. No grupo com controle bom da HbA1c a média foi de 1,9 ± 0,5, no grupo intermediário a média foi de 2,4 ± 0,8 e no grupo com controle ruim a média foi de 2,7 ± 0,8 (p=0,008). Não foram observadas características da população estudada que determinaram o resultado do desfecho, embora pacientes com diagnóstico de DM1 e em uso de análogos exclusivo, neste estudo, tiveram melhores níveis de HbA1c. Conclusão: Os níveis de HbA1c estão diretamente relacionados ao impacto na qualidade de vida do paciente com DM, sendo que melhores níveis de HbA1c correlacionam-se com melhor percepção de qualidade de vida. Palavras-chave: Diabetes mellitus. Qualidade de Vida Relacionada à Saúde. Medidas de Resultados Relatados pelo Paciente.

Quantum Advantage in a Molecular Spintronic Engine that Harvests Thermal Fluctuation Energy.

Recent theory and experiments have showcased how to harness quantum mechanics to assemble heat/information engines with efficiencies that surpass the classical Carnot limit. So far, this has required atomic engines that are driven by cumbersome external electromagnetic sources. Here, using molecular spintronics, an implementation that is both electronic and autonomous is proposed. The spintronic quantum engine heuristically deploys several known quantum assets by having a chain of spin qubits formed by the paramagnetic Co center of phthalocyanine (Pc) molecules electronically interact with electron-spin-selecting Fe/C60 interfaces. Density functional calculations reveal that transport fluctuations across the interface can stabilize spin coherence on the Co paramagnetic centers, which host spin flip processes. Across vertical molecular nanodevices, enduring dc current generation, output power above room temperature, two quantum thermodynamical signatures of the engine's processes, and a record 89% spin polarization of current across the Fe/C60 interface are measured. It is crucially this electron spin selection that forces, through demonic feedback and control, charge current to flow against the built-in potential barrier. Further research into spintronic quantum engines, insight into the quantum information processes within spintronic technologies, and retooling the spintronic-based information technology chain, can help accelerate the transition to clean energy.

BSACI guideline for the diagnosis and management of pollen food syndrome in the UK.

Pollen food syndrome (PFS) is a highly prevalent food allergy affecting pollen-sensitized children and adults. Sufferers experience allergic symptoms when consuming raw plant foods, due to the homology between the pollen allergens and unstable proteins in these foods. The triggers involved can vary depending on the pollen sensitization, which in turn is affected by geographical location. The British Society of Allergy and Clinical Immunology (BSACI) Standards of Care Committee (SOCC) identified a need to develop a guideline for the diagnosis and management of PFS in the United Kingdom (UK). Guidelines produced by the BSACI use either the GRADE or SIGN methodology; due to a lack of high-quality evidence these recommendations were formulated using the SIGN guidelines, which is acknowledged to be less robust than the GRADE approach. The correct diagnosis of PFS ensures the avoidance of a misdiagnosis of a primary peanut or tree nut allergy or confusion with another plant food allergy to non-specific lipid transfer proteins. The characteristic foods involved, and rapid-onset oropharyngeal symptoms, mean PFS can often be diagnosed from the clinical history alone. However, reactions involving tree nuts, peanuts and soya milk or severe/atypical reactions to fruits and vegetables may require additional diagnostic tests. Management is through the exclusion of known trigger foods, which may appear to be simple, but is highly problematic if coupled with a pre-existing food allergy or for individuals following a vegetarian/vegan diet. Immunotherapy to pollens is not an effective treatment for PFS, and although oral or sublingual immunotherapy to foods seems more promising, large, controlled studies are needed. The typically mild symptoms of PFS can lead to an erroneous perception that this condition is always easily managed, but severe reactions can occur, and anxiety about the onset of symptoms to new foods can have a profound effect on quality of life.

An unexpected location for a metastasis from esophageal squamous carcinoma.

We report the case of a 69-year-old male with a relevant alcohol consumption and a history of prostate cancer who underwent screening upper gastrointestinal endoscopy and colonoscopy. The upper gastrointestinal endoscopy revealed an ulcerated mass in the middle esophagus occupying half the circumference. Histologic examination was compatible with a squamous cell carcinoma. Staging with endoscopic ultrasound and computed tomography of the neck, chest and abdomen was consistent with a T3N1M0.

Intravenous SPION-labeled adipocyte-derived stem cells targeted to the brain by magnetic attraction in a rat stroke model: An ultrastructural insight into cell fate within the brain.

Mesenchymal stem cell therapy after stroke is a promising option investigated in animal models and clinical trials. The intravenous route is commonly used in clinical settings guaranteeing an adequate safety profile although low yields of engraftment. In this report, rats subjected to ischemic stroke were injected with adipose-derived stem cells (ADSCs) labeled with superparamagnetic iron oxide nanoparticles (SPIONs) applying an external magnetic field in the skull to retain the cells. Although most published studies demonstrate viability of ADSCs, only a few have used ultrastructural techniques. In our study, the application of a local magnetic force resulted in a tendency for higher yields of SPION-ADSCs targeting the brain. However, grafted cells displayed morphological signs of death, one day after administration, and correlative microscopy showed active microglia and astrocytes associated in the process of scavenging. Thus, we conclude that, although successfully targeted within the brain, SPION-ADSCs viability was rapidly compromised.

Binding Sites, Vibrations and Spin-Lattice Relaxation Times in Europium(II)-Based Metallofullerene Spin Qubits.

To design molecular spin qubits with enhanced quantum coherence, a control of the coupling between the local vibrations and the spin states is crucial, which could be realized in principle by engineering molecular structures via coordination chemistry. To this end, understanding the underlying structural factors that govern the spin relaxation is a central topic. Here, we report the investigation of the spin dynamics in a series of chemically designed europium(II)-based endohedral metallofullerenes (EMFs). By introducing a unique structural difference, i. e. metal-cage binding site, while keeping other molecular parameters constant between different complexes, these manifest the key role of the three low-energy metal-displacing vibrations in mediating the spin-lattice relaxation times (T1 ). The temperature dependence of T1 can thus be normalized by the frequencies of these low energy vibrations to show an unprecedentedly universal behavior for EMFs in frozen CS2 solution. Our theoretical analysis indicates that this structural difference determines not only the vibrational rigidity but also spin-vibration coupling in these EMF-based qubit candidates.

Enhancing the Accuracy of Non-Invasive Glucose Sensing in Aqueous Solutions Using Combined Millimeter Wave and Near Infrared Transmission.

We reported measurement results relating to non-invasive glucose sensing using a novel multiwavelength approach that combines radio frequency and near infrared signals in transmission through aqueous glucose-loaded solutions. Data were collected simultaneously in the 37-39 GHz and 900-1800 nm electromagnetic bands. We successfully detected changes in the glucose solutions with varying glucose concentrations between 80 and 5000 mg/dl. The measurements showed for the first time that, compared to single modality systems, greater accuracy on glucose level prediction can be achieved when combining transmission data from these distinct electromagnetic bands, boosted by machine learning algorithms.

Near Isotropic D4d Spin Qubits as Nodes of a Gd(III)-Based Metal-Organic Framework.

Embedding coherent spin motifs in reproducible molecular building blocks is a promising pathway for the realization of quantum technologies. Three-dimensional (3D) MOFs are a versatile platform for the rational design of extended structures employing coordination chemistry. Here, we report the synthesis and characterization of a gadolinium(III)-based MOF, [Gd(bipyNO)4](TfO)3·xMeOH (bipyNO = bipyridine,N,N'-dioxide; TfO = triflate; and MeOH = methanol) (quMOF-1), which presents a unique coordination geometry that leads to a tiny magnetic anisotropy (in terms of D, an equivalent zero-field splitting would be achieved by D = 0.006 cm-1) even compared with regular Gd(III) complexes. Pulsed electron paramagnetic resonance experiments on its magnetically diluted samples confirm the preservation of quantum coherence of single Gd(III) qubit units in this 3D extended molecular architecture (T2 = 612 ns and T1 = 66 µs at 3.5 K), which allows for the detection of Rabi oscillations at 40 K.

A smart switching system to enable automatic tuning and detuning of metamaterial resonators in MRI scans.

We present a radio-frequency-activated switching system that can automatically detune a metamaterial resonator to enhance magnetic resonance imaging (MRI) performance. Local sensitivity-enhancing metamaterials typically consist of resonant components, which means that the transmitted radio frequency field is spatially inhomogeneous. The switching system shows for the first time that a metamaterial resonator can be detuned during transmission and tuned during reception using a digital circuit. This allows a resonating system to maintain homogeneous transmit field while maintaining an increased receive sensitivity. As a result, sensitivity can be enhanced without changing the system-provided specific absorption rate (SAR) models. The developed digital circuit consists of inductors sensitive to the transmit radio-frequency pulses, along with diodes acting as switches to control the resonance frequency of the resonator. We first test the automatic resonator detuning on-the-bench, and subsequently evaluate it in a 1.5 T MRI scanner using tissue-mimicking phantoms. The scan results demonstrate that the switching mechanism automatically detunes the resonator in transmit mode, while retaining its sensitivity-enhancing properties (tuned to the Larmor frequency) in receive mode. Since it does not require any connection to the MRI console, the switching system can have broad applications and could be adapted for use with other types of MRI scanners and field-enhancing resonators.

Feasibility Study of Enhancing Microwave Brain Imaging Using Metamaterials.

We present an approach to enhance microwave brain imaging with an innovative metamaterial (MM) planar design based on a cross-shaped split-ring resonator (SRR-CS). The proposed metasurface is incorporated in different setups, and its interaction with EM waves is studied both experimentally and by using CST Microwave Studio® and is compared to a "no MM" case scenario. We show that the MM can enhance the penetration of the transmitted signals into the human head when placed in contact with skin tissue, acting as an impedance-matching layer. In addition, we show that the MM can improve the transceivers' ability to detect useful "weak" signals when incorporated in a headband scanner for brain imaging by increasing the signal difference from a blood-like dielectric target introduced into the brain volume. Our results suggest that the proposed MM film can be a powerful hardware advance towards the development of scanners for brain haemorrhage detection and monitoring.

Giant Enhancement in the Supercapacitance of NiFe-Graphene Nanocomposites Induced by a Magnetic Field.

The rapid rise in energy demand in the past years has prompted a search for low-cost alternatives for energy storage, supercapacitors being one of the most important devices. It is shown that a dramatic enhancement (≈1100%, from 155 to 1850 F g-1 ) of the specific capacitance of a hybrid stimuli-responsive FeNi3 -graphene electrode material can be achieved when the charge/discharge cycling is performed in the presence of an applied magnetic field of 4000 G. This result is related to an unprecedented magnetic-field-induced metal segregation of the FeNi3 nanoparticles during the cycling, which results in the appearance of small Ni clusters (<5 nm) and, consequently, in an increase in pseudocapacitive sites. The results open the door to a systematic improvement of the capacitance values of hybrid supercapacitors, while moving the research in this area towards the development of magnetically addressable energy-storage devices.

An Unusual Cause of Papules on the Face.

Dear Editor, Angiolymphoid hyperplasia with eosinophilia (ALHE) is a rare, locally proliferating disorder that affects predominantly the head and neck region (1,2). There seems to be a higher incidence in middle-aged Caucasian women (2,3). A 28-year-old female patient with no relevant personal or family medical history and only taking an oral contraceptive, presented to our department with multiple, well delimited, infracentimetric erythematous papules with a smooth surface on the left frontal, temporal, and preauricular regions (Figure 1). The lesions had appeared 7 months earlier, with progressive growth in number and dimensions since. The patient reported pruritus and denied previous trauma, topical application of any sort, insect bite at these locations, and any other accompanying symptoms. A thorough physical examination revealed no additional abnormalities. An excisional biopsy of one of the left temporal papules revealed a prominent lymphoid component, with a dense multinodular infiltrate in the superficial and deep dermis, with reactive germinative centers of considerable dimensions (Figure 2). Large and atypical lymphocytes were confined to the germinative centers, with reactive characteristics. Lymphocytes surrounding the germinative centers were predominantly small, accompanied by a significant number of scattered eosinophils. CD3 and CD20 immunohistochemical staining revealed B-cells predominantly in the nodular areas corresponding to the germinative centers, while T-cells displayed a diffuse peripheral distribution. There was severe neovascularization, with thick-walled vascular channels lined by enlarged plump endothelial cells with an "epithelioid" appearance. These findings supported the diagnosis of angiolymphoid hyperplasia with eosinophilia (ALHE). Laboratory workup did not show any abnormalities, including eosinophilia or elevation of immunoglobulin E levels. Due to pruritus and aesthetic concerns, surgical excision of the larger and most symptomatic papules was performed. The patient was assured of the benign nature of the disease and informed about the possible development of new lesions. Kept under clinical surveillance, the patient remained free of new lesions at 6-month follow-up. ALHE generally presents as solitary or multiple erythematous or hyperpigmented dome-shaped papulonodules. Lesions can be pruritic or painful and do not tend to resolve spontaneously (4). The pathogenesis of ALHE remains controversial, although some theories have been suggested. The most widely accepted hypothesis is that it is an angioproliferative process, accompanied by an inflammatory infiltrate, reactive to several stimuli (3). Some authors believe it is an allergic reaction, but no specific sole agent has been identified (5). Others claim ALHE may represent a T-cell lymphoproliferative disorder of benign or low-grade malignant nature (6). Some recent studies suggest that ALHE pathogenesis may be related to a vascular malformation secondary to a subcutaneous arteriovenous shunt (1-3). Histologically there are both vascular and inflammatory components, with an abnormal vascular proliferation and diffuse lymphocytic infiltrates with eosinophils. The vascular component is formed by capillaries clustered around arterial or venous vessels, dilated and atypical, with a protruded endothelium (3). The main differential diagnosis of ALHE is Kimura's disease, and there has been some discussion regarding the relationship between these two entities due to their clinical and histopathological similarities. However, most studies currently agree that they are distinct diseases. The differential diagnosis also includes angiosarcoma, particularly the epithelioid variant, epithelioid hemangioendothelioma, Kaposi sarcoma, pyogenic granuloma, and cutaneous metastasis (3). ALHE usually requires treatment as spontaneous regression, although reported in the literature, is rare (1,3). Many options have been suggested, with variable levels of success, but there is no definitive treatment for this condition (2). Surgical excision is the preferred choice, but recurrence may happen if the excision is incomplete (1). Mohs micrographic surgery with excision of abnormal vessels at the base of the lesion may be more effective in reducing recurrences (4). Other treatments reported include laser therapy (pulsed dye, CO2, copper vapor), systemic or intralesional corticosteroid injection, cryotherapy, imiquimod, tacrolimus, isotretinoin, radiotherapy, interferon alfa 2a, anti-interleukin-5 antibody, photodynamic therapy, and methotrexate (1). In the present case the diagnosis of ALHE was established through the conjunction of clinical and histological findings. Although a rare entity, its predominantly facial involvement in young adults and the absence of a satisfactory treatment can produce a significant impact that can include the quality of life of the patients.

Enhancing Light Emission in Interface Engineered Spin-OLEDs through Spin-Polarized Injection at High Voltages.

The quest for a spin-polarized organic light-emitting diode (spin-OLED) is a common goal in the emerging fields of molecular electronics and spintronics. In this device, two ferromagnetic (FM) electrodes are used to enhance the electroluminescence intensity of the OLED through a magnetic control of the spin polarization of the injected carriers. The major difficulty is that the driving voltage of an OLED device exceeds a few volts, while spin injection in organic materials is only efficient at low voltages. The fabrication of a spin-OLED that uses a conjugated polymer as bipolar spin collector layer and ferromagnetic electrodes is reported here. Through a careful engineering of the organic/inorganic interfaces, it is succeeded in obtaining a light-emitting device showing spin-valve effects at high voltages (up to 14 V). This allows the detection of a magneto-electroluminescence (MEL) enhancement on the order of a 2.4% at 9 V for the antiparallel (AP) configuration of the magnetic electrodes. This observation provides evidence for the long-standing fundamental issue of injecting spins from magnetic electrodes into the frontier levels of a molecular semiconductor. The finding opens the way for the design of multifunctional devices coupling the light and the spin degrees of freedom.

Dielectric permittivity of human blood of different lactate levels measured at millimeter waves.

The investigation of variations in dielectric properties of blood based on its biochemical profile is important for determining the feasibility of developing electromagnetic non-invasive sensing systems for monitoring the levels of various metabolites in blood. In this paper, the real and imaginary parts of dielectric permittivity are measured as a function of lactate concentration in the 30-60 GHz frequency range using two different measurement techniques. The blood samples are collected from a healthy subject undergoing three different exercise modes and the dielectric properties are measured with an open-ended coaxial probe technique and a custom-made millimeter wave transmission system. Good correlation is observed in measurements from the two methods, suggesting that an increase in lactate concentration lowers the imaginary part of permittivity and thus causing higher attenuation.

Feasibility Experiments to Detect Skin Hydration Using a Bio-Impedance Sensor.

We present proof of concept experiment of a sensing method to detect skin hydration using a low-cost bio-impedance sensor. The sensing system is validated by testing its current output over frequencies between 1 kHz and 50 kHz and comparing measured values of impedance. A series of experiments with salt-water mixtures as well as a gelatin-based phantom were carried out to test the sensor's ability to detect small changes in impedance due to changes in water content. We also compared impedance measurements from the phantom to human skin to confirm that the manufactured phantoms can mimic skin properties successfully. Our experimental results show that the sensor can detect small changes in salt concentration and can capture the correlation between the impedance and skin hydration in a reliable manner.

Metasurface Resonator for 1.5 T MRI Based on BaTiO3 Host Material.

Magnetic resonance imaging (MRI) is a widely used clinical tool for medical diagnosis and therapy. Several research studies focus on passively improving MRI sensitivity using high dielectric constant (HDC) materials and metamaterials. In this work, we investigate a new metasurface resonator which can enhance local transmit and receive efficiency in 1.5T MRI. The metasurface has been realized with an array of non-magnetic rods embedded in two blocks of a BaTiO3 aqueous mixture. BaTiO3 when mixed with water exhibits high dielectric permittivity values in the 40-200 MHz range, allowing the design of a compact and safe device for practical use in an MRI scanner. Simulation results show 50% enhancement of the magnetic field in the region-of-interest. The resonance frequency of the metasurface is also validated experimentally with a small loop antenna and a vector network analyzer (VNA) in a laboratory-controlled environment.

Neoadjuvant Trabectedin plus Radiotherapy in High-Grade Sarcoma of the Leg: A Case Report.

Here, we present the case of a 78-year-old male patient with undifferentiated spindle cell sarcoma on the posteromedial surface of the right leg who experienced a long-lasting progression-free survival. Due to an underlying cardiac disease, the patient was not suitable for anthracyclines. In September 2015, he received first-line chemotherapy with trabectedin (Yondelis®) at the approved dosage and regimen - concomitant with external radiotherapy (RT). After the first 9 cycles of trabectedin plus RT given in the neoadjuvant setting, the patient underwent surgical resection. At that stage, we observed a very good pathological response with 80% of necrotic area. The patient resumed the therapy with trabectedin; however, approximately 5 months later, we observed a new nodular heterogeneous lesion with ill-defined margins in the right leg and suggestive of tumor relapse. Subsequently an above-the-knee amputation was performed, and the patient resumed his trabectedin therapy with the same dosage and regimen. In January 2018, almost 2 1/2 years after the start of trabectedin treatment and 30+ cycles of trabectedin, the patient is locoregionally and distant metastatically disease-free. Currently, the treatment with trabectedin is maintained without any significant serious toxicity. Future clinical trials are needed to gain additional insights into the role of trabectedin maintenance therapy until disease progression in the neoadjuvant setting and to identify predictive and prognostic criteria for response to trabectedin in patients with advanced sarcoma.

Peptides as Versatile Platforms for Quantum Computing.

The pursuit of novel functional building blocks for the emerging field of quantum computing is one of the most appealing topics in the context of quantum technologies. Herein we showcase the urgency of introducing peptides as versatile platforms for quantum computing. In particular, we focus on lanthanide-binding tags, originally developed for the study of protein structure. We use pulsed electronic paramagnetic resonance to demonstrate quantum coherent oscillations in both neodymium and gadolinium peptidic qubits. Calculations based on density functional theory followed by a ligand field analysis indicate the possibility of influencing the nature of the spin qubit states by means of controlled changes in the peptidic sequence. We conclude with an overview of the challenges and opportunities opened by this interdisciplinary field.

Sublimable chloroquinolinate lanthanoid single-ion magnets deposited on ferromagnetic electrodes.

A new family of chloroquinolinate lanthanoid complexes of the formula A+[Ln(5,7Cl2q)4]-, with Ln = Y3+, Tb3+ and Dy3+ and A+ = Na+, NEt4+ and K0.5(NEt4)0.5+, is studied, both in bulk and as thin films. Several members of the family are found to present single-molecule magnetic behavior in bulk. Interestingly, the sodium salts can be sublimed under high vacuum conditions retaining their molecular structures and magnetic properties. These thermally stable compounds have been deposited on different substrates (Al2O3, Au and NiFe). The magnetic properties of these molecular films show the appearance of cusps in the zero-field cooled curves when they are deposited on permalloy (NiFe). This indicates a magnetic blocking caused by the interaction between the single-ion magnet and the ferromagnet. X-ray absorption spectroscopy confirms the formation of hybrid states at the molecule/metal interface.