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Resumo Fundamento: A síndrome de Brugada é um distúrbio arritmogênico hereditário caracterizado pela presença de características eletrocardiográficas específicas com ou sem sintomas. Os pacientes apresentam risco aumentado de morte súbita por fibrilação ventricular. A prevalência desse padrão eletrocardiográfico difere de acordo com a região estudada. Porém, informações epidemiológicas, incluindo a população brasileira, são escassas. Objetivo: Avaliar a prevalência do padrão eletrocardiográfico da síndrome de Brugada e o perfil epidemiológico associado a ela. Métodos: Estudo transversal que incluiu 846.533 registros ECG de 716.973 pacientes do banco de dados de eletrocardiograma (ECG) da Rede de Telemedicina de Santa Catarina por um período de quatro anos. Todos os exames foram ECG de 12 derivações convencionais (sem V1 e V2 em posições altas). Os exames identificados com o diagnóstico de “Síndrome de Brugada” (tipos 1 e 2) foram revisados por um eletrofisiologista. Foram considerados significativos valores de p

Background Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer pain from temporomandibular disorder (TMD). Still, routines for the assessment of temporomandibular joint (TMJ) pain in health and dental care are lacking. The aims of this study were to examine the prevalence of TMD in children and adolescents with JIA compared to their healthy peers and to investigate potential associations between JIA and TMD. Methods This comparative cross-sectional study is part of a longitudinal multicentre study performed during 2015–2020, including 228 children and adolescents aged 4–16 years with a diagnosis of JIA according to the ILAR criteria. This particular substudy draws on a subset of data from the first study visit, including assessments of TMD as part of a broader oral health examination. Children and adolescents with JIA were matched with healthy controls according to gender, age, and centre site. Five calibrated examiners performed the clinical oral examinations according to a standardised protocol, including shortened versions of the diagnostic criteria for TMD (DC/TMD) and the TMJaw Recommendations for Clinical TMJ Assessment in Patients Diagnosed with JIA. Symptoms were recorded and followed by a clinical examination assessing the masticatory muscles and TMJs. Results In our cohort of 221 participants with JIA and 221 healthy controls, 88 (39.8%) participants with JIA and 25 (11.3%) healthy controls presented with TMD based on symptoms and clinical signs. Painful TMD during the last 30 days was reported in 59 (26.7%) participants with JIA vs. 10 (5.0%) of the healthy controls (p Conclusion Symptoms and clinical signs of TMD were seen in approximately half of the JIA patients compared to about one fourth of their healthy peers. Painful palpation to masticatory muscles and decreased vertical unassisted jaw movement were more frequent in participants with JIA than among healthy controls and should be part of both medical and dental routine examinations in patients with JIA.

Background: Advancements in technology offer new opportunities for the prevention and management of type 2 diabetes. Venture capital companies have been investing in digital diabetes companies that offer digital behavior change interventions (DBCIs). However, little is known about the scientific evidence underpinning such interventions or the degree to which these interventions leverage novel technology-driven automated developments such as conversational agents (CAs) or just-in-time adaptive intervention (JITAI) approaches. Objective: Our objectives were to identify the top-funded companies offering DBCIs for type 2 diabetes management and prevention, review the level of scientific evidence underpinning the DBCIs, identify which DBCIs are recognized as evidence-based programs by quality assurance authorities, and examine the degree to which these DBCIs include novel automated approaches such as CAs and JITAI mechanisms. Methods: A systematic search was conducted using 2 venture capital databases (Crunchbase Pro and Pitchbook) to identify the top-funded companies offering interventions for type 2 diabetes prevention and management. Scientific publications relating to the identified DBCIs were identified via PubMed, Google Scholar, and the DBCIs’ websites, and data regarding intervention effectiveness were extracted. The Diabetes Prevention Recognition Program (DPRP) of the Center for Disease Control and Prevention in the United States was used to identify the recognition status. The DBCIs’ publications, websites, and mobile apps were reviewed with regard to the intervention characteristics. Results: The 16 top-funded companies offering DBCIs for type 2 diabetes received a total funding of US $2.4 billion as of June 15, 2021. Only 4 out of the 50 identified publications associated with these DBCIs were fully powered randomized controlled trials (RCTs). Further, 1 of those 4 RCTs showed a significant difference in glycated hemoglobin A1c (HbA1c) outcomes between the intervention and control groups. However, all the studies reported HbA1c improvements ranging from 0.2% to 1.9% over the course of 12 months. In addition, 6 interventions were fully recognized by the DPRP to deliver evidence-based programs, and 2 interventions had a pending recognition status. Health professionals were included in the majority of DBCIs (13/16, 81%,), whereas only 10% (1/10) of accessible apps involved a CA as part of the intervention delivery. Self-reports represented most of the data sources (74/119, 62%) that could be used to tailor JITAIs. Conclusions: Our findings suggest that the level of funding received by companies offering DBCIs for type 2 diabetes prevention and management does not coincide with the level of evidence on the intervention effectiveness. There is considerable variation in the level of evidence underpinning the different DBCIs and an overall need for more rigorous effectiveness trials and transparent reporting by quality assurance authorities. Currently, very few DBCIs use automated approaches such as CAs and JITAIs, limiting the scalability and reach of these solutions., Journal of Medical Internet Research, 24 (1), ISSN:1438-8871

Papanicolaou is an inexpensive and non-invasive method, generally applied to detect cervical cancer, that can also be useful to detect cancer on oral cavities. Although oral cancer is considered a global health issue with 350.000 people diagnosed over a year it can successfully be treated if diagnosed at early stages. The manual process of analyzing cells to detect abnormalities is time-consuming and subject to variations in perceptions from different professionals. To evaluate a possible solution to the automation of this process, in this paper we employ the object detection deep learning approach in the analysis of this type of image using 3 models: RetinaNet, Faster R-CNN, and Mask R-CNN. We trained and tested the models using images from 6 cytology slides (4 cancer cases and 2 healthy samples) and our results show that Mask R-CNN was the best model for localization and classification of nuclei with an IoU of 0.51 and recall of abnormal nuclei of 0.67.

Background: Mental health disorders affect 1 in 10 people globally, of whom approximately 300 million are affected by depression. At least half of the people affected by depression remain untreated. Although cognitive behavioral therapy (CBT) is an effective treatment, access to mental health specialists, habitually challenging, has worsened because of the COVID-19 pandemic. Internet-based CBT is an effective and feasible strategy to increase access to treatment for people with depression. Mental health apps may further assist in facilitating self-management for people affected by depression; however, accessing the correct app may be cumbersome given the large number and wide variety of apps offered by public app marketplaces. Objective: This study aims to systematically assess the features, functionality, data security, and congruence with evidence of self-guided CBT-based apps targeting users affected by depression that are available in major app stores. Methods: We conducted a systematic assessment of self-guided CBT-based apps available in Google Play and the Apple App Store. Apps launched or updated since August 2018 were identified through a systematic search in the 42matters database using CBT-related terms. Apps meeting the inclusion criteria were downloaded and assessed using a Samsung Galaxy J7 Pro (Android 9) and iPhone 7 (iOS 13.3.1). Apps were appraised using a 182-question checklist developed by the research team, assessing their general characteristics, technical aspects and quality assurance, and CBT-related features, including 6 evidence-based CBT techniques (ie, psychoeducation, behavioral activation, cognitive restructuring, problem solving, relaxation, and exposure for comorbid anxiety) as informed by a CBT manual, CBT competence framework, and a literature review of internet-based CBT clinical trial protocols. The results were reported as a narrative review using descriptive statistics. Results: The initial search yielded 3006 apps, of which 98 met the inclusion criteria and were systematically assessed. There were 20 well-being apps; 65 mental health apps, targeting two or more common mental health disorders, including depression; and 13 depression apps. A total of 28 apps offered at least four evidence-based CBT techniques, particularly depression apps. Cognitive restructuring was the most common technique, offered by 79% (77/98) of the apps. Only one-third of the apps offered suicide risk management resources, whereas 17% (17/98) of the apps offered COVID-19-related information. Although most apps included a privacy policy, only a third of the apps presented it before account creation. In total, 82% (74/90) of privacy policies stated sharing data with third-party service providers. Half of the app development teams included academic institutions or health care providers. Conclusions: Only a few self-guided CBT-based apps offer comprehensive CBT programs or suicide risk management resources. Sharing of users' data is widespread, highlighting shortcomings in health app market governance. To fulfill their potential, self-guided CBT-based apps should follow evidence-based clinical guidelines, be patient centered, and enhance users' data security., Journal of Medical Internet Research, 23 (7), ISSN:1438-8871

Background: Chronic and mental health conditions are increasingly prevalent worldwide. As devices in our everyday lives offer more and more voice-based self-service, voice-based conversational agents (VCAs) have the potential to support the prevention and management of these conditions in a scalable manner. However, evidence on VCAs dedicated to the prevention and management of chronic and mental health conditions is unclear. Objective: This study provides a better understanding of the current methods used in the evaluation of health interventions for the prevention and management of chronic and mental health conditions delivered through VCAs. Methods: We conducted a systematic literature review using PubMed MEDLINE, Embase, PsycINFO, Scopus, and Web of Science databases. We included primary research involving the prevention or management of chronic or mental health conditions through a VCA and reporting an empirical evaluation of the system either in terms of system accuracy, technology acceptance, or both. A total of 2 independent reviewers conducted the screening and data extraction, and agreement between them was measured using Cohen kappa. A narrative approach was used to synthesize the selected records. Results: Of 7170 prescreened papers, 12 met the inclusion criteria. All studies were nonexperimental. The VCAs provided behavioral support (n=5), health monitoring services (n=3), or both (n=4). The interventions were delivered via smartphones (n=5), tablets (n=2), or smart speakers (n=3). In 2 cases, no device was specified. A total of 3 VCAs targeted cancer, whereas 2 VCAs targeted diabetes and heart failure. The other VCAs targeted hearing impairment, asthma, Parkinson disease, dementia, autism, intellectual disability, and depression. The majority of the studies (n=7) assessed technology acceptance, but only few studies (n=3) used validated instruments. Half of the studies (n=6) reported either performance measures on speech recognition or on the ability of VCAs to respond to health-related queries. Only a minority of the studies (n=2) reported behavioral measures or a measure of attitudes toward intervention-targeted health behavior. Moreover, only a minority of studies (n=4) reported controlling for participants’ previous experience with technology. Finally, risk bias varied markedly. Conclusions: The heterogeneity in the methods, the limited number of studies identified, and the high risk of bias show that research on VCAs for chronic and mental health conditions is still in its infancy. Although the results of system accuracy and technology acceptance are encouraging, there is still a need to establish more conclusive evidence on the efficacy of VCAs for the prevention and management of chronic and mental health conditions, both in absolute terms and in comparison with standard health care., Journal of Medical Internet Research, 23 (3), ISSN:1438-8871

Objective: Describe our experiences using teleconsultation approach to care for pediatric subspecialty follow-up patients during pandemic period. Methods: Synchronous teleconsultation solution was developed and implemented as a multiplatform/multimodality service, capable or running on desktop browsers and smartphones, and capable to handle chat, audio, and video. Term of consent was applied. Absolute number and percentage of patients assisted, as well as the form of consultation and the mean of attendance per patient were presented. Results: A telemedicine service was started using tools provided by The Santa Catarina State Integrated Telemedicine and Telehealth System offering real-time chat, through an online-based teleconsultation service. We assisted 75 patients in 109 consultations in 3 months, of which 69.7% were performed by chat. Mean of consultations per patient was 1.45. Conclusion: To our knowledge this is the first service in offering this modality of medicine for Brazilian public health care system. Patients and health care personnel reported satisfaction.

Background: Conversational agents (CAs) for chronic disease management are receiving increasing attention in academia and the industry. However, long-term adherence to CAs is still a challenge and needs to be explored. Personalization of CAs has the potential to improve long-term adherence and, with it, user satisfaction, task efficiency, perceived benefits, and intended behavior change. Research on personalized CAs has already addressed different aspects, such as personalized recommendations and anthropomorphic cues. However, detailed information on interaction styles between patients and CAs in the role of medical health care professionals is scant. Such interaction styles play essential roles for patient satisfaction, treatment adherence, and outcome, as has been shown for physician-patient interactions. Currently, it is not clear (1) whether chronically ill patients prefer a CA with a paternalistic, informative, interpretive, or deliberative interaction style, and (2) which factors influence these preferences. Objective: We aimed to investigate the preferences of chronically ill patients for CA-delivered interaction styles. Methods: We conducted two studies. The first study included a paper-based approach and explored the preferences of chronic obstructive pulmonary disease (COPD) patients for paternalistic, informative, interpretive, and deliberative CA-delivered interaction styles. Based on these results, a second study assessed the effects of the paternalistic and deliberative interaction styles on the relationship quality between the CA and patients via hierarchical multiple linear regression analyses in an online experiment with COPD patients. Patients’ sociodemographic and disease-specific characteristics served as moderator variables. Results: Study 1 with 117 COPD patients revealed a preference for the deliberative (50/117) and informative (34/117) interaction styles across demographic characteristics. All patients who preferred the paternalistic style over the other interaction styles had more severe COPD (three patients, Global Initiative for Chronic Obstructive Lung Disease class 3 or 4). In Study 2 with 123 newly recruited COPD patients, younger participants and participants with a less recent COPD diagnosis scored higher on interaction-related outcomes when interacting with a CA that delivered the deliberative interaction style (interaction between age and CA type: relationship quality: b=−0.77, 95% CI −1.37 to −0.18; intention to continue interaction: b=−0.49, 95% CI −0.97 to −0.01; working alliance attachment bond: b=−0.65, 95% CI −1.26 to −0.04; working alliance goal agreement: b=−0.59, 95% CI −1.18 to −0.01; interaction between recency of COPD diagnosis and CA type: working alliance goal agreement: b=0.57, 95% CI 0.01 to 1.13). Conclusions: Our results indicate that age and a patient’s personal disease experience inform which CA interaction style the patient should be paired with to achieve increased interaction-related outcomes with the CA. These results allow the design of personalized health care CAs with the goal to increase long-term adherence to health-promoting behavior. --> Background: Conversational agents (CAs) for chronic disease management are receiving increasing attention in academia and the industry. However, long-term adherence to CAs is still a challenge and needs to be explored. Personalization of CAs has the potential to improve long-term adherence and, with it, user satisfaction, task efficiency, perceived benefits, and intended behavior change. Research on personalized CAs has already addressed different aspects, such as personalized recommendations and anthropomorphic cues. However, detailed information on interaction styles between patients and CAs in the role of medical health care professionals is scant. Such interaction styles play essential roles for patient satisfaction, treatment adherence, and outcome, as has been shown for physician-patient interactions. Currently, it is not clear (1) whether chronically ill patients prefer a CA with a paternalistic, informative, interpretive, or deliberative interaction style, and (2) which factors influence these preferences. Objective: We aimed to investigate the preferences of chronically ill patients for CA-delivered interaction styles. Methods: We conducted two studies. The first study included a paper-based approach and explored the preferences of chronic obstructive pulmonary disease (COPD) patients for paternalistic, informative, interpretive, and deliberative CA-delivered interaction styles. Based on these results, a second study assessed the effects of the paternalistic and deliberative interaction styles on the relationship quality between the CA and patients via hierarchical multiple linear regression analyses in an online experiment with COPD patients. Patients’ sociodemographic and disease-specific characteristics served as moderator variables. Results: Study 1 with 117 COPD patients revealed a preference for the deliberative (50/117) and informative (34/117) interaction styles across demographic characteristics. All patients who preferred the paternalistic style over the other interaction styles had more severe COPD (three patients, Global Initiative for Chronic Obstructive Lung Disease class 3 or 4). In Study 2 with 123 newly recruited COPD patients, younger participants and participants with a less recent COPD diagnosis scored higher on interaction-related outcomes when interacting with a CA that delivered the deliberative interaction style (interaction between age and CA type: relationship quality: b=−0.77, 95% CI −1.37 to −0.18; intention to continue interaction: b=−0.49, 95% CI −0.97 to −0.01; working alliance attachment bond: b=−0.65, 95% CI −1.26 to −0.04; working alliance goal agreement: b=−0.59, 95% CI −1.18 to −0.01; interaction between recency of COPD diagnosis and CA type: working alliance goal agreement: b=0.57, 95% CI 0.01 to 1.13). Conclusions: Our results indicate that age and a patient’s personal disease experience inform which CA interaction style the patient should be paired with to achieve increased interaction-related outcomes with the CA. These results allow the design of personalized health care CAs with the goal to increase long-term adherence to health-promoting behavior., Journal of Medical Internet Research, 23 (5), ISSN:1438-8871

ObjectivesTo characterise the safety and tolerability of nintedanib and the dose adjustments used to manage adverse events in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).MethodsIn the SENSCIS trial, patients with SSc-ILD were randomised to receive nintedanib 150 mg two times per day or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg two times per day. We assessed adverse events and dose adjustments over 52 weeks.ResultsA total of 576 patients received nintedanib (n=288) or placebo (n=288). The most common adverse event was diarrhoea, reported in 75.7% of patients in the nintedanib group and 31.6% in the placebo group; diarrhoea led to permanent treatment discontinuation in 6.9% and 0.3% of patients in the nintedanib and placebo groups, respectively. In the nintedanib and placebo groups, respectively, 48.3% and 12.2% of patients had ≥1 dose reduction and/or treatment interruption, and adverse events led to permanent discontinuation of the trial drug in 16.0% and 8.7% of patients. The adverse events associated with nintedanib were similar across subgroups defined by age, sex, race and weight. The rate of decline in forced vital capacity in patients treated with nintedanib was similar irrespective of dose adjustments.ConclusionsThe adverse event profile of nintedanib in patients with SSc-ILD is consistent with its established safety and tolerability profile in patients with idiopathic pulmonary fibrosis. Dose adjustment is important to minimise the impact of adverse events and help patients remain on therapy.

Background The high prevalence of office stress and its detrimental health consequences are of concern to individuals, employers and society at large. Laboratory studies investigating office stress have mostly relied on data from participants that were tested individually on abstract tasks. In this study, we examined the effect of psychosocial office stress and work interruptions on the psychobiological stress response in a realistic but controlled group office environment. We also explored the role of cognitive stress appraisal as an underlying mechanism mediating the relationship between work stressors and the stress response. Methods and Materials Ninety participants (44 female; mean age 23.11 ± 3.80) were randomly assigned to either a control condition or one of two experimental conditions in which they were exposed to psychosocial stress with or without prior work interruptions in a realistic multi-participant laboratory setting. To induce psychosocial stress, we adapted the Trier Social Stress Test for Groups to an office environment. Throughout the experiment, we continuously monitored heart rate and heart rate variability. Participants repeatedly reported on their current mood, calmness, wakefulness and perceived stress and gave saliva samples to assess changes in salivary cortisol and salivary alpha-amylase. Additionally, cognitive appraisal of the psychosocial stress test was evaluated. Results Our analyses revealed significant group differences for most outcomes during or immediately after the stress test (i.e., mood, calmness, perceived stress, salivary cortisol, heart rate, heart rate variability) and during recovery (i.e., salivary cortisol and heart rate). Interestingly, the condition that experienced work interruptions showed a higher increase of cortisol levels but appraised the stress test as less threatening than individuals that experienced only psychosocial stress. Exploratory mediation analyses revealed a blunted response in subjective measures of stress, which was partially explained by the differences in threat appraisal. Discussion The results showed that experimentally induced work stress led to significant responses of subjective measures of stress, the hypothalamic-pituitary-adrenal axis and the autonomic nervous system. However, there appears to be a discrepancy between the psychological and biological responses to preceding work interruptions. Appraising psychosocial stress as less threatening but still as challenging could be an adaptive way of coping and reflect a state of engagement and eustress., Psychoneuroendocrinology, 121

Summary BI 836826 is a chimeric immunoglobulin G1 antibody targeting CD37, a tetraspanin transmembrane protein predominantly expressed on normal and malignant B cells. This phase I, open-label study used a modified 3 + 3 design to evaluate the safety, maximum tolerated dose (MTD), pharmacokinetics, and preliminary activity of BI 836826 in patients with relapsed/refractory B cell non-Hodgkin lymphoma (NHL; NCT01403948). Eligible patients received up to three courses comprising an intravenous infusion (starting dose: 1 mg) once weekly for 4 weeks followed by an observation period of 27 (Course 1, 2) or 55 days (Course 3). Patients had to demonstrate clinical benefit before commencing treatment beyond course 2. Forty-eight patients were treated. In the dose escalation phase (1–200 mg) involving 37 Caucasian patients, the MTD was 100 mg. Dose-limiting toxicities occurred in four patients during the MTD evaluation period, and included stomatitis, febrile neutropenia, hypocalcemia, hypokalemia, and hypophosphatemia. The most common adverse events were neutropenia (57%), leukopenia (57%), and thrombocytopenia (41%), and were commonly of grade 3 or 4. Overall, 18 (38%) patients experienced infusion-related reactions, which were mostly grade 1 or 2. Preliminary evidence of anti-tumor activity was seen; three patients responded to treatment, including one complete remission in a Korean patient with diffuse large B cell lymphoma. BI 836826 plasma exposure increased more than proportionally with increasing doses. BI 836826 demonstrated preliminary activity; the most frequent adverse events were hematotoxicity and infusion-related reactions which were manageable after amending the infusion schedule. Although BI 856826 will not undergo further clinical development, these results confirm CD37 as a valid therapeutic target in B cell NHL. Electronic supplementary material The online version of this article (10.1007/s10637-020-00916-3) contains supplementary material, which is available to authorized users.

Although oral cancer is considered a global health issue with 350,000 people diagnosed over a year, it can successfully be treated if diagnosed at early stages. Papanicolaou is an inexpensive and non-invasive method, generally applied to detect cervical cancer, but it can also be useful to detect cancer on oral cavities. The manual process of analyzing cells to detect abnormalities is a time-consuming cell analysis and is subject to variations in perceptions from different professionals. This paper compares three different deep learning (DL) approaches: segmentation, object detection, and image classification. Our results show that the binary object detection with Faster R-CNN is the best approach for nuclei detection and localization (0.76 IoU). Since ResNet 34 had a good performance on abnormal nuclei classification (0.86 $$F_1$$ score), we concluded that these two models can be used in combination to perform a reliable localization and classification pipeline. This work reinforces that the automated analysis of oral cytology to build a pipeline for nuclei classification and localization using DL can contribute to minimize the subjectivity of the human analysis and also support the detection of cancer at early stages.

Here, we describe a new immersion-based clearing method suitable for optical clearing of thick adult human brain samples while preserving its lipids and lipophilic labels such as 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI). This clearing procedure is simple, easy to implement, and allowed for clearing of 5 mm thick human brain tissue samples within 12 days. Furthermore, we show for the first time the advantageous effect of the Periodate-Lysine-Paraformaldehyde (PLP) fixation as compared to the more commonly used 4% paraformaldehyde (PFA) on clearing performance.

Background: Chronic obstructive pulmonary disease (COPD) is one of the most common disorders in the world. COPD is characterized by airflow obstruction, which is not fully reversible. Patients usually experience breathing-related symptoms with periods of acute worsening and a substantial decrease in the health-related quality-of-life. Active and comprehensive disease management can slow down the progressive course of the disease and improve patients’ disabilities. Technological progress and digitalization of medicine have the potential to make elaborate interventions easily accessible and applicable to a broad spectrum of patients with COPD without increasing the costs of the intervention. Objective: This study aims to develop a comprehensive telemonitoring and hybrid virtual coaching solution and to investigate its effects on the health-related quality of life of patients with COPD. Methods: A monocentric, assessor-blind, two-arm (intervention/control) randomized controlled trial will be performed. Participants randomized to the control group will receive usual care and a CAir Desk (custom-built home disease-monitoring device to telemonitor disease-relevant parameters) for 12 weeks, without feedback or scores of the telemonitoring efforts and virtual coaching. Participants randomized to the intervention group will receive a CAir Desk and a hybrid digital coaching intervention for 12 weeks. As a primary outcome, we will measure the delta in the health-related quality of life, which we will assess with the St. George Respiratory Questionnaire, from baseline to week 12 (the end of the intervention). Results: The development of the CAir Desk and virtual coach has been completed. Recruitment to the trial started in September 2020. We expect to start data collection by December 2020 and expect it to last for approximately 18 months, as we follow a multiwave approach. We expect to complete data collection by mid-2022 and plan the dissemination of the results subsequently. Conclusions: To our knowledge, this is the first study investigating a combination of telemonitoring and hybrid virtual coaching in patients with COPD. We will investigate the effectiveness, efficacy, and usability of the proposed intervention and provide evidence to further develop app-based and chatbot-based disease monitoring and interventions in COPD. © 2020 JMIR Publications. All rights reserved., JMIR Research Protocols, 9 (10), ISSN:1929-0748

Background There are limited treatment options for squamous non-small cell lung cancer (sqNSCLC) and prognosis remains poor. The safety and pharmacokinetics (PK) of nintedanib, a triple angiokinase inhibitor, plus cisplatin/gemcitabine as first-line treatment for advanced sqNSCLC patients, were evaluated. Materials and methods A phase I, dose-escalation study administering drugs in a 21-day cycle: cisplatin (75 mg/m2, Day 1), gemcitabine (1250 mg/m2, Days 1 and 8) and nintedanib (Days 2–7, 9–21) were given for 4–6 cycles, followed by monotherapy until disease progression or adverse events (AEs). Two nintedanib doses were tested, 150 mg twice daily (bid) and 200 mg bid, to determine maximum tolerated dose (MTD) based on occurrence of dose-limiting toxicities (DLTs) during Cycle 1. DLTs were primarily defined as drug-related non-hematologic (Grade ≥3) or hematologic (Grade 4) AEs. Results Sixteen patients were treated with nintedanib; n = 4 for 150 mg bid, n = 12 for 200 mg bid. No DLTs were observed in Cycle 1; therefore, the MTD was 200 mg bid. In subsequent cycles, two patients had DLTs: renal failure and reduced blood magnesium levels. The most common AEs were gastrointestinal. Three patients discontinued last study medication due to AEs and one had a nintedanib dose reduction. No relevant PK interactions were observed. Five patients had partial responses (31.3%) and eight had stable disease (50.0%); disease control rate was 81.3%. There were three long-term survivors (17–35 months). Conclusions The safety profile of nintedanib 200 mg bid plus cisplatin/gemcitabine was manageable, with AEs consistent with previous observations. PK data demonstrated no interaction, and preliminary antitumor activity was observed.

Nintedanib is a substrate for p-glycoprotein which can impact bioavailability. We investigated the effects of ketoconazole, a p-glycoprotein inhibitor, and rifampicin, a p-glycoprotein inducer, on the pharmacokinetics of nintedanib. In the ketoconazole study, 34 healthy subjects received nintedanib 50 mg orally alone and 1 h after the last dose of ketoconazole given orally at a dose of 400 mg once daily for 3 days in 1 of 2 randomized sequences. In the rifampicin study, 26 subjects received nintedanib 150 mg orally alone and the morning after the last dose of rifampicin given orally at a dose of 600 mg once daily for 7 days. The primary objective was to determine the relative bioavailability of nintedanib administered following multiple doses of ketoconazole or rifampicin versus alone, based on AUC from time 0 extrapolated to infinity (AUC0–∞) and maximum concentration (Cmax) calculated using an analysis of variance. Geometric mean ratios and 2-sided 90% CIs were calculated. Exposure to nintedanib increased when it was administered following ketoconazole versus alone (AUC0–∞: geometric mean ratio, 160.5% [90% CI, 148.2–173.7]; Cmax: geometric mean ratio, 179.6% [90% CI, 157.6–204.8]) and decreased when it was administered following rifampicin versus alone (AUC0–∞: geometric mean ratio, 50.1% [90% CI, 47.2–53.3]; Cmax: geometric mean ratio, 59.8% [90% CI, 53.8–66.4]). The time to reach Cmax (tmax) and half-life (t½) of nintedanib were unaffected by co-administration of ketoconazole or rifampicin. Exposure to nintedanib is increased by co-administration of ketoconazole and decreased by co-administration of rifampicin, likely due to effects on bioavailability of the absorbed fraction. ClinicalTrials.govidentifiers:NCT01679613, NCT01770392.

The aim was to investigate the clinical performance of two different types of automated external defibrillators (AEDs).Three investigators reviewed 2938 rhythm analyses performed by AEDs in 240 consecutive patients (median age 72, q1-q3=62-83) who had suffered cardiac arrest between January 2011 and March 2015. Two different AEDs were used (AED A n=105, AED B n=135) in-hospital (n=91) and out-of-hospital (n=149).Among 194 shockable rhythms, 17 (8.8%) were not recognized by AED A, while AED B recognized 100% (n=135) of shockable episodes (sensitivity 91.2 vs 100%, p0.01). In AED A, 8 (47.1%) of these episodes were judged to be algorithm errors while 9 (52.9%) were caused by external artifacts. Among 1039 non-shockable rhythms, AED A recommended shock in 11 (1.0%), while AED B recommended shock in 63 (4.1%) of 1523 episodes (specificity 98.9 vs 95.9, p0.001). In AED A, 2 (18.2%) of these episodes were judged to be algorithm errors (AED B, n=40, 63.5%), while 9 (81.8%) were caused by external artifacts (AED B, n=23, 36.5%).There were significant differences in sensitivity and specificity between the two different AEDs. A higher sensitivity of AED B was associated with a lower specificity while a higher specificity of AED A was associated with a lower sensitivity. AED manufacturers should work to improve the algorithms. In addition, AED use should always be reviewed with a routine for giving feedback, and medical personnel should be aware of the specific strengths and shortcomings of the device they are using.

A high quality of chest compressions, e.g. sufficient depth (5-6 cm) and rate (100-120 per min), has been associated with survival. The patient's underlay affects chest compression depth. Depth and rate can be assessed by feedback systems to guide rescuers during cardiopulmonary resuscitation.The purpose of this study was to describe the quality of chest compressions by healthcare professionals using real-time audiovisual feedback during in-hospital cardiopulmonary resuscitation.An observational descriptive study was performed including 63 cardiac arrest events with a resuscitation attempt. Data files were recorded by Zoll AED Pro, and reviewed by RescueNet Code Review software. The events were analysed according to depth, rate, quality of chest compressions and underlay.Across events, 12.7% (median) of the compressions had a depth of 5-6 cm. Compression depth of6 cm was measured in 70.1% (median). The underlay could be identified from the electronic patient records in 54 events. The median compression depth was 4.5 cm (floor) and 6.7 cm (mattress). Across events, 57.5% (median) of the compressions were performed with a median frequency of 100-120 compressions/min and the most common problem was a compression rate of100 (median=22.3%).Chest compression quality was poor according to the feedback system. However, the distribution of compression depth with regard to underlay points towards overestimation of depth when treating patients on a mattress. Audiovisual feedback devices ought to be further developed. Healthcare professionals need to be aware of the strengths and weaknesses of their devices.

With the objective to perform a first evaluation of the impact of the integration of a graphic spatial epidemiology tool that allows quasi-realtime georeferenced data visualization into a telemedicine infrastructure, this work presents GISTelemed, an online module specialized on indexing structured and semi-structured data, as well as querying the indexed content using structured and free-text search.We evaluated GISTelemed accordingly to the guidelines published by the US Centers for Disease Control and Prevention and input provided by a questionnaire customized according to AdEQUATE (questionnAire for Evaluation of QUAlity in TElemedicine systems).39 healthcare professionals from 13 municipalities participated in the evaluation. We analyzed data from questionnaires using descriptive statistics, being Lernability and Comfort the characteristics that received the best evaluation. Quantitative evaluation based upon leprosis cases detected through tele-dermatology showed a sensitivity and PPV of respectively 77.2% and 95.3%. 22.8% of the cases detected were un-notified cases.Results from our case study show a good evaluation regarding the perceived software quality”. We conclude that the integration of spatial epidemiology tools to the STT/SC system, besides enabling visualization of data in maps, allowed users to analyze the evolution of morbidities and their co-occurrences.

Background Nintedanib targets VEGF receptors 1-3, PDGF receptors alpha and beta, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma. Methods This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged >= 18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100. Findings Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5.3 months (IQR 2.8-7.3) in the nintedanib group and 5.1 months (2.7-7.8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6.8 months [95% CI 6.1-7.0]) and the placebo group (7.0 months [6.7-7.2]; HR 1.01 [95% CI 0.79-1.30], p=0.91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%]). Interpretation The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Purpose LUME-Meso is a phase II/III randomized, double-blind trial designed to assess efficacy and safety of nintedanib plus chemotherapy as first-line treatment of malignant pleural mesothelioma (MPM). Phase II results are reported here. Patients and Methods Chemotherapy-naïve patients with unresectable, nonsarcomatoid MPM (Eastern Cooperative Oncology Group performance status 0 to 1), stratified by histology (epithelioid or biphasic), were randomly assigned in a 1:1 ratio to up to six cycles of pemetrexed and cisplatin plus nintedanib (200 mg twice daily) or placebo followed by nintedanib plus placebo monotherapy until progression. The primary end point was progression-free survival (PFS). Results Eighty-seven patients were randomly assigned. The median number of pemetrexed and cisplatin cycles was six; the median treatment duration for nintedanib was 7.8 months and 5.3 months for placebo. Primary PFS favored nintedanib (hazard ratio [HR], 0.56; 95% CI, 0.34 to 0.91; P = .017), which was confirmed in updated PFS analyses (HR, 0.54; 95% CI, 0.33 to 0.87; P = .010). A trend toward improved overall survival also favored nintedanib (HR, 0.77; 95% CI, 0.46 to 1.29; P = .319). Benefit was evident in epithelioid histology, with a median overall survival gain of 5.4 months (HR, 0.70; 95% CI, 0.40 to 1.21; P = .197; median [nintedanib v placebo], 20.6 months v 15.2 months) and median PFS gain of 4.0 months (HR, 0.49; 95% CI, 0.30 to 0.82; P = .006; median [nintedanib v placebo], 9.7 v 5.7 months). Neutropenia was the most frequent grade ≥ 3 adverse event (AE; nintedanib 43.2% v placebo 12.2%); rates of febrile neutropenia were low (4.5% in nintedanib group v 0% in placebo group). AEs leading to discontinuation were reported in 6.8% of those receiving nintedanib versus 17.1% of those in the placebo group. Conclusion Addition of nintedanib to pemetrexed plus cisplatin resulted in PFS improvement. AEs were manageable. The clinical benefit was evident in patients with epithelioid histology. The confirmatory phase III part of the study is ongoing.

In the literature, PACS and Telemedicine are located in different or complementary works. However, when integrated as part of the same solution, both contribute to the healthcare process as a whole. This work describes the experience on integrating a PACS infrastructure to a statewide telemedicine system, allowing to the latter to benefit from concepts defined by the former in terms of acquisition, transmission and storage of digital images. The obtained results attest the viability of such approach, allowing the construction of a robust, scalable, and secure solution attending scheduled procedures, image acquisition, content transmission, content storage, content evaluation, and the return of examination reports.

Large-scale telemedicine systems provide extensive amounts of data that can be used to gather epidemiological information. Epidemiologists have been using GIS systems for the easy and quick visualization of data and to perform georeferenced epidemiological analysis. This paper presents GISTelemed, a georeferenced epidemiological analysis tool developed as part of the Santa Catarina State Integrated Telemedicine and Telehealth System (STT/SC), a statewide telemedicine infrastructure in Brazil. The GISTelemed module offers an architecture supporting real-time recovery, information visualization and epidemiological analysis from structured and semi-structured data. The architecture uses controlled vocabularies for data catalogization and a specially developed ETL process that allows sending and receiving data on a large number of protocols, including DICOM SR and SQL. We performed a case study with users that indicates good perceived ease of use and usefulness of GISTelemed by both medical staff and health care managers.

This study assessed the influence of acquisition parameters of tomographic volumes on the reproduction of thin bone structures for rapid prototyping purposes. Two parameters were investigated: Field of View (FOV) and Slice Thickness (ST). The specimen was comprised of five pairs of 0.6 mm, 1.1 mm, 1.5 mm, 2.0 mm and 2.8 mm thick cortical bone plates. The plates were stuck into utility wax; the first plate of the pair was in vertical position while the second plate was oblique to the first one. Forty-five tomographic images were captured and separated into 3 groups of fifteen images. Each group had a specific FOV: 180 mm; 250 mm and 430 mm, respectively. Within each of these three groups, tomographic slice thickness was varied for every five of the fifteen slices. Acquisitions were carried out with STs of 1 mm, 2.5 mm and 5 mm. The Cyclops Medical Station software was used in the voxel-to-voxel analysis of radiologic density, reaching a total of 1350 assessed images. ST and FOV variation influenced the reproduction of thin bone walls, and FOV was shown to be a very important parameter. The larger the acquisition FOV, the more reduction in the number of voxels within the range of reconstruction for cortical bone in all of the bone plates. The visual analysis of the images of very thin bone walls showed that there could be a sharp drop in the radiologic density value in several adjacent voxels, resulting in areas which might not be reproduced in the reconstruction.

Telemedicine and Telehealth are disciplines dedicated to provide health care and health care education when distance is an issue. Nowadays, Telemedicine and Telehealth Stations (TTSs) are used to provide physicians and educators with tools that concentrate and integrate different technologies, contributing to organize and simplify their workload. To support scenarios involving features related to teleconsultation and tele-education, TTSs must consider the adoption of hardware platforms robust enough to reach minimal requirements while providing service deliverability and continuity. Despite being usually built for execution on desktops and laptops, it is possible that TTSs be reorganized to use Single-Board Computers (SBCs) as a most portable-and cost-effective solution. Aiming to evaluate such possibility, this work presents a performance study of four of the most popular SBCs available on the market, focusing the execution of web conferences in the context of the Santa Catarina State Integrated Telemedicine and Telehealth System (STT/SC), in Brazil. Using descriptive statistics, we concluded that the Raspberry Pi 2 SBC is the best option to be adopted, considering its results regarding CPU consumption, memory utilization, and video delay.

User satisfaction analyses in synchronous telemedicine and teleconsultation environments have been widely performed and generally show satisfied users. In the field of asynchronous telemedicine, however, satisfaction studies were performed only in one single location or with a restricted set of users. With the aim of offering an exemplar evaluation of the impact of the statewide use of a large-scale asynchronous telemedicine network on the satisfaction of the involved users, this study presents the results obtained from a survey of the perceived quality of the service by both patients and healthcare staff. For this purpose, a survey with satisfaction questionnaires was performed with 564 patients from seven upstate municipalities and 56 healthcare professionals from 46 municipalities, using a methodology from the process improvement field. The collected data were quantified and underwent statistical analysis, which showed a clear perception of the improvement in the quality of service by both pat...

8568Background: We evaluated the relationship between PFSR and OS in the Phase II part of LUME-Meso, a double-blind, placebo-controlled study that showed improved PFS (primary endpoint; hazard rati...

Tympanic membrane pathological findings such as perforations and tympanosclerotic plaques (along with conductive hearing loss and purulent drainage) are the most typical trademarks of either active or burned-out chronic otitis media. These findings are normally evaluated by an expert using visual subjective analysis. In this work, we present a computational semi-automated method to quantify these pathologies. We also present a validation study of the method using a subset of 39 cases randomly extracted from a set of more than 2000 cases (perforations and tympanosclerosis) of the Hospital de Clínicas de Porto Alegre. The validation was performed using Ground Truth images, generated by experts, and has shown promising results.

The literature has shown that subjective concepts lead to interobserver variations in the definitions and identifications of cephalometric landmarks. Observers must be trained and calibrated to conduct scientific research using cephalometric comparisons. In this study, we aimed to develop and test a computational model called Cyclops cephalometry in radiographic cephalometry training and calibration.This system uses the concepts of evaluation process managers, examiners, and testers, thus affording uniformity in cephalometric evaluations. The system was tested with 5 orthodontists and 5 postgraduate students who located 28 landmarks in 10 lateral cephalometric radiographs before and after training.Before training, the Student t test showed significant differences (P0.05) in accuracy between the orthodontists and the students (71.4% and 54.9%, respectively). However, considerable improvement in accuracy was observed after training in both groups (86.5% and 83%, respectively), without significant differences (P = 0.30) between groups. Users of the system agreed about its usability aspects such as effectiveness, efficiency, and satisfaction.This model was shown to be a useful and efficient tool in the calibration process, and might be helpful in various comparative cephalometric investigations.

It has been suggested that cancer ought to be regarded as a disease of cell differentiation. In multicellular organisms, indeed, the control of cell multiplication is linked to cell specialization: During the process of differentiation embryonic cells, while cycling, acquire the ability to perform specialized functions. This ability is incompatible with cell cycling which, as a consequence, is repressed with forthcoming differentiation. Thus, the number of amplification divisions that occur during the period while differentiation is proceeding decides on the number of specialized cells produced. The progress in differentiation, contrary to usual assumptions, is accompanied by an increase in the cellular content of cytoplasm. The reason must be that cell specialization requires a specific amount and array of membrane-bounded cytoplasmic structures. Since the multiplication of these structures depends on membranous templates, their amount increases only if more cytoplasm is produced per cycle than required for a doubling, thus constituting an intracellular timer of differentiation: The larger the net rate of cytoplasmic growth per cell cycle, the fewer cycles occur. Extracellular signals modulate cell multiplication by altering the net rate of cytoplasmic growth. Each persisting alteration, however, that reduces this rate to zero, prevents differentiation, and thus causes the cells to retain embryonic capabilities and to initiate cancer. Cancer cells can be induced to differentiate and cease proliferation by support of cytoplasmic growth. This corroborates the suggestion that cancer must be regarded as a disease of cell differentiation and our conclusion that cancer is caused by a deficiency in cytoplasmic growth. Support of the latter must be an efficient principle in cancer therapy although limited by the organism's dependence on cell renewal.

Motivated by the need to reduce the cost of patient transport to health centers, the authors designed a prototype national telemedicine network in Brazil. As a result of this project, we now have an agile, easy-to-use, high-quality telemedicine network that provides greater access to patient data and helps in medical decisions, cutting unnecessary costs to the state and benefiting the population as a whole.

8506 Background: LUME-Meso is a Phase (Ph) II/III, double-blind, randomized study. N targets MPM by inhibiting VEGFR 1–3, PDGFR α/β, FGFR 1–3, Src and Abl kinases. Primary analysis of the Ph II data demonstrated improved progression-free survival (PFS; hazard ratio [HR]=0.56; 95% confidence interval [CI] 0.34–0.91; p=0.017). Mature Ph 2 OS and updated PFS results are reported here. Methods: Pts with unresectable MPM (ECOG PS 0–1) were stratified by histology (epithelioid/biphasic) and randomized 1:1 to receive ≤6 cycles PEM (500 mg/m2)/CIS (75 mg/m2) Day 1 + N or P (200 mg bid, Days 2–21), followed by N or P monotherapy until progression or toxicity. The primary endpoint was PFS. The primary OS analysis and updated PFS analysis were performed as predefined. Results: 87 pts were randomly assigned (N=44, P=43). OS benefit favored N over P treatment (HR=0.77; 95% CI 0.46–1.29; p=0.319; 62 [71%] OS events) and was greatest in epithelioid pts (HR=0.70; 95% CI 0.40–1.21; p=0.197) with a median (m) OS gain of 5.4 months (mOS [95% CI]: 20.6 [16.2–28.8] N vs 15.2 [12.2–23.6] P). Updated PFS results (HR=0.54; 95% CI 0.33–0.87; p=0.010) also showed greatest benefit for epithelioid pts (HR=0.49; 95% CI 0.30–0.82; p=0.006) with a mPFS gain of 4.0 months (mPFS [95% CI]: 9.7 [7.2–12.4] N vs 5.7 [5.5–7.0] P). Improved forced vital capacity, objective response rates and duration of response were also observed with N treatment. Drug-related adverse events (AEs) in N- vs P-treated pts were 97.7% vs 97.6%. Grade ≥3 AEs of note included neutropenia (27.3% vs 4.9%), ALT (11.4% vs 0) and GGT (6.8% vs 0) elevations, and diarrhea (6.8% vs 0). AEs led to trial discontinuation in only 3 (6.8%) N vs 7 (17.1%) P pts. Conclusions: Mature Ph II OS data show that adding N to standard 1st-line treatment gives a strong signal towards improved OS. Updated PFS confirmed the primary analysis; AEs were manageable. The greatest clinical benefit was observed in pts with epithelioid histology. Median survival of 20.6 months in epithelioid pts treated with N is unprecedented in advanced MPM trials. Ph III is actively recruiting in this pt population. Clinical trial information: NCT01907100.

Laser photocoagulation is currently the standard treatment for sight-threatening diseases worldwide, namely diabetic retinopathy and retinal vein occlusions. The slit lamp biomicroscope is the most commonly used device for this procedure, specially for the treatment of the eye periphery. However, only a small portion of the retina can be visualized through the biomicroscope, complicating the task of localizing and identifying surgical targets, increasing treatment duration and patient discomfort. In order to assist surgeons, we propose a method for creating intraoperative retina maps for view expansion using a slit-lamp device. Based on the mosaicking method described by Richa et al, 2012, the proposed method is a combination of direct and feature-based methods, suitable for the textured nature of the human retina. In this paper, we describe three major enhancements to the original formulation. The first is a visual tracking method using local illumination compensation to cope with the challenging visualization conditions. The second is an efficient pixel selection scheme for increased computational efficiency. The third is an entropy-based mosaic update method to dynamically improve the retina map during exploration. To evaluate the performance of the proposed method, we conducted several experiments on human subjects with a computer-assisted slit-lamp prototype. We also demonstrate the practical value of the system for photo documentation, diagnosis and intraoperative navigation.

Neuropsychological tests were applied to 20 patients with focal epilepsy related to calcified neurocysticercosis (NCC) (mean: three lesions/patient; NCC group), 22 patients with focal epilepsy without NCC (EPI group), and 29 healthy controls matched for age, sex, and educational level. The EPI and NCC groups were matched for age at onset of epilepsy, epilepsy duration, frequency of attacks, seizure semiology, interictal EEG findings, and antiepileptic drugs used. There were no differences in the digit span, word span, calculus, and Mini-Mental State examination among the three groups studied. The NCC and EPI groups showed lower scores than controls in immediate and delayed verbal memory, famous faces test, spatial recognition span, abstractions and judgment, and visuoconstructional abilities. The EPI group, but not the NCC group, also had lower scores in a praxis tests. There were no differences between the NCC and EPI groups in any of the tests applied (P > 15), except for the spatial recognition span, which was lower in the former. Cognitive impairment is a prevalent neuropsychological feature of patients with epilepsy and NCC.

Various observations suggest that an intracellular timer is involved in the control of cell proliferation and differentiation that supplements control by extracellular signaling and depends on quantitative relations between cytoplasm and nucleus. To further elucidate the mechanism of this timer, we examined the results of experiments with mice in which cell cycle regulating genes were inactivated: the inactivation of negative cell cycle regulators extends cell proliferation, whereas inactivation of positive regulators decreases cell proliferation. We conclude that this is caused in the former case by shortening of G 1 which decreases the cytoplasmic growth rate per cell cycle, whereas in the latter case this rate is increased due to G 1 prolongation. This is consistent with our hypothesis according to which the cytoplasmic/nuclear ratio must increase to a certain level to induce end stage differentiation and cell cycle arrest. A new basis of this hypothesis is the fact that end stage differentiation requires large quantities of membranous cytoplasmic structures that the cells are unable to produce de novo . Embryonic cells, however, possess only few of these structures. The only feasible way to multiply these structures is by growing more cytoplasm per cell cycle than needed for a doubling so that successively, the level of the cytoplasmic/nuclear ratio is reached that is required for differentiation. A consequence is that the cytoplasmic growth rate per cell cycle determines the number of amplification divisions. We suggest that the differentiation signal may be triggered when a differentiation-preventing protein (for example Bcl-2) is diluted out by the expansion of cytoplasmic membrane structures, thus simultaneously determining the cell size. The intracellular timer and extracellular signals cooperate in adjusting cell production to the organism's need and in determining when and how the cells respond to extracellular signals or transmit extracellular signals.

Purpose Laser photocoagulation is the standard treatment for sight-threatening diseases worldwide, namely diabetic retinopathy. The slit lamp biomicroscope coupled to the laser permit the visualisation of only a small portion of the retina, complicating the task of localizing and identifying laser targets, increasing treatment duration and patient discomfort. Aim: to assist ophthalmologist, we propose a method for creating intra-operative retina maps for view expansion using a slit-lamp biomicroscope Methods Based on the mosaicking method previously described by Richa R (Medical Image Computing and Computer-Assisted Intervention (MICCAI’12) the method was a combination of direct and feature-based methods, suitable for the textured nature of the human retina. We used two major enhancements to the original formulation: (1) an efficient pixel selection scheme for increased computational efficiency; (2) an entropy-based mosaic update method for coping with the variable visualization conditions during the procedure. We also implemented a blending method to generate a photo-realistic retina mosaic Results Several experiments on retinal mosaicking in live on human (without laser at this moment) with a computer-assisted slit-lamp prototype will be presented Conclusion Computer-assisted slit-lamp prototype could be usefull in a next future for retinal documentation and laser navigation Commercial interest