Improving eSource Site Start-Up Practices.

Background: eSource software that copies patient electronic health record data into a clinical trial electronic case report form holds promise for increasing data quality while reducing data collection, monitoring and source document verification costs. Integrating eSource into multicenter clinical trial start-up procedures could facilitate the use of eSource technologies in clinical trials. Methods: We conducted a qualitative integrative analysis to identify eSource site start-up key steps, challenges that might occur in executing those steps, and potential solutions to those challenges. We then conducted a value analysis to determine the challenges and solutions with the greatest impacts for eSource implementation teams. Results: There were 16 workshop participants: 10 pharmaceutical sponsor, 3 academic site, and 1 eSource vendor representatives. Participants identified 36 Site Start-Up Key Steps, 11 Site Start-Up Challenges, and 14 Site Start-Up Solutions for eSource-enabled studies. Participants also identified 77 potential impacts of the Challenges upon the Site Start-Up Key Steps and 70 ways in which the Solutions might impact Site Start-Up Challenges. The most important Challenges were: (1) not being able to identify a site eSource champion and (2) not agreeing on an eSource approach. The most important Solutions were: (1) vendors accepting electronic data in the FHIR standard, (2) creating standard content for eSource-related legal documents, and (3) creating a common eSource site readiness checklist. Conclusions: Site start-up for eSource-enabled multi-center clinical trials is a complex socio-technical problem. This study's Start-Up Solutions provide a basic infrastructure for scalable eSource implementation.

EADV Task Force Pruritus White Paper on chronic pruritus and chronic prurigo: Current challenges and future solutions.

Chronic pruritus (CP) is frequent in general medicine and the most common complaint in general dermatology. The prevalence of CP is expected to rise in the future due to the ageing population. The clinical presentation, underlying aetiology and treatment strategy of CP are heterogeneous. Also, individual treatment aims and physical, psychic and economic burdens of patients might vary. Chronic prurigo (CPG) is the most severe disease in the chronic pruritus spectrum, being associated with long-standing scratch-induced skin lesions and a therapy refractory itch-scratch-cycle. It is thus important to raise disease awareness for CP and CPG in the general public and among decision-makers in the health system. Further, there is a need to support a rational clinical framework to optimize both diagnostics and therapeutics. Currently, there is still a shortcoming regarding approved therapies and understanding CP/CPG as severe medical conditions. Therefore, the EADV Task Force Pruritus decided to publish this white paper based on several consensus meetings. The group consented on the following goals: (a) ensure that CP is recognized as a serious condition, (b) increase public awareness and understanding of CP and CPG as chronic and burdensome diseases that can greatly affect a person's quality of life, (c) clarify that in most cases CP and CPG are non-communicable and not caused by a psychiatric disease, (d) improve the support and treatment given to patients with CP to help them manage their disease and (e) publicize existing therapies including current guidelines. We aim to point to necessary improvements in access and quality of care directed to decision-makers in health policy, among payers and administrations as well as in practical care.

Standard methods for marking caudate amphibians do not impair animal welfare over the short term: An experimental approach.

Major advancements in ecology and biodiversity conservation have been made thanks to methods for marking and individually tracking animals. Marking animals is both widely used and controversial due to the potential consequences for animal welfare, which are often incompletely evaluated prior to implementation. Two outstanding knowledge gaps concerning the welfare consequences of individual marking are their short-term behavioural impacts and the relative impacts from marking versus the handling of animals while carrying out procedures. We addressed these knowledge gaps through an experimental study of alpine newts (Ichthyosaura alpestris) in which we varied handling and marking procedures. Examining individual responses to handling, toe clipping and visible implant elastomer (VIE) injection over 21 days showed that handling and marking elicited increased newt activity and hesitancy to feed compared to animals that did not get handled or marked. These effects were apparent even when animals were handled only (not marked), and marking did not further increase the magnitude of responses. Increases in newt activity and feeding hesitancy were transient; they were not observed in the weeks following handling and marking. While previous studies emphasise the welfare impacts of marking procedures themselves, these findings highlight that handling alone can elicit behavioural changes with possible costs to welfare. Yet, the transient nature of behavioural responses suggests that immediate costs of handling may be subsequently compensated for in the short term.

Unravelling the molecular interactions behind the formation of PEG/PPG aqueous two-phase systems.

The understanding of molecular interactions that control phase separation in polymer/polymer aqueous two-phase systems (ATPS) has been a subject of debate up to this day. In light of this, we set out to investigate the molecular interactions occurring in ternary mixtures composed of polyethylene glycol (PEG600), polypropylene glycol (PPG400) and water. The ternary phase diagram was plotted at two temperatures (298 K and 323 K), revealing a transition from a type 0 to a type I diagram. Molecular dynamics (MD) simulations were performed to elucidate the polymer-polymer and polymer-water interactions occurring at different temperatures and water concentrations. COnductor-like Screening Model for Realistic Solvents (COSMO-RS) was used to assess the thermodynamic properties of the polymer-water binary mixtures and their correlation with ATPS formation. The MD simulations clearly demonstrate the effect of segregation/separation with increasing water content and temperature, highlighting a significant reduction in PPG-water interactions compared to PEG-water counterparts. Polymer-water interactions were identified as those controlling the phase separation mechanism, and the thermodynamic properties determined with COSMO-RS for the polymer-water binary systems further support this view.

Prevalence of dermatitis including allergic contact dermatitis from medical devices used by children and adults with Type 1 diabetes mellitus: A systematic review and questionnaire study.

Use of medical devices (MDs), that is, glucose sensors and insulin pumps, in patients with Type 1 diabetes mellitus (T1D) has proven an enormous advantage for disease control. Adverse skin reactions from these MDs may however hamper compliance. The objective of this study was to systematically review and analyse studies assessing the prevalence and incidence of dermatitis, including allergic contact dermatitis (ACD) related to MDs used in patients with T1D and to compare referral routes and the clinical investigation routines between clinics being part of the European Environmental and Contact Dermatitis Research Group (EECDRG). A systematic search of PubMed, EMBASE, CINAHL and Cochrane databases of full-text studies reporting incidence and prevalence of dermatitis in persons with T1D using MDs was conducted until December 2021. The Newcastle-Ottawa Scale was used to assess study quality. The inventory performed at EECRDG clinics focused on referral routes, patient numbers and the diagnostic process. Among the 3145 screened abstracts, 39 studies fulfilled the inclusion criteria. Sixteen studies included data on children only, 14 studies were on adults and nine studies reported data on both children and adults. Participants were exposed to a broad range of devices. Skin reactions were rarely specified. It was found that both the diagnostic process and referral routes differ in different centres. Further data on the prevalence of skin reactions related to MDs in individuals with T1D is needed and particularly studies where the skin reactions are correctly diagnosed. A correct diagnosis is delayed or hampered by the fact that, at present, the actual substances within the MDs are not declared, are changed without notice and the commercially available test materials are not adequately updated. Within Europe, routines for referral should be made more standardized to improve the diagnostic procedure when investigating patients with possible ACD from MDs.

Another step through the crux: a new microendemic rock-dwelling Paroedura (Squamata, Gekkonidae) from south-central Madagascar.

Using an integrative taxonomic approach including genetic and morphological data, we formally describe a new microendemic gecko species belonging to the Paroedurabastardi clade, previously referred to as P.bastardi D. We name this taxon currently known from Anja Reserve and Tsaranoro Valley Forest (south-central Madagascar), as P.manongavatosp. nov. The new species differs from other species of the P.bastardi clade by ≥ 12.4% uncorrected p-distance at the mitochondrial 16S rRNA gene and it forms a monophyletic group in the COI mtDNA phylogenetic tree. It lacks haplotype sharing at the nuclear KIAA1239 and CMOS genes with the other species of the same complex, including the syntopic P.rennerae. Given its limited extent of occurrence and high levels of habitat fragmentation linked to forest clearances and fires, we propose the IUCN Red List Category of Critically Endangered, based on the B1ab(iii) criterion. The conservation value of Anja Reserve and Tsaranoro Valley Forest is remarkable. Preserving the remaining deciduous forest habitat is of paramount importance to protect these narrow-range reptile species.

Relationship between two pathogens in an amphibian community that experienced mass mortalities.

Because host species tend to harbor multiple parasitic species, coinfection in a host is common. The chytrid fungus Batrachochytrium dendrobatidis (Bd) and the viruses in the genus Ranavirus (Rv) are responsible for the decline of amphibians worldwide. Despite wide geographical co-occurrence and the serious conservation problem that coinfection with these pathogens could represent, little is known about their possible synergistic interactions and effects in a host community. We investigated the occurrence and associations between these two pathogens in an amphibian community after Rv-driven disease outbreaks were detected in four populations of the Iberian ribbed newt (Pleurodeles waltl) in northwestern Spain. We collected tissue samples from amphibians and fish and estimated Bd and Rv infection loads by qPCR. A few months after the most recent mass mortality event, Rv infection parameters at the affected sites decreased significantly or were lower than such registered at the sites where no outbreaks were recorded. Both pathogens were simultaneously present in almost all sites, but coinfection in a single host was rare. Our findings suggest that the co-occurrence of Bd and Rv does not predict adverse outcomes (e.g., enhanced susceptibility of hosts to one pathogen due to the presence or infection intensity of the other) following an outbreak. Other variables (such as species identity or site) were more important than infection with a pathogen in predicting the infection status and severity of infection with the other pathogen. Our results highlight the importance of host-specific and environmental characteristics in the dynamics of infections, coinfection patterns, and their impacts.

Relaciones entre dos patógenos en una comunidad anfibia que experimentó mortalidad masiva Resumen La coinfección es común en especies hospederas ya que estas especies tienden a albergar muchas especies parasíticas. El hongo quitridio Batrachochytrium dendrobatidis (Bd) y los virus del género Ranavirus (Rv) son responsables de la declinación mundial de anfibios. A pesar de la amplia co-ocurrencia geográfica y el problema serio de conservación que podría representar la coinfección con estos patógenos, se conoce muy poco sobre sus posibles interacciones sinérgicas y sus efectos en una comunidad hospedera. Investigamos la incidencia y las asociaciones entre estos dos patógenos en una comunidad anfibia después de que se detectaron brotes de enfermedades causados por Rv en cuatro poblaciones del tritón estriado ibérico (Pleurodeles waltl) en el noroeste de España. Recolectamos muestras de tejido de anfibios y peces y estimamos la carga infecciosa de Bd y Rv con una qPCR. Unos meses después del evento de mortalidad masiva más reciente, los parámetros de infección de Rv en los sitios afectados disminuyeron significativamente o fueron más bajos que los registrados en sitios sin brotes. Ambos patógenos estuvieron presentes de forma simultánea en casi todos los sitios, pero fue raro encontrar la coinfección en un solo hospedero. Nuestros descubrimientos sugieren que la coocurrencia de Bd y Rv no pronostica resultados adversos (aumento en la susceptibilidad de los hospederos a un patógeno debido a la presencia o intensidad de infección del otro patógeno) después de un brote. Otras variables, como la identidad de la especie o el sitio, fueron más importantes que la infección con un patógeno en la predicción del estado de infección y la severidad de la infección con otro patógeno. Nuestros resultados resaltan la importancia de las características ambientales y aquellas específicas del hospedero en las dinámicas de infección, los patrones de coinfección y sus impactos.

Spatial Ecology of an Arboreal Iguana (Oplurus cyclurus) in a Treeless Landscape.

Understanding the spatial ecology of species has important implications for conservation, as it helps identify suitable habitats and minimum requirements for biodiversity monitoring and management. The spiny-tailed lizard Oplurus cyclurus is a widespread endemic iguanid occurring in dry areas of southern and western Madagascar. While the species is known to be mostly arboreal, populations of the Isalo sandstone massif suggest local adaptation to a less forested savannah and a more exposed habitat. We radio-tracked 19 spiny-tailed lizards to investigate the species' rock-dwelling behaviour and spatial ecology at Isalo National Park. Tracked individuals showed high site and burrow fidelity, and a basking behaviour mostly tied to the accessibility of their burrow, the time of day, and their life stage. Activity peaked during the sunniest hours, while juveniles were more active than adults with unfavourable weather conditions. Despite high burrow fidelity, lizards used shelters non-exclusively, regularly changing (approx. once a week) with neighbouring burrows (average distance between burrows = 13.6 m). However, there was no obvious relation between lizards' body and/or tail size and the width and depth of selected burrows. Dynamic Brownian Bridge Movement Models estimated frequented areas over 247.8 m2 (95% isopleth), where territorial overlap is common. Our results challenge the notion that burrow-site fidelity is the sole driving factor behind space utilization in the studied population. We argue that the apparently unusual saxicolous habits imposed by habitat features (the absence of trees) may lead to local behavioural adjustments influencing antipredatory and foraging strategies, as well as intraspecific interactions.

The path towards type V deep eutectic solvents: inductive effects and steric hindrance in the system tert-butanol + perfluoro tert-butanol.

The solid-liquid phase behaviour of two tertiary alcohols, perfluoro-tert-butanol and tert-butanol, was studied here using experimental (ITC, DSC and density measurements) and theoretical (MD simulations) approaches. The phase diagram of the binary mixture reveals highly negative deviations from ideality at low concentrations, as well as the formation of co-crystals and is characterized by two eutectic points, a congruent melting point and a peritectic reaction corresponding to TBH : TBF stoichiometries of 2 : 1 and 1 : 1 respectively. Excess molar enthalpies and volumes were calculated, showing negative and positive deviations from ideality, respectively. The effect of acidity, stereochemical hindrance and phobic effects and how they affect intermolecular interactions in these binary mixtures is discussed, with the aim of designing and fine-tuning type V deep eutectic solvents. The results showed that the fluorination of tertiary alcohols can be used for the tuning of the mixing properties and solid-liquid phase diagrams.

Genipin prevents alpha-synuclein aggregation and toxicity by affecting endocytosis, metabolism and lipid storage.

Parkinson's Disease (PD) is a common neurodegenerative disorder affecting millions of people worldwide for which there are only symptomatic therapies. Small molecules able to target key pathological processes in PD have emerged as interesting options for modifying disease progression. We have previously shown that a (poly)phenol-enriched fraction (PEF) of Corema album L. leaf extract modulates central events in PD pathogenesis, namely α-synuclein (αSyn) toxicity, aggregation and clearance. PEF was now subjected to a bio-guided fractionation with the aim of identifying the critical bioactive compound. We identified genipin, an iridoid, which relieves αSyn toxicity and aggregation. Furthermore, genipin promotes metabolic alterations and modulates lipid storage and endocytosis. Importantly, genipin was able to prevent the motor deficits caused by the overexpression of αSyn in a Drosophila melanogaster model of PD. These findings widens the possibility for the exploitation of genipin for PD therapeutics.

Post-acute phase and sequelae management of epidermal necrolysis: an international, multidisciplinary DELPHI-based consensus.

BACKGROUND: Long-term sequelae are frequent and often disabling after epidermal necrolysis (Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)). However, consensus on the modalities of management of these sequelae is lacking. OBJECTIVES: We conducted an international multicentric DELPHI exercise to establish a multidisciplinary expert consensus to standardize recommendations regarding management of SJS/TEN sequelae. METHODS: Participants were sent a survey via the online tool "Survey Monkey" consisting of 54 statements organized into 8 topics: general recommendations, professionals involved, skin, oral mucosa and teeth, eyes, genital area, mental health, and allergy workup. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). Results were analyzed according to the RAND/UCLA Appropriateness Method. RESULTS: Fifty-two healthcare professionals participated. After the first round, a consensus was obtained for 100% of 54 initially proposed statements (disagreement index < 1). Among them, 50 statements were agreed upon as 'appropriate'; four statements were considered 'uncertain', and ultimately finally discarded. CONCLUSIONS: Our DELPHI-based expert consensus should help guide physicians in conducting a prolonged multidisciplinary follow-up of sequelae in SJS-TEN.

Non-Lethal Detection of Ranavirus in Fish.

Emergent infectious diseases have an increasing impact on both farmed animals and wildlife. The ability to screen for pathogens is critical for understanding host-pathogen dynamics and informing better management. Ranavirus is a pathogen of concern, associated with disease outbreaks worldwide, affecting a broad range of fish, amphibian, and reptile hosts, but research has been limited. The traditional screening of internal tissues, such as the liver, has been regarded as the most effective for detecting and quantifying Ranavirus. However, such methodology imposes several limitations from ethical and conservation standpoints. Non-lethal sampling methods of viral detection were explored by comparing the efficacy of both buccal swabbing and fin clipping. The study was conducted on two Iberian, threatened freshwater fish (Iberochondrostoma lusitanicum and Cobitis paludica), and all samples were screened using qPCR. While for C. paludica both methods were reliable in detecting Ranavirus, on I. lusitanicum, there was a significantly higher detection rate in buccal swabs than in fin tissue. This study, therefore, reports that fin clipping may yield false Ranavirus negatives when in small-bodied freshwater fish. Overall, buccal swabbing is found to be good as an alternative to more invasive procedures, which is of extreme relevance, particularly when dealing with a threatened species.

Evaluating old truths: Final adult size in holometabolous insects is set by the end of larval development.

For centuries, it has been understood that the final size of adult holometabolous insects is determined by the end of the larval stage, and that once they transform to adults, holometabolous insects do not grow. Despite this, no previous study has directly tested these "old truths" across holometabolous insects. Here, we demonstrate that final adult size is set at the end of the last larval stage in species representing each of the four orders of holometabolous insects: the fruit fly Drosophila melanogaster (Diptera), the tobacco hornworm Manduca sexta (Lepidoptera), the dung beetle Onthophagus taurus (Coleoptera), and the Florida carpenter ant Camponotus floridanus (Hymenoptera). Furthermore, in both D. melanogaster and C. floridanus, we show that the size of adult individuals fluctuates but does not significantly change. Therefore, our study finally confirms these two basic assumptions in the biology of insects, which have for centuries served as the foundation for studies of insect growth, size, and allometry.

Overnutrition during Pregnancy and Lactation Induces Gender-Dependent Dysmetabolism in the Offspring Accompanied by Heightened Stress and Anxiety.

Maternal obesity and gestational diabetes predispose the next generation to metabolic disturbances. Moreover, the lactation phase also stands as a critical phase for metabolic programming. Nevertheless, the precise mechanisms originating these changes remain unclear. Here, we investigate the consequences of a maternal lipid-rich diet during gestation and lactation and its impact on metabolism and behavior in the offspring. Two experimental groups of Wistar female rats were used: a control group (NC) that was fed a standard diet during the gestation and lactation periods and an overnutrition group that was fed a high-fat diet (HF, 60% lipid-rich) during the same phases. The offspring were analyzed at postnatal days 21 and 28 and at 2 months old (PD21, PD28, and PD60) for their metabolic profiles (weight, fasting glycemia insulin sensitivity, and glucose tolerance) and euthanized for brain collection to evaluate metabolism and inflammation in the hypothalamus, hippocampus, and prefrontal cortex using Western blot markers of synaptic dynamics. At 2 months old, behavioral tests for anxiety, stress, cognition, and food habits were conducted. We observed that the female offspring born from HF mothers exhibited increased weight gain and decreased glucose tolerance that attenuated with age. In the offspring males, weight gain increased at P21 and worsened with age, while glucose tolerance remained unchanged. The offspring of the HF mothers exhibited elevated levels of anxiety and stress during behavioral tests, displaying decreased predisposition for curiosity compared to the NC group. In addition, the offspring from mothers with HF showed increased food consumption and a lower tendency towards food-related aggression. We conclude that exposure to an HF diet during pregnancy and lactation induces dysmetabolism in the offspring and is accompanied by heightened stress and anxiety. There was sexual dimorphism in the metabolic traits but not behavioral phenotypes.

Impacts of ocean warming and acidification on the energy budget of three commercially important fish species.

A mechanistic model based on Dynamic Energy Budget (DEB) theory was developed to predict the combined effects of ocean warming, acidification and decreased food availability on growth and reproduction of three commercially important marine fish species: white seabream (Diplodus sargus), zebra seabream (Diplodus cervinus) and Senegalese sole (Solea senegalensis). Model simulations used a parameter set for each species, estimated by the Add-my-Pet method using data from laboratory experiments complemented with bibliographic sources. An acidification stress factor was added as a modifier of the somatic maintenance costs and estimated for each species to quantify the effect of a decrease in pH from 8.0 to 7.4 (white seabream) or 7.7 (zebra seabream and Senegalese sole). The model was used to project total length of individuals along their usual lifespan and number of eggs produced by an adult individual within one year, under different climate change scenarios for the end of the 21st century. For the Intergovernmental Panel on Climate Change SSP5-8.5, ocean warming led to higher growth rates during the first years of development, as well as an increase of 32-34% in egg production, for the three species. Ocean acidification contributed to reduced growth for white seabream and Senegalese sole and a small increase for zebra seabream, as well as a decrease in egg production of 48-52% and 14-33% for white seabream and Senegalese sole, respectively, and an increase of 4-5% for zebra seabream. The combined effect of ocean warming and acidification is strongly dependent on the decrease of food availability, which leads to significant reduction in growth and egg production. This is the first study to assess the combined effects of ocean warming and acidification using DEB models on fish, therefore, further research is needed for a better understanding of these climate change-related effects among different taxonomic groups and species.