Kanamycin treatment in the pre-symptomatic stage of a Drosophila PD model prevents the onset of non-motor alterations.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor alterations, which is preceded by a prodromal stage where non-motor symptoms are observed. Over recent years, it has become evident that this disorder involves other organs that communicate with the brain like the gut. Importantly, the microbial community that lives in the gut plays a key role in this communication, the so-called microbiota-gut-brain axis. Alterations in this axis have been associated to several disorders including PD. Here we proposed that the gut microbiota is different in the presymptomatic stage of a Drosophila model for PD, the Pink1B9 mutant fly, as compared to that observed in control animals. Our results show this is the case: there is basal dysbiosis in mutant animals evidenced by substantial difference in the composition of midgut microbiota in 8-9 days old Pink1B9 mutant flies as compared with control animals. Further, we fed young adult control and mutant flies kanamycin and analyzed motor and non-motor behavioral parameters in these animals. Data show that kanamycin treatment induces the recovery of some of the non-motor parameters altered in the pre-motor stage of the PD fly model, while there is no substantial change in locomotor parameters recorded at this stage. On the other hand, our results show that feeding young animals the antibiotic, results in a long-lasting improvement of locomotion in control flies. Our data support that manipulations of gut microbiota in young animals could have beneficial effects on PD progression and age-dependent motor impairments. This article is part of the Special Issue on "Microbiome & the Brain: Mechanisms & Maladies".

Can there be a common, risk-based framework for decisions around live insect trade?

A network of scientists involved in shipment of live insects has met and generated a series of articles on issues related to live insect transport. The network is diverse, covering large-scale commercial interests, government operated areawide control programmes, biomedical research and many smaller applications, in research, education and private uses. Many insect species have a record of safe transport, pose minimal risks and are shipped frequently between countries. The routine shipments of the most frequently used insect model organism for biomedical research, Drosophila melanogaster, is an example. Successful large scale shipments from commercial biocontrol and pollinator suppliers also demonstrate precedents for low-risk shipment categories, delivered in large volumes to high quality standards. Decision makers need access to more information (publications or official papers) that details actual risks from the insects themselves or their possible contaminants, and should propose proportionate levels of management. There may be harm to source environments when insects are collected directly from the wild, and there may be harm to receiving environments. Several risk frameworks include insects and various international coordinating bodies, with experience of guidance on relevant risks, exist. All stakeholders would benefit from an integrated overview of guidance for insect shipping, with reference to types of risk and categories of magnitude, without trying for a single approach requiring universal agreement. Proposals for managing uncertainty and lack of data for smaller or infrequent shipments, for example, must not disrupt trade in large volumes of live insects, which are already supporting strategic objectives in several sectors.

À l'occasion d'une réunion d'experts, un réseau de chercheurs travaillant sur l'expédition d'insectes vivants a produit un ensemble d'articles traitant des questions liées au transport des insectes vivants. Ce réseau est diversifié et représente un large éventail d'intérêts privés et de programmes de lutte biologique à grande échelle menés par les pouvoirs publics, en plus du secteur de la recherche biomédicale et de nombreux acteurs intervenant dans des applications de plus petite envergure relevant de la recherche, de l'enseignement ou du secteur privé. Un grand nombre d'espèces d'insectes sont transportées en toute sécurité avec un niveau de risque minimal, y compris lors des fréquentes expéditions internationales. Un exemple de ces expéditions régulières concerne l'espèce la plus utilisée par la recherche biomédicale en tant qu'organisme modèle, à savoir Drosophila melanogaster. Les exemples réussis d'expéditions à grande échelle provenant de fournisseurs d'agents de lutte biologique et de pollinisateurs produits par le secteur privé offrent également un relevé documenté des diverses catégories d'expéditions à faible risque pour des livraisons d'insectes vivants en grandes quantités et répondant à des normes de qualité élevées. Les décideurs politiques devraient pouvoir accéder à plus d'informations (à travers des publications ou des articles officiels) décrivant en détail les risques réels associés aux insectes eux-mêmes ou à leurs contaminants éventuels, et proposer en connaissance de cause des niveaux de gestion proportionnels à ces risques. La récolte d'insectes prélevés directement de la nature peut être dommageable aussi bien pour les environnements source que pour ceux de destination. Plusieurs cadres fondés sur le risque intègrent désormais les insectes dans leurs directives. Par ailleurs, nombre d'organismes internationaux de coordination ont acquis une expérience dans l'élaboration de lignes directrices face à ces risques. Il serait bénéfique pour toutes les parties prenantes de disposer d'une vue d'ensemble intégrée des directives applicables aux expéditions d'insectes, qui recense les différents types de risque et leurs ordres de grandeur sans se prononcer sur une approche unique qui nécessiterait une adhésion universelle. Ni les propositions visant à gérer l'incertitude ni l'insuffisance des données disponibles sur les expéditions d'insectes en petits nombres ou occasionnelles ne doivent perturber les échanges commerciaux d'insectes vivants en grandes quantités, échanges qui participent aujourd'hui aux objectifs stratégiques de nombreux secteurs.

Una red de científicos relacionados de un modo u otro con el transporte de insectos vivos mantuvo un encuentro y generó una serie de artículos en torno a la cuestión. En la red, muy heterogénea, convergen desde intereses comerciales de gran calado hasta programas públicos de lucha biológica en grandes territorios, pasando por la investigación biomédica y por numerosas aplicaciones de menor dimensión en ámbitos como la investigación, la enseñanza u otros usos privados. Muchas especies de insectos cuentan con un buen historial de seguridad en el transporte, presentan un riesgo mínimo y son expedidas a menudo de un país a otro. Buen ejemplo de ello son los envíos sistemáticos de ejemplares de Drosophila melanogaster, que es el insecto utilizado con más frecuencia como organismo modelo en la investigación biomédica. Otro precedente de envíos voluminosos cuyo transporte y entrega se ajusta a los más exigentes criterios de calidad lo sientan las remesas de grandes cantidades de polinizadores y agentes de control biológico remitidos por proveedores comerciales. Los responsables de adoptar decisiones deben disponer de más y más detallada información (publicaciones o documentos oficiales) sobre los riesgos reales derivados de los propios insectos o sus posibles contaminantes para proponer a partir de ahí medidas de gestión proporcionadas. Los perjuicios ambientales pueden darse tanto en origen (cuando hay captura salvaje de insectos, o sea recolección directa en el medio) como en destino. Hay varios sistemas de determinación del riesgo que incluyen a los insectos y también existen diversos organismos de coordinación internacional que ya tienen experiencia en sentar pautas sobre los riesgos en la materia. Todos los interlocutores del sector se beneficiarían de una visión global e integrada del transporte de insectos, que remita a diferentes tipos de riesgo y categorías de magnitud, sin necesidad de buscar un sistema único que exija consenso universal. Las propuestas para gestionar la incertidumbre y la falta de información en el caso de envíos infrecuentes o de pequeñas dimensiones, por ejemplo, no deben interferir en el transporte de grandes cantidades de insectos vivos, que ya está sirviendo a objetivos estratégicos en varios sectores.

Issues and gaps in international guidance and national regulatory systems affecting international live insect trade.

International trade in live insects involves the shipping of many different species, for various purposes, with a variety of handling requirements regulated by numerous authorities with varying objectives. The diversity of factors at play has both created and been subject to a complex regulatory landscape. A review of global production, shipping and use experiences from a range of perspectives has shown gaps and inconsistencies in international guidance and national implementation. Private carriers add another layer of uncertainty that is disproportionate to risks, resulting in variable practices and charges. Many benefits can come from international trade in insects, including pollinator services, control of pests and of disease vectors, and enhanced international scientific research and innovation. These benefits will be better achieved through a more evidence-based and efficient approach to regulating trade. This change in approach will in turn require an improved and widely accepted risk-management landscape for insect trade.

Le commerce international d'insectes vivants s'appuie sur les expéditions de nombreuses espèces différentes à diverses fins, assorties de multiples exigences relatives à la manutention régies par des autorités différentes poursuivant des objectifs distincts. La diversité des facteurs en jeu a rendu nécessaire la création d'un paysage normatif complexe, avec les contraintes qui lui sont associées. L'examen à l'échelle mondiale de la production, du transport et des expériences dans ce domaine depuis diverses perspectives a révélé un certain nombre de lacunes et d'incohérences au niveau des directives internationales et de leurs applications concrètes dans les pays. Les transporteurs privés ajoutent une dimension d'incertitude supplémentaire qui est disproportionnée par rapport aux risques, ce qui entraîne une forte variabilité des pratiques et des charges. Les échanges internationaux d'insectes génèrent nombre d'activités bénéfiques, parmi lesquelles les services de pollinisation, la lutte contre les ravageurs et les vecteurs de maladie, et l'accroissement de la recherche scientifique internationale et de l'innovation. Les objectifs attendus seront mieux atteints en adoptant une approche de la réglementation des échanges qui s'appuie davantage sur des éléments factuels et sur les gains d'efficacité. Ce changement méthodologique nécessitera à son tour la mise en place d'un cadre amélioré et plus largement accepté de la gestion des risques dans le domaine du commerce des insectes.

El comercio internacional de insectos vivos, que supone el transporte de muchas especies diferentes con fines diversos, se acompaña de requisitos de manipulación que dictan numerosas autoridades con todo tipo de objetivos. La diversidad de los factores que entran en juego ha sido a la vez causa y consecuencia de un complejo panorama reglamentario. Los autores, tras describir un estudio a escala mundial de la experiencia de producción, transporte y utilización de insectos vivos desde diferentes puntos de vista, exponen las carencias e incoherencias observadas en las directrices internacionales y su traslación a escala nacional. Los transportistas privados añaden otro factor de incertidumbre que tiene un peso desproporcionado en relación con el nivel de riesgo y se traduce en procedimientos y precios heterogéneos. El comercio internacional de insectos puede traer consigo muchos beneficios, en particular servicios de polinización, control de plagas y de vectores de enfermedad, y avances de la investigación e innovación científica a escala internacional. Pero obtener esos beneficios será más fácil si se aborda la regulación del comercio de manera más eficaz y científicamente fundamentada, operando un cambio de lógica que exigirá, a su vez, la aplicación al comercio de insectos de un régimen más sofisticado y ampliamente aceptado de gestión de los riesgos.

Streamlining cross-border shipping of live invertebrates.

The logistics of shipping live invertebrates should be straightforward: it requires timely delivery and packaging that ensures survival and confinement. The packaging is the responsibility of the shipper, whose interest is to maintain the product's quality during shipment and to ensure that no specimens escape. Timely delivery relies on the ability of the shipping agent to organise an efficient route of transport and carriers to fulfil their function effectively. This article explores this underserviced sector. While similar logistics capacity exists for other goods that require fast delivery (such as vaccines and fresh food), stakeholders who require live invertebrate shipping often have difficulties in finding transporters able or willing to handle such services. The authors bring examples from biocontrol, showing the current complexity and inconsistency of logistics. For some countries and stakeholders, this issue can be a significant barrier to the growth of a sustainable biocontrol sector. The authors also explore misconceptions (about packaging, liability and paperwork) and unclear rules (such as requiring generic veterinary certificates that are rarely relevant for invertebrates) that may cause express courier companies to refuse carrying live invertebrates. These issues often result in packages not being handled as a priority during transport connections or customs clearance, and significant delivery delays. The authors propose improvements that could streamline transport through changes that fit within existing shipping processes. This article is furthermore intended as a call to transport and inspection stakeholders to use the existing guidance and other resources to support this underdeveloped sector more effectively.

La logistique en appui des expéditions d'invertébrés vivants devrait être simple : elle doit veiller au respect des délais de livraison et s'assurer d'un conditionnement qui garantisse à la fois la survie des insectes et un confinement sans failles. Le conditionnement relève de la responsabilité de l'expéditeur, qui a tout intérêt à préserver la qualité du produit durant le transport et à veiller à ce qu'aucun spécimen ne s'échappe. Le respect des délais de livraison est déterminé par la capacité de l'opérateur à organiser un itinéraire de transport rapide et par l'efficacité mise en oeuvre par les transporteurs dans l'exercice de leur mission. Les auteurs examinent ce secteur sous-exploité. Alors que des capacités logistiques du même ordre sont déployées pour d'autres marchandises exigeant une livraison rapide (par exemple les vaccins et les produits alimentaires frais), les parties prenantes souhaitant organiser une expédition d'invertébrés vivants peinent souvent à trouver des transporteurs capables d'assurer cette prestation, voire acceptant de le faire. À partir de quelques exemples tirés de la lutte biologique, les auteurs font ressortir la complexité et les incohérences de la logistique mise en oeuvre. Pour certains pays et acteurs, ce problème peut constituer un obstacle majeur à la croissance et à la durabilité du secteur de la lutte biologique. Les auteurs relèvent également les idées fausses (concernant le conditionnement, la responsabilité légale et les contraintes administratives) et le manque de clarté réglementaire (par exemple l'obligation de fournir un certificat vétérinaire générique alors qu'un tel document est rarement pertinent pour des invertébrés), facteurs probablement à l'origine du refus de certaines entreprises de livraison express de transporter des invertébrés vivants. Ces problèmes ont pour conséquence que les lots ne sont pas traités de manière prioritaire pendant les liaisons de transport ou les procédures de dédouanement, ce qui entraîne des retards importants. Les auteurs proposent des améliorations qui pourraient rationaliser ces transports en introduisant des changements adaptés aux procédures d'expédition en vigueur. En outre, les auteurs exhortent les acteurs du transport et de l'inspection à utiliser les orientations existantes et d'autres ressources disponibles afin d'apporter un soutien plus efficace à ce secteur sous-développé.

Los aspectos logísticos ligados al envío de invertebrados vivos deberían estar meridianamente claros: lo que se requiere es una entrega puntual y un embalaje que garantice la supervivencia y el confinamiento de los animales. El embalaje es responsabilidad del expedidor, que es el primer interesado en que la calidad del producto no se resienta durante el envío y en que los especímenes no escapen. La puntualidad de la entrega depende de la capacidad del agente de expedición para organizar un itinerario adecuado y de la eficacia del transportista a la hora de cumplir su cometido. Los autores describen este sector, hoy algo desatendido. Mientras que para otros bienes que requieren una entrega rápida (como vacunas o sangre fresca) existen tales medios logísticos, los profesionales que dependen del envío de invertebrados vivos tienen a menudo dificultades para encontrar transportistas que estén en condiciones o tengan la voluntad de asumir tales servicios. Los autores presentan ejemplos de control biológico que evidencian la complejidad e incoherencia de la logística que actualmente rodea estas actividades. Para ciertos países y partes interesadas, la cuestión puede llegar a suponer un importante freno al crecimiento de un sector de lucha biológica que sea sostenible. Los autores exponen asimismo una serie de ideas equivocadas (sobre el embalaje, la responsabilidad o los trámites burocráticos) y de reglas confusas (como la exigencia de certificados veterinarios genéricos que rara vez son aplicables a los invertebrados) que pueden hacer que las empresas de transporte urgente se nieguen a transportar invertebrados vivos. Debido a estos problemas, ocurre a menudo que los bultos no sean considerados prioritarios en las conexiones de transporte o los despachos de aduanas, cosa que provoca importantes retrasos en las entregas. Los autores proponen mejoras que podrían agilizar el transporte y a la vez encajarían en los procesos de envío tal como discurren actualmente. Además, con este artículo desean alentar a cuantas partes intervienen en las actividades de transporte e inspección a que utilicen las guías y demás recursos existentes para prestar un apoyo más eficaz a este infradesarrollado sector.

International live insect trade: a survey of stakeholders.

There are significant numbers of transboundary shipments of live insects for pollination, pest management, industrial processes, research and other uses, but data collection and analysis have proved difficult. The World Organisation for Animal Health and Collectif TIS (Technique de l'Insecte Stérile), a French think tank, carried out a stakeholder survey to understand the nature of the live insect trade and potential challenges to safety and efficiency. Target respondents had experience in the areas of biocontrol, sterile insect technique, entomological research and regulatory affairs. Although the survey was sent globally, the responses were unintentionally biased towards Europe, where interest is high, since this region is developing a comprehensive framework to promote the use of beneficial insects to replace pesticides. The survey also explored respondents' knowledge of several international agreements on the movement and risk management of beneficial or invasive insects. Knowledge of the various regulations was generally poor, and respondents highlighted a perceived lack of clarity regarding live insect shipments in the existing international regulations and guidelines. Almost two-thirds of participants reported reluctance by carriers to accept live insects for shipment, and three-quarters described occasional to systematic delays that resulted in a reduction of quality or viability. Some respondents reported that they instead hand-carry live insects, mostly in small quantities. Participants described being directly involved in trade covering 70 species of live insects and ticks transported among 37 countries, with volumes ranging from fewer than ten insects to over a million per shipment. Of these, 30% were potential vectors of pathogens to humans or animals, 42% were potential plant pest species (including some used for biocontrol), and 17% were classical biocontrol agents. The results of this survey begin to define the current scope, scale and issues for those involved in shipping live insects and ticks across political boundaries. The survey's aim is to persuade regulatory bodies and shipping operators to facilitate safety, efficiency and consistency in this underdeveloped sector.

Les insectes vivants font l'objet d'un nombre important d'expéditions transfrontalières à des fins de pollinisation, de gestion des nuisibles, d'utilisation dans des processus industriels et de recherche, parmi d'autres emplois ; or, la collecte et l'analyse de données sur le sujet se sont révélées difficiles. L'Organisation mondiale de la santé animale et le Collectif TIS (Technique de l'insecte stérile), groupe de réflexion français, ont mené une enquête auprès de parties prenantes afin de comprendre la nature du commerce international d'insectes vivants ainsi que les éventuels problèmes de sécurité et d'efficacité qui lui sont associés. Les répondants sont des acteurs expérimentés dans les domaines du contrôle biologique, de la technique de l'insecte stérile, de la recherche entomologique et des questions réglementaires. Si le questionnaire a été distribué dans toutes les régions du monde, les réponses ont toutefois présenté un biais involontaire privilégiant l'Europe, région où l'intérêt pour cette question est élevé compte tenu du cadre réglementaire qui y est actuellement mis en place pour promouvoir l'utilisation des insectes utiles en replacement des pesticides. L'enquête visait également à déterminer le niveau de connaissance des répondants sur les divers accords internationaux relatifs aux mouvements d'insectes utiles ou envahissants, ainsi que sur la gestion des risques en la matière. Il en ressort que les diverses réglementations sont généralement méconnues, les répondants mettant en avant leur perception d'un manque de clarté des réglementations et directives internationales applicables aux expéditions d'insectes vivants. Près des deux tiers des participants ont fait état des réticences des transporteurs à accepter des cargaisons d'insectes vivants et les trois quarts d'entre eux ont rapporté des retards occasionnels ou systématiques se traduisant par une perte de qualité ou de viabilité. Certains répondants ont déclaré qu'ils préféraient transporter eux-mêmes les insectes vivants, la plupart du temps en petites quantités. Les répondants ont décrit leur participation directe dans des échanges couvrant au total 70 espèces de tiques et d'insectes vivants transportés dans 37 pays, avec des volumes allant de moins de dix insectes à plus d'un million d'insectes par cargaison. Parmi les espèces transportées, 30 % étaient potentiellement vectrices d'agents pathogènes pour les humains ou les animaux, 42 % étaient des nuisibles potentiels pour les végétaux (y compris certaines espèces utilisées à des fins de lutte biologique) et 17 % étaient des agents classiques de la lutte biologique. Les résultats de cette enquête permettent d'esquisser la portée et l'échelle des expéditions transfrontalières d'insectes vivants et de tiques, ainsi que la teneur des problèmes rencontrés par ceux qui y prennent part. L'objectif de l'enquête est de convaincre les organismes chargés de la réglementation ainsi que les transporteurs internationaux de la nécessité d'apporter de meilleures conditions de sécurité et d'efficacité à ce secteur sous-développé et d'en assurer la cohérence.

Pese al importante número de envíos transfronterizos de insectos vivos que se realizan con fines de polinización, gestión de plagas, procesos industriales, investigación u otros usos, hasta ahora ha resultado difícil reunir y analizar datos al respecto. La Organización Mundial de Sanidad Animal y el grupo de reflexión francés Collectif TIS (Technique de l'Insecte Stérile) hicieron una encuesta entre las partes interesadas con el fin de conocer mejor las características del comercio de insectos vivos y los factores que pueden amenazar su seguridad y eficacia. La encuesta iba dirigida a personas con experiencia en materia de control biológico, uso de la técnica del insecto estéril, investigaciones entomológicas o aspectos reglamentarios. Aunque la encuesta fue distribuida por todo el mundo, las respuestas presentaban un involuntario sesgo «europeo¼ debido al gran interés que el tema suscita en Europa, donde se está elaborando un marco reglamentario para promover el uso de insectos beneficiosos en sustitución de los plaguicidas. La encuesta indagaba asimismo en el grado de conocimiento que tenían los participantes de varios acuerdos internacionales relativos al desplazamiento de insectos beneficiosos o invasores y a la gestión de los riesgos conexos. En términos generales, los encuestados conocían poco las diversas reglamentaciones y destacaban lo que a su juicio era falta de claridad de las vigentes normativas y directrices internacionales por lo que respecta a los cargamentos de insectos vivos. Casi dos tercios de los participantes afirmaron que los transportistas eran reacios a aceptar cargamentos de insectos vivos y tres cuartas partes refirieron demoras ocasionales o sistemáticas que mermaban la calidad o viabilidad de las remesas. Algunos dijeron haber optado a cambio por el transporte manual de insectos vivos, casi siempre en pequeñas cantidades. Los encuestados afirmaron tomar parte directamente en un comercio que mueve 70 especies de insectos o ácaros vivos por 37 países, en cantidades que van desde menos de diez insectos a más de un millón de ejemplares por envío. De esas especies, un 30% correspondía a posibles vectores de patógenos humanos o animales, un 42% a posibles plagas vegetales (algunas de ellas utilizadas con fines de control biológico) y un 17% a agentes clásicos de control biológico. Los resultados permiten empezar a acotar el alcance, la escala y la naturaleza de los problemas a que se enfrentan quienes intervienen en el envío transfronterizo de insectos y ácaros vivos. La encuesta tiene por objetivo convencer a organismos de reglamentación y transportistas de que procuren fomentar la seguridad, eficiencia y coherencia de este infradesarrollado sector.

Gray matter heterotopia: clinical and neuroimaging report on 22 children.

OBJECTIVE: To investigate the clinical characteristics and neuroimaging features of childhood presenting with gray matter heterotopia observed in a single tertiary Pediatric Department in Catania and compare the data with those reported in the literature. METHODS: A retrospectively review of the history, clinical findings, electrophysiological features and magnetic resonance images of 22 children presenting with gray matter heterotopia observed from January 2010 to January 2020. RESULTS: Among the 22 children included in the study, 17 presented with periventricular heterotopia (PVNH), two with Subcortical Band Heterotopia (SBH), and three with other subcortical heterotopia (SUBH). In the affected children, the ages at first diagnosis ranged from 3 months to 16 years with a mean age of 8.2 years (± 5.4); twelve (54.5%) suffered by developmental delay and intellectual deficit; eleven children (50%) complained of epileptic seizures, mostly focal to bilateral tonic-clonic seizure. In addition, in the periventricular heterotopia group (PVNH), cerebral and systemic malformations were reported in twelve (70%) and in ten (58%) children, respectively, out of seventeen. In the SBH plus SUBH group, epileptic seizures were recorded in 3 (60%) out of 5 children, cerebral malformations in one child and systemic malformations in two children. CONCLUSIONS: Heterotopic gray matter malformations include a group of disorders that manifest with a variety of neurological implications, such as cognitive impairment and epilepsy, and often related with epilepsy, other cerebral malformations and systemic anomalies.

The impact of COVID-19 on cancer care and oncology clinical research: an experts' perspective.

The coronavirus disease-19 (COVID-19) pandemic promises to have lasting impacts on cancer clinical trials that could lead to faster patient access to new treatments. In this article, an international panel of oncology experts discusses the lasting impacts of the pandemic on oncology clinical trials and proposes solutions for clinical trial stakeholders, with the support of recent data on worldwide clinical trials collected by IQVIA. These lasting impacts and proposed solutions encompass three topic areas. Firstly, acceleration and implementation of new operational approaches to oncology trials with patient-centric, fully decentralized virtual approaches that include remote assessments via telemedicine and remote devices. Geographical differences in the uptake of remote technology, including telemedicine, are discussed in the article, focusing on the impact of the local adoption of new operational approaches. Secondly, innovative clinical trials. The pandemic has highlighted the need for new trial designs that accelerate research and limit risks and burden for patients while driving optimization of clinical trial objectives and endpoints, while testing is being minimized. Areas of considerations for clinical trial stakeholders are discussed in detail. In addition, the COVID-19 pandemic has exposed the underrepresentation of minority groups in clinical trials; the approach for oncology clinical trials to improve generalizability of efficacy and outcomes data is discussed. Thirdly, a new problem-focused collaborative framework between oncology trial stakeholders, including decision makers, to leverage and further accelerate the innovative approaches in clinical research developed during the COVID-19 pandemic. This could shorten timelines for patient access to new treatments by addressing the cultural and technological barriers to adopting new operational approaches and innovative clinical trials. The role of the different stakeholders is described, with the aim of making COVID-19 a catalyst for positive change in oncology clinical research and eventually in cancer care.

Complication Rates of Hemiarthroplasty Conversion to Total Hip Arthroplasty Versus Primary Total Hip Arthroplasty.

BACKGROUND: One of the most common surgical options for treatment of a femoral neck fracture is hemiarthroplasty (HA). However, progression of arthritis or pain can necessitate conversion to total hip arthroplasty (THA). While conversion to a THA is a viable option, it does carry multiple risks. The purpose of this study was to identify whether performing conversion from HA to THA carries an increased risk of post-operative joint complications when compared to elective THA. METHODS: An administrative claims database was queried to identify patients who underwent conversion from a HA to a THA. Incidences of prosthetic dislocation, prosthetic joint infection (PJI), periprosthetic fracture, aseptic loosening, and revision were collected and compared to elective primary THA with multivariable logistic regression. RESULTS: Patients undergoing conversion THA had significantly higher risks of all joint complications examined at both 1 and 2 years after surgery. These included prosthetic dislocation (1-year: OR 2.95; 2 years: OR 3.77), PJI (1-year: OR 1.38; 2 years: OR 2.13), periprosthetic fracture (1-year: OR 2.95; 2 years: OR 3.75), aseptic loosening (1-year: OR 6.86; 2 years: OR 7.70), and revision (1-year: OR 3.65; 2 years: OR 6.73). CONCLUSION: Performing conversion arthroplasty from HA to THA is associated with an increased risk of multiple joint complications in both the short and mid-term follow-up period. Surgeons should consider these complications when indicating HA for femoral neck fractures and elective conversion arthroplasty.

Efficacy and safety of oral administration of a product based on hydroxytyrosol as preventive therapy for recurrent vulvo-vaginal candidosis: a prospective observational pilot study.

OBJECTIVE: The aim of the study is to evaluate the efficacy and safety of hydroxytyrosol for the prevention of the vulvar vaginal candida infections recurrence. PATIENTS AND METHODS: This study is a prospective observational pilot study. Eligible subjects were at least 18 years old, with at least 4 documented episodes of vulvovaginal candidiasis in the last 12 months. Patients were instructed to therapy (2 tabs daily for the first month and then 1 tab daily for 2 other months). Each capsule consists of hydroxytyrosol (HT) and other components: tea tree oil, tabebuia, juglans regia, and copper. Clinical and microbiological assessments took place at baseline and 12 weeks after. The impact on Quality of Life (QoL) was evaluated with the SF-36 and the Patient Global Impression of Improvement (PGI-I) after 3 months of treatment was calculated. RESULTS: Sixty patients were enrolled in the study. In the last 1 year the mean number of previous infections was 5.83 ± 2.76. Forty-nine patients (83%) did not have candida episodes during 3 months of treatment. A significant reduction in clinical symptoms, vaginal signs, such as pruritus, burning and vulvar erythema (< 0.0001). The SF-36 showed a significant change (55.67±8.43 vs. 84.56±11.56, p < 0.0001) and the total success at PGI-I was reported in 54 patients (90%). CONCLUSIONS: The HT-based product is effective and safe in preventing recurrent candida episodes and improves the quality of life and sexual function of treated women.

Usefulness of dual imaging stress echocardiography for the diagnosis of coronary allograft vasculopathy in heart transplant recipients.

BACKGROUND: Coronary allograft vasculopathy (CAV) is the main factor limiting long-term survival after cardiac transplantation. Dual imaging stress echocardiography with wall motion and Doppler-derived coronary flow reserve (CRF) of the left anterior descending artery (LAD) is a state-of-the-art methodology during dipyridamole stress echocardiography (DiSE). This study involving 74 heart transplanted patients has the purpose to assess the diagnostic value of dipyridamole stress echocardiography with evaluation of wall motion (WM) and Doppler-derived coronary flow reserve for the diagnosis of coronary allograft vasculopathy. METHODS AND RESULTS: All patients underwent DiSE and coronary angiography. Moderate-severe CAV was defined according to International Society of Heart and Lung Transplant (ISHLT) recommended nomenclature for CAV, and CFR < 2 was considered to be impaired. Moderate-severe CAV was present in 11 patients. WM analysis revealed four patients (5%) with rest WM abnormalities. CFR analysis revealed that 40 (54%) individuals had an abnormal result. The combined evaluation of WM analysis and CFR resulted in a sensitivity of 72.7% (95% CI: 39.3 to 92.6%), a specificity of 49.2% (95% CI: 36.5 to 61.9%), a positive predictive value of 20% (95% CI: 9.6 to 36.1%), and negative predictive value of 91.1% (95% CI: 75.1 to 97.6%) for the diagnosis of CAV. CONCLUSIONS: Our results support the inclusion of DiSE performance in Heart transplant follow up protocol. The addition of CFR evaluation offers valuable information to the angiography findings in the detection of CAV and could be helpful in selected patients to adjust the time and indications of coronary angiography.

Surgical sponge associated with platelets rich plasma in skin mesh grafts and layer in rabbits (Oryctolagus cuniculus) / Esponja cirúrgica associada com plasma rico em plaquetas em enxertos cutâneos em malha e camada em coelhos (Oryctolagus cuniculus)

The aim of this study was to evaluate of the efficacy of PRP employment associated with surgical sponges to improve the integration of the graft in the recipient bed. It was held at the Veterinary Hospital UNESP, Campus of Jaboticabal - SP, a study of 64 rabbits, divided into eight groups with eight animals. The groups were divided in control with saline solution 0,9%, control with PRP both without the sponge, surgical sponge with PRP, surgical sponge without PRP, and were used mesh and layer grafts in the respective groups. The data were submitted to statistical analysis (paired t-test, Kruskal-Wallis test, with subsequent use of the multiple comparison tests of Dunn, analysis of variance (F) test, Tukey test, P< 0.05). Edema and exudate with 3 and 3 and 7 days (P= 0,03 e P= 0,0049); coloring on the 14th day (P= 0,0001); cosmetic appearance on the 7th and 14th day (P= 0,0026 and P= 0,0001); mononuclear cells (P= 0,01) and polymorphonuclear (P= 0,01); fibroblast proliferation (P= 0,01); collagenous (P= 0,05); hemorrhage (P-007); necrosis and re-epithelialization (P= 0,2928 and P= 0,1). We concluded that the use of Platelet Rich Plasma Gel on skin grafts associated with a sponge as a compressive dressing promote the skin graft survival without a previous granulation tissue.(AU)

O objetivo deste estudo foi avaliar a eficácia do PRP associado com esponjas cirúrgicas na integração do enxerto ao leito receptor. Realizou-se, no Hospital Veterinário da Unesp, Jaboticabal, SP, um estudo com 64 coelhos, separados em oito grupos, com oito animais. Os grupos foram: Gprpc (PRP, sem esponja cirúrgica, enxerto camada), Gprpce (PRP, esponja cirúrgica, enxerto camada), Gcc (solução fisiológica 0,9%, sem esponja cirúrgica, enxerto camada), Gcce (solução fisiológica 0,9%, esponjas cirúrgicas, enxerto camada), Gprpm (PRP, sem esponja cirúrgica, enxerto malha), Gprpme (PRP, esponja cirúrgica, enxerto malha), Gcm (solução fisiológica 0,9%, sem esponja cirúrgica, enxerto malha) e Gcce (solução fisiológica 0,9%, esponjas cirúrgicas, malha). Os dados foram analisados pelo teste t emparelhado, Kruskal-Wallis, análise de variância, e teste de Tukey (P<0,05). Edema e exsudato presente com três e sete dias (P=0,03 e P=0,0049); coloração cianótica no 14º dia (P=0,0001); aspecto cosmético bom no sétimo e no 14º dia (P=0,00026 e P=0,0001); presença de células mononucleares (P=0,01) e polimorfonucleares (P=0,01); proliferação de fibroblastos discreta (P=0,01); colagenização intensa (P=0,05); hemorragia discreta (P=0,007); ausência de diferença significativa em necrose e reepitelização (P=0,2928 e P=0,1). Conclui-se que o emprego do PRP gel em enxertos cutâneos associando esponjas cirúrgicas como curativo compressivo favorece sua integração ao leito receptor sem a presença prévia de tecido de granulação.(AU)

Extremity soft tissue sarcoma with multiple primary malignancies--Characteristics and outcome.

BACKGROUND: Understanding the incidence and characteristics of multiple primary malignancies (MPM) has implications for guiding appropriate treatment and surveillance of extremity soft tissue sarcoma (STS). OBJECTIVES: We sought to examine the incidence of MPM in STS (MPM-STS), and compare their clinicopathologic characteristics and survival to those with STS only. METHODS: 585 patients who underwent surgery for extremity STS were reviewed. Logistic regression analyses to identify factors contributing to the development of MPMs and a 1:2 matched case-control analysis to compare survival outcome were performed. RESULTS: Of the 585 patients analyzed, 34 (6%) with MPM were identified. On univariate logistic regression analysis, older age (>49 years) at STS diagnosis (p = 0.008) and histologic types of undifferentiated pleomorphic sarcoma or myxofibrosarcoma (p = 0.033) were significant. In multivariate analysis, only older age at STS diagnosis remained significant (OR = 2.5, p = 0.029). Cancer-specific survival of the MPM-STS group was significantly lower than that of the STS-only group (p = 0.031). However, there was no significant difference in STS-specific survival between the two groups (p = 0.208). CONCLUSION: Our study suggests that MPM is not uncommon in extremity STS and older age at STS diagnosis is associated with risk of MPM. Prognosis of STS in the MPM-STS group seems similar to that of the STS-only group.

Quality of life in caregivers of children with asthma: Validity and reliability of the IFABI-R questionnaire.

BACKGROUND: Parents'/caregivers' quality of life is an important aspect to consider when handling paediatric asthma, but there is a paucity of valid and reliable instruments to measure it. The Family Impact of Childhood Bronchial Asthma (IFABI-R) is a recently developed questionnaire to facilitate the assessment of asthma-related parents'/caregivers' quality of life. This study researches the psychometric properties of IFABI-R. METHODS: Parents/main caregivers of 462 children between 4 and 14 years of age with active asthma were included in the sample. IFABI-R was administered on two different occasions and a number of other variables related to the parents'/caregivers' quality of life were measured: child's asthma control, family functioning, and parents'/caregivers' perception of asthma symptoms in the child. IFABI-R evaluative and discriminative properties were analysed, and the minimal important change in the IFABI-R score was identified. RESULTS: IFABI-R showed high internal consistency (Cronbach's alpha=0.941), cross-sectional construct validity (correlation with the degree of child's asthma control, family functioning and parent/caregiver perception of the child's asthma symptoms), longitudinal construct validity (correlation of changes in the IFABI-R with changes in asthma control and changes in the perception of symptoms), sensitivity to change and test-retest reliability. An absolute change of 0.3 units in IFABI-R related to a minimal significant change in the parents'/caregivers' quality of life. CONCLUSIONS: IFABI-R is a reliable and valid instrument to study the quality of life of parents/caregivers of children with asthma.

X-ray-induced sterility in Aedes albopictus (Diptera: Culicidae) and male longevity following irradiation.

The mosquito Aedes albopictus (Skuse, 1895) is a potent vector of several arboviral diseases, most notably chikungunya and dengue fever. In the context of the sterile insect technique (SIT), the sterilization of the male mosquitoes before their release can be achieved by gamma-ray irradiation. As gamma-ray irradiators are becoming increasingly problematic to purchase and transport, the suitability of an X-ray irradiator as an alternative for the sterilization of Ae. albopictus males was studied. The sterilization of up to 200,000 pupae at one time can be achieved with relative ease, and the sterility results obtained were comparable with those achieved by gamma irradiation, where 99% sterility is induced with a dose of 40 Gy. A significant reduction of longevity was observed in the latter stages of the males' life after irradiation treatments, especially at doses > 40 Gy, which is consistent with the negative effects on longevity induced by similar radiation doses using gamma rays. Females irradiated at 40 Gy were not only 100% sterile, but also failed to oviposit entirely, i.e., all of the females laid 0 eggs. Overall, it was found that the X-ray irradiator is generally suitable for the sterilization process for sterile insect technique programs, as it showed a high processing capacity, practicality, high effectiveness, and reproducibility.

Component analysis of hospital cost of pancreas-kidney transplant and correlations with different variables in a Brazilian hospital.

INTRODUCTION: Simultaneous pancreas-kidney transplantation is associated with a high rate of complications when it is compared with transplantation of other organs; these increased complications can result in increased financial costs of the procedure. The objective of this study was to determine operating costs and financial results of simultaneous pancreas-kidney transplantation and its different variables in a Brazilian hospital. PATIENTS AND METHODS: Between January 2008 and December 2011, the monthly costs of 105 patients were calculated. These patients were divided into 2 groups; the first consecutive 53 patients were labeled group I and the second set of 52 patients were labeled group II. The cost evaluation was made in US dollars. RESULTS: A total of 89 patients corresponded to the public health system and 16 patients to the supplementary health system. The percentage of hospital discharge was 92.4%. There was an increase in operating room costs in group II compared with group I with no statistically significant difference ($18,749.33 for group I and $17,608.26 for group II). The outcome of the operation was positive; it was greater for group II than for group I ($16,303.22 vs $3494.53). CONCLUSIONS: Simultaneous pancreas-kidney transplantation is a financially feasible procedure in Brazil, with the public health system being the main payment source.

Effects of tetrahydrohyperforin in mouse hippocampal slices: neuroprotection, long-term potentiation and TRPC channels.

Tetrahydrohyperforin (IDN5706) is a semi-synthetic compound derived from hyperforin (IDN5522) and is the main active principle of St. John's Wort. IDN5706 has shown numerous beneficial effects when administered to wild-type and double transgenic (APPswe/PSEN1ΔE9) mice that model Alzheimer's disease. However, its mechanism of action is currently unknown. Toward this end, we analysed field excitatory postsynaptic potentials (fEPSPs) in mouse hippocampal slices incubated with IDN5706 and in the presence of the TRPC3/6/7 activator 1-oleoyl-2-acetyl-sn-glycerol (OAG), the TRPC channel blocker SKF96365, and neurotoxic amyloid ß-protein (Aß) oligomers. To study spatial memory, Morris water maze (MWM) behavioural tests were conducted on wild-type mice treated with IDN5706 and SKF96365. In silico studies were conducted to predict a potential pharmacophore. IDN5706 and OAG had a similar stimulating effect on fEPSPs, which was inhibited by SKF96365. IDN5706 protected from reduced fEPSPs induced by Aß oligomers. IDN5706 improved spatial memory in wild-type mice, an effect that was counteracted by co-administration of SKF96365. Our in silico studies suggest strong pharmacophore similarity of IDN5706 and other reported TRPC6 activators (IDN5522, OAG and Hyp9). We propose that the effect of IDN5706 is mediated through activation of the TRPC3/6/7 channel subfamily. The unveiling of the drug's mechanism of action is a necessary step toward the clinical use of IDN5706 in Alzheimer's disease.

An organizational model to improve the robotic system among general surgeons.

INTRODUCTION: Robotic surgery has gained wide acceptance in recent years. However its development is slower and the lack of high level experience with this technique is an important limitation. This manuscript discusses some of the reasons of it and aims to describe the organizational system we have progressively established in our center in order to improve the development of Robotic program in our surgical area. METHODS: Some points may be required to improve the robotic program development in a general surgical department, including: a broad availability of robotic system in a surgical area; an ideal setting area with mainly oncological and hepato-biliary-pancreatic disease; the need of a mainly young team; a broad application of the robotic system in more general surgical fields; a high motivation on robotic use; a departmental and institutional economical effort. We have tried to achieve these goals before starting the robotic program in our department at October 2010. RESULTS: From October 2010 until November 2013 a total of 170 procedures have been performed, 92% of them for malignant diseases. Conversion rate and overall morbidity was 5% and 19%, respectively. CONCLUSIONS: The organizational model defined in our center is facilitating the constant and progressive development of the robotic program. A broad and flexible availability of the robotic system, a progressive increase of young surgeons joining this technology as well as the institutional and departmental economical effort are the points with which the robotic system may increase its development in a surgical department.

Double heterozygosity for BRCA1 and hMLH1 gene mutations in a 46-year-old woman with five primary tumors.

Germline mutations in BRCA1 and BRCA2 genes predispose to hereditary breast cancer, whereas carriers of mutations in any of the mismatch repair genes (MMR; hMLH1, hMSH2, hMSH6, hPMS2) are highly susceptible to Lynch syndrome. In the present study, we describe a woman affected by unilateral breast cancer at the age of 35 years. After 4 years, during the follow-up she developed synchronous (and asymptomatic) endometrial cancer, ovarian carcinoma and renal clear cell carcinoma. After 7 years (at age 46), the patient developed an infiltrating carcinoma of the contralateral breast and died in a few months of metastatic disease. Initial investigations led to the detection of a constitutional mutation in the BRCA1 gene. The extended genealogical tree disclosed a suspected history of colorectal carcinoma in the maternal branch. Endometrial cancer of the proband was investigated for microsatellite instability (MSI) and immunohistochemical expression of MLH1, MSH2 and MSH6 proteins. An high MSI status and lack of expression of MLH1 protein were detected. hMLH1 gene sequencing revealed the presence of a constitutional mutation, which was also found in the mother of the proband. Loss of the wild-type hMLH1 allele was detected in both breast tumors, thus suggesting that the MMR defect contributed to the development of the breast cancer.

Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments.

PURPOSE: This non-randomized, patient-access protocol, assessed both safety and efficacy outcomes following liposomal muramyl-tripeptide-phosphatidylethanolamine (L-MTP-PE; mifamurtide) in patients with high-risk, recurrent and/or metastatic osteosarcoma. METHODS: Patients received mifamurtide 2 mg/m(2) intravenously twice-weekly ×12 weeks, then weekly ×24 weeks with and without chemotherapy. Serum concentration-time profiles were collected. Adverse events within 24 hours of drug administration were classified as infusion-related adverse events (IRAE); other AEs and overall survival (OS) were assessed. RESULTS: The study began therapy in January 2008; the last patient completed therapy in October 2012. Two hundred five patients were enrolled; median age was 16.0 years and 146/205 (71%) had active disease. Mifamurtide serum concentrations declined rapidly in the first 30 minutes post-infusion, then in a log-linear manner 2-6 hours post-dose; t1/2 was 2 hours. There were no readily apparent relationships between age and BSA-normalized clearance, half-life, or pharmacodynamic effects, supporting the dose of 2 mg/m(2) mifamurtide across the age range. Patients reported 3,679 IRAE after 7,482 mifamurtide infusions. These were very rarely grade 3 or 4 and most commonly included chills + fever or headache + fatigue symptom clusters. One- and 2-year OS was 71.7% and 45.9%. Patients with initial metastatic disease or progression approximated by within 9 months of diagnosis (N = 40) had similar 2-year OS (39.9%) as the entire cohort (45.9%) CONCLUSIONS: Mifamurtide had a manageable safety profile; PK/PD of mifamurtide in this patient access study was consistent with prior studies. Two-year OS was 45.9%. A randomized clinical trial would be required to definitively determine impact on patient outcomes.