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Phyllanthus sellowianusMüll (Klotzch) Arg. is a native plant used for diabetes treatment. It is currently of interest to evaluate its activity on the mechanical properties of human red blood cells to elucidate its mechanism of action as an antidiabetic. For this, aqueous extracts were prepared by various extractive techniques. Using the Erythrocyte Rheometer, the in vitroeffect on the viscoelastic parameters of glycated human red blood cells, as occurs by hyperglycemiain diabetes, was evaluated. The results obtained from the treatment with the extracts show that they affect erythrocyte viscoelasticity and can reverse the glycation effects.

BackgroundEvery day, we see more patients present to hospitals and clinics seeking gender-affirmation care to ameliorate the symptoms of gender dysphoria. However, to provide a multidisciplinary approach, it is important to offer an integrated clinical program that provides mental health assessment, endocrine therapy, physical therapy, research, and the full spectrum of surgical services devoted to transgender patients. This article describes our experience on building a specialized, multidisciplinary, academic state-of-the-art gender-affirmation program.MethodsHerein, we describe the main and critical components on how to build a multidisciplinary academic gender-affirmation program. We share our lessons learned from this experience and describe how to overcome some of the obstacles during the process.ResultsBuilding a multidisciplinary academic gender-affirmation program requires an invested team, as each and every member is essential for feedback, referrals, and to improve patient's experience. Institutional support is essential and by far the most important component to overcome some of the obstacles during the process. Having all team members working under the same institution provides all the critical components needed to improve outcomes and patient satisfaction. In addition, the collection of prospective data with a well-structured research team will provide information needed to improve clinical services and standardize clinical protocols, while leaving space for innovation.ConclusionsThis article describes the steps and experience needed to build a multidisciplinary holistic academic gender-affirmation program. We provide our lessons learned during the process that will help guide those who intend to start an academic gender-affirmation program.

Anticipating the learning consequences of actions is crucial to plan efficient information seeking. Such a capacity is needed for learners to determine which actions are most likely to result in learning. Here, we tested the early ontogeny of the human capacity to anticipate the amount of learning gained from seeing. In study 1, we tested infants' capacity to anticipate the availability of sight. Fourteen-month-old infants (N = 72) were invited to search for a toy hidden inside a container. The participants were faster to attempt at opening a shutter when this action allowed them to see inside the container. Moreover, this effect was specifically observed when seeing inside the container was potentially useful to the participants' goals. Thus, infants anticipated the availability of sight, and they calibrated their information-seeking behaviors accordingly. In studies 2 and 3, we tested toddlers' capacity to anticipate whether data would be cognitively useful for their goals. Two-and-a-half-year-olds (N = 72) had to locate a target character hidden among distractors. The participants flipped the characters more often, and were comparatively faster to initiate this action when it yielded access to visual data allowing them to locate the target. Thus, toddlers planned their information-seeking behaviors by anticipating the cognitive utility of sight. In contrast, toddlers did not calibrate their behaviors to the cognitive usefulness of auditory data. These results suggest that cognitive models of learning guide toddlers' search for information. The early developmental onset of the capacity to anticipate future learning gains is crucial for active learning.

Background The targets of minimally invasive surgery (MIVA) could be summarised by: achievement of the same results as those obtained with traditional surgery, less trauma, better post-operative course, early discharge from hospital and improved cosmetic results. The minimally invasive techniques in thyroid surgery can be described as either endoscopic "pure" approach (completely closed approach with or without CO2 insufflation), or "open approach" with central neck mini-incision or "open video-assisted approach". Traditionally, open thyroidectomy requires a 6 to 8 cm, or bigger, transverse wound on the lower neck. The minimally invasive approach wound is much shorter (1.5 cm for small nodules, up to 2–3 cm for the largest ones, in respect of the exclusion criteria) upon the suprasternal notch. Patients also experience much less pain after MIVA surgery than after conventional thyroidectomy. This is due to less dissection and destruction of tissues. Pathologies treated are mainly nodular goiter; the only kind of thyroid cancer which may be approached with endoscopic surgery is a small differentiated carcinoma without lymph node involvement. The patients were considered eligible for MIVA hemithyroidectomy and thyroidectomy on the basis of some criteria, such as gland volume and the kind of disease. In our experience we have chosen the minimally invasive open video-assisted approach of Miccoli et al. (2002). The aim of this work was to verify the suitability of the technique and the applicability in clinical practice. Methods A completely gasless procedure was carried out through a 15–30 mm central incision about 20 mm above the sternal notch. Dissection was mainly performed under endoscopic vision using conventional endoscopic instruments. The video aided group included 11 patients. All patients were women with a average age of 54. Results We performed thyroidectomy in 8 cases and hemithyroidectomy in 3 cases. The operative average time has been 170 minutes. Conclusion Nowadays this minimally invasive surgery, in selected patients, clearly demonstrates excellent results regarding patient cure rate and comfort, with shorter hospital stay, reduced postoperative pain and most attractive cosmetic results.

Introdução: O CDT tem bom prognóstico, com sobrevida em longo prazo superior a 90%. Entretanto, quando o CDT é refratário à radioiodoterapia (CDT RAIR) a taxa de sobrevida, em dez anos, é 10%. A despeito da constante evolução nas opções terapêuticas, na perspectiva da Saúde Suplementar, o tratamento disponível baseia-se na quimioterapia citotóxica, que apresenta baixa eficácia e importante toxicidade aos pacientes com CDT RAIR. Objetivos: Avaliar a eficácia, segurança, custo- utilidade e impacto orçamentário do mesilato de Lenvatinibe na perspectiva da Saúde Suplementar no tratamento de pacientes com CDT RAIR. Material e Método: A eficácia e segurança do mesilato de Lenvatinibe foi avaliada a partir de uma revisão sistemática conduzida até setembro de 2022 nas bases de dados The Cochrane Library, MEDLINE via Pubmed, LILACS, CRD e EMBASE. Para análise de custo-utilidade, foi utilizado modelo de sobrevida particionado de três estados de saúde com um horizonte de tempo lifetime. O comparador selecionado foi o padrão de tratamento com doxorrubicina. Foram considerados somente custos médicos diretos, sendo anos de vida ajustados pela qualidade (AVAQ), o desfecho clínico utilizado. Na análise de impacto orçamentário,a população elegível foi determinada a partir do método epidemiológico, considerando um cenário de incorporação gradual do mesilato de Lenvatinibe no mercado ao longo de cinco anos. Resultados: A revisão sistemática incluiu dois ensaios clínicos randomizados (ECRs) de fase III e dez outros estudos adicionais. O estudo SELECT, responsável pela aprovação do Lenvatinibe para CDT RAIR no FDA e ANVISA, proporcionou significativa redução no risco progressão ou morte na população global do estudo (redução de 79%; hazard ratio: 0,21 [intervalo de confiança 95%: 0,14 a 0,31]) quando comparado ao placebo, proporcionando um aumento significativo na sobrevida livre de progressão (18,3 meses vs. 3,6 meses do grupo placebo). Lenvatinibe foi considerado seguro, visto que os eventos adversos relatados nos ECRs foram toleráveis. A avaliação econômica sugere que a incorporação de Lenvatinibe na Saúde Suplementar resultaria em um incremento de custo por paciente acompanhada de benefícios clínicos significativos como incremento de 2,40 AVAQs, resultando em razão de custo- utilidade incremental de aproximadamente R$ 215 mil por AVAQ ganho. Estimou-se impacto orçamentário incremental de aproximadamente R$ 3,3 milhões no primeiro ano após a incorporação, com um total acumulado de aproximadamente R$78 milhões em cinco anos. Após a apresentação dos dados à ANS, a agência conduziu análise e reunião técnica para avaliação destes dados seguida por consulta pública com recomendação inicial favorável à incorporação e confirmada por 98,7% dos participantes da consulta pública, os quais foram favoráveis à incorporação. Discussão e Conclusões: Os dados apresentados são robustos e favoráveis a disponibilização desta tecnologia em saúde (mesilato de Lenvatinibe) para os beneficiários da ANS.

Mechanism-based strategies to overcome resistance to PD-1 blockade therapy are urgently needed. We developed genetic acquired resistant models of JAK1, JAK2, and B2M loss-of-function mutations by gene knockout in human and murine cell lines. Human melanoma cell lines with JAK1/2 knockout became insensitive to IFN-induced antitumor effects, while B2M knockout was no longer recognized by antigen-specific T cells and hence was resistant to cytotoxicity. All of these mutations led to resistance to anti-PD-1 therapy in vivo. JAK1/2-knockout resistance could be overcome with the activation of innate and adaptive immunity by intratumoral Toll-like receptor 9 agonist administration together with anti-PD-1, mediated by natural killer (NK) and CD8 T cells. B2M-knockout resistance could be overcome by NK-cell and CD4 T-cell activation using the CD122 preferential IL2 agonist bempegaldesleukin. Therefore, mechanistically designed combination therapies can overcome genetic resistance to PD-1 blockade therapy. SIGNIFICANCE: The activation of IFN signaling through pattern recognition receptors and the stimulation of NK cells overcome genetic mechanisms of resistance to PD-1 blockade therapy mediated through deficient IFN receptor and antigen presentation pathways. These approaches are being tested in the clinic to improve the antitumor activity of PD-1 blockade therapy.This article is highlighted in the In This Issue feature, p. 1079.

Abstract Background COVID-19 is a new multi-organ disease causing considerable worldwide morbidity and mortality. While many recognized pathophysiological mechanisms are involved, their exact causal relationships remain opaque. Better understanding is needed for predicting their progression, targeting therapeutic approaches, and improving patient outcomes. While many mathematical causal models describe COVID-19 epidemiology, none have described its pathophysiology. Methods In early 2020, we began developing such causal models. The SARS-CoV-2 virus’s rapid and extensive spread made this particularly difficult: no large patient datasets were publicly available; the medical literature was flooded with sometimes conflicting pre-review reports; and clinicians in many countries had little time for academic consultations. We used Bayesian network (BN) models, which provide powerful calculation tools and directed acyclic graphs (DAGs) as comprehensible causal maps. Hence, they can incorporate both expert opinion and numerical data, and produce explainable, updatable results. To obtain the DAGs, we used extensive expert elicitation (exploiting Australia’s exceptionally low COVID-19 burden) in structured online sessions. Groups of clinical and other specialists were enlisted to filter, interpret and discuss the literature and develop a current consensus. We encouraged inclusion of theoretically salient latent (unobservable) variables, likely mechanisms by extrapolation from other diseases, and documented supporting literature while noting controversies. Our method was iterative and incremental: systematically refining and validating the group output using one-on-one follow-up meetings with original and new experts. 35 experts contributed 126 hours face-to-face, and could review our products. Results We present two key models, for the initial infection of the respiratory tract and the possible progression to complications, as causal DAGs and BNs with corresponding verbal descriptions, dictionaries and sources. These are the first published causal models of COVID-19 pathophysiology. Conclusions Our method demonstrates an improved procedure for developing BNs via expert elicitation, which other teams can implement to model emergent complex phenomena. Our results have three anticipated applications: (i) freely disseminating updatable expert knowledge; (ii) guiding design and analysis of observational and clinical studies; (iii) developing and validating automated tools for causal reasoning and decision support. We are developing such tools for the initial diagnosis, resource management, and prognosis of COVID-19, parameterized using the ISARIC and LEOSS databases.

A modelling approach based on high-resolution in-vivo recordings in mouse brain, reproduces features of the non-stationary and non-linear dynamics, including cortical waves.

Abstract Brain states, such as wake, sleep, or different depths of anesthesia are usually assessed using electrophysiological techniques, such as the local field potential (LFP) or the electroencephalogram (EEG), which are ideal signals for detecting activity patterns such as asynchronous or oscillatory activities. However, it is technically challenging to have these types of measures during calcium imaging recordings such as two-photon or wide-field techniques. Here, using simultaneous two-photon and LFP measurements, we demonstrate that despite the slower dynamics of the calcium signal, there is a high correlation between the LFP and two-photon signals taken from the neuropil outside neuronal somata. Moreover, we find the calcium signal to be systematically delayed from the LFP signal, and we use a model to show that the delay between the two signals is due to the physical distance between the recording sites. These results suggest that calcium signals alone can be used to detect activity patterns such as slow oscillations and ultimately assess the brain state and level of anesthesia.

Abstract Background Behcet’s disease is a multi-system inflammatory disorder. A small subset of patients with Behcet’s develop relapsing polychondritis which is classified as a separate disease known as Mouth and Genital ulcers with inflamed cartilage (MAGIC syndrome). It has previously been observed that this condition can also affect the cartilaginous tissue in the tracheobronchial tree. Case presentation We present the case of a 44-year-old lady with Behcet’s Disease, Mouth and Genital ulcers with inflamed cartilage (MAGIC) syndrome and an aortic Frozen Elephant Trunk (FET) who presented to hospital with recurrent episodes of left lobar collapse of the lung. During bronchoscopy, we found the presence of multiple inflammatory endobronchial webs occluding segments of the left bronchial tree. Repeated examinations showed evidence that these inflammatory webs were progressing in size, density and location. Furthermore, we noticed herniation of her descending aortic FET into her left bronchial tree forming an aorto-bronchial fistula which was complicated by a graft infection. Her descending aortic FET section was surgically replaced with an open procedure and bronchoscopic interventions attempted to remove the occlusions in her bronchial tree. Despite optimisation of medical management and surgical correction, this patient continued to develop progressive occlusion of her left bronchial tree, resulting in a chronically collapsed left lung. Conclusions A multi-disciplinary team approach is of paramount importance in order to optimally manage patients with Behcet’s disease, balancing immunosuppressive regimens that need close monitoring and titration in the context of potential surgical intervention and the risk for intercurrent infection.