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Monitoring disease evolution in Multiple sclerosis (MS) subjects may aid in decision making for personalizing treatment and disease evolution prediction. We investigate the use of disability progression, using clinical features, the expanded disability status scale (EDSS), and their relationship with texture features and Amplitude Modulation-Frequency Modulation (AM-FM) features extracted from MRI MS detectable lesions for the prognosis of future disability on magnetic resonance imaging (MRI). MS detectable brain lesions from N=38 symptomatic untreated subjects diagnosed with clinically isolated syndrome (CIS), were manually segmented, by an experienced MS neurologist, on transverse T2-weighted (T2W) images obtained from serial brain MRI scans at the baseline (Time0M) and the repeat (Time16-12M) examinations. The subjects were separated into two different groups based on their EDSS: (G1: 1≤EDSS2Y ≤ 3.5 (N=26) and G2: 3.5 < EDSS2Y ≤ 8.5 (N=12) and were monitored over ten years' time (Time10). After intensity normalization and image registration, texture and AM-FM features were extracted from all MS lesions at Time0M and Time6-12M. The extracted features were used to develop models that correlated with the disease progression in Time10Y. We found statistically significant differences for features extracted from the two different groups (G1 vs G2 at Time10Y) and these might be used to predict the development and or the severity of the MS disease. The best model for classifying G1 vs G2 subjects at Time10Y included information taken from the MS lesion images, texture features and AM-FM features extracted from those MS lesion images (with a correct classification score of %CC=94). The proposed methodology may contribute to additional factors for predicting the development and assessing the severity of the MS disease. However, a larger scale study is needed to establish the application in clinical practice and for computing additional features that may provide information for better and earlier differentiation between normal tissue and MS lesions.

The aims of this study were to describe the trends in the behavior of pediatric CD during the last decade and to describe the seasonal variation of disease presentation.Patients under 18 years old and diagnosed between 2009 and 2019 were included. The clinical, endoscopic, histological, and laboratory data were collected from the medical records. We analyzed the trends of these parameters according to the year and season of diagnosis.654 patients were included in the study. The number of incident CD cases increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR 2.53, p = 0.02), had more perianal diseases (OR: 2.30, p 0.0001) and more granulomas (OR: 1.61, p = 0.003), but fewer eosinophils (OR: 0.35, p 0.0001) and less chronic lymphoplasmacytic infiltrate (OR: 0.56, p = 0.008) as compared to the 2009-2014 cohort. There was fewer CD diagnosis during winter. Patients diagnosed in the fall had lower PCDAIs, less failure to thrive and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall.The clinical and histological phenotype of CD has changed over time and there are important seasonal trends in the frequency and severity on disease behavior suggesting possible disease triggers.

Rapid advances in large-scale next-generation sequencing studies of human samples have progressively defined the highly heterogeneous genetic landscape of chronic lymphocytic leukemia (CLL). At the same time, the numerous challenges posed by the difficulties in rapid manipulation of primary B cells and the paucity of CLL cell lines have limited the ability to interrogate the function of the discovered putative disease “drivers,” defined in human sequencing studies through statistical inference. Mouse models represent a powerful tool to study mechanisms of normal and malignant B-cell biology and for preclinical testing of novel therapeutics. Advances in genetic engineering technologies, including the introduction of conditional knockin/knockout strategies, have opened new opportunities to model genetic lesions in a B-cell–restricted context. These new studies build on the experience of generating the MDR mice, the first example of a genetically faithful CLL model, which recapitulates the most common genomic aberration of human CLL: del(13q). In this review, we describe the application of mouse models to the studies of CLL pathogenesis and disease transformation from an indolent to a high-grade malignancy (ie, Richter syndrome [RS]) and treatment, with a focus on newly developed genetically inspired mouse lines modeling recurrent CLL genetic events. We discuss how these novel mouse models, analyzed using new genomic technologies, allow the dissection of mechanisms of disease evolution and response to therapy with greater depth than previously possible and provide important insight into human CLL and RS pathogenesis and therapeutic vulnerabilities. These models thereby provide valuable platforms for functional genomic analyses and treatment studies.

Introduction: The T315I mutation in patients with chronic myeloid leukemia (CML) has been associated with therapeutic resistance and an unfavourable prognosis. Aim: To study the frequency of T315I mutation in patients with CML, BCR-ABL(+), their clinical characteristics, disease evolution, and median survival. Patients and methods: We studied 75 patients with CML and BCR-ABL1(+). T315I mutation was detected by digital droplet PCR and BCR-ABL1 was analyzed by RT-PCR. A comparative analysis was performed by sex, age, disease phase, risk group, treatment, molecular response (MR), and median survival in T315I(+) and T315I(−) patients. Results: T315I mutation was detected in 11 patients (14.7%). No significant difference was found in the phase, risk group, and first-line therapy. A significantly higher proportion of T315I(+) did not achieve MR>3.5 log: 8 (72.7%) vs. 22 (34.4%) (p=0.023). The lowest mean BCR-ABL1 levels were significantly higher in the CML T315I(+) group compared to the CML T315I(−) group: 12.1±6.0 vs. 3.77±1.28 (p=0.009). The median survival of T315I(+) patients was significantly shorter: 73 months vs. 175 months (p Conclusions: Our data confirm the world experience on the frequency of T315I mutation, including the unfavourable evolution, resistance to TKI treatment and short survival. ddPCR is a highly sensitive method for early detection of genetic mutations which gives the chance for effective treatment.

Research background: In recent times, the whole world has been severely affected by the COVID-19 pandemic. The influence of the epidemic on the society and the economy has caused a great deal of scientific interest. The development of the pandemic in many countries was analyzed using various models. However, the literature on the dissemination of COVID-19 lacks econometric analyzes of the development of this epidemic in Polish voivodeships. Purpose of the article: The aim of the study is to find similarities in time series for infected with and those who died of COVID-19 in Polish voivodeships using the method of dynamic time warping. Methods: The dynamic time warping method allows to calculate the distance between two time series of different lengths. This feature of the method is very important in our analysis because the coronavirus epidemic did not start in all voivodeships at the same time. The dynamic time warping also enables an adjustment of the timeline to find similar, but shifted, phases. Using this method, we jointly analyze the number of infected and deceased people in each province. In the next step, based on the measured similarity of the time series, the voivodeships are grouped hierarchically. Findings & value added: We use the dynamic time warping to identify groups of voivodeships affected by the epidemic to a different extent. The classification performed may be useful as it indicates patterns of the COVID-19 disease evolution in Polish voivodeships. The results obtained at the regional level will allow better prediction of future infections. Decision makers should formulate further recommendations for lockdowns at the local level, and in the long run, adjust the medical infrastructure in the regions accordingly. Policymakers in other countries can benefit from the findings by shaping their own regional policies accordingly. Copyright © Instytut Badan Gospodarczych

Physiological dynamics in living cells and tissues are crucial for maintenance and regulation of their normal activities and functionalities. Tiny fluctuations in physiological microenvironments can leverage significant influences on cell growth, metabolism, differentiation, and apoptosis as well as disease evolution. Fluorescence imaging based on aggregation-induced emission luminogens (AIEgens) exhibits superior advantages in real-time sensing and monitoring of the physiological dynamics in living systems, including its unique properties such as high sensitivity and rapid response, flexible molecular design, and versatile nano- to mesostructural fabrication. The introduction of canonic AIEgens with long-wavelength, near-infrared, or microwave emission, persistent luminescence, and diversified excitation source (e.g., chemo- or bioluminescence) offers researchers a tool to evaluate the resulting molecules with excellent performance in response to subtle fluctuations in bioactivities with broader dimensionalities and deeper hierarchies.

The unexpectable variations of the diagnosed disease symptoms are quite often observed during medical diagnosis. In stochastics, such behavior is called “grey swan” or “black swan” as synonyms of sudden, unpredictable change. Evolution of the disease’s symptoms is usually described by means of Markov processes, where dependency on process history is neglected. The common expectation is that such processes are Gaussian. It is demonstrated here that medical observation can be described as a Markov process and is non-Gaussian. Presented non-Gaussian processes have “fat tail” probability density distribution (pdf). “Fat tail” permits a slight change of probability density distribution and triggers an unexpectable big variation of the diagnosed parameter. Such “fat tail” solution is delivered by the anomalous diffusion model applied here to describe disease evolution and to explain the possible presence of “swans” mentioned above. The proposed model has been obtained as solution of the Fractal Fokker–Planck equation (FFPE). The paper shows a comparison of the results of the theoretical model of anomalous diffusion with experimental results of clinical studies using bioimpedance measurements in cardiology. This allows us to consider the practical usefulness of the proposed solutions.

A pandemic caused by a new coronavirus has spread worldwide, affecting Argentina. We implement an SEIR model to analyze the disease evolution in Buenos Aires and neighbouring cities. The model parameters are calibrated using the number of casualties officially reported. Since infinite solutions honour the data, we show different cases. In all of them the reproduction ratio $R_0$ decreases after early lockdown, but then raises, probably due to an increase in contagion in highly populated slums. Therefore it is mandatory to reverse this growing trend in $R_0$ by applying control strategies to avoid a high number of infectious and dead individuals. The model provides an effective procedure to estimate epidemic parameters (fatality rate, transmission probability, infection and incubation periods) and monitor control measures during the epidemic evolution., Comment: arXiv admin note: substantial text overlap with arXiv:2004.03575

Brown rust is an important disease that can affect the production of sugarcane in susceptible varieties. Reaction to brown rust has influenced the improvement programs in the process of clonal selection. Bru1 is one of the main resistance genes for brown rust. Therefore, the knowledge of the reaction to brown rust in the genotypes most used as parents in hybridizations would avoid crosses between susceptible genotypes. In this sense, the objectives of this work were to evaluate the reaction to brown rust in the field and the pattern of disease evolution; and the presence of the Bru1 gene in sugarcane parents of the RIDESA genetic improvement program. The experiment was carried out at the Paranavai experimental station, where 64 genotypes were planted in a randomized block design with three replications. The severity of brown rust in the field under natural infection conditions and the presence of the Bru1 gene were evaluated. Of the 63 genotypes evaluated, 38 were classified as resistant, 13 as intermediate and 12 as susceptible. Lower values of severity of brown rust were observed in intermediate genotypes with a slow evolution of the disease when compared with susceptible parents, indicating a quantitative resistance. Bru1 was detected in 58.7% of the evaluated genotypes. The frequency of Bru1 increased from 0% in the genotypes used as parents in the 1970s to 20, 64.71 and 76% in the 1980, 1990 and 2000s, respectively.

The aim is to explore a COVID-19 SEIR model involving Atangana-Baleanu Caputo type (ABC) fractional derivatives. Existence, uniqueness, positivity, and boundedness of the solutions for the alternative model are established. Some stability results of the proposed system are also presented. Numerical simulations results obtained in this paper, according to the real data, show that the model is more suitable for the disease evolution. © 2021. All Rights Reserved.

Anticancer drug development is a costly and protracted activity, and failure at late phases of clinical testing is common. We have previously proposed the Pharmacological Audit Trail (PhAT) intended to improve the efficiency of drug development, with a focus on the use of tumour tissue-based biomarkers. Blood-based ‘liquid biopsy’ approaches, such as targeted or whole-genome sequencing studies of plasma circulating cell-free tumour DNA (ctDNA) and circulating tumour cells (CTCs), are of increasing relevance to this drug development paradigm. Liquid biopsy assays can provide quantitative and qualitative data on prognostic, predictive, pharmacodynamic and clinical response biomarkers, and can also enable the characterization of disease evolution and resistance mechanisms. In this Perspective, we examine the promise of integrating liquid biopsy analyses into the PhAT, focusing on the current evidence, advances, limitations and challenges. We emphasize the continued importance of analytical validation and clinical qualification of circulating tumour biomarkers through prospective clinical trials. In this Perspective, members of the group that previously proposed the Pharmacological Audit Trail (PhAT) as a tool to improve and accelerate drug development through the use of tissue biomarkers discuss the promise of integrating liquid biopsy approaches into this paradigm. They focus on the potential applications of plasma circulating cell-free tumour DNA and circulating tumour cells as prognostic, predictive, pharmacodynamic, clinical response and resistance biomarkers, while also highlighting key technological considerations, limitations and challenges, and the importance of analytical validation and clinical qualification.

Introduction Efficient evaluation with an early surrogate endpoint, taking into account the process of disease evolution, may not only clarify inconsistent or underpowered results but also provide a new insight into the exploration of a new antiviral therapy for treating COVID-19 patients. Methods We assessed the dynamics of COVID-19 disease spectrum, commencing from low-risk (no or low oxygen supplement), medium-risk (non-invasive ventilator or high oxygen supplement), and high-risk (extracorporeal membrane oxygenation or invasive ventilator) risk state on enrollment, and then the subsequent progression and regression of risk states until discharge or death. The efficacy of antiviral therapy in altering the dynamics was assessed by using the high-risk state as a surrogate endpoint based on the data retrieved from the two-arm Adaptive Covid-19 Treatment Trial. Results Using the high-risk state as a surrogate endpoint, remdesivir treatment led to a decrease in the high-risk COVID-19 state by 34.8% (95% CI 26.7–42.0%) for a 14-day period and 29.3% (95% CI 28.8–29.8%) up to 28 days, which were consistent with a statistically significant reduction of death by 30.5% (95% CI 6.6, 50.9%) up to a 28-day period. The estimates of numbers needed to be treated were 100.9 (95% CI 88.1, 115.7) for using the high-risk COVID-19 state as a surrogate endpoint for a 14-day period and 133.3 (95% CI 112.5, 158.0) were required for averting one death from COVID-19 up to 28 days. Conclusions We demonstrate the expedient use of the high-risk COVID-19 disease status as a surrogate endpoint for evaluating the primary outcome of the earliest death. Supplementary Information The online version contains supplementary material available at 10.1007/s40121-021-00431-9.

A doença periodontal abrange uma gama variada de condições inflamatórias da gengiva, osso e ligamento periodontal dependentes da microbiota do biofilme, de respostas imunes inatas, inflamatórias e adaptativas do hospedeiro e, ainda, fatores individuais genéticos e ambientais. Já as fissuras labiopalatinas são deformidades anatômicas decorrentes da fusão parcial dos processos maxilares nas primeiras semanas de vida intrauterina, especialmente, envolvendo o rebordo alveolar, resultando em alterações no arco dentário e vestíbulo, podendo provocar anomalias dentárias, mal posicionamento dentário e alterações na oclusão, como atresia maxilar e mordida cruzada. Este trabalho tem como objetivo revisar a literatura a respeito da prevalência de alterações periodontais em indivíduos com fissura labiopalatina em diferentes grupos etários e tipos de fissura, bem como comparar os achados com indivíduos sem fissura labiopalatina. Indivíduos com fissura labiopalatina têm sido considerados mais suscetíveis ao desenvolvimento de doença periodontal em função de sua condição anatômica particular e das consequências da fissura para o indivíduo, como muitas vezes o tratamento ortodôntico prolongado, que leva a maior acúmulo de biofilme. Entretanto, conhecimentos mais recentes têm demonstrado que a doença periodontal é uma alteração multifatorial mediada por complexos mecanismos, além do acúmulo de biofilme, como por exemplo, a condição imunológica individual, preponderante para a evolução da doença. Assim, novos estudos são necessários para compreender melhor o comportamento das doenças periodontais nos indivíduos com fissura labiopalatina. Palavras-chaves: Fenda Labial. Fissura Palatina. Doenças Periodontais. Abstract Periodontal disease covers a wide range of inflammatory conditions of the gingiva, bone and periodontal ligament dependent on the biofilm microbiota, host’s innate, inflammatory and adaptive immune responses, as well as individual genetic and environmental factors. Cleft lip and palate are anatomical deformities resulting from the maxillary processes partial fusion in the first weeks of intrauterine life, especially involving the alveolar ridge, resulting in changes in the dental arch and vestibule, which can also cause dental anomalies, dental malposition and changes in occlusion such as maxillary atresia and crossbite. This work aims to review the literature regarding the prevalence of periodontal changes in individuals with cleft lip and palate in different age groups and types of cleft, as well as to compare the findings with individuals without cleft lip and palate. Individuals with cleft lip and palate have been considered more susceptible to the development of periodontal disease due to their particular anatomical condition and the consequences of the cleft for the individual, such as often the prolonged orthodontic treatment that leads to greater biofilm accumulation. However, more recent knowledge has shown that periodontal disease is a multifactorial alteration mediated by complex mechanisms in addition to the biofilm accumulation, such as, for example, the individual immune condition, which is preponderant for the disease evolution. Thus, further studies are needed to better understand the periodontal diseases behavior in individuals with cleft lip and palate. Keywords: Cleft Lip. Cleft Palate. Periodontal Diseases.

Objectives: Boger’s Synoptic Key is a less frequently used repertory. Homoeopaths can use it very effectively if they have the appropriate understanding of Boger’s philosophy and the background concepts. This paper explores the essential background concepts for using Boger’s Synoptic Key through a case series. Materials and Methods: A retrospective study was done of the cases successfully treated by the author in his private practice using Boger’s Synoptic Key. Analysis of symptoms and prescribing totality was done to identify the background concepts applied when using Boger’s Synoptic Key. Results: Concepts of tissue affinity, pathological generals, generalisation and consideration of modality and concomitant were identified as applied in case analysis and remedies arrived at through the use of Boger’s Synoptic Key. Conclusion: Boger’s Synoptic Key is a tool well integrated with the concepts of generalisation, tissue affinity, time dimension and pathological generals and their importance in disease evolution. Hence, it needs to be used with consideration of these concepts in case processing.

INTRODUCTION: Tuberculosis affects commonly the lungs, but any other organs can be affected as well. Urogenital tuberculosis is usually misdiagnosed. In this perspective, we aimed to give an update on the epidemiological, clinical and evolutionary features of urogenital tuberculosis in Southern Tunisia. METHODS: We conducted a retrospective study including all patients with extrapulmonary tuberculosis notified during the period from 1992 to 2017 in Southern Tunisia. We specified the particularities of urogenital tuberculosis cases, and we compared them with other extrapulmonary tuberculosis cases. RESULTS: Overall, we analyzed 240 cases with urogenital tuberculosis, among 1702 patients with extrapulmonary tuberculosis (14.1%). There were 121 women (50.4%). The mean age was 49±17 years. Multifocal tuberculosis was noted in 29 cases (12.1%). There were 169 cases with urinary tract tuberculosis (70.4%). Chronological trends analysis showed that the median age at diagnosis increased significantly (Rho=0.41; p=0.039) and the number of urogenital tuberculosis declined during the study period, without a statistical significance (Rho = -0.07; p=0.721). Compared to other extrapulmonary tuberculosis sites, patients aged 60 years and above (OR=2.7; p

Después de su descubrimiento en China, en diciembre de 2019, el virus SARS-CoV-2 causante de la enfermedad COVID-19, comenzó a propagarse por la mayoría de los países del mundo, provocando una cantidad importante de infectados y muertos, situación que ha generado una gran presión en los sistemas de salud y gobiernos de los diferentes países, que en muchos casos no contaban con los recursos e infraestructuras para enfrentar una pandemia provocada por el virus, como fue el caso de República Dominicana. Usando los datos públicos del avance de la pandemia en la Republica Dominicana, desde el 1 de marzo hasta el 30 de abril, se modeló y pronosticó la posible evolución del COVID-19 en este país, utilizando de tres modelos matemáticos SIR, SEIR-Extendido y log-lineal. Estos modelos permitieron proyectar los diferentes escenarios de contagios y evolución de la enfermedad, además de pronosticar el pico y el descenso de la curva de casos. Según los resultados obtenidos, el país se encontraba en un proceso de crecimiento exponencial de los contagios; el pico de los contagios fue pronosticado ocurriría entre la segunda mitad del mes de mayo y la primera mitad del mes de junio, con un estimado de infectados entre 100,000 y 200,000 individuos. Los resultados obtenidos en este estudio permiten obtener una idea de cuál podría ser el impacto humano y social del COVID-19 en la República Dominicana.

Objective: To evaluate the characteristics and prognosis of hospitalized geriatric COVID-19-positive patients during the first 30 days of the Swiss confinement period. Design: A retrospective case series analyzing the characteristics and disease evolution for 81 patients admitted to the geriatric COVID-19-positive ward during a 30-day period from March 24 to April 22, 2020. Setting and participants: Any COVID-19-positive patients who was admitted to one of four geriatric hospital sites who were >65 years old and did not desire intubation. Methods: Data collection on patients admitted throughout the study period, as well as chart review for those discharged within the 30-day period to ensure that information was complete.

Objective To characterize disease evolution in amyotrophic lateral sclerosis using an event‐based model designed to extract temporal information from cross‐sectional data. Conventional methods for understanding mechanisms of rapidly progressive neurodegenerative disorders are limited by the subjectivity inherent in the selection of a limited range of measurements, and the need to acquire longitudinal data. Methods The event‐based model characterizes a disease as a series of events, each comprising a significant change in subject state. The model was applied to data from 154 patients and 128 healthy controls selected from five independent diffusion MRI datasets acquired in four different imaging laboratories between 1999 and 2016. The biomarkers modeled were mean fractional anisotropy values of white matter tracts implicated in amyotrophic lateral sclerosis. The cerebral portion of the corticospinal tract was divided into three segments. Results Application of the model to the pooled datasets revealed that the corticospinal tracts were involved before other white matter tracts. Distal corticospinal tract segments were involved earlier than more proximal (i.e., cephalad) segments. In addition, the model revealed early ordering of fractional anisotropy change in the corpus callosum and subsequently in long association fibers. Interpretation These findings represent data‐driven evidence for early involvement of the corticospinal tracts and body of the corpus callosum in keeping with conventional approaches to image analysis, while providing new evidence to inform directional degeneration of the corticospinal tracts. This data‐driven model provides new insight into the dynamics of neuronal damage in amyotrophic lateral sclerosis.

HELLP syndrome is a rare and severe pregnancy complication which exposes to severe maternal and fetal morbidity. Management of HELLP syndrome occurring before 34 weeks of gestation (WG) is still controversial but conservative management may be beneficial in patients with stable HELLP syndrome. The aim of the study was thus to identify which maternal and fetal prognostic factors could be predictive of HELLP syndrome evolution.From 2003 to 2016, all patients with HELLP syndrome occurring between 26 and 34 WG were retrospectively enrolled. Study population was stratified according to obstetrical management. Patients in whom delivery was initiated within 48 h following diagnosis constituted the active management group. In the expectant management group, pregnancy was prolonged until maternal or fetal follow up indicated delivery.Ninety-nine patients were included in our study. Among them, 61 were managed expectantly. At baseline, the active management group was more likely to suffer from persistent hyperreflexia (While expectant management in HELLP syndrome might be beneficial through its reduction of prematurity, it cannot be conducted in all patients. Identification of baseline parameters predictive of disease evolution is thus of tremendous importance to define which obstetrical approach should be prioritized.

Canine distemper virus (CDV) and phocine distemper virus (PDV) are major pathogens to terrestrial and marine mammals. Yet little is known about the timing and geographical origin of distemper viruses and to what extent it was influenced by environmental change and human activities. To address this, we (i) performed the first comprehensive time-calibrated phylogenetic analysis of the two distemper viruses, (ii) mapped distemper antibody and virus detection data from marine mammals collected between 1972 and 2018, and (iii) compiled historical reports on distemper dating back to the eighteenth century. We find that CDV and PDV diverged in the early seventeenth century. Modern CDV strains last shared a common ancestor in the nineteenth century with a marked radiation during the 1930s–1950s. Modern PDV strains are of more recent origin, diverging in the 1970s–1980s. Based on the compiled information on distemper distribution, the diverse host range of CDV and basal phylogenetic placement of terrestrial morbilliviruses, we hypothesize a terrestrial CDV-like ancestor giving rise to PDV in the North Atlantic. Moreover, given the estimated timing of distemper origin and radiation, we hypothesize a prominent role of environmental change such as the Little Ice Age, and human activities like globalization and war in distemper virus evolution.

Developing a vaccine takes time especially for a newly emerging disease and a first generation of such vaccine may not to be 100 percent effective. Using mathematical modeling, we aimed in this work to evaluate the effect of a futur perfect COVID-19 vaccine on the disease evolution.

Simple Summary:& nbsp;The identification of cancer driver genes is, for statistical reasons, often biased toward genes that are altered frequently in a cohort. However, genes that are less frequently mutated can also alter cancer hallmarks. To detect such rarely mutated genes involved in driving metastatic prostate cancer, we analyzed the Hartwig Medical Foundation metastatic prostate cancer cohort. Hereto, we developed GoNetic, a novel network-based method that can detect genes with a lower mutational rate as members of recurrently mutated sets of genes connected on a prior interaction network. In contrast to state-of-the-art network-based driver identification methods, GoNetic retains information on sample-specific mutations and uses more properties of the prior interaction network. When applied to the Hartwig Medical Foundation cohort, GoNetic successfully prioritized both known drivers and rarely mutated driver candidates of metastatic prostate cancer. Comprehensive validation with other public data sets further supported the driver potential of these novel candidates.& nbsp;Most known driver genes of metastatic prostate cancer are frequently mutated. To dig into the long tail of rarely mutated drivers, we performed network-based driver identification on the Hartwig Medical Foundation metastatic prostate cancer data set (HMF cohort). Hereto, we developed GoNetic, a method based on probabilistic pathfinding, to identify recurrently mutated subnetworks. In contrast to most state-of-the-art network-based methods, GoNetic can leverage sample-specific mutational information and the weights of the underlying prior network. When applied to the HMF cohort, GoNetic successfully recovered known primary and metastatic drivers of prostate cancer that are frequently mutated in the HMF cohort (TP53, RB1, and CTNNB1). In addition, the identified subnetworks contain frequently mutated genes, reflect processes related to metastatic prostate cancer, and contain rarely mutated driver candidates. To further validate these rarely mutated genes, we assessed whether the identified genes were more mutated in metastatic than in primary samples using an independent cohort. Then we evaluated their association with tumor evolution and with the lymph node status of the patients. This resulted in forwarding several novel putative driver genes for metastatic prostate cancer, some of which might be prognostic for disease evolution.

Approximately 15% of chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL) transform into aggressive lymphomas, often diffuse large B cell lymphomas (DLBCL), known as Richter Syndrome ...

The illness-death model is the simplest multistate model where the transition from the initial state 0 to the absorbing state 2 may involve an intermediate state 1 (e.g., disease relapse). The impact of the transition into state 1 on the subsequent transition hazard to state 2 enables insight to be gained into the disease evolution. The standard approach of analysis is modeling the transition hazards from 0 to 2 and from 1 to 2, including time to illness as a time-varying covariate and measuring time from origin even after transition into state 1. The hazard from 1 to 2 can be also modeled separately using only patients in state 1, measuring time from illness and including time to illness as a fixed covariate. A recently proposed approach is a model where time after the transition into state 1 is measured in both scales and time to illness is included as a time-varying covariate. Another possibility is a model where time after transition into state 1 is measured only from illness and time to illness is included as a fixed covariate. Through theoretical reasoning and simulation protocols, we discuss the use of these models and we develop a practical strategy aiming to (a) validate the properties of the illness-death process, (b) estimate the impact of time to illness on the hazard from state 1 to 2, and (c) quantify the impact that the transition into state 1 has on the hazard of the absorbing state. The strategy is also applied to a literature dataset on diabetes.

In sarcoidosis, the appropriate management strategy remains challenging especially because of the lack of confident diagnosis, considerable variability in initial presentation, disease evolution, and outcome. Although asymptomatic patients with limited cardiac involvement have been described to have a benign outcome, cardiac sarcoidosis is associated with high morbidity and mortality and even sudden cardiac death in a significant proportion of patients. Higher morbidity and mortality can be related with both the disease activity and extent of fibrosis.Historical series suggested a 5-year mortality rate of 60% in patients with cardiac sarcoidosis. This has definitely improved with the appropriate use of anti-inflammatory medications as well as heart failure treatment, antiarrhythmic medication and device implantation. Timely recognition and vigorous initial approach is essential in avoiding life-threatening arrhythmias and sudden cardiac death. Advanced imaging modalities have proven to be helpful in the diagnostic approach and guiding treatment decisions. However, there is no optimal screening and risk stratification strategy available and further studies are required to determine, which patients would benefit from the available treatments.This review concentrates on the broad principles of management in cardiac sarcoidosis and the efficacy of sarcoidosis-specific medication and cardiac-specific therapies for cardiac dysfunction and rhythm disturbances.

Acquired immunodeficiency syndrome and lupus erythematosus are multisystem diseases that can affect several organs and systems at different stages of disease evolution. Both diseases share common clinical manifestations, which may lead to diagnostic difficulties, especially at the onset of the disease. Another additional challenge is when there is an association of the two pathologies. The objective of this brief review is to describe the clinical manifestations of the diseases and to make considerations regarding the moment of onset of symptoms. Knowledge of these common manifestations and their peculiarities may alert clinicians to possible diagnoses and avoid errors in the evaluation and conduction of these patients.

Multiphoton microscopy (MPM) is expected to become a powerful clinical tool, with its unique advantages of being label-free, high resolution, deep imaging depth, low light photobleaching and low phototoxicity. Nanomaterials, with excellent physical and chemical properties, are biocompatible and easy to prepare and functionalize. The addition of nanomaterials exactly compensates for some defects of MPM, such as the weak endogenous signal strength, limited imaging materials, insufficient imaging depth and lack of therapeutic effects. Therefore, combining MPM with nanomaterials is a promising biomedical imaging method. Here, we mainly review the principle of MPM and its application in liver cancer, especially in disease evolution and clinical applications, including monitoring tumor progression, diagnosing tumor occurrence, detecting tumor metastasis, and evaluating cancer therapy response. Then, we introduce the latest advances in the combination of MPM with nanomaterials, including the MPM imaging of gold nanoparticles (AuNPs) and carbon dots (CDs). Finally, we also propose the main challenges and future research directions of MPM technology in HCC.

Diabetic foot ulcers (DFUs) are a serious complication from diabetes mellitus, with a huge economic, social and psychological impact on the patients life. One of the main reasons why DFUs are so difficult to heal is related to the presence of biofilms. Biofilms promote wound inflammation and a remarkable lack of response to host defences/treatment options, which can lead to disease progression and chronicity. In fact, appropriate treatment for the elimination of these microbial communities can prevent the disease evolution and, in some cases, even avoid more serious outcomes, such as amputation or death. However, the detection of biofilm-associated DFUs is difficult due to the lack of methods for diagnostics in clinical settings. In this review, the current knowledge on the involvement of biofilms in DFUs is discussed, as well as how the surrounding environment influences biofilm formation and regulation, along with its clinical implications. A special focus is also given to biofilm-associated DFU diagnosis and therapeutic strategies. An overview on promising alternative therapeutics is provided and an algorithm considering biofilm detection and treatment is proposed., This work was supported by: Base Funding—UIDB/00511/2020 of the Laboratory for Process Engineering, Environment, Biotechnology and Energy—LEPABE—funded by national funds through the FCT/MCTES (PIDDAC); Project Biocide_for_Biofilm-PTDC/BII-BTI/30219/2017- POCI-01-0145-FEDER-030219, ABFISH–PTDC/ASP-PES/28397/2017-POCI-01-0145-FEDER- 028397 and Germirrad-POCI-01-0247-FEDER-072237, funded by FEDER funds through COMPETE2020— Programa Operacional Competitividade e Internacionalização (POCI) and by national funds (PID DAC) through FCT/MCTES. The authors also thank the CITAB (Centre for the Research and Technol ogy of Agro-Environmental and Biological Sciences) under the scope of the FCT funds with reference UIDB/AGR/04033/2020. Ana Afonso (2020.04773.BD) and Diana Oliveira (SFRH/BD/138217/2018) acknowledge the FCT grants. Anabela Borges thanks the FCT for the financial support of their work contract through the Scientific Employment Stimulus—Individual Call—[CEECIND/01261/2017]., info:eu-repo/semantics/publishedVersion

PURPOSE Neurotrophic tyrosine receptor kinase (NTRK) gene fusions encode oncogenic, chimeric tropomyosin receptor kinase (TRK) proteins. Larotrectinib, an approved TRK inhibitor, is efficacious in locally advanced or metastatic (adv/met) TRK fusion cancer. We evaluated the time from initial diagnosis to locally advanced or metastatic disease and to initiation of larotrectinib treatment as well as larotrectinib impact on disease course. MATERIALS AND METHODS Patients were grouped by prior lines of therapy (0, 1-2, and ≥ 3) and pre-larotrectinib duration of adv/met disease (short [< 3.5 months], medium [3.5 to < 15.7 months], and long [≥ 15.7 months]). Overall response rate (ORR), duration of response (DOR), and progression-free survival were assessed. RESULTS One hundred sixty-four patients were evaluated. The median time from initial diagnosis to development of locally adv/met stage was 2.1 months; the duration of pre-larotrectinib adv/met disease was 7.3 months (n = 153). In patients with 0, 1-2, and ≥ 3 prior lines of therapy, the median time from diagnosis to adv/met stage was 0.9, 1.2, and 9.4 months, and 1.5, 5.8, and 29.0 months from adv/met disease to larotrectinib initiation, respectively. Clinical outcomes were independent of line of therapy (ORR: 86%, 63%, and 80%, respectively; median DOR: 27.6, not reached, and 32.9 months), and similar across subgroups of short, medium, and long duration of pre-larotrectinib adv/met disease status (ORR: 88%, 65%, and 69%, respectively; median DOR: not reached, 27.6, and 32.9 months). CONCLUSION The short time from initial diagnosis to adv/met stage before larotrectinib suggests that NTRK gene fusion does not generally have a positive prognostic value. Patients on larotrectinib had high, sustained ORR, independent of number of prior therapies or duration of adv/met disease, suggesting that the effect of TRK inhibition in molecularly selected patients is independent of prior treatments or disease course., Patients with NTRK gene fusion do not seem to carry a more favorable prognosis and they benefit durably from Larotrectinib

Body fluids of cancer patients have attracted increasing attention in biomedical research within the last 15 years since—as so-called liquid biopsies—they represent a non-invasive source of clinically exploitable biomarkers, including circulating tumor cells (CTCs) and cell-free tumor DNA (ctDNA). Assessment of CTCs in peripheral blood from solid cancer patients has proven useful for detection of subclinical disease which otherwise remains invisible for current staging techniques. Based on results from large cohort studies in breast and colon cancer, diagnostic tests for enumeration of CTCs have been developed which can be used for tumor staging, prognosis, and post-treatment surveillance. Circulating plasma DNA derived from Epstein–Barr or human papilloma viruses has been established as a sensitive and highly specific biomarker for early cancer detection and disease monitoring. More recently, first studies have been initiated for studying the diagnostic value of mutant variants in plasma-derived ctDNA for treatment selection, response assessment and early detection of treatment failure.Advanced Head and Neck Squamous Cell Carcinoma (HNSCC) represents a malignancy associated with locoregionally advanced stage at presentation, dismal prognosis and little improvement in treatment outcome over the past decade, especially for patients with metastatic disease. HNSCC patients might therefore benefit from incorporation of liquid biopsy-based assays in clinical management. In the following chapters, I will summarize current evidence of the diagnostic value of liquid biopsies in HNSCC and give examples of potential clinical applications.

Clinical studies have demonstrated that subclinical actinic keratoses (AKs) may be clinically evidenced following treatment of multiple AKs with a topical immunotherapy agent known to reveal a "field cancerization". The aim of our study was to investigate if subclinical AKs may be evidenced also in single AKs. Ten patients with single, solitary AKs were treated with IQ 3.75% cream applied on the lesion and on a 5x5 cm surrounding area once daily for two 2-week treatment cycles separated by a 2-week treatment-free period. Lesions were evaluated by clinical, dermoscopic and RCM examination. At the end of treatment, subclinical lesions were evidenced in 8 out of 10 patients revealing the presence of a field cancerization. If larger studies will confirm these results, field cancerization could likely be considered also in case of solitary AKs, resulting in a different approach in terms of disease evolution and treatment. This article is protected by copyright. All rights reserved.

The molecular pathogenesis of myelodysplastic syndrome (MDS) is complex due to the high rate of genomic heterogeneity. Significant advances have been made in the last decade which elucidated the landscape of molecular alterations (cytogenetic abnormalities, gene mutations) in MDS. Seminal experimental studies have clarified the role of diverse gene mutations in the context of disease phenotypes, but the lack of faithful murine models and/or cell lines spontaneously carrying certain gene mutations have hampered the knowledge on how and why specific pathways are associated with MDS pathogenesis. Here, we summarize the genomics of MDS and provide an overview on the deregulation of pathways and the latest molecular targeted therapeutics.

Severe alcoholic hepatitis (AH) is a dynamic process with patients presenting at different phases of disease. Change in bilirubin over 7 days has been used as an indicator of prognosis and response to corticosteroid treatment in AH. However clinical decisions are influenced by disease trajectory in the first few days of admission. We aimed to test the prognostic validity of bilirubin change within four days of admission prior to exposure to corticosteroid treatment. Data collected from patients recruited to the STOPAH trial from three Scottish centres were analysed retrospectively. The gradient of the best fit line (m) was used to calculate change in bilirubin across the first four days (mBili4) and first seven days (mBili7) of admission for each patient. Bilirubin difference (Δ) from baseline was calculated from the average bilirubin of day three/four (ΔBili4) and day six/seven (ΔBili7) and compared to baseline bilirubin (bBili). Patients exposed to corticosteroids within these time periods were excluded from analysis. Area under the receiver operator curve (AUC) was performed for day 28 and day 90 survival. A total of 155 patients had at least two datapoints across the four days, including a bBili and values at either day three or four. A total of 106 patients had at least three datapoints across seven days including a bBili and values at either day six or seven. bBili did not predict day 28 survival (AUC 0.53, p = 0.70), or day 90 survival (AUC 0.52, p = 0.74). mBili4 and ΔBili4 did not predict day 28 survival (AUC 0.57, p = 0.26; AUC 0.53, p = 0.69) or day 90 survival (AUC 0.46, p = 0.46; AUC 0.48, p = 0.67). mBili7 moderately predicted day 28 survival (AUC 0.67, p = 0.04) but not so ΔBili7 (AUC 0.66, p = 0.05). Neither mBili7 or ΔBili7 predicted day 90 survival (AUC 0.57, p = 0.27; AUC 0.57, p = 0.31). Baseline bilirubin and changes in bilirubin within the first four days of admission were not predictive of day 28 and day 90 outcome. Only 7 days after admission did a change in bilirubin reflect subsequent outcome at day 28 but not at day 90. These results suggest that the trajectory of bilirubin in the first four days of admission with severe AH prior to corticosteroid treatment are not indicative of subsequent outcome. Alternative biomarkers of disease evolution are required if informed therapeutic decisions are to be made within this early stage of hospital admission.

Pediatric obstructive sleep apnea affects a large number of children and has multiple end-organ sequelae. Although many of these have been demonstrated to be reversible, the effects on some of the organ systems, including the brain, have not shown easy reversibility. Progress in this area has been hampered by lack of a preclinical model to study the disease. Therefore, perioperative and sleep physicians are tasked with making a number of difficult decisions, including optimal surgical timing to prevent disease evolution, but also to keep the perioperative morbidity in a safe range for these patients.

Introducción: muchos pacientes que viven con VIH-SIDA (PVVS) se sienten discriminados por su enfermedad, tanto en el ámbito social como en establecimientos de salud, incluyendo la atención odontológica. Sin embargo, en la actualidad no existen en Argentina estudios que permitan establecer las preferencias de estos pacientes al momento de acudir a un odontólogo, como el lugar donde prefieren ser atendidos, o si mencionan su condición de VIH(+), entre otros aspectos. Objetivo: determinar la apreciación de las PVVS sobre la atención odontológica en Salta, Argentina. Métodos: estudio descriptivo, de corte transversal. La población estudiada fueron sujetos que acudieron al Programa Provincial VIH/ITS de Salta entre junio y septiembre de 2015. Se recolectaron datos sociodemográficos, enfermedad de base y atención odontológica, en una encuesta diseñada para tal fin. Resultados: se encuestaron 200 PVVS: 54% de género masculino, con una edad promedio de 37 años (RIC 29,2-45), tiempo mediano de evolución de la enfermedad de 78 meses (RIC 30-126). Un 78% consultó al odontólogo en los últimos dos años y 60% utilizó establecimientos públicos como lugar de atención. Un 70% percibió que el odontólogo tiene conocimientos sobre VIH. El 50,5% manifestó su estado serológico al profesional tratante. 87% refirió que recibieron atención odontológica sin ningún prejuicio. Del 49,6% que no dio a conocer su diagnóstico, el 55% adujo miedo a la discriminación. Conclusión: si bien la apreciación de las PVVS sobre la atención odontológica fue positiva, mayoritariamente sin prejuicios, el miedo a la discriminación es la principal causa para no dar a conocer el diagnóstico al odontólogo. El trabajo interdisciplinario ayudaría a las PVVS en la atención integral, evitando ser un motivo más para la falta de adherencia al tratamiento.

Parkinson's disease (PD) is commonly characterized by asymmetrical motor impairment. This study aimed to clarify the iron distributions in PD patients with significant motor asymmetry and their longitudinal alterations. This study included 123 PD patients and 121 normal controls. Thirty-eight PD patients were revisited. PD patients with significant motor asymmetry were identified by using an objective criterion. Inter-group, inter-hemisphere and inter-visit differences of regional tissue susceptibility were analyzed. Iron accumulation in dominantly and non-dominantly affected substantia nigra (SN) were observed in PD patients with motor asymmetry compared with normal controls (p < 0.005, Bonferroni corrected). Iron accumulation in the dominantly affected SN was significantly higher than that in the non-dominantly affected SN (p < 0.01, Bonferroni corrected). After follow-up, time effect on the iron content in SN was observed, directing to decrease in PD patients with motor asymmetry without hemispherical difference (p < 0.05). In conclusion, asymmetrical iron accumulation in SN was associated with the motor asymmetry in PD at baseline, while along the disease evolution iron content in SN became longitudinally decreased. All these findings provide new evidence for PD pathogenesis that the abnormal iron metabolism in SN is complicated and not always unidirectional.

Background/Purpose In Systemic Lupus Erythematosus (SLE) the presence of some autoantibodies is related to specific clinical manifestations. We aimed to define SLE patient groups according to an autoantibody profile and to analyze the correlation of these profiles to clinical manifestations. Methods A cross-sectional observational study of SLE (SLICC 2012 criteria) was conducted. A clinical and analytical evaluation was performed. Clinical manifestations were described according to RELESSER study. We selected 8 autoantibodies to classify SLE patients: anti-dsDNA, anti-Sm, anti-RNP, anticardiolipin IgG/IgM (aCL IgG/M), anti-s2microglobulin IgG/IgM (as2M IgG/M), lupus anticoagulant (LA), anti-Ro and anti-La. Immunological profiles were created according to previous study of Artim-Esen B et al. 2014. Results 142 SLE patients with a mean age at diagnosis of 33.29 (13.53) and a mean time of disease evolution of 15.82 (10.56) years were evaluated. Mean SLEDAI score was 5.91 (5.6) and mean SLICC value 1.1 (1.46). Autoantibody frequencies are: ANAs 87.3%, anti-dsDNA 36.62%, anti-Sm 9.2%, anti-RNP 3.5%, aCL IgG/M 20.15%, as2M IgG/M 21.88%, LA 26.27%, anti-Ro 45.07% and anti-La 16.2%. Profile n°2 included SLE patients with anti-Sm/RNP positivity. Profile n°3 included patients with anti-Ro/La positivity. Profile n°4 included patients with aCL IgG/M or aB2M IgG/M or LA positivity. Profile n°5 included patients who exclusively showed anti-DNA positivity. Profile n°1 included all patients excluded from the other profiles. Profile n°1 patients were diagnosed earlier and had a longer disease evolution, whereas Profile n°5 patients were diagnosed later and with shorter disease evolution. We observed a significant association among hematological affection and high levels of anti-Ro (P Conclusions An association between the presence of anti-Ro/La and hematological affection, as well as high incidence of Sjogren syndrome in these subgroup of patients was described.

Background: Monitoring the number of deaths due to COVID-19 in different nations and settings is essential for response planning. In the UK many COVID-19 deaths occurred outside of Hospitals. We aim to use monitoring data from national statistical agencies in the UK to model of the number of COVID-19 deaths ahead of upcoming peaks. Methods: We analysed publicly available data on place of occurrence of COVID-19 deaths from national statistical agencies in the UK between March 9 and September 13, 2020. We dynamically normalise the data, modelling the proportion of deaths due to COVID-19 with an inverse Weibull distribution and the relative COVID-19 deaths in each setting with a double logistic distribution. Findings: Our results show deaths due to COVID-19 peaked in England (39.4%), Scotland (37.0%), Wales (37.0%) and Northern Ireland (25.2%) between 13 April and April 19, 2020. Peaks in deaths due to COVID-19 first occur in Homes with a peak in Care Homes two weeks later in all nations. Timings of peaks in Hospitals vary, occurring after either the peak in Homes or Care Homes. Scotland and Northern Ireland are the only nations where more COVID-19 deaths occur in Care Homes compared to Hospitals during the pandemic. The proportion of COVID-19 deaths in Care Homes increases from the start of the pandemic, reaching a maximum after the peak in number of COVID-19 deaths (England [2.6 weeks], Scotland [2.0 weeks] and Wales [1.4 weeks]) then gradually decreasing. In concordance, the proportion of COVID-19 deaths in Hospitals reduces from the start of the pandemic, reaching a minimum after the peak in number of COVID-19 deaths (England [3.1 weeks], Scotland [3.4 weeks], Wales [1.4 weeks]) then gradually increasing. In Northern Ireland, the peak in number of COVID-19 deaths coincides with proportion of COVID-19 deaths reaching a maximum in Care Homes and a minimum in Hospitals. Interpretation: The two-week delay in peaks of deaths due to COVID-19 between Homes and Care Homes indicates this as a potential transmission vehicle in the UK. The proportion of COVID-19 deaths in Care Homes continues to increase after the peak in number of deaths further indicating a delay in the disease evolution in this setting compared to Homes. Funding: Department for Business, Energy and Industrial Strategy. Declaration of Interests: The author declares no competing interests.

Bronchopulmonary dysplasia has evolved over the past few decades as our treatment modalities have changed and as more immature infants are surviving. Our field has struggled somewhat in finding a suitable definition that does not rely on the severity of treatment to describe the severity of disease. Nonetheless, this disease is essentially maldevelopment of the lung secondary to prematurity, with an optimal lung growth environment not yet being achievable outside of the womb. In this chapter, we focus on definition, disease evolution, the contributions of a recent large cohort study, and the effect of maldevelopment on both pulmonary alveolar structure and pulmonary vasculature.

The range of pathologies that are related to primitive vasculitis is broad, complex and not as typical as we would expect. Clinicians should be aware that several forms of primitive and systemic vasculitis, regardless of the size of the affected vessel, may exhibit identical histological alterations. This observation has important clinical implications as it means that cases of vasculitis do not correspond clinically and histologically. Thus, while histology remains the diagnostic gold standard, it can be used only as part of the most complete clinical assessment possible. Another point worth of the clinician’s attention is that vasculitis histology changes over time, as do disease evolution and activity, even without considering the masking effects of treatment and the possibility of sampling error due to the patchy occurrence of vasculitis. The purpose of this review is to identify the most common forms of vasculitis in clinical practice, and to provide guidance to the clinician on the pathology of the vessels.

This review summarizes the literature currently available for cutaneous tuberculosis (CTB), as well as providing data for clinical utility. Available studies in CTB are scarce; however, they provide important information about efficacy and outcome in clinical practice. We can detect differences in the clinical aspect and disease evolution; this is due to the individual immunity, environmental factors, and the type of inoculum. Treatment options for CTB are currently limited to the conventional oral therapy and the occasional surgical intervention in cases where needed. The development of multidrug-resistant strains and extremely resistant to drugs has also threatened treatment effectiveness. The aim of the article is to review the current status of CTB, in addition to a better knowledge of the molecular and cellular mechanisms regulating host-agent interaction.

Introduction: Transformation of chronic myelomonocytic leukaemia (CMML) to secondary acute myeloid leukaemia (sAML) is frequent and invariably fatal, but poorly characterized. Understanding the transcriptional programs driving progression could reveal therapeutic strategies to prevent/delay transformation. We integrated serial single-cell CITE-seq on CD34+ cells from CMML patients before and after sAML, to evaluate transcriptional and hierarchical dynamics in the hematopoietic stem and progenitor (HSPC) compartment. Methods: Four CMML patients with matched bone marrow (BM) from CMML and sAML (± interim remission after azacitidine) were included. Three age-matched healthy controls were sourced from elective hip arthroplasties. Total 13 samples were processed. BM mononuclear cells were thawed and double MACS/FACS-enriched for CD34+ HSPCs. Cells were incubated with 14 HSPC/lineage-defining TotalSeq-A oligonucleotide-conjugated antibodies before parallel analysis of transcriptome and surface protein expression by 10X (Fig 1A). Results: Total 68,244 HSPCs were analyzed. Controls displayed near-identical UMAP distributions so were pooled for analyses. Optimal UMAP embeddings were generated for each CMML series independently (Fig 1B). UMAP clearly separated populations unique to CMML and sAML samples. Cell identities were inferred by unsupervised annotation from public datasets. CMML samples displayed loss of lymphoid progenitors, but also near-total absence of transcriptionally normal apical HSCs. All patients displayed aberrant expansions of progenitor populations, variously dominated by MPPs, CMPs or GMPs, as validated by antibody-derived tag (ADT) expression patterns. Pseudotime resolved patient-specific transformation trajectories, with blast expansions emerging from GMP (n=2), CMP/LMPP (n=1) or HSC/MPP (n=1). However, blasts consistently upregulated HSC-like transcriptional programs, in some cases with clear stepwise reversion from committed to stem-like transcriptional states along the computed trajectory (Fig 1B). Accordingly, blasts expressed classical HSC marker genes (ID2, DUSP1, CD52) alongside surface expression of private lineage markers but lacking ADT profiles of apical HSCs (Fig 1C). This decoupling, together with the pseudotime profiles, suggested progressive restoration of an HSC-like signature in downstream progenitors as a consistent feature. Post azacitidine there was marked expansion of megakaryocyte-erythroid progenitors, but despite recovery of normal hematopoiesis no restoration of the depleted apical HSCs. Subsequent sAML represented expansion of pre-existing (treatment-resistant) blasts in 3 case, but emergence of a new, transcriptionally-distinct blast population in the other. To characterise populations emergent at sAML we evaluated differentially expressed genes (DEG) vs respective CMML counterparts, then intersected gene lists across series. We found 319 genes upregulated in sAML conserved across ≥3 series. Among the most consistently upregulated genes at sAML were DUSP2 and all subunits of ITM2 (notably ITM2A, recently linked to AML). Pathways enriched in sAML included mTOR/PI3K/AKT and VEGF signalling (Fig 1D-E). Also overexpressed were several surface proteins (CD63, CD74, CD82, CD99) also aberrantly upregulated at earlier CMML, suggesting potential as biomarkers to predict/track transformation. Of the sAML signature genes 68 are considered 'druggable', including PIK3R1, NFKBIA and CXCL8. To identify early drivers of transformation we performed unsupervised clustering for each pooled series, comparing DEGs for successive intermediate CMML-to-sAML clusters along the computed trajectories. Common upregulated pathways included VEGF, MAPK and IL18 signaling, with 4 genes, notably the AP1 component JUNB, progressively upregulated during early transformation in all series (Fig 1F-G). Conclusions: We characterize the repartitioning of HSPC subsets in CMML, including loss of transcriptionally-normal apical HSCs, not restored upon azacitidine response; this may partially explain the transient nature of responses. Cell-of-origin and paths to acute transformation were heterogeneous, but with consistent co-opting of HSC-like programs in lineage-committed blasts. PIK3R1 and JUNB, and the PI3K/AKT/mTOR and VEGF pathways, emerge as candidate mediators of CMML transformation. Figure 1 Figure 1. Disclosures Somervaille: Novartis: Consultancy, Honoraria. Wiseman: Novartis: Consultancy; StemLine: Consultancy; Bristol Myers Squibb: Consultancy; Takeda: Consultancy; Astex: Research Funding.

espanolLos hongos patogenos de las plantas son la mayor amenaza para la agricultura en el mundo; Para contrarrestar su efecto se utilizan fungicidas quimicos sinteticos, que causan efectos adversos sobre la salud humana y el medio ambiente. Los metodos fisicos para controlar patogenos estan surgiendo como una alternativa para manejar las enfermedades de los cultivos; sin embargo, han sido poco explorados. El tomate (Solanum lycopersicum) es el vegetal mas frecuentemente cultivado en el mundo y crece en una amplia gama de climas, tanto en campo como en invernadero. Uno de los factores mas limitantes para la produccion de tomate es la enfermedad foliar conocida como mildeo polvoso. El rendimiento y la calidad del fruto pueden reducirse debido a que la enfermedad puede desarrollarse rapidamente y los foliolos gravemente afectados mueren. En este trabajo, se evaluo el efecto de UV-C (254 nm) sobre el desarrollo del mildeo polvoso en condiciones de invernadero. Los foliolos se sometieron a diferentes tiempos de exposicion de UV-C y con la adquisicion de imagenes RGB y el analisis de imagenes se determino la tasa de crecimiento de la lesion. Los tiempos de exposicion que no causaron lesiones visibles en foliolos sanos, se utilizaron para medir el efecto sobre foliolos con la enfermedad. Despues de la infeccion natural, se determino el area de la lesion, el numero total de lesiones y la tasa de crecimiento con respecto al area inicial de la lesion. Comparando con foliolos no tratados, aplicaciones de 30 s o 60 s de UV-C cada 48 h por 10 dias, redujo significativamente la severidad del mildeo polvoso en los foliolos de tomate. Tambien comparamos la determinacion tradicional de la tasa de crecimiento utilizando un calibrador con un programa personalizado basado en la adquisicion y analisis de imagenes, indica que el ultimo es un sistema mas completo para seguir con precision la evolucion de la enfermedad. Este trabajo es un enfoque importante para aplicar la luz a los problemas agricolas de manera no invasiva en condiciones de precosecha de plantas, lo cual ha sido pobremente explorado, y demuestra la aplicacion del analisis de imagenes en el estudio de variables agricolas importantes. EnglishThe plant pathogenic fungi are the greatest threat to agriculture in the world; to counteract its effect synthetic chemical fungicides are used, which cause adverse effects on human health and the environment. Physical methods to control pathogens are emerging as an alternative for managing crop diseases; however, they have been little explored. Tomato (Solanum lycopersicum) is the most frequently cultivated vegetable in the world and it grows in a wide range of climates, both field and greenhouse. One of the most limiting factors for tomato production is the foliar disease known as powdery mildew. The yield and quality of the fruit can be reduced because the disease can develop rapidly and severely affected leaflets die. In this paper, the effect of UV-C (254 nm) on the development of powdery mildew under greenhouse conditions was evaluated. The leaflets were submitted to different UV-C exposure times and with the acquisition of RGB images and image analysis the growth rate of the lesion was determined. The exposure times that did not cause visible injuries in healthy leaflets were used to measure the effect on leaflets with the disease. After natural infection, the lesion area, the number of total lesions and the growth rate with respect to the initial lesion area were determined. Comparing with non-treated leaflets, 30 s or 60 s applications of UV-C each 48 h for 10 days, significantly reduced powdery mildew severity on tomato leaflets. We also compared traditional growth rate determination using a caliper with a custom program based on image acquisition and analysis, reporting that the latest is a more complete system to follow accurately the disease evolution. This work is an important approach of applying light to agricultural problems noninvasively in preharvest conditions, which has been poorly explored in agriculture, and it demonstrates the application of image analysis in the study of important agricultural variables.

Retrospective research from patients with schizophrenia suggests that remission becomes increasingly less likely the longer psychosis goes untreated. Yet symptoms of schizophrenia are insidious and disease evolution varies between patients, requiring an ongoing diagnostic process. One way of justifying early treatment is by focusing on functionality rather than symptomatology. Most patients are diagnosed with schizophrenia between the ages of 17 and 25-when many young adults are undergraduates or pursuing post-graduate education. The extent to which schools partner with mental health services has implications for the short-term success of students' recovery and their future employability. Translating study findings on schizophrenia to the college setting remains an important area of investigation.

Cutaneous melanoma remains a major health issue and still an important challenge for research. Thus, omics complex evaluation can provide a more specific molecular classification for this heterogeneous disease. Complex omics analysis based on genomic and proteomic microarrays can identify disease markers that prognosticate disease evolution or can monitor therapies efficacy. Among the technologies that gained momentum in the last years, array-based comparative genomic hybridization offered the possibility to analyze chromosomal numerical aberrations within cutaneous melanomas providing important support for molecular classification of melanoma tumors. This technology can identify new chromosomal alterations and discover new deregulated melanoma genes that can be further used as therapy targets. Integrating genetic profiling with clinical and pathological parameters would lead to seminal improvements in diagnosis, prognosis, and therapy.

Aim of the review - to illuminate the problem of proton pump inhibitor(PPI)-refractory form of gastroesophageal reflux disease (RFGERD) at a modern scientific level. It is shown that PPI remain the standard and the most effective therapy for GERD. Patients, whose GERD symptoms are refractory to PPI, should be further examined to exclude other diseases. It is possible to use different treatment options: medication, endoscopic or surgical treatment. The response to IPP therapy can be complete (no symptoms), partial or absent. In patients with complete response to treatment with PPI no other therapy is provided. Currently, new methods of RFGERD treatment are being actively developed. Patients with partial response may require endoscopic or surgical intervention.

Introduction: Clonal hematopoiesis (CH) denotes somatic mutations in genes related to myeloid neoplasms present at any variant allele frequency (VAF). Clonal hematopoiesis increases the risk of cardiovascular disease, de novo myeloid neoplasms and therapy-related myeloid neoplasms (tMN). It is well established that CH can be detected years before disease onset. Furthermore, the impact of specific mutations with regards to progression from CH to tMN is currently being unraveled. When exposed to cytoreductive therapy, a proliferative advantage of stem cells with CH over normal hematopoietic stem cells (HSCs) has been demonstrated. However, it remains unclear whether CH is to be considered a mere tMN risk factor, or if the mutations directly impact or even drive the development of tMN. We hypothesized that CH contributes to the development of tMN, and pursued this by investigating the evolution of CH, present in patients with lymphoma and multiple myeloma, prior to autologous stem cell transplantation (ASCT) and at time of tMN diagnosis. Methods: Patients included were treated with ASCT at the Department of Hematology, Aarhus University Hospital, Denmark, between 1989 and 2016. Inclusion criteria were (i) treatment with ASCT on the indication of a non-myeloid primary disease; (ii) subsequent development of tMN, and (iii) available mononuclear cells (MNCs) at pre-ASCT and time of tMN. All tMN diagnoses were reviewed by an experienced pathologist. Data from time of ASCT of this cohort has previously been reported (Soerensen et al., 2020, PMID: 32150606). Twelve patients with available MNCs at both time points were identified out of 36 tMN patients. Samples (either leukapheresis products or bone marrow MNCs) were subjected to targeted next-generation sequencing, utilizing a 30-gene panel (Myeloid Tumor Solution, SOPHiA Genetics, Saint Sulpice, Switzerland). Variant exclusion criteria were (1) read depth < 3000; (2) VAF < 0.003; (3) variant location outside ±25 nucleotides of coding region; (4) indel present in homopolymeric stretch, and (5) potential germline variants at pre-ASCT with VAF > 0.95 or between 0.45 and 0.55, representing homo- and heterozygosity, and reported in the Exome Aggregation Consortium (ExAC) database. Results: The cohort included 12 patients with a median age at ASCT of 63 years (range 37-69) and male predominance (75%). Median time to tMN following ASCT was 3.9 years (range 0.7-15.3), with 7 patients developing therapy-related myelodysplastic syndrome and 5 therapy-related acute myeloid leukemia. A total of 36 and 38 mutations were detected at ASCT and tMN, respectively. Prior to ASCT, DNMT3A (39%) and TET2 (19%) were the most frequently mutated genes, whereas the mutational landscape at tMN proved to be more heterogenous, with TP53 (21%), DNMT3A (18%), RUNX1 (13%) and ASXL1 (13%) comprising the majority of mutated genes. Nine patients (75%) had one or more mutations that could be detected at pre-ASCT as well as at tMN. Seven patients (58%) had CH at pre-ASCT that were present at higher VAF (>0.15 VAF) in bone marrow samples at tMN. Of these, 6 patients had CH at VAF < 0.02 at baseline. We found a total of 14 mutations that were detected at both prior to ASCT and tMN diagnosis, distributed among TP53, SRSF2, DNMT3A, ASXL1, TET2, NRAS and EZH2. Importantly, all clones harboring mutations in non-DNMT3A genes expanded until diagnosis of tMN to VAF > 0.30, with the exception of TET2, which displayed only a modest increase in VAF from 0.01 to 0.15. Conclusion: In this cohort of patients treated with ASCT and who subsequently developed tMN, we found the majority of patients to harbor CH in HSCs pre-ASCT that, at time of tMN, completely dominated the malignant clone. Our data suggests both a persistency of CH identified in HSCs in peripheral blood prior to ASCT to the leukemic stem cells in bone marrow at tMN diagnosis, as well as an expansion of the clones over time. These findings provide evidence to support the emerging theories that tMNs are instigated by subsets of hematopoietic cells that gain malignant somatic mutations and drive the pathogenesis years before onset disease. Figure Disclosures No relevant conflicts of interest to declare.

In 2017, extensive research into multiple sclerosis (MS) resulted in improved diagnostic criteria, development of biomarkers that enable monitoring of disease evolution and treatment response over time, and identification of novel genetic markers of disease susceptibility. In addition, 2017 saw the first successful clinical trials of remyelination strategies and treatments for progressive MS.