Mechanical life support algorithm for emergency management of patient receiving extracorporeal membrane oxygenation.

BACKGROUND: There are limited practical advanced life support algorithms to aid teams in the management of cardiac arrest in patients on extracorporeal membrane oxygenation (ECMO). METHODS: In our specialist tertiary referral centre we developed, by iteration, a novel resuscitation algorithm for ECMO emergencies which we validated through simulation and assessment of our multi-disciplinary team. A Mechanical Life Support course was established to provide theoretical and practical education combined with simulation to consolidate knowledge and confidence in algorithm use. We assessed these measures using confidence scoring, a key performance indicator (the time taken to resolve gas line disconnection) and a multiple choice question (MCQ) examination. RESULTS: Following this intervention the median confidence scores increased from 2 (Interquartile range IQR 2, 3) to 4 (IQR 4, 4) out of maximum 5 (n = 53, p < 0.0001). Theoretical knowledge assessed by median MCQ score increased from 8 (6, 9) to 9 (7, 10) out of maximum 11 (n = 53, p0.0001). The use of the ECMO algorithm reduced the time taken by teams in a simulated emergency to identify a gas line disconnection and resolve the problem from median 128 s (65, 180) to 44 s (31, 59) (n = 36, p 0.001) and by a mean of 81.5 s (CI 34, 116, p = 0.001). CONCLUSIONS: We present an evidence based practical ECMO resuscitation algorithm that provides guidance to clinical teams responding to cardiac arrest in ECMO patients covering both patient and ECMO troubleshooting.

Effects of Graphene Oxide Nanosheets in Freshwater Biofilms.

Graphene oxide (GO) properties make it a promising material for graphene-based applications in areas such as biomedicine, agriculture, and the environment. Thus, its production is expected to increase, reaching hundreds of tons every year. One GO final destination is freshwater bodies, possibly affecting the communities of these systems. To clarify the effect that GO may impose in freshwater communities, a fluvial biofilm scraped from submerged river stones was exposed to a range (0.1 to 20 mg/L) of GO concentrations during 96 h. With this approach, we hypothesized that GO can: (1) cause mechanical damage and morphological changes in cell biofilms; (2) interfere with the absorption of light by biofilms; (3) and generate oxidative stress, causing oxidative damage and inducing biochemical and physiological alterations. Our results showed that GO did not inflict mechanical damage. Instead, a positive effect is proposed, linked to the ability of GO to bind cations and increase the micronutrient availability to biofilms. High concentrations of GO increased photosynthetic pigment (chlorophyll a, b, and c, and carotenoids) content as a strategy to capture the available light more effectively as a response to the shading effect. A significant increase in the enzymatic (SOD and GSTs activity) and low molecular weight (lipids and carotenoids) antioxidant response was observed, that efficiently reduced oxidative stress effects, reducing the level of peroxidation, and preserving membrane integrity. Being complex entities, biofilms are more similar to environmental communities and may provide more accurate information to evaluate the impact of GO in aquatic systems.

Nanoformulation of Seaweed Eisenia bicyclis in Albumin Nanoparticles Targeting Cardiovascular Diseases: In Vitro and In Vivo Evaluation.

Natural products, especially those derived from seaweeds, are starting to be seen as effective against various diseases, such as cardiovascular diseases (CVDs). This study aimed to design a novel oral formulation of bovine albumin serum nanoparticles (BSA NPs) loaded with an extract of Eisenia bicyclis and to validate its beneficial health effects, particularly targeting hypercholesterolemia and CVD prevention. Small and well-defined BSA NPs loaded with Eisenia bicyclis extract were successfully prepared exhibiting high encapsulation efficiency. Antioxidant activity and cholesterol biosynthesis enzyme 3-hydroxy-3 methylutaryl coenzyme A reductase (HMGR) inhibition, as well as reduction of cholesterol permeation in intestinal lining model cells, were assessed for the extract both in free and nanoformulated forms. The nanoformulation was more efficient than the free extract, particularly in terms of HMGR inhibition and cholesterol permeation reduction. In vitro cytotoxicity and in vivo assays in Wistar rats were performed to evaluate its safety and overall effects on metabolism. The results demonstrated that the Eisenia bicyclis extract and BSA NPs were not cytotoxic against human intestinal Caco-2 and liver HepG2 cells and were also safe after oral administration in the rat model. In addition, an innovative approach was adopted to compare the metabolomic profile of the serum from the animals involved in the in vivo assay, which showed the extract and nanoformulation's impact on CVD-associated key metabolites. Altogether, these preliminary results revealed that the seaweed extract and the nanoformulation may constitute an alternative natural dosage form which is safe and simple to produce, capable of reducing cholesterol levels, and consequently helpful in preventing hypercholesterolemia, the main risk factor of CVDs.

Impact of COVID-19 confinement on eating behaviours across 16 European countries: The COVIDiet cross-national study.

We aimed to evaluate the changes in eating behaviours of the adult population across 16 European countries due to the COVID-19 confinement and to evaluate whether these changes were somehow related to the severity of the containment measures applied in each country. An anonymous online self-reported questionnaire on socio-demographic characteristics, validated 14-items Mediterranean diet (MedDiet) Adherence Screener (MEDAS) as a reference of a healthy diet, eating and lifestyle behaviours prior to and during the COVID-19 confinement was used to collect data. The study included an adult population residing in 16 European countries at the time of the survey. Aggregated Stringency Index (SI) score, based on data from the Oxford COVID-19 Government Response Tracker, was calculated for each country at the time the questionnaire was distributed (range: 0-100). A total of 36,185 participants completed the questionnaire (77.6% female, 75.2% with high educational level and 42.7% aged between 21 and 35 years). In comparison to pre-confinement, a significantly higher adherence to the MedDiet during the confinement was observed across all countries (overall MEDAS score prior to- and during confinement: 5.23 ± 2.06 vs. 6.15 ± 2.06; p < 0.001), with the largest increase seen in Greece and North Macedonia. The highest adherence to MedDiet during confinement was found in Spain and Portugal (7.18 ± 1.84 and 7.34 ± 1.95, respectively). Stricter contingency restrictions seemed to lead to a significantly higher increase in the adherence to the MedDiet. The findings from this cross-sectional study could be used to inform current diet-related public health guidelines to ensure optimal nutrition is followed among the population, which in turn would help to alleviate the current public health crisis.

Phonological characteristics of European and Brazilian Portuguese in children with Speech Sound Disorders.

This study aims to describe and compare the phonological characteristics of European Portuguese and Brazilian Portuguese preschool and school age children with Speech Sound Disorders (SSD). Speech samples for the European Portuguese Group (EPG) (n = 13) were collected using Subteste Fonético e Fonológico of Teste Fonético e Fonológico Avaliação da Linguagem Pré-Escolar. For the Brazilian Portuguese Group (BPG) (n = 13) Prova de Nomeação de Fonologia of Teste de Linguagem Infantil ABFW was applied. Different phonological measures were considered. Groups were matched according to sex, age, and percentage of correct consonants (revised). EPG presented more weak syllable deletion (p = .00); absolute index and relative index had a higher number of omissions (p = .003). BPG had more substitutions (p = .004). Intragroup analysis showed differences between groups in the occurrence of phonological processes (p ≤ 0.00). The most occurring was gliding of liquids, cluster reduction and devoicing in both groups; for the absolute index and relative index, the EPG presented differences in omission (p = .003), and the BPG in substitution (p = .002). Results suggested differences between groups in phonological processes occurrence and a relation with the most frequent type of error. These findings may occur due to the variation of phonetic and phonological characteristics between European Portuguese and Brazilian Portuguese in the two phonological tests. Linguistic variations had not directly influenced the measures studied, which characterized SSD. European Portuguese and Brazilian Portuguese children with SSD demonstrated similar characteristics as to the type of errors and phonological processes.

Unravelling the anticancer potential of functionalized chromeno[2,3-b]pyridines for breast cancer treatment.

A selection of new chromeno[2,3-b]pyridines was prepared from chromenylacrylonitriles and N-substituted piperazines, using a novel and efficient synthetic procedure. The compounds were tested for their anticancer activity using breast cancer cell lines MCF-7, Hs578t and MDA-MB-231 and the non-neoplastic cell line MCF-10A for toxicity evaluation. In general, compounds showed higher activity towards the luminal breast cancer subtype (MCF-7), competitive with the reference compound Doxorubicin. The in vivo toxicity assay using C. elegans demonstrated a safe profile for the most active compounds. Chromene 3f revealed a promising drug profile, inhibiting cell growth and proliferation, inducing cell cycle arrest in G2/M phase, apoptosis and microtubule destabilization. The new compounds presented exciting bioactive features and may be used as lead compounds in cancer related drug discovery.

[Initial care for migrants in Chile: status of a primary health care initiative after one year of implementationAtenção inicial a populações migrantes no Chile: iniciativa em atenção primária à saúde após um ano da sua implementação]. / Atención inicial de migrantes en Chile: iniciativa en atención primaria de salud a un año de su implementación.

OBJECTIVE: Describe sociodemographic characteristics, health needs, effective referrals, and immediate evaluation of international migrants who participated in the Initial Care for Migrants program during its first year of implementation (May to December 2016) at the Ignacio Domeyko Family Health Center in Santiago, Chile. METHODS: Descriptive study. An intervention was designed and implemented to welcome international migrants. It included an initial comprehensive evaluation, a situation assessment, identification of needs, referral to other health services, and transfer of information. Statistical analysis was performed, using measures of central tendency and absolute and relative frequencies to describe sociodemographic characteristics, migratory processes, health needs, and effective referrals after one year of monitoring, as well as the results of a user satisfaction survey. RESULTS: 436 people were registered, of whom 270 (61.9%) participated; 80% were women, mostly from Peru and Venezuela. The largest number of referrals were to pregnancy services (32.6%), followed by family planning (30%) and social services (27.04%). After one year of monitoring, there was 100% compliance for referrals to cardiovascular testing, 97.7% for pregnancy, and 87.7% for social services. The lowest compliance was for referrals to mental health services (11.1%). CONCLUSIONS: This intervention, the first of its kind in Chile, welcomed international migrants and provided them with key information, while providing referrals based on health needs and promoting the inclusion of the immigrant population in the Chilean health system.

OBJETIVO: Descrever as características sociodemográficas, necessidades em saúde, encaminhamentos efetivados e avaliação imediata da população migrante internacional que participou do Programa de Atenção Inicial ao Migrante no primeiro ano da sua implementação (entre maio e dezembro de 2016) no Centro de Saúde Familiar Ignacio Domeyko, na cidade de Santiago, no Chile. MÉTODOS: Estudo descritivo com base em uma intervenção que foi concebida e implementada para acolher populações migrantes internacionais. A intervenção consistiu de uma avaliação inicial completa, diagnóstico da situação, identificação das necessidades em saúde e encaminhamento a outros serviços de atendimento, além de um componente informativo. A análise se baseou em medidas de tendência central e frequências absolutas e relativas usadas para descrever características sociodemográficas, processo migratório, necessidades em saúde, efetivação dos encaminhamentos em um ano de acompanhamento e resultados da pesquisa de satisfação dos usuários. RESULTADOS: Dos 436 inscritos, 270 participaram do programa (61,9%). Destes, 80% eram mulheres e a maioria era proveniente do Peru e da Venezuela. Os principais encaminhamentos efetivados foram ao atendimento pré-natal (32,6%), planejamento familiar (30%) e serviços sociais (27,04%). Após um ano de acompanhamento, os encaminhamentos para avaliação cardiovascular foram efetivados em 100%, para atenção pré-natal em 97,7% e para serviços sociais em 87,7%. O encaminhamento à atenção de saúde mental foi o menos efetivado (11,1%). CONCLUSÕES: Esta foi uma intervenção pioneira no Chile que possibilitou acolher e instruir as populações migrantes internacionais, além de realizar encaminhamentos a serviços conforme as necessidades em saúde e promover a inserção da população imigrante no sistema de saúde chileno.

Exonic splicing signals impose constraints upon the evolution of enzymatic activity.

Exon splicing enhancers (ESEs) overlap with amino acid coding sequences implying a dual evolutionary selective pressure. In this study, we map ESEs in the placental alkaline phosphatase gene (ALPP), absent in the corresponding exon of the ancestral tissue-non-specific alkaline phosphatase gene (ALPL). The ESEs are associated with amino acid differences between the transcripts in an area otherwise conserved. We switched out the ALPP ESEs sequences with the sequence from the related ALPL, introducing the associated amino acid changes. The resulting enzymes, produced by cDNA expression, showed different kinetic characteristics than ALPL and ALPP. In the organism, this enzyme will never be subjected to selection because gene splicing analysis shows exon skipping due to loss of the ESE. Our data prove that ESEs restrict the evolution of enzymatic activity. Thus, suboptimal proteins may exist in scenarios when coding nucleotide changes and consequent amino acid variation cannot be reconciled with the splicing function.

Transcriptional regulation of Culex pipiens mosquitoes by Wolbachia influences cytoplasmic incompatibility.

Cytoplasmic incompatibility (CI) induced by the endosymbiont Wolbachia pipientis causes complex patterns of crossing sterility between populations of the Culex pipiens group of mosquitoes. The molecular basis of the phenotype is yet to be defined. In order to investigate what host changes may underlie CI at the molecular level, we examined the transcription of a homolog of the Drosophila melanogaster gene grauzone that encodes a zinc finger protein and acts as a regulator of female meiosis, in which mutations can cause sterility. Upregulation was observed in Wolbachia-infected C. pipiens group individuals relative to Wolbachia-cured lines and the level of upregulation differed between lines that were reproductively incompatible. Knockdown analysis of this gene using RNAi showed an effect on hatch rates in a Wolbachia infected Culex molestus line. Furthermore, in later stages of development an effect on developmental progression in CI embryos occurs in bidirectionally incompatible crosses. The genome of a wPip Wolbachia strain variant from Culex molestus was sequenced and compared with the genome of a wPip variant with which it was incompatible. Three genes in inserted or deleted regions were newly identified in the C. molestus wPip genome, one of which is a transcriptional regulator labelled wtrM. When this gene was transfected into adult Culex mosquitoes, upregulation of the grauzone homolog was observed. These data suggest that Wolbachia-mediated regulation of host gene expression is a component of the mechanism of cytoplasmic incompatibility.

British societies guideline on the management of emergencies in implantable left ventricular assist device recipients in transplant centres.

An implantable left ventricular assist device (LVAD) is indicated as a bridge to transplantation or recovery in the United Kingdom (UK). The mechanism of action of the LVAD results in a unique state of haemodynamic stability with diminished arterial pulsatility. The clinical assessment of an LVAD recipient can be challenging because non-invasive blood pressure, pulse and oxygen saturation measurements may be hard to obtain. As a result of this unusual situation and complex interplay between the device and the native circulation, resuscitation of LVAD recipients requires bespoke guidelines. Through collaboration with key UK stakeholders, we assessed the current evidence base and developed guidelines for the recognition of clinical deterioration, inadequate circulation and time-critical interventions. Such guidelines, intended for use in transplant centres, are designed to be deployed by those providing immediate care of LVAD patients under conditions of precipitous clinical deterioration. In summary, the Joint British Societies and Transplant Centres LVAD Working Group present the UK guideline on management of emergencies in implantable LVAD recipients for use in advanced heart failure centres. These recommendations have been made with a UK resuscitation focus but are widely applicable to professionals regularly managing patients with implantable LVADs.

In vitro and in vivo evaluation of novel chromeno[2,3-d]pyrimidinones as therapeutic agents for triple negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and the limited therapeutic options show poor efficacy in patients, associated to severe side effects and development of resistance. Considering that chromene-based scaffolds proved to be attractive candidates for cancer therapy, herein we prepared new chromeno[2,3-d]pyrimidinone derivatives by a simple two step procedure, starting from the reaction of cyanoacetamide and a salicylaldehyde. A cell viability screening in several breast cancer cell lines allowed to identify two promising compounds with IC50 values in the low micromolar range for TNBC cells. These chromenes inhibited cell proliferation, induced cell cycle arrest and triggered cell death through apoptosis. In vivo studies revealed a safe profile in invertebrate and vertebrate animal models and confirmed their capacity to inhibit tumor growth in the CAM model, inducing significant tumor regression after 4 days of treatment. The two compounds identified in this study are promising drug candidates for TNBC treatment and valuable hits for future optimization, using the versatile synthetic platform that was developed.

Edible Seaweeds Extracts: Characterization and Functional Properties for Health Conditions.

Seaweeds are popular foods due to claimed beneficial health effects, but for many there is a lack of scientific evidence. In this study, extracts of the edible seaweeds Aramé, Nori, and Fucus are compared. Our approach intends to clarify similarities and differences in the health properties of these seaweeds, thus contributing to target potential applications for each. Additionally, although Aramé and Fucus seaweeds are highly explored, information on Nori composition and bioactivities is scarce. The aqueous extracts of the seaweeds were obtained by decoction, then fractionated and characterized according to their composition and biological activity. It was recognized that fractioning the extracts led to bioactivity reduction, suggesting a loss of bioactive compounds synergies. The Aramé extract showed the highest antioxidant activity and Nori exhibited the highest potential for acetylcholinesterase inhibition. The identification of the bioactive compounds in the extracts allowed to see that these contained a mixture of phloroglucinol polymers, and it was suggested that Nori's effect on acetylcholinesterase inhibition may be associated with a smaller sized phlorotannins capable of entering the enzyme active site. Overall, these results suggest a promising potential for the use of these seaweed extracts, mainly Aramé and Nori, in health improvement and management of diseases, namely those associated to oxidative stress and neurodegeneration.

Targeted treatment of triple-negative-breast cancer through pH-triggered tumour associated macrophages using smart theranostic nanoformulations.

Triple-negative breast cancer (TNBC) represents 15-25 % of the new breast cancer cases diagnosed worldwide every year. TNBC is among the most aggressive and worst prognosis breast cancer, mainly because targeted therapies are not available. Herein, we developed a magnetic theranostic hybrid nanovehicle for targeted treatment of TNBC through pH-triggered tumour associated macrophages (TAMs) targeting. The lipid core of the nanovehicle was composed of a Carnaúba wax matrix that simultaneously incorporated iron oxide nanoparticles and doxorubicin (DOX) - a chemotherapeutic drug. These drug-loaded wax nanovehicles were modified with a combination of two functional and complementary molecules: (i) a mannose ligand (macrophage targeting) and (ii) an acid-sensitive sheddable polyethylene glycol (PEG) moiety (specificity). The TAMs targeting strategy relied on the mannose - mannose receptor recognition exclusively after acid-sensitive "shedding" of the PEG in the relatively low tumour microenvironment pH. The pH-induced targeting capability towards TAMs was confirmed in vitro in a J774A.1 macrophage cell line at different pH (7.4 and 6.5). Biocompatibility and efficacy of the final targeted formulations were demonstrated in vitro in the TNBC MDA-MB-231 cell line and in vivo in an M-Wnt tumour-bearing (TNBC) mouse model. A preferential accumulation of the DOX-loaded lipid nanovehicles in the tumours of M-Wnt-tumour bearing mice was observed, which resulted both on an efficient tumour growth inhibition and a significantly reduced off-target toxicity compared to free DOX. Additionally, the developed magnetic hybrid nanovehicles showed outstanding performances as T2-contrast agents in magnetic resonance imaging (r2 ≈ 400-600 mM-1·s-1) and as heat generating sources in magnetic hyperthermia (specific absorption rate, SAR ≈ 178 W·g-1Fe). These targeted magnetic hybrid nanovehicles emerge as a suitable theranostic option that responds to the urgent demand for more precise and personalized treatments, not only because they are able to offer localized imaging and therapeutic potential, but also because they allow to efficiently control the balance between safety and efficacy.

Wolbachia stimulates immune gene expression and inhibits plasmodium development in Anopheles gambiae.

The over-replicating wMelPop strain of the endosymbiont Wolbachia pipientis has recently been shown to be capable of inducing immune upregulation and inhibition of pathogen transmission in Aedes aegypti mosquitoes. In order to examine whether comparable effects would be seen in the malaria vector Anopheles gambiae, transient somatic infections of wMelPop were created by intrathoracic inoculation. Upregulation of six selected immune genes was observed compared to controls, at least two of which (LRIM1 and TEP1) influence the development of malaria parasites. A stably infected An. gambiae cell line also showed increased expression of malaria-related immune genes. Highly significant reductions in Plasmodium infection intensity were observed in the wMelPop-infected cohort, and using gene knockdown, evidence for the role of TEP1 in this phenotype was obtained. Comparing the levels of upregulation in somatic and stably inherited wMelPop infections in Ae. aegypti revealed that levels of upregulation were lower in the somatic infections than in the stably transinfected line; inhibition of development of Brugia filarial nematodes was nevertheless observed in the somatic wMelPop infected females. Thus we consider that the effects observed in An. gambiae are also likely to be more pronounced if stably inherited wMelPop transinfections can be created, and that somatic infections of Wolbachia provide a useful model for examining effects on pathogen development or dissemination. The data are discussed with respect to the comparative effects on malaria vectorial capacity of life shortening and direct inhibition of Plasmodium development that can be produced by Wolbachia.

Wolbachia surface protein induces innate immune responses in mosquito cells.

BACKGROUND: Wolbachia endosymbiotic bacteria are capable of inducing chronic upregulation of insect immune genes in some situations and this phenotype may influence the transmission of important insect-borne pathogens. However the molecules involved in these interactions have not been characterized. RESULTS: Here we show that recombinant Wolbachia Surface Protein (WSP) stimulates increased transcription of immune genes in mosquito cells derived from the mosquito Anopheles gambiae, which is naturally uninfected with Wolbachia; at least two of the upregulated genes, TEP1 and APL1, are known to be important in Plasmodium killing in this species. When cells from Aedes albopictus, which is naturally Wolbachia-infected, were challenged with WSP lower levels of upregulation were observed than for the An. gambiae cells. CONCLUSIONS: We have found that WSP is a strong immune elicitor in a naturally Wolbachia-uninfected mosquito species (Anopheles gambiae) while a milder elicitor in a naturally-infected species (Aedes albopictus). Since the WSP of a mosquito non-native (nematode) Wolbachia strain was used, these data suggest that there is a generalized tolerance to WSP in Ae. albopictus.

Discovery of Plasmodium modulators by genome-wide analysis of circulating hemocytes in Anopheles gambiae.

Insect hemocytes mediate important cellular immune responses including phagocytosis and encapsulation and also secrete immune factors such as opsonins, melanization factors, and antimicrobial peptides. However, the molecular composition of these important immune cells has not been elucidated in depth, because of their scarcity in the circulating hemolymph, their adhesion to multiple tissues and the lack of primary culture methods to produce sufficient material for a genome-wide analysis. In this study, we report a genome-wide molecular characterization of circulating hemocytes collected from the hemolymph of adult female Anopheles gambiae mosquitoes--the major mosquito vector of human malaria in subSaharan Africa. Their molecular profile identified 1,485 transcripts with enriched expression in these cells, and many of these genes belong to innate immune gene families. This hemocyte-specific transcriptome is compared to those of Drosophila melanogaster and two other mosquitoes, Aedes aegypti and Armigeres subalbatus. We report the identification of two genes as ubiquitous hemocyte markers and several others as hemocyte subpopulation markers. We assess, via an RNAi screen, the roles in development of Plasmodium berghei of 63 genes expressed in hemocytes and provide a molecular comparison of the transcriptome of these cells during malaria infection.

Eating Patterns and Dietary Interventions in ADHD: A Narrative Review.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood, affecting ~7% of children and adolescents. Given its adverse health outcomes and high healthcare and societal costs, other treatment options beyond pharmacotherapy have been explored. Case-control studies have shown that dietary patterns may influence the risk of ADHD, and specific dietary interventions have been proposed as coadjuvant treatments in this disorder. These include nutritional supplements, gut microbiome-targeted interventions with biotics, and elimination diets. The purpose of this review is to examine which dietary patterns are most associated with ADHD and to summarize the existing evidence for the clinical use of dietary interventions. The literature showed that non-healthy dietary patterns were positively associated with ADHD, whereas healthy patterns were negatively associated. As for nutritional supplements, only vitamin D and vitamin D + magnesium appeared to improve ADHD symptoms when baseline levels of vitamin D were insufficient/deficient. Regarding biotics, evidence was only found for Lactobacillus rhamnosus GG and for multi-species probiotic supplementation. Elimination diets have scarce evidence and lead to nutritional deficiencies, so caution is advised. Overall, more robust scientific evidence is required for these dietary interventions to be implemented as part of ADHD therapy.

Renal cell carcinoma therapy: Current and new drug candidates.

Renal cell carcinoma (RCC) is the most common and lethal tumor of the urological system. Curative treatment of localized RCC includes nephrectomy, radio-ablation, and active surveillance, whereas metastatic RCC (mRCC) requires a combination of surgery and systemic therapy. Response to conventional therapy is limited but, recently, many novel therapies for mRCC have emerged, including targeted therapies and new immunotherapeutic agents. Nevertheless, development of resistance and limited durable responses demand new anticancer candidates with improved selectivity and efficacy. In this review, we summarize recent preclinical studies of novel natural and synthetic compounds to treat RCC, detailing their mechanisms of action and anticancer activities.

Estimating the effect of the wMel release programme on the incidence of dengue and chikungunya in Rio de Janeiro, Brazil: a spatiotemporal modelling study.

BACKGROUND: Introgression of genetic material from species of the insect bacteria Wolbachia into populations of Aedes aegypti mosquitoes has been shown in randomised and non-randomised trials to reduce the incidence of dengue; however, evidence for the real-world effectiveness of large-scale deployments of Wolbachia-infected mosquitoes for arboviral disease control in endemic settings is still scarce. A large Wolbachia (wMel strain) release programme was implemented in 2017 in Rio de Janeiro, Brazil. We aimed to assess the effect of this programme on the incidence of dengue and chikungunya in the city. METHODS: 67 million wMel-infected mosquitoes were released across 28 489 locations over an area of 86·8 km2 in Rio de Janeiro between Aug 29, 2017 and Dec 27, 2019. Following releases, mosquitoes were trapped and the presence of wMel was recorded. In this spatiotemporal modelling study, we assessed the effect of the release programme on the incidence of dengue and chikungunya. We used spatiotemporally explicit mathematical models applied to geocoded dengue cases (N=283 270) from 2010 to 2019 and chikungunya cases (N=57 705) from 2016 to 2019. FINDINGS: On average, 32% of mosquitoes collected from the release zones between 1 month and 29 months after the initial release tested positive for wMel. Reduced wMel introgression occurred in locations and seasonal periods in which cases of dengue and chikungunya were historically high, with a decrease to 25% of mosquitoes testing positive for wMel during months in which disease incidence was at its highest. Despite incomplete introgression, we found that the releases were associated with a 38% (95% CI 32-44) reduction in the incidence of dengue and a 10% (4-16) reduction in the incidence of chikungunya. INTERPRETATION: Stable establishment of wMel in the geographically diverse, urban setting of Rio de Janeiro seems to be more complicated than has been observed elsewhere. However, even intermediate levels of wMel seem to reduce the incidence of disease caused by two arboviruses. These findings will help to guide future release programmes. FUNDING: Bill & Melinda Gates Foundation and the European Research Council.

The Lockdown Impact on the Relations between Portuguese Parents and Their 1- to 3-Year-Old Children during the COVID-19 Pandemic.

Many countries have applied mandatory confinement measures in response to the COVID-19 pandemic, such as school and kindergarten closures, which confined families to their homes. The study concerns the impacts of the first COVID-19 lockdown on the relationships between Portuguese parents and their children, in a non-clinical population composed of fathers and mothers of children between the ages of 12 months and 3 years and 364 days. An online questionnaire (set by the research team) and the Parenting Daily Hassles Scale (PDHS) concerning the confinement period were applied between 17 June and 29 July 2020. To assess the impacts of the lockdown, outcomes regarding the impacts perceived by the parents, the potential regression in the development of children, and the willingness to promote changes in family routines in the future, were considered. Of the total sample (n = 1885), 95.4% of the parents (n = 1798) said that, after confinement, the relationship with their children had improved or remained similar to the pre-confinement period; 97.3% (n = 1835) noticed positive changes in the development of their children, and 63.7% (n = 1200) noted that the relationships with their children during the confinement period would lead to some changes in family routines in the future. Multivariate regression analyses showed that most of the sociodemographic variables chosen were not associated with the outcomes. However, significant levels of pressure over parenting and parental overload (reported by high scores in the PDHS intensity and frequency scales), challenging behaviors of the children, and the impacts they had on parental tasks had negative influences on the studied outcomes. On the contrary, the number of adults living with their children, the perceptions regarding the development of their children, and sharing new experiences with them were significant factors for positively-perceived impacts on the relationships between them or in the desire to bring about changes in family routines in the future. The impacts of the lockdown on the relationships between parents and children aged between 1 and 3 years old were more dependent on relational aspects and on the parents' sense of competence in exercising parental functions. We conclude that, despite the increased demands imposed by the lockdown, nearly all of the parents evaluated the quality of the relationship with their children as positive after this period.