Esophageal stent dysfunction: unclogging the Red Sea.

Self-expandable metal stents (SEMS) have been widely used for the palliation of esophageal malignant dysphagia. Stent-related dysphagia is frequent and should raise the suspicion of stent migration, tumor ingrowth or overgrowth. In addition, bleeding has been reported in nearly 7% of patients. Nonetheless, this is the first case report of a complete stent obstruction by abundant blood clot formation. The authors present a 76-year-old male with severe ischemic heart disease and atrial fibrillation, requiring cardiac resynchronization therapy defibrillator and anticoagulation. After being diagnosed with metastasized squamous cell mid-esophageal cancer, he was proposed for chemotherapy and palliative esophageal stenting.

Integrative analysis reveals the divergence and speciation between sister Sooty Copper butterflies Lycaena bleusei and L. tityrus.

The comparison of closely related taxa is cornerstone in biology, as understanding mechanisms leading up to differentiation in relation to extant shared characters are powerful tools in interpreting the evolutionary process. Hotspots of biodiversity such as the west-Mediterranean, where many lineages meet are ideal grounds to study these processes. We set to explore the interesting example of Sooty Copper butterflies: widespread Eurasian Lycaena tityrus (Poda, 1761) comes into contact in Iberia with closely related and local endemic, L. bleusei (Oberthür, 1884), which hasn't always been considered a distinct species. An integrative analysis was designed, combining the use of extensive molecular data (five genes), geometric morphometrics analyses, verified and up-to-date distribution data, and environmental niche modelling, aimed at deciphering their true relationship, their placement within European Lycaena and trace their evolutionary history. We revealed several levels of differentiation: L. bleusei and L. tityrus appear to be reciprocally monophyletic independent gene-pools, distinct in all genes analysed, having mutually diverged 4.8 Ma ago. L. tityrus but not L. bleusei, further displays a genetic structure compatible with several glacial refugia, where populations assignable to infraspecific taxa surface. Conversely, L. bleusei shows a loss in mtDNA diversity in relation to nuDNA. Morphological analyses differentiate both species according to size and shape but also discriminate strong seasonal and sexual traits and a geographical phenotype segregation in L. tityrus. Finally, updated distribution and its modelling for current and glacial timeframes reveal both species respond differently to environmental variables, defining a mostly parapatric distribution and an overlapping belt where sympatry was recovered. During the last glacial maximum, a wider expansion in L. bleusei distribution explains current isolated populations. Our study highlights the importance of gathering several lines of evidence when deciphering the relationships between closely related populations in the fringe of cryptic species realm.

Testing drivers of acoustic divergence in cicadas (Cicadidae: Tettigettalna).

Divergence in acoustic signals may have a crucial role in the speciation process of animals that rely on sound for intra-specific recognition and mate attraction. The acoustic adaptation hypothesis (AAH) postulates that signals should diverge according to the physical properties of the signalling environment. To be efficient, signals should maximize transmission and decrease degradation. To test which drivers of divergence exert the most influence in a speciose group of insects, we used a phylogenetic approach to the evolution of acoustic signals in the cicada genus Tettigettalna, investigating the relationship between acoustic traits (and their mode of evolution) and body size, climate and micro-/macro-habitat usage. Different traits showed different evolutionary paths. While acoustic divergence was generally independent of phylogenetic history, some temporal variables' divergence was associated with genetic drift. We found support for ecological adaptation at the temporal but not the spectral level. Temporal patterns are correlated with micro- and macro-habitat usage and temperature stochasticity in ways that run against the AAH predictions, degrading signals more easily. These traits are likely to have evolved as an anti-predator strategy in conspicuous environments and low-density populations. Our results support a role of ecological selection, not excluding a likely role of sexual selection in the evolution of Tettigettalna calling songs, which should be further investigated in an integrative approach.

A "window" in the duodenal bulb: an atypical presentation of chronic cholecystitis.

A 74-year-old male presented with melena and fatigue, without fever or abdominal pain. Laboratory examination revealed anemia, leukocytosis, elevated C-reactive protein levels and conjugated hyperbilirubinemia with elevated liver enzymes. Upper endoscopy identified blood in the stomach and duodenum and a 6 mm hole in the anterosuperior surface of the duodenal bulb with spontaneous drainage of a bloody brownish content. The mucosa surrounding the hole was normal and there was a discrete mucosal flap that throbbed with air insufflation. Abdominal computed tomography identified a fistulous tract between the duodenal bulb and the gallbladder with a 2 mm caliber, suggesting a cholecystoduodenal fistula. Diagnosis is often difficult because symptoms are nonspecific and variable but gastrointestinal bleeding is a rare clinical presentation.

Single-cell functional and chemosensitive profiling of combinatorial colorectal therapy in zebrafish xenografts.

Cancer is as unique as the person fighting it. With the exception of a few biomarker-driven therapies, patients go through rounds of trial-and-error approaches to find the best treatment. Using patient-derived cell lines, we show that zebrafish larvae xenotransplants constitute a fast and highly sensitive in vivo model for differential therapy response, with resolution to reveal intratumor functional cancer heterogeneity. We screened international colorectal cancer therapeutic guidelines and determined distinct functional tumor behaviors (proliferation, metastasis, and angiogenesis) and differential sensitivities to standard therapy. We observed a general higher sensitivity to FOLFIRI [5-fluorouracil(FU)+irinotecan+folinic acid] than to FOLFOX (5-FU+oxaliplatin+folinic acid), not only between isogenic tumors but also within the same tumor. We directly compared zebrafish xenografts with mouse xenografts and show that relative sensitivities obtained in zebrafish are maintained in the rodent model. Our data also illustrate how KRAS mutations can provide proliferation advantages in relation to KRASWT and how chemotherapy can unbalance this advantage, selecting for a minor clone resistant to chemotherapy. Zebrafish xenografts provide remarkable resolution to measure Cetuximab sensitivity. Finally, we demonstrate the feasibility of using primary patient samples to generate zebrafish patient-derived xenografts (zPDX) and provide proof-of-concept experiments that compare response to chemotherapy and biological therapies between patients and zPDX. Altogether, our results suggest that zebrafish larvae xenografts constitute a promising fast assay for precision medicine, bridging the gap between genotype and phenotype in an in vivo setting.

Resistance of Rice Varieties to the Stored-Product Insect, Sitophilus zeamais (Coleoptera: Curculionidae).

Four common Portuguese rice varieties--Thaibonnet, Gladio, Albatros, and Eurosis--were tested for their relative susceptibility to Sitophilus zeamais Motschulsky, a common pest of stored rice in Portugal and in tropical countries. Physical (moisture content, hardness, length, and width) and chemical (by attenuated total reflection-Fourier transform infrared spectroscopy) properties of rice kernels were measured. Insect bioassays measured median developmental time, Dobie's index of susceptibility, percentage of damaged grains and weight loss, and progeny developed. This was done for paddy, brown rice, and polished rice for each variety. There were small, but significant, differences in insect resistance among the varieties. However, it was different for paddy and polished rice. In paddy, these differences were correlated with hull damage, and Eurosis was the most susceptible variety. In polished rice, resistance was correlated with hardness, and Thaibonnet was the most susceptible variety. In general, paddy rice was more resistant to insect attack, followed by polished rice and then brown rice. Paddy kernels selected with undamaged hull were completely resistant to attack. Implications for IPM and breeding for resistant varieties are discussed.

Epstein-Barr virus associated colitis in kidney transplant patients: a case series.

BACKGROUND: Gastrointestinal complications are common in kidney transplant (KT) patients and can be a consequence of the chronic use of immunosuppression. The differential diagnosis of colitis in KT patients includes intolerance to immunosuppressive agents, namely mycophenolate mofetil, de novo inflammatory bowel disease (IBD) and opportunistic infections. Epstein-Barr virus (EBV) infection may cause post-transplant colitis or trigger de novo IBD, although is seldom thought as the causative pathogen. OBJECTIVES: To describe clinical characteristics, endoscopic and histological findings, treatment and outcome of three patients that developed EBV associated colitis following kidney transplantation. METHODS: We retrospectively analyzed three patients with EBV associated colitis; clinical data including transplantation, gastrointestinal symptoms, endoscopy findings, and follow-up data was obtained. RESULTS: We present a case series of three patients with EBV colitis following KT, with an average age at clinical presentation of 59 years and elapsed time since the KT ranging from five to 22 years. Clinical manifestations included bloody diarrhoea, abdominal pain, weight loss and/or fever. Cytomegalovirus colitis, mycophenolate mofetil-related colitis, lymphoproliferative disease and graft versus host disease were excluded. One patient had a prior diagnosis of IBD. Two of the three patients had an unfavourable outcome with death despite reduction and/or switching of immunosuppressants, optimal medical treatment (including antiviral and intravenous immunoglobulin therapies) and salvage surgical therapy. CONCLUSION: A multidisciplinary approach is necessary to allow an expeditious diagnosis of a rare entity such as EBV associated colitis in KT. Long-term surveillance of these patients and the development of effective and safe therapies is essential.

Endoscopic Submucosal Dissection for Resections Larger than 10 cm: Outcomes from a Portuguese Center.

Background: Endoscopic submucosal dissection (ESD) is a minimally invasive technique for en bloc resection of superficial neoplastic lesions, independent of their size. However, for giant gastrointestinal superficial neoplasia, the risk of invasive cancer is higher, and ESD is typically challenging. Despite the increasing literature on giant resections, data on their efficacy and safety are still lacking. Objective: The aim of this study was to describe ESD outcomes from a Portuguese center, compare them with other international studies, and analyze the possible risk factors influencing outcomes. Methods: We conducted a retrospective single-center review using a prospectively collected database, including patients with rectal ESD resections larger than 10 cm, between January 2016 and December 2021. Clinical, procedural, and pathological data were collected and analyzed. Revision of the literature for comparison with international results was done through PubMed. Data were analyzed and statistical analysis performed, using Microsoft Excel and SPSS, to identify significant risk factors. Results: The study included 15 rectal resections, with a mean diameter of 140.9 mm (range 105-270), corresponding to lesions of 125.9 mm (87-238). The overall en bloc resection rate was 100% (n = 15). According to ESGE criteria, procedure was considered curative in 53.3% (n = 8), non-curative with high risk in 13.3% (n = 2), and local-risk recurrence in 33.3% (n = 5). Adverse events occurred in 26.7% (n = 4): 1 minor perforation and 3 stenosis, most endoscopically managed. For non-curative resections with local-risk recurrence, surveillance without adjuvant therapy was performed in all cases. For high-risk non-curative resections, surgery was performed in 1 patient and adjuvant chemoradiation therapy in another. Follow-up (mean 16 months) demonstrated a recurrence rate of 0%. Statistical analysis revealed resection size ≥20 cm as a risk factor for perforation (p value 0.067), and involvement of ≥90% of the circumference and procedural time ≥4 h as risk factors for stenosis (p value 0.029 and 0.009, respectively). Conclusions: Although challenging, ESD for giant lesions seems effective and safe, with a still relevant rate of complications, which were mostly endoscopically treated. Rigorous characterization of lesions is crucial to predict and avoid complications or the need for therapy escalation.

Background: A dissecao endoscopica da submucosa (DES) e uma tecnica minimamente invasiva para ressecao em bloco de tumores superficiais, independentemente do seu tamanho. No entanto, nas neoplasias superficiais gastrointestinais gigantes, o risco de cancro invasivo esta aumentado e a DES e tipicamente desafiante. Apesar do incremento da literatura acerca de ressecoes gigantes, dados da sua eficacia e seguranca sao ainda escassos. Objetivo: Descricao de outcomes de DES de um centro portugues e comparacao com estudos internacionais. Analise de eventuais fatores de risco influenciando os outcomes. Métodos: Revisao retrospetiva de um centro, usando a sua base de dados prospectivamente colhida, incluindo pacientes com ressecoes rectais por DES maiores que 10 cm, entre janeiro 2016 e dezembro 2021. Dados clinicos, endoscopicos e patologicos foram colhidos e analisados. A literatura foi revista atraves do PubMed, para comparacao com resultados internacionais. A analise dos resultados e estatistica foi realizada, utilizando o Microsoft Excel e SPSS, para a identificacao de fatores de risco com impacto significativo nos outcomes. Resultados: O estudo incluiu um total de 15 ressecoes retais, com uma media de diametros de 140,9 mm (intervalo 105­270), correspondendo a lesoes 125,9 mm (intervalo 87­238). A taxa de ressecao em bloco foi de 100% (n = 15). Segundo os criterios da ESGE, o procedimento foi curativo em 53,3% (n = 8), nao curativo com alto risco em 13,3% (n = 2) e com risco de recorrencia local em 33,3% (n = 5). Eventos adversos ocorreram em 26,7% (n = 4): 1 microperfuracao e 3 estenoses, a maioria geridas endoscopicamente. Os 5 casos nao curativos com risco de recorrencia local ficaram apenas sob vigilancia. Nas resseccoes nao curativas de alto risco, um paciente foi submetido a cirurgia e outro a quimioradioterapia adjuvante. O follow-up (media de 16 meses) demonstrou uma taxa de recorrencia de 0%. A analise estatistica demonstrou o tamanho da resseccao ≥20 cm como fator de risco significativo para perfuracao (p value 0.067); e envolvimento de ≥ 90% da circunferencia do lumen e tempo de procedimento ≥4h como fatores de risco significativos para estenose (p value 0.029 e 0.009, respetivamente). Conclusão: Apesar de desafiante, a DES para lesoes gigantes parece eficaz e segura, com uma taxa de complicacoes importante, possiveis de tratamento endoscopico. A caracterizacao rigorosa destas lesoes e crucial para predizer e evitar complicacoes ou a necessidade de escalada terapeutica.

Targeted anatomical and functional identification of antinociceptive and pronociceptive serotonergic neurons that project to the spinal dorsal horn.

Spinally projecting serotonergic neurons play a key role in controlling pain sensitivity and can either increase or decrease nociception depending on physiological context. It is currently unknown how serotonergic neurons mediate these opposing effects. Utilizing virus-based strategies and Tph2-Cre transgenic mice, we identified two anatomically separated populations of serotonergic hindbrain neurons located in the lateral paragigantocellularis (LPGi) and the medial hindbrain, which respectively innervate the superficial and deep spinal dorsal horn and have contrasting effects on sensory perception. Our tracing experiments revealed that serotonergic neurons of the LPGi were much more susceptible to transduction with spinally injected AAV2retro vectors than medial hindbrain serotonergic neurons. Taking advantage of this difference, we employed intersectional chemogenetic approaches to demonstrate that activation of the LPGi serotonergic projections decreases thermal sensitivity, whereas activation of medial serotonergic neurons increases sensitivity to mechanical von Frey stimulation. Together these results suggest that there are functionally distinct classes of serotonergic hindbrain neurons that differ in their anatomical location in the hindbrain, their postsynaptic targets in the spinal cord, and their impact on nociceptive sensitivity. The LPGi neurons that give rise to rather global and bilateral projections throughout the rostrocaudal extent of the spinal cord appear to be ideally poised to contribute to widespread systemic pain control.

Current Approach to Dysphagia: A Review Focusing on Esophageal Motility Disorders and Their Treatment.

Background: Dysphagia is a prevalent condition which may severely impact the patient's quality of life. However, there are still lacking standardized therapeutic options for esophageal motility disorders. Summary: Dysphagia is defined as a subjective sensation of difficulty swallowing which can result from oropharyngeal or esophageal etiologies. Regarding esophageal dysphagia, after excluding structural causes and esophageal mucosal lesions, high-resolution manometry (HRM) is the gold standard for the diagnosis of esophageal motility disorders. HRM has not only improved the sensitivity for detecting achalasia but has also expanded our understanding of spastic and hypomotility disorders of the esophageal body. The Chicago Classification v4.0 uses a hierarchical approach and provides a standardized diagnosis of esophageal motility disorders, allowing a tailored therapeutic approach. Dysphagia is often a long-term health problem that broadly impacts health and well-being and leads to physical and psychosocial disability, namely, malnutrition and aspiration pneumonia, as well as social isolation, depression, and anxiety. Apart from achalasia, most esophageal motility disorders tend to have a benign long-term course with symptoms of dysphagia and noncardiac chest pain that can improve significantly over time. Patient-reported outcomes (PROs) are self-assessment tools that capture the patients' illness experience and help providers better understand symptoms from the patients' perspective. Therefore, PROs have a critical role in providing patient-centered care. Key Messages: Motility disorders should be ruled out in the presence of nonobstructive esophageal dysphagia, and treatment options should be considered according to the severity of symptoms reported by the patient.

Contexto: A disfagia é uma condição prevalente que poderá ter impacto negativo na qualidade de vida dos doentes. No entanto, a abordagem terapêutica dos distúrbios da motilidade esofágica não está ainda padronizada. Sumário: A disfagia define-se como uma sensação subjetiva de dificuldade de deglutição que pode resultar de uma etiologia orofaríngea ou esofágica. Na disfagia esofágica, após exclusão de causas estruturais e lesões da mucosa esofágica, o estudo por manometria de alta resolução (MAR) está indicado como avaliação por excelência para o diagnóstico de distúrbios da motilidade esofágica. A implementação da MAR aumentou a sensibilidade para o diagnóstico de acalásia, como também melhorou a nossa compreensão dos distúrbios espásticos e de hipomotilidade do corpo esofágico. A Classificação de Chicago v4.0 utiliza uma abordagem hierárquica fornecendo um diagnóstico padronizado dos distúrbios da motilidade esofágica, o que permite uma abordagem terapêutica adaptada às diferentes condições. Frequentemente manifesta-se como uma condição clínica crónica com amplo impacto na saúde e bem-estar dos afetados, dada as suas consequências físicas e psicossociais. Pode estar associada a complicações graves, incluindo desnutrição e pneumonia por aspiração, bem como isolamento social, depressão e ansiedade, com redução acentuada da qualidade de vida. A maioria dos distúrbios da motilidade esofágica, à exceção da acalásia, tende a ter um curso benigno a longo prazo com sintomas de disfagia e de dor torácica não cardíaca que podem melhorar significativamente ao longo do tempo. Os outcomes reportados pelo doente (PRO) são ferramentas de autoavaliação que captam a experiência da doença dos afetados e ajudam os profissionais a entender melhor os sintomas na perspetiva dos doentes. Portanto, os PROs têm um papel crítico na prestação de cuidados centrados no doente. Mensagens-Chave: Doenças motoras deverão ser excluídas na presença de disfagia esofágica não obstrutiva. A terapêutica instituída deverá ser definida mediante a gravidade dos sintomas reportados pelo doente.

Early intervention with biologic therapy in Crohn´s disease: how early is early?

BACKGROUND: Early biologic therapy within the first 18-24 months after diagnosis is associated with improved clinical outcomes in Crohn's disease [CD]. However, the definition of the best time to initiate biologic therapy remains unclear. We aimed to assess if there is an optimal timing for early biologic therapy initiation. METHODS: This was a multicentre retrospective cohort study including newly diagnosed CD patients who started anti-tumour necrosis factor [TNF] therapy within 24 months from diagnosis. The timing of initiation of biologic therapy was categorised as ≤6, 7-12, 13-18, and 19-24 months. The primary outcome was CD-related complications defined as a composite of progression of Montreal disease behaviour, CD-related hospitalisations, or CD-related intestinal surgeries. Secondary outcomes included clinical, laboratory, endoscopic, and transmural remission. RESULTS: We included 141 patients where 54%, 26%, 11%, and 9% started biologic therapy at ≤6, 7-12, 13-18, and 19-24 months after diagnosis, respectively. A total of 34 patients [24%] reached the primary outcome: 8% had progression of disease behaviour, 15% were hospitalised, and 9% required surgery. There was no difference in the time to a CD-related complication according to the time of initiation of biologic therapy within the first 24 months. Clinical, endoscopic, and transmural remission was achieved in 85%, 50%, and 29%, respectively, but no differences were found according to the time of initiation of biologic therapy. CONCLUSION: Starting anti-TNF therapy within the first 24 months after diagnosis was associated with a low rate of CD-related complications and high rates of clinical and endoscopic remission, although we found no differences with earlier initiation within this window of opportunity.

c-Maf-positive spinal cord neurons are critical elements of a dorsal horn circuit for mechanical hypersensitivity in neuropathy.

Corticospinal tract (CST) neurons innervate the deep spinal dorsal horn to sustain chronic neuropathic pain. The majority of neurons targeted by the CST are interneurons expressing the transcription factor c-Maf. Here, we used intersectional genetics to decipher the function of these neurons in dorsal horn sensory circuits. We find that excitatory c-Maf (c-MafEX) neurons receive sensory input mainly from myelinated fibers and target deep dorsal horn parabrachial projection neurons and superficial dorsal horn neurons, thereby connecting non-nociceptive input to nociceptive output structures. Silencing c-MafEX neurons has little effect in healthy mice but alleviates mechanical hypersensitivity in neuropathic mice. c-MafEX neurons also receive input from inhibitory c-Maf and parvalbumin neurons, and compromising inhibition by these neurons caused mechanical hypersensitivity and spontaneous aversive behaviors reminiscent of c-MafEX neuron activation. Our study identifies c-MafEX neurons as normally silent second-order nociceptors that become engaged in pathological pain signaling upon loss of inhibitory control.

Prevalence of metabolic syndrome in Brazilian children using three different sets of international criteria.

INTRODUCTION: Background: the aim of the present study was to compare the prevalence of metabolic syndrome in Brazilian children aged 6-10 years using three different international criteria. Methods: systolic and diastolic blood pressure (SBP and DBP), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, fasting glucose, and insulin levels were measured in 290 schoolchildren, and the presence of metabolic syndrome was analyzed according to the criteria established by Cook, Boney, and Ferreira. Results: the prevalence of metabolic syndrome was 2.27 % (Boney and Ferreira criteria) and 7.58 % (Cook criteria) for girls, and 3.8 % (Boney and Ferreira criteria) and 5.06 % (Cook criteria) for boys. Agreement in pairs showed a concordance of 57.5 % (Kappa = 0.57) between Boney and Cook criteria, and 65.2 % (Kappa = 0.65) between Cook and Ferreira. The greatest concordance found was 77 % (Kappa = 0.77) between Boney and Ferreira criteria, demonstrating a substantial agreement. Conclusion: prevalence according to Boney and Ferreira criteria was lower than according to Cook criteria. Therefore, we suggest the use of Cook criteria in clinical practice for the diagnosis of metabolic syndrome, since this criterion provided a wider diagnostic range, thereby reducing the risk of underdiagnosis.

INTRODUCCIÓN: Antecedentes: el objetivo del presente estudio fue comparar la prevalencia del síndrome metabólico en niños brasileños de 6 a 10 años de edad, usando tres diferentes criterios internacionales. Métodos: se midieron la presión arterial sistólica y diastólica, el colesterol de alta y baja densidad, los triglicéridos, la glucemia en ayunas y la insulinemia en 290 escolares, y se analizó la presencia del síndrome metabólico de acuerdo con los criterios de Cook, Boney y Ferreira. Resultados: las prevalencias del síndrome metabólico encontradas fueron del 2,27 % (criterios de Boney y Ferreira) y 7,58 % (criterios de Cook) para las niñas, y del 3,8 % (criterios de Boney y Ferreira) y 5,06 % (criterios de Cook) para los niños. La concordancia por pares fue del 57,5 % (Kappa = 0,57) entre los criterios de Boney y Cook, y del 65,2 % (Kappa = 0,65) entre los criterios de Cook y Ferreira. La mayor concordancia encontrada fue del 77 % (Kappa = 0,77) entre los criterios de Boney y Ferreira, demostrando una concordancia sustancial. Conclusiones: la prevalencia de acuerdo con los criterios de Boney y Ferreira fue inferior a la encontrada con los criterios de Cook. Por lo tanto, sugerimos el uso de los criterios de Cook en la práctica clínica para el diagnóstico del síndrome metabólico, ya que utilizando este criterio se obtiene un rango diagnóstico más amplio, reduciéndose así el riesgo del infradiagnóstico.

Zebrafish Avatars towards Personalized Medicine-A Comparative Review between Avatar Models.

Cancer frequency and prevalence have been increasing in the past decades, with devastating impacts on patients and their families. Despite the great advances in targeted approaches, there is still a lack of methods to predict individual patient responses, and therefore treatments are tailored according to average response rates. "Omics" approaches are used for patient stratification and choice of therapeutic options towards a more precise medicine. These methods, however, do not consider all genetic and non-genetic dynamic interactions that occur upon drug treatment. Therefore, the need to directly challenge patient cells in a personalized manner remains. The present review addresses the state of the art of patient-derived invitro and invivo models, from organoids to mouse and zebrafish Avatars. The predictive power of each model based on the retrospective correlation with the patient clinical outcome will be considered. Finally, the review is focused on the emerging zebrafish Avatars and their unique characteristics allowing a fast analysis of local and systemic effects of drug treatments at the single-cell level. We also address the technical challenges that the field has yet to overcome.

Zebrafish xenografts as a fast screening platform for bevacizumab cancer therapy.

Despite promising preclinical results, average response rates to anti-VEGF therapies, such as bevacizumab, are reduced for most cancers, while incurring in remarkable costs and side effects. Currently, there are no biomarkers available to select patients that can benefit from this therapy. Depending on the individual tumor, anti-VEGF therapies can either block or promote metastasis. In this context, an assay able to predict individual responses prior to treatment, including the impact on metastasis would prove of great value to guide treatment options. Here we show that zebrafish xenografts are able to reveal different responses to bevacizumab in just 4 days, evaluating not only individual tumor responses but also the impact on angiogenesis and micrometastasis. Importantly, we perform proof-of-concept experiments where clinical responses in patients were compared with their matching zebrafish Patient-Derived Xenografts - zAvatars, opening the possibility of using the zebrafish model to screen bevacizumab therapy in a personalized manner.

Brain-Sparing Sympathofacilitators Mitigate Obesity without Adverse Cardiovascular Effects.

Anti-obesity drugs in the amphetamine (AMPH) class act in the brain to reduce appetite and increase locomotion. They are also characterized by adverse cardiovascular effects with origin that, despite absence of any in vivo evidence, is attributed to a direct sympathomimetic action in the heart. Here, we show that the cardiac side effects of AMPH originate from the brain and can be circumvented by PEGylation (PEGyAMPH) to exclude its central action. PEGyAMPH does not enter the brain and facilitates SNS activity via theß2-adrenoceptor, protecting mice against obesity by increasing lipolysis and thermogenesis, coupled to higher heat dissipation, which acts as an energy sink to increase energy expenditure without altering food intake or locomotor activity. Thus, we provide proof-of-principle for a novel class of exclusively peripheral anti-obesity sympathofacilitators that are devoid of any cardiovascular and brain-related side effects.

Pediatric Asthma Control and Communication Instrument: translation into Portuguese and cross-cultural adaptation for use in Brazil.

OBJECTIVE: To translate the Pediatric Asthma Control and Communication Instrument (PACCI) to Portuguese and adapt it for use in Brazil, ensuring the cultural validity of the content and semantic equivalence of the target version. METHODS: The Brazilian Portuguese-language version of the PACCI was developed according to the most commonly used methodology, which included the following steps: translation; synthesis of the translation; review by the author of the original questionnaire; back-translation; synthesis of the back-translation; review by a native external researcher who is a native speaker of English; approval of the author of the original questionnaire; review by a specialist in Portuguese; review by a multidisciplinary committee of experts to determine the agreement of the items, considering the clarity of each and its appropriateness in the cultural context; cognitive debriefing; and development of the final version. The cognitive debriefing involved 31 parents/legal guardians of children 1-21 years of age with a clinical diagnosis of asthma, as defined by the Global Initiative for Asthma, with the objective of determining the comprehensibility and clarity of the items for the target population. RESULTS: The multidisciplinary committee of experts indicated that the items on the questionnaire were clear and comprehensible, with kappa values above 0.61, indicating substantial agreement. In the cognitive debriefing, the parents/legal guardians presented no difficulties in understanding any of the items (agreement > 0.90); therefore, no further changes were needed. CONCLUSIONS: The translation and cross-cultural adaptation of the PACCI for use in Brazil were successful.

Morphology, songs and genetics identify two new cicada species from Morocco: Tettigettalna afroamissa sp. nov. and Berberigetta dimelodica gen. nov. & sp. nov. (Hemiptera: Cicadettini).

Morocco has been the subject of very few expeditions on the last century with the objective of studying small cicadas. In the summer of 2014 an expedition was carried out to Morocco to update our knowledge with acoustic recordings and genetic data of these poorly known species. We describe here two new small-sized cicadas that could not be directly assigned to any species of North African cicadas: Tettigettalna afroamissa sp. nov. and Berberigetta dimelodica gen. nov. & sp. nov. In respect to T. afroamissa it is the first species of the genus to be found outside Europe and we frame this taxon within the evolutionary history of the genus. Acoustic analysis of this species allows us to confidently separate T. afroamissa from its congeners. With B. dimelodica, a small species showing a remarkable calling song characterized by an abrupt frequency modulation, a new genus had to be erected. Bayesian inference and maximum likelihood phylogenetic analyses with DNA-barcode sequences of Cytochrome C Oxidase 1 support the monophyly of both species, their distinctness and revealed genetic structure within B. dimelodica. Alongside the descriptions we also provide GPS coordinates of collection points, distributions and habitat preferences.