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A randomized phase-II study was performed in low/int-1 risk MDS (IPSS) to study efficacy and safety of lenalidomide without (arm A) or with (arm B) ESA/G-CSF. In arm B, patients without erythroid response (HI-E) after 4 cycles received ESA; G-CSF was added if no HI-E was obtained by cycle 9. HI-E served as primary endpoint. Flow cytometry and next-generation sequencing were performed to identify predictors of response. The final evaluation comprised 184 patients; 84% non-del(5q), 16% isolated del(5q); median follow-up: 70.7 months. In arm A and B, 39 and 41% of patients achieved HI-E; median time-to-HI-E: 3.2 months for both arms, median duration of-HI-E: 9.8 months. HI-E was significantly lower in non-del(5q) vs. del(5q): 32% vs. 80%. The same accounted for transfusion independency-at-week 24 (16% vs. 67%), but similar in both arms. Apart from presence of del(5q), high percentages of bone marrow lymphocytes and progenitor B-cells, a low number of mutations, absence of ring sideroblasts, and SF3B1 mutations predicted HI-E. In conclusion, lenalidomide induced HI-E in patients with non-del(5q) and del(5q) MDS without additional effect of ESA/G-CSF. The identified predictors of response may guide application of lenalidomide in lower-risk MDS in the era of precision medicine. (EudraCT 2008-002195-10).

Tick-borne encephalitis virus (TBEV) is an emerging pathogen that was first detected in ticks and humans in the Netherlands in 2015 (ticks) and 2016 (humans). To learn more about its distribution and prevalence in the Netherlands, we conducted large-scale surveillance in ticks and rodents during August 2018-September 2020. We tested 320 wild rodents and >46,000 ticks from 48 locations considered to be at high risk for TBEV circulation. We found TBEV RNA in 3 rodents (0.9%) and 7 tick pools (minimum infection rate 0.02%) from 5 geographically distinct foci. Phylogenetic analyses indicated that 3 different variants of the TBEV-Eu subtype circulate in the Netherlands, suggesting multiple independent introductions. Combined with recent human cases outside known TBEV hotspots, our data demonstrate that the distribution of TBEV in the Netherlands is more widespread than previously thought.

Impulsivity and poor executive control have been implicated in the pathogenesis of many developmental and neuropsychiatric disorders. Similarly, concussions/mild traumatic brain injuries (mTBI) have been associated with increased risk for neuropsychiatric disorders and the development of impulsivity and inattention. Researchers and epidemiologists have therefore considered whether or not concussions induce symptoms of attention-deficit/hyperactivity disorder (ADHD), or merely unmask impulsive tendencies that were already present. The purpose of this study was to determine if a single concussion in adolescence could induce ADHD-like impulsivity and impaired response inhibition, and subsequently determine if inherent impulsivity prior to a pediatric mTBI would exacerbate post-concussion symptomology with a specific emphasis on impulsive and inattentive behaviours. As these behaviours are believed to be associated with the frontostriatal circuit involving the nucleus accumbens (NAc) and the prefrontal cortex (PFC), the expression patterns of 8 genes (Comt, Drd2, Drd3, Drd4, Maoa, Sert, Tph1, and Tph2) from these two regions were examined. In addition, Golgi-Cox staining of medium spiny neurons in the NAc provided a neuroanatomical examination of mTBI-induced structural changes. The study found that a single early brain injury could induce impulsivity and impairments in response inhibition that were more pronounced in males. Interestingly, when animals with inherent impulsivity experienced mTBI, injury-related deficits were exacerbated in female animals. The single concussion increased dendritic branching, but reduced synaptic density in the NAc, and these changes were likely associated with the increase in impulsivity. Finally, mTBI-induced impulsivity was associated with modifications to gene expression that differed dramatically from the gene expression pattern associated with inherent impulsivity, despite very similar behavioural phenotypes. Our findings suggest the need to tailor treatment strategies for mTBI in light of an individual's premorbid characteristics, given significant differences in molecular profiles of the frontostriatal circuits that depend upon sex and the etiology of the behavioural phenotype.

Following a traumatic brain injury (TBI), inflammation is a well-documented but poorly understood phenomenon, especially at later time-points (i.e., beyond 72 h) and in brain areas outside the cortex. The cerebellum, important for motor and cognitive functioning, represents an area of the brain equally affected by TBI that is seldom evaluated despite its potential involvement in persistent deficits after injury. In the context of TBI and inflammation, most studies focus on severe TBI in adult males, with fewer studies on pediatric mild TBI in both sexes. Our study addresses this gap by profiling neurological function and cerebellar inflammation over time in the juvenile male and female rat brain following a mild, closed-head weight-drop injury (mTBI). At 24 h, 72 h, 7 days, and 21 days post-mTBI, animals were subjected to behavioral testing to evaluate TBI effects over time. Alongside behavioral deficits up to 7 days post-injury, inflammatory profiling by multi-plex enzyme-linked immunosorbent assay (ELISA) revealed increased inflammatory markers, including CXCL1, interleukin (IL)-5, and vascular endothelial growth factor alpha (VEGFα), in plasma at 24–72 h and in the cerebellum at 72 h post-injury. Network analysis of cytokines also showed increased inter-relationships between multiple mediators at all time-points, emphasizing the persistent and dynamic changes to inflammatory patterns after mTBI. Transcript levels of microglia/macrophage activation markers, including Iba1 and CX3CR1, were significantly elevated at 7 days post-TBI in both sexes, and at 21 days in females, suggesting activation of immune cells in the cerebellum. When examining the protein expression of GFAP and CX3CR1, a significant increase in CX3CR1 was noted in males at 21 days but not in females. Characterizing the evolution of cerebellar inflammation in pediatric mTBI provides insight into potential mechanisms of persistent changes that could contribute to neurological dysfunction.

The distribution of tick-borne encephalitis virus (TBEV) is expanding to Western European countries, including the Netherlands, but the contribution of different rodent species to the transmission of TBEV is poorly understood. We investigated whether two species of wild rodents native to the Netherlands, the wood mouse Apodemus sylvaticus and the yellow-necked mouse Apodemus flavicollis , differ in their relative susceptibility to experimental infection with TBEV. Wild-caught individuals were inoculated subcutaneously with the classical European subtype of TBEV (Neudoerfl) or with TBEV-NL, a genetically divergent TBEV strain from the Netherlands. Mice were euthanised and necropsied between 3 and 21 days post-inoculation. None of the mice showed clinical signs or died during the experimental period. Nevertheless, TBEV RNA was detected up to 21 days in the blood of both mouse species and TBEV was also isolated from the brain of some mice. Moreover, no differences in infection rates between virus strains and mouse species were found in blood, spleen, or liver samples. Our results suggest that the wood mouse and the yellow-necked mouse may equally contribute to the transmission cycle of TBEV in the Netherlands. Future experimental infection studies that include feeding ticks will help elucidate the relative importance of viraemic transmission in the epidemiology of TBEV.

Compared to traumatic brain injury (TBI) in the adult population, pediatric TBI has received less research attention, despite its potential long-term impact on the lives of many children around the world. After numerous clinical trials and preclinical research studies examining various secondary mechanisms of injury, no definitive treatment has been found for pediatric TBIs of any severity. With the advent of high-throughput and high-resolution molecular biology and imaging techniques, inflammation has become an appealing target, due to its mixed effects on outcome, depending on the time point examined. In this review, we outline key mechanisms of inflammation, the contribution and interactions of the peripheral and CNS-based immune cells, and highlight knowledge gaps pertaining to inflammation in pediatric TBI. We also introduce the application of network analysis to leverage growing multivariate and non-linear inflammation data sets with the goal to gain a more comprehensive view of inflammation and develop prognostic and treatment tools in pediatric TBI.

Habitat fragmentation is a primary driver of wildlife loss, and establishment of biological corridors is a common strategy to mitigate this problem. A flagship example is the Mesoamerican Biological Corridor (MBC), which aims to connect protected forest areas between Mexico and Panama to allow dispersal and gene flow of forest organisms. Because forests across Central America have continued to degrade, the functioning of the MBC has been questioned, but reliable estimates of species occurrence were unavailable. Large mammals are suitable indicators of forest functioning, so we assessed their conservation status across the Isthmus of Panama, the narrowest section of the MBC. We used large-scale camera-trap surveys and hierarchical multispecies occupancy models in a Bayesian framework to estimate the occupancy of 9 medium to large mammals and developed an occupancy-weighted connectivity metric to evaluate species-specific functional connectivity. White-lipped peccary (Tayassu pecari), jaguar (Panthera onca), giant anteater (Myrmecophaga tridactyla), white-tailed deer (Odocoileus virginianus), and tapir (Tapirus bairdii) had low expected occupancy along the MBC in Panama. Puma (Pumaconcolor), red brocket deer (Mazamatemama), ocelot (Leopardus pardalis), and collared peccary (Pecari tajacu), which are more adaptable, had higher occupancy, even in areas with low forest cover near infrastructure. However, the majority of species were subject to ≥ 1 gap that was larger than their known dispersal distances, suggesting poor connectivity along the MBC in Panama. Based on our results, forests in Darien, Donoso–Santa Fe, and La Amistad International Park are critical for survival of large terrestrial mammals in Panama and 2 areas need restoration. La fragmentación del hábitat es un causante primario de la pérdida de biodiversidad, y el establecimiento de corredores biológicos es una estrategia común para mitigar este problema. El Corredor Biológico Mesoamericano (CBM) es un ejemplo notable que pretende conectar áreas boscosas protegidas entre México y Panamá para permitir la dispersión y flujo genético de organismos del bosque. El funcionamiento del CBM se ha cuestionado debido a que la degradación de los bosques en Centroamérica continúa, pero no se dispone de estimaciones confiables de la ocurrencia de especies. Los mamíferos grandes son indicadores adecuados del funcionamiento de los bosques tropicales Por lo tanto evaluamos su estado de conservación en el Istmo de Panamá, la sección más angosta del CBM. Utilizamos muestreos con cámaras trampa y modelos de ocupación para múltiples especies bajo un modelo Bayesiano para estimar la ocupación de 9 especies de mamíferos medianos a grandes, y desarrollamos una métrica de conectividad ponderada por la ocupación para evaluar la conectividad funcional para cada especie. El puerco de monte (Tayassu pecari), jaguar (Panthera onca), hormiguero gigante (Myrmecophaga tridactyla), venado cola blanca (Oidocoileus virginianus), y tapir (Tapirus bairdii) presentaron una ocupación baja en el CBM en Panamá. El puma (Puma concolor), venado corzo (Mazama temama), ocelote (Leopardus pardalis) y el saino (Pecari tajacu), que son más adaptables, presentaron mayor ocupación, aún en áreas con poca cobertura boscosa, cercanas a infraestructura. Sin embargo, la mayoría de las especies estuvo sujeta a ≥ 1vacío que era mayor que sus distancias de dispersión conocidas, lo que sugiere una conectividad pobre a lo largo del CBM en Panamá. Basados en nuestros resultados, los bosques de Darién, Donoso-Santa Fé y el Parque Internacional La Amistad son críticos para la supervivencia de mamíferos terrestres grandes en Panamá mientras que 2 áreas requieren restauración. 生境破碎化是野生动物数量下降的首要原因,而应对这ー问题的常用策略则是建设生物廊道。ー个典 型的例子是中美洲生物廊道 (Mesoamerican Biological Corridor), 它的建立旨在连接墨西哥和巴拿马之间的 森林保护地,帮助森林中的生物进行扩散和基因交流。然而,由于中美洲范围内的森林在持续退化,中美洲生 物廊道的功能已受到质疑, 但目前仍没有该地区物种分布的可靠评估。大型哺乳动物可以作为森林功能的指 示种,因此, 我们评估了中美洲生物廊道最狭窄的地区一一巴拿马地峡大型哺乳动物的保护状况。我们利用大 规模红外相机调查和贝叶斯框架下的分级多物种占有模型, 估计了九种中大型哺乳动物的分布情况, 并发展出 一个生境占有率加权的连接度指标来评估物种特异的功能连接度。结果显示,白唇西揣 (Tayassu pecan)、美 洲 豹 (Panthera onca) ヽ大 食 蚁 兽 (Myrmecopbaga tridactyla)ヽ白尾鹿 (Odocoileus virginianus) 和中美疆 (Tapirus bairdii) 在巴拿马的中美洲生物廊道一带估计的生境占有率较低。美洲狮 (Puma concolor) 、墨西哥 鹿 (Mazama temama) 、美洲豹猫 (Leopardus pardalis) 和领西揣 (Pecari taiacu) 则适应性更强, 生境占有率 更高,即便是在基础设施附近森林覆盖率较低的地区也是如此。然而,大多数物种都面临着至少ー个超出其已 知扩散距离的问题, 这表明巴拿马的中美洲生物廊道沿线连接度较低。基于以上結果, 达里恩、多诺索 - 圣达菲 和拉米斯塔德国际公园的森林对于巴拿马及其连接的两个需要恢复的地区所生存的大型哺乳动物则显得至关重 要。

Arboviruses represent a significant burden to public health and local economies due to their ability to cause unpredictable and widespread epidemics. To maximize early detection of arbovirus emergence in non-endemic areas, surveillance efforts should target areas where circulation is most likely. However, identifying such hotspots of potential emergence is a major challenge. The ecological conditions leading to arbovirus outbreaks are shaped by complex interactions between the virus, its vertebrate hosts, arthropod vector, and abiotic environment that are often poorly understood. Here, we systematically review the ecological risk factors associated with the circulation of six arboviruses that are of considerable concern to northwestern Europe. These include three mosquito-borne viruses (Japanese encephalitis virus, West Nile virus, Rift Valley fever virus) and three tick-borne viruses (Crimean-Congo hemorrhagic fever virus, tick-borne encephalitis virus, and louping-ill virus). We consider both intrinsic (e.g. vector and reservoir host competence) and extrinsic (e.g. temperature, precipitation, host densities, land use) risk factors, identify current knowledge gaps, and discuss future directions. Our systematic review provides baseline information for the identification of regions and habitats that have suitable ecological conditions for endemic circulation, and therefore may be used to target early warning surveillance programs aimed at detecting multi-virus and/or arbovirus emergence.

Background Host specificity is a fundamental determinant of tick population and pathogen transmission dynamics, and therefore has important implications for human health. Tick host specificity is expected to be particularly high in the tropics, where communities of ticks, hosts and pathogens are most diverse. Yet the degree to which tropical tick species are host-specific remains poorly understood. Combining new field data with published records, we assessed the specificity of tick-host associations in Panama, a diverse Neotropical region. Methods The resulting dataset includes 5,298 adult ticks belonging to 41 species of eight genera that were directly collected from 68 vertebrate host species of 17 orders. We considered three important aspects of tick host specificity: (i) the relative ecological importance of each host species (structural specificity); (ii) relatedness among host species (phylogenetic specificity); and (iii) spatial scale-dependence of tick-host relationships (geographical specificity). Applying quantitative network analyses and phylogenetic tools with null model comparisons, we assessed the structural and phylogenetic specificity across three spatial scales, ranging from central Panama to countrywide. Further, we tested whether species-rich tick genera parasitized a wider variety of hosts than species-poor genera, as expected when ticks specialize on different host species. Results Most tick species showed high structural and/or phylogenetic specificity in the adult stage. However, after correcting for sampling effort, we found little support for geographical specificity. Across the three scales, adult ticks tended to be specific to a limited number of host species that were phylogenetically closely related. These host species in turn, were parasitized by tick species from distinct genera, suggesting switching among distantly related hosts is common at evolutionary timescales. Further, there was a strong positive relationship between the taxonomic richness of the tick genera and that of their hosts, consistent with distinct tick species being relatively specific to different host species. Conclusions Our results indicate that in the adult stage, most ticks in the diverse Neotropical community studied are host specialists. This contrasts with earlier assessments, but agrees with findings from other host-parasite systems. High host specificity in adult ticks implies high susceptibility to local tick-host co-extirpation, limited ability to colonize new habitats and limited potential for interspecific pathogen transmission.