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Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma.
ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure.
ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.
Introduced species can have strong ecological, social and economic effects on their non-native environment. Introductions of megafaunal species are rare and may contribute to rewilding efforts, but they may also have pronounced socio-ecological effects because of their scale of influence. A recent introduction of the hippopotamus Hippopotamus amphibius into Colombia is a novel introduction of a megaherbivore onto a new continent, and raises questions about the future dynamics of the socio-ecological system into which it has been introduced. Here we synthesize current knowledge about the Colombian hippopotamus population, review the literature on the species to predict potential ecological and socio-economic effects of this introduction, and make recommendations for future study. Hippopotamuses can have high population growth rates (7–11%) and, on the current trajectory, we predict there could be 400–800 individuals in Colombia by 2050. The hippopotamus is an ecosystem engineer that can have profound effects on terrestrial and aquatic environments and could therefore affect the native biodiversity of the Magdalena River basin. Hippopotamuses are also aggressive and may pose a threat to the many inhabitants of the region who rely upon the Magdalena River for their livelihoods, although the species could provide economic benefits through tourism. Further research is needed to quantify the current and future size and distribution of this hippopotamus population and to predict the likely ecological, social and economic effects. This knowledge must be balanced with consideration of social and cultural concerns to develop appropriate management strategies for this novel introduction.
Wake modes of a three-dimensional blunt-based body near a wall are investigated at a Reynolds number
. The targeted modes are the static symmetry-breaking mode and two antisymmetric periodic modes. The static mode orientation is aligned with the horizontal major
-axis of the base and randomly switches between a positive
and a negative
state leading to long-time bistable dynamics of the turbulent wake. The modifications of these modes are studied when continuous blowing is applied at different locations through four slits along the base edges (denoted L for left, R for right, T for top and B for bottom) in either four single asymmetric configurations or two double symmetric configurations (denoted LR and TB). Two regimes, referred to as mass and momentum, are clearly identifiable for all configurations. The mass regime, which is fairly insensitive to blowing momentum and location, is characterized by the growth of the recirculating bubble as the total injected flow rate is increased, and is associated with a base drag reduction and interpreted as resulting from the equilibrium between mass fluxes feeding and emptying the recirculating region. A simple budget model is shown to be in agreement with entrainment velocities measured for isolated turbulent mixing layers. The strength of the static mode is reduced up to 20 % when the bubble length is maximum, whereas no change in the periodic mode frequencies is found. On the other hand, the momentum regime is characterized by the deflating of the recirculating bubble, leading to base drag increase, and it is interpreted by the free shear layer forcing, which increases the entrainment velocity, thus emptying the recirculating bubble. In this regime the static mode orientation is imposed by the blowing symmetry. Lateral L and R (respectively top/bottom T and B) blowing configurations select
states in the horizontal (respectively vertical) direction, while bistable dynamics persists for the symmetric LR and TB configurations. The shape of periodic modes follows the changes in wake static orientation. The transition between the two regimes is governed by both the total injected flow rate and the location of the injection.
Triatomine bugs carry the parasitic protozoa Trypanosoma cruzi, the causal agent of Chagas disease. It is known that both the parasite and entomopathogenic fungi can decrease bug survival, but the combined effect of both pathogens is not known, which is relevant for biological control purposes. Herein, the survival of the triatomine Meccus pallidipennis (Stal, 1872) was compared when it was coinfected with the fungus Metarhizium anisopliae (Metschnikoff) and T. cruzi, and when both pathogens acted separately. The immune response of the insect was also studied, using phenoloxidase activity in the bug gut and hemolymph, to understand our survival results. Contrary to expectations, triatomine survival was higher in multiple than in single challenges, even though the immune response was lower in cases of multiple infection. We postulate that T. cruzi exerts a protective effect and/or that the insect reduced the resources allocated to defend itself against both pathogens. Based on the present results, the use of M. anisopliae as a control agent should be re-considered.
Social cognition has been associated with functional outcome in patients with first episode psychosis (FEP). Social cognition has also been associated with neurocognition and cognitive reserve. Although cognitive reserve, neurocognitive functioning, social cognition, and functional outcome are related, the direction of their associations is not clear. Therefore, the main aim of this study was to analyze the influence of social cognition as a mediator between cognitive reserve and cognitive domains on functioning in FEP both at baseline and at 2 years.
The sample of the study was composed of 282 FEP patients followed up for 2 years. To analyze whether social cognition mediates the influence of cognitive reserve and cognitive domains on functioning, a path analysis was performed. The statistical significance of any mediation effects was evaluated by bootstrap analysis.
At baseline, as neither cognitive reserve nor the cognitive domains studied were related to functioning, the conditions for mediation were not satisfied. Nevertheless, at 2 years of follow-up, social cognition acted as a mediator between cognitive reserve and functioning. Likewise, social cognition was a mediator between verbal memory and functional outcome. The results of the bootstrap analysis confirmed these significant mediations (95% bootstrapped CI (−10.215 to −0.337) and (−4.731 to −0.605) respectively).
Cognitive reserve and neurocognition are related to functioning, and social cognition mediates in this relationship.
The relationship between epilepsy and the presence of visceral larva migrans caused by Toxocara canis in Mexican children remains uncertain; however, this relationship needs to be elucidated because these parasite larvae can invade the human central nervous system. Accordingly, this study aimed to determine the frequency and specificity of anti-T. canis antibodies in the sera of children with epilepsy to determine the relationship between this parasite and epilepsy. The sera samples of 214 children were examined: 111 children diagnosed with epilepsy and 103 clinically healthy children without neurological disorders. In the sera of each group, the presence and specificity of anti-T. canis and anti-Ascaris lumbricoides antibodies, as well as the cross-reactivity between them, were assessed using enzyme-linked immunosorbent assay and Western blotting analysis. Among the children with epilepsy, 25.2% exhibited seropositivity to T. canis. Cross-reactivity against the A. lumbricoides antigen was present in 46.8% of the children with epilepsy, whereas 11.7% of the children with epilepsy and anti-T. canis antibodies did not exhibit cross-reactivity against this antigen. The Western blotting analysis of the sera from the children with epilepsy demonstrated the presence of T. canis proteins, with molecular weights of 24, 35, 55, 70, 120 and 210 kDa, and A lumbricoides proteins with molecular weights of 70, 80 and 110 kDa. Our results revealed the presence of anti-T. canis antibodies in the children with epilepsy; furthermore, cross-reactivity tests with A. lumbricoides showed the importance of the presence of anti-T. canis antibodies in revealing the relationship between this parasite and epilepsy in children.
This study assessed the in vitro anthelmintic (AH) activity of methanol and acetone:water leaf extracts from Annona squamosa, A. muricata and A. reticulata against Haemonchus contortus eggs. The egg hatch test was used to determine the effective concentrations required to inhibit 50% of eggs hatching (EC50). The role of polyphenols on AH activity was measured through bioassays with and without polyvinylpolypyrrolidone (PVPP). Methanolic extracts mainly caused the death of eggs at the morula stage (ovicidal activity). Meanwhile, acetone:water extracts caused egg-hatching failure of developed larvae (larvae failing eclosion (LFE) activity). The lowest EC50 values against H. contortus eggs were observed for the methanolic extracts from A. reticulata and A. muricata (274.2 and 382.9 µg/ml, respectively). From the six extracts evaluated, the methanolic extracts of A. muricata, A. reticulata and A. squamosa showed the highest ovicidal activity, resulting in 98.9%, 92.8% and 95.1% egg mortality, respectively. When the methanolic extract of A. squamosa was incubated with PVPP, its AH activity increased. Similarly, when acetone:water extracts of A. muriata and A. reticulata were incubated with PVPP, their LFE activity increased. Alkaloids were only evident in methanolic extracts, irrespective of PVPP incubation. The presence of acetogenins was not observed. In conclusion, methanolic extracts obtained from leaves of A. muricata, A. reticulata and A. squamosa showed ovicidal activity affecting the morula of H. contortus eggs, with minor LFE activity. Meanwhile, acetone:water extracts showed mostly LFE activity, with a lower proportion of ovicidal activity.
Meteorological and even human-made disasters are increasing every year in frequency and magnitude. The passage of a disaster affects a society without distinction, but groups with social vulnerability (low socioeconomic status, chronic medical, or psychological conditions, limited access to resources) face the most significant impact. As a result, psychological and behavioral symptoms (eg, depression and anxiety) can ensue, making the immediate response of mental health services crucial. Secondary data from a database of a temporary healthcare unit were analyzed. A total of 54 records were reviewed to collect information; univariate and bivariate analyses were done. The purpose of this article is to present our experience regarding the incorporation of a mental health services model, with its respective benefits and challenges, into a temporary healthcare unit, after Hurricane Maria in 2017.
First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.
We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.
In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.
The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene–environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.
Establishing neurobiological markers of posttraumatic stress disorder (PTSD) is essential to aid in diagnosis and treatment development. Fear processing deficits are central to PTSD, and their neural signatures may be used as such markers.
Here, we conducted a meta-analysis of seven Pavlovian fear conditioning fMRI studies comparing 156 patients with PTSD and 148 trauma-exposed healthy controls (TEHC) using seed-based d-mapping, to contrast neural correlates of experimental phases, namely conditioning, extinction learning, and extinction recall.
Patients with PTSD, as compared to TEHCs, exhibited increased activation in the anterior hippocampus (extending to the amygdala) and medial prefrontal cortex during conditioning; in the anterior hippocampus-amygdala regions during extinction learning; and in the anterior hippocampus-amygdala and medial prefrontal areas during extinction recall. Yet, patients with PTSD have shown an overall decreased activation in the thalamus during all phases in this meta-analysis.
Findings from this metanalysis suggest that PTSD is characterized by increased activation in areas related to salience and threat, and lower activation in the thalamus, a key relay hub between subcortical areas. If replicated, these fear network alterations may serve as objective diagnostic markers for PTSD, and potential targets for novel treatment development, including pharmacological and brain stimulation interventions. Future longitudinal studies are needed to examine whether these observed network alteration in PTSD are the cause or the consequence of PTSD.
The hippocampus plays an important role in psychopathology and treatment outcome. While posterior hippocampus (PH) may be crucial for the learning process that exposure-based treatments require, affect-focused treatments might preferentially engage anterior hippocampus (AH). Previous studies have distinguished the different functions of these hippocampal sub-regions in memory, learning, and emotional processes, but not in treatment outcome. Examining two independent clinical trials, we hypothesized that anterior hippocampal volume would predict outcome of affect-focused treatment outcome [Interpersonal Psychotherapy (IPT); Panic-Focused Psychodynamic Psychotherapy (PFPP)], whereas posterior hippocampal volume would predict exposure-based treatment outcome [Prolonged Exposure (PE); Cognitive Behavioral Therapy (CBT); Applied Relaxation Training (ART)].
Thirty-five patients with posttraumatic stress disorder (PTSD) and 24 with panic disorder (PD) underwent structural magnetic resonance imaging (MRI) before randomization to affect-focused (IPT for PTSD; PFPP for PD) or exposure-based treatments (PE for PTSD; CBT or ART for PD). AH and PH volume were regressed with clinical outcome changes.
Baseline whole hippocampal volume did not predict post-treatment clinical severity scores in any treatment. For affect-focused treatments, but not exposure-based treatments, anterior hippocampal volume predicted clinical improvement. Smaller AH correlated with greater affect-focused treatment improvement. Posterior hippocampal volume did not predict treatment outcome.
This is the first study to explore associations between hippocampal volume sub-regions and treatment outcome in PTSD and PD. Convergent results suggest that affect-focused treatment may influence the clinical outcome through the ‘limbic’ AH, whereas exposure-based treatments do not. These preliminary, theory-congruent, therapeutic findings require replication in a larger clinical trial.
The microstructure homogeneity and variability in mechanical properties of 316L stainless steel components fabricated using selective laser melting (SLM) have been investigated. The crack free, 99.9% dense samples were made starting from SS316L alloy powder, and the melt pool morphology was analysed using optical and scanning electron microscopy. Extremely fast cooling rates after laser melting/solidification process, accompanied by slow diffusion of alloying elements, produced characteristic microstructures with colonies of cellular substructure inside grains, grown along the direction of the principal thermal gradient during laser scanning. In some areas of the microstructure, a significant number of precipitates were observed inside grains and at grain boundaries. Micro hardness measurements along the build direction revealed slight but gradual increase in hardness along the sample height. Uniaxial tensile tests of as manufactured samples showed the effect of un-melted areas causing scatter in room-temperature mechanical properties of samples extracted from the same SLM build. The ultimate tensile strength (UTS) varied from 458MPa to 509MPa along with a variation in uniform elongation from 3.3% to 14.4%. The UTS of a sample exposed to the Cl- rich corrosion environment at 46oC temperature revealed a similar strength as of the original sample, indicating good corrosion resistance of SLM samples under those corrosion conditions.
The precise control of curing reaction parameters allows a better crosslinking polymer. Modelling and optimization of this process require a correct kinetic of curing model. The kinetics of the crosslinking reaction is studied for the ethylene propylene diene monomer (EPDM) synthetic elastomer by mobile die rheometer (MDR). The kinetic parameters of reaction were calculated from Kamal-Ryan, Sestak-Berggren, and the Isayev-Deng methods at different temperatures. An Arrhenius-type function for the order of reaction n is introduced to improve the adjusting. Finally, a graphical and analytical description of the cure kinetics was developed. The order of reaction is predicted to better establishment of processing time. It was noted that for EPDM at higher temperatures, the increase of the rate of reaction occurs in short period of time, which could cause premature curing if the supply system is inadequate.
Unusual mafic rock fragments deposited in Plio-Pleistocene-aged marine sediments were recorded at Integrated Ocean Drilling Program (IODP) Site U1359, in Wilkes Land, East Antarctica. These fragments were identified from sediment layers deposited between c. 3 and 1.2 Ma, indicating a sustained supply during this time interval. Clinopyroxenes in these basalts are Al–Ti diopside–hedenbergite, uncommon in terrestrial magmatic rocks. A single strong peak in the Raman spectra of a phosphate-bearing mineral at 963 cm-1 supports the presence of merrillite. Although not conclusive, petrological traits and oxygen isotopic compositions also suggest that the fragments may be extra-terrestrial fragments affected by shock metamorphism. Nevertheless, it is concluded that the basaltic fragments incorporated in marine sediments at Site U1359 represent ice-rafted material supplied to the continental rise of East Antarctica, probably from the bedrocks near the proximal Ninnis Glacier. Further studies on Plio-Pleistocene sediments near Site U1359 are required to characterize the unusual mafic rocks described.
High unemployment is a hallmark of psychotic illness. Individual placement and support (IPS) may be effective at assisting the vocational recoveries of young people with first-episode psychosis (FEP).
To examine the effectiveness of IPS at assisting young people with FEP to gain employment (Australian and Clinical Trials Registry ACTRN12608000094370).
Young people with FEP (n = 146) who were interested in vocational recovery were randomised using computer-generated random permuted blocks on a 1:1 ratio to: (a) 6 months of IPS in addition to treatment as usual (TAU) or (b) TAU alone. Assessments were conducted at baseline, 6 months (end of intervention), 12 months and 18 months post-baseline by research assistants who were masked to the treatment allocations.
At the end of the intervention the IPS group had a significantly higher rate of having been employed (71.2%) than the TAU group (48.0%), odds ratio 3.40 (95% CI 1.17–9.91, z = 2.25, P = 0.025). However, this difference was not seen at 12- and 18-month follow-up points. There was no difference at any time point on educational outcomes.
This is the largest trial to our knowledge on the effectiveness of IPS in FEP. The IPS group achieved a very high employment rate during the 6 months of the intervention. However, the advantage of IPS was not maintained in the long term. This seems to be related more to an unusually high rate of employment being achieved in the control group rather than a gross reduction in employment among the IPS group.
This is the first report on the development and characterization of eight monoclonal antibodies (MABs) generated against whole- and membrane-enriched tachyzoite extracts of the apicomplexan parasite Besnoitia besnoiti. Confocal laser scanning immunofluorescence microscopy was used to localize respective epitopes in B. besnoiti tachyzoites along the lytic cycle. A pattern compatible with dense granule staining was observed with MABs 2.A.12, 2.F.3 and 2.G.4, which could be confirmed by immunogold electron microscopy for MABs 2.A.12 and 2.F.3. In particular, MABs 2.F.3 and 2.G.4 were secreted during early invasion, proliferation and egress phases. MABs 3.10.8 and 5.5.11 labelled the tachyzoite surface, whilst MABs 1.17.8, 8.9.2 and 2.G.A recognized the apical tip, which is reminiscent for microneme localization. Besides, the epitopes recognized by the latter two (MABs 8.9.2 and 2.G.A) exhibited a redistribution from the anterior part across the parasite surface towards the posterior end during invasion. Most MABs developed were genus-specific. Indeed, the MABs cross-reacted neither with T. gondii nor with N. caninum tachyzoites. In summary, we have generated MABs that will be useful to study the key processes in the lytic cycle of the parasite and with additional promising diagnostic value. However, the molecular identity of the antigens recognized remains to be elucidated.
Phenological and aerobiological research into major crops is of great value in adapting traditional processes to the new conditions prompted by global climate change. Data on flowering phenology and airborne pollen have also proved useful for harvest forecasting purposes. The current paper reports on an agrometeorological study carried out in the Montilla-Moriles Protected Designation of Origin area (Córdoba, southern Spain) in 2015 and 2016. The study focused on four grape cultivars produced at seven local vineyards (Pedro Ximénez, the most widely grown in the area; Verdejo; Muscat blanc à petits grains; and Chardonnay, which has been recently introduced). Phenological observations were performed on a weekly basis using the Biologische Bundesanstalt, Bundessortenamt und Chemische Industrie scale adapted for grapevine. Airborne pollen concentrations were monitored using one Hirst-type volumetric sampler and seven passive samplers. Airborne pollen was mainly detected in vineyards during inflorescence emergence and flowering. Year-on-year differences in climatic conditions led to differences in airborne pollen levels. The main variables affecting pollen concentrations were dew point and temperature. The life-cycles recorded here were shorter than in temperate climates but longer than in tropical climates. In terms of flowering period, the cultivars studied here were classed as ‘early cultivars’. Data obtained using local passive samplers located directly in the vineyard confirmed that the airborne pollen concentrations recorded by the volumetric sampler were representative of the study area.
In this work, we study the hard-magnetic properties and its influence on the microstructure of MnBi-based glass-coated microwires obtained by Taylor-Ulitovsky process, as well as their magnetic and thermal dependence in the range of 200 K-360 K. We obtained glass-coated microwires pieces trough of the Taylor-Ulitovsky process. Glass-coated microwires exhibited the formation of Low-Temperature Intermetallic Phase (LTIP)-MnBi, as confirmed by scanning electron microscopy (SEM). Energy Dispersive Spectroscopy (EDS) elemental chemical composition analysis showed LTIP regions interspersed within Bi- and Mn-rich areas. Magnetic properties were determined by vibrating sample magnetometry (VSM), for which a considerable intrinsic coercivity field (iHc) up to 6000 Oe at 360 K, together with a saturation magnetization (Ms) of 57.49 emu/cm3. Therefore, this combination of properties renders LTIP is a promising precursor with potential for applications at high temperatures.