Spatial and temporal intra-tumoral heterogeneity in advanced HGSOC: Implications for surgical and clinical outcomes.

Limited evidence exists on the impact of spatial and temporal heterogeneity of high-grade serous ovarian cancer (HGSOC) on tumor evolution, clinical outcomes, and surgical operability. We perform systematic multi-site tumor mapping at presentation and matched relapse from 49 high-tumor-burden patients, operated up front. From SNP array-derived copy-number data, we categorize dendrograms representing tumor clonal evolution as sympodial or dichotomous, noting most chemo-resistant patients favor simpler sympodial evolution. Three distinct tumor evolutionary patterns from primary to relapse are identified, demonstrating recurrent disease may emerge from pre-existing or newly detected clones. Crucially, we identify spatial heterogeneity for clinically actionable homologous recombination deficiency scores and for poor prognosis biomarkers CCNE1 and MYC. Copy-number signature, phenotypic, proteomic, and proliferative-index heterogeneity further highlight HGSOC complexity. This study explores HGSOC evolution and dissemination across space and time, its impact on optimal surgical cytoreductive effort and clinical outcomes, and its consequences for clinical decision-making

Introducing an adolescent cognitive maturity index

Children show substantial variation in the rate of physical, cognitive, and social maturation as they traverse adolescence and enter adulthood. Differences in developmental paths are thought to underlie individual differences in later life outcomes, however, there remains a lack of consensus on the normative trajectory of cognitive maturation in adolescence. To address this problem, we derive a Cognitive Maturity Index (CMI), to estimate the difference between chronological and cognitive age predicted with latent factor estimates of inhibitory control, risky decision-making and emotional processing measured with standard neuropsychological instruments. One hundred and forty-one children from the Adolescent Development Study (ADS) were followed longitudinally across three time points from ages 11–14, 13–16, and 14–18. Age prediction with latent factor estimates of cognitive skills approximated age within ±10 months (r = 0.71). Males in advanced puberty displayed lower cognitive maturity relative to peers of the same age; manifesting as weaker inhibitory control, greater risk-taking, desensitization to negative affect, and poor recognition of positive affect

Enhanced formation of giant cells in common variable immunodeficiency: Relation to granulomatous disease.

Peripheral monocytes from patients with common variable immunodeficiency (CVID) had on average a 2 fold greater tendency to form giant cells in medium without additional cytokines. Giant cell formation was faster and 3 to 5 fold higher in most CVID cells compared to normal. Addition of IL4, GMCSF, IFNγ, TNFa and both T cell and monocyte conditioned media promoted monocyte fusion of some CVID individuals over 5 fold the normal average level, with combinations of cytokines and monokines acting synergistically. The reduction of normal giant cell formation by anti-IFNγ antibody and a greater tendency of CVID cells to fuse in immunoglobulin conditioned media suggests that standard IVIg treatment contributes to granuloma formation. CVID and normal giant cells expressed similar levels of phenotypic molecules and had similar phagocytic activity. Monocytes from many CVID patients have an elevated tendency to fuse which may explain the high incidence of granulomatous complications in CVID

Early Target Cells of Measles Virus after Aerosol Infection of Non-Human Primates

Measles virus (MV) is highly infectious, and has long been thought to enter the host by infecting epithelial cells of the respiratory tract. However, epithelial cells do not express signaling lymphocyte activation molecule (CD150), which is the high-affinity cellular receptor for wild-type MV strains. We have generated a new recombinant MV strain expressing enhanced green fluorescent protein (EGFP), based on a wild-type genotype B3 virus isolate from Khartoum, Sudan (KS). Cynomolgus macaques were infected with a high dose of rMVKSEGFP by aerosol inhalation to ensure that the virus could reach the full range of potential target cells throughout the entire respiratory tract. Animals were euthanized 2, 3, 4 or 5 days post-infection (d.p.i., n = 3 per time point) and infected (EGFP+) cells were identified at all four time points, albeit at low levels 2 and 3 d.p.i. At these earliest time points, MV-infected cells were exclusively detected in the lungs by fluorescence microscopy, histopathology and/or virus isolation from broncho-alveolar lavage cells. On 2 d.p.i., EGFP+ cells were phenotypically typed as large mononuclear cells present in the alveolar lumen or lining the alveolar epithelium. One to two days later, larger clusters of MV-infected cells were detected in bronchus-associated lymphoid tissue (BALT) and in the tracheo-bronchial lymph nodes. From 4 d.p.i. onward, MV-infected cells were detected in peripheral blood and various lymphoid tissues. In spite of the possibility for the aerosolized virus to infect cells and lymphoid tissues of the upper respiratory tract, MV-infected cells were not detected in either the tonsils or the adenoids until after onset of viremia. These data strongly suggest that in our model MV entered the host at the alveolar level by infecting macrophages or dendritic cells, which traffic the virus to BALT or regional lymph nodes, resulting in local amplification and subsequent systemic dissemination by viremia

Asthma control in adolescents 10 to 11 y after exposure to the World Trade Center disaster

Background: Little is known about asthma control in adolescents who were exposed to the World Trade Center (WTC) attacks of 11 September 2001 and diagnosed with asthma after 9/11. This report examines asthma and asthma control 10–11 y after 9/11 among exposed adolescents. Methods: The WTC Health Registry adolescent Wave 3 survey (2011–2012) collected data on asthma diagnosed by a physician after 11 September 2001, extent of asthma control based on modified National Asthma Education and Prevention Program criteria, probable mental health conditions, and behavior problems. Parents reported healthcare needs and 9/11-exposures. Logistic regression was used to evaluate associations between asthma and level of asthma control and 9/11-exposure, mental health and behavioral problems, and unmet healthcare needs. Results: Poorly/very poorly controlled asthma was significantly associated with a household income of ≤$75,000 (adjusted odds ratio (AOR): 3.0; 95% confidence interval (CI): 1.1–8.8), having unmet healthcare needs (AOR: 6.2; 95% CI: 1.4–27.1), and screening positive for at least one mental health condition (AOR: 5.0; 95% CI: 1.4–17.7), but not with behavioral problems. The impact of having at least one mental health condition on the level of asthma control was substantially greater in females than in males. Conclusions: Comprehensive care of post-9/11 asthma in adolescents should include management of mental health-related comorbidities. The collapse and burning of the World Trade Center (WTC) towers on 11 September 2001 (9/11) exposed hundreds of thousands of people to a complex mixture of dust, debris, and jet fuel combustion byproducts (1). It is estimated that over 25,000 persons in lower Manhattan developed asthma symptoms after exposure to the WTC terrorist attacks and the subsequent rescue and recovery efforts (1). In the years immediately following 9/11, new-onset asthma rates were elevated among exposed adults and many of those affected continued to experience respiratory symptoms (i.e., coughing, shortness of breath) years later (1,2). An estimated 25,000 children were living or attending school in lower Manhattan near the WTC on 9/11, and potentially were in the path of the dust cloud of building debris and smoke after the collapse of the towers, as well as for several months following the attacks, and could have inhaled particulate matter and toxic substances (3,4). Associations between 9/11-related exposures and both asthma diagnosis and persistent respiratory symptoms among children and adolescents have been documented (4,5,6). A previous report found that 2 to 3 y after 9/11, over half of children under 18 y of age who were enrolled in the World Trade Center Health Registry (Registry) reported new or worsening respiratory symptoms (53%), and 5.7% reported a post-9/11 diagnosis of asthma, both of which were associated with exposure to the dust cloud that resulted from the collapse of buildings on 9/11 (4). A subsequent study of Registry enrollees under 18 y old found that respiratory symptoms persisted up to 7 y post-9/11 (5). The WTC Environmental Health Center which collected clinical data on a sample of children an average of 7.8 y after 9/11, reported new onset provider-diagnosed asthma in 21.4% of children, and found that dust cloud exposure was associated with pulmonary function abnormalities, such as isolated low forced vital capacity pattern and an obstructive pattern consistent with asthma (6). Although the association between asthma and 9/11-exposure in children and adolescents has been documented, little is known about asthma control in this population. Large population-based surveys consistently show that poor asthma control is common in many children with asthma (7,8). Asthma control is affected by many factors, including healthcare access (9,10), socioeconomic status (9,10), and comorbid mental health conditions (11,12,13). It has been observed that adolescents with symptomatic asthma are more likely than adolescents without asthma to have lower perceived well-being, more negative behaviors, and a greater number of physical and mental health comorbidities (14). Several studies found that depression has been associated with uncontrolled asthma (11,12). In adults with 9/11-related asthma, having at least one mental health condition has been associated with poorly controlled asthma (15). However, little is known about the association between mental health conditions and the level of asthma control especially among 9/11-exposed adolescents. Previous studies of adult Registry enrollees found that those with unmet healthcare needs are more likely to have severe mental health symptoms, comorbid mental and physical health problems, and have lower quality of life (1,16). Unmet healthcare needs among adolescents have been shown to be associated with poorer health status and functioning, including asthma control (17). Poorly controlled asthma has also been associated with unmet healthcare needs related to cost or access barriers (18), such as an inability to pay for asthma medications and not having access to asthma specialists (19). The goal of this study was to evaluate asthma control 10–11 y after 9/11 among Registry as children, and to determine whether poor asthma control is associated with specific factors including adolescent 9/11-exposure, adverse mental health, behavior problems, and unmet healthcare needs

Transactional paths between children and parents in pediatric asthma: Associations between family relationships and adaptation

Introduction. The particular challenges posed by pediatric asthma may have a negative impact on the adaptation of children and their parents. From a transactional approach it is important to examine how reciprocal links between children and parents contribute to explain their adaptation and under which conditions these associations occur. This cross-sectional study aimed at examining the direct and indirect links between children’s and parents’ perceptions of family relationships and adaptation, separately (within-subjects) and across participants (cross-lagged effects), and the role of asthma severity in moderating these associations. Method. The sample comprised 257 children with asthma, aged between 8 and 18 years-old, and one of their parents. Both family members completed self-reported questionnaires on family relationships (cohesion and expressiveness) and adaptation indicators (quality of life and psychological functioning). Physicians assessed asthma severity. Structural Equation Modeling was used to test within-subjects and cross-lagged paths between children’s and parents’ family relationships and adaptation. Results. The model explained 47% of children’s and 30% of parents’ adaptation: family relationships were positively associated with adaptation, directly for children and parents, and indirectly across family members. Asthma severity moderated the association between family relationships and health-related quality of life for children: stronger associations were observed in the presence of persistent asthma. Conclusion. These results highlight the need of including psychological interventions in pediatric healthcare focused on family relationships as potential targets for improving children’s and parents’ quality of life and psychological functioning, and identified the children with persistent asthma as a group that would most benefit from family-based interventions.This study was supported by the R&D Unit Institute of Cognitive Psychology, Vocational and Social Development of the University of Coimbra (PEst-OE/PSI/UI0192/2011) and by the Portuguese Foundation for Science and Technology (PhD Grant SFRH/BD/69885/2010)

Adult attention deficit hyperactivity disorder is associated with asthma

<p>Abstract</p> <p>Background</p> <p>Attention deficit hyperactivity disorder (ADHD) is increasingly recognized as a common disorder not only in children, but also in the adult population. Similarly, asthma also has a substantial prevalence among adults. Previous studies concerning a potential relationship between ADHD and asthma have not presented consistent results.</p> <p>Methods</p> <p>A cross-sectional study of 594 adult patients diagnosed with ADHD, compared with 719 persons from the general population. Information was collected between 1997 and 2005 using auto-questionnaires rating past and present symptoms of ADHD, co-morbid conditions, including asthma, and work status.</p> <p>Results</p> <p>The prevalence of asthma was significantly higher in the ADHD patient group compared to the controls, 24.4% vs. 11.3% respectively (OR = 2.54, 95% CI 1.89-3.44), and controls with asthma scored higher on ratings of both past and present symptoms of ADHD. Female ADHD patients had a significantly higher prevalence of asthma compared to male ADHD patients (30.9% vs. 18.2%, OR = 2.01, CI 1.36-2.95), but in controls a slight female preponderance was not statistically significant. In both ADHD patients and controls, having asthma was associated with an increased prevalence of symptoms of mood- and anxiety disorders.</p> <p>Conclusions</p> <p>The present findings point to a co-morbidity of ADHD and asthma, and these patients may represent a clinical and biological subgroup of adult patients with ADHD.</p

Perceptions of complementary/alternative medicine use and influence on evidence-based asthma medicine adherence in Malaysian children

Abstract Complementary and alternative medicine (CAM) is widely used especially in Asia including for childhood asthma. The use of CAM could influence adherence to evidence-based (E-B) medicine. We explored the views of carers of Malaysian children with asthma regarding the use of CAM for childhood asthma, and its relationship with self-reported adherence to E-B medicine. We used a screening questionnaire to identify children diagnosed with asthma from seven suburban primary schools in Malaysia. Informed consent was obtained prior to the interviews. We conducted the interviews using a semi-structured topic guide in participants’ preferred language (Malay, Mandarin, or Tamil). All interviews were audio-recorded, transcribed verbatim and coded using Nvivo. Analysis was performed thematically, informed by the Necessity-Concerns Framework. A total of 46 carers (16 Malays, 21 Indians, 9 Chinese) contributed to 12 focus groups and one individual interview. We categorised participants’ as ‘Non-CAM’; ‘CAM’; or ‘combination’ user. Cultural practices and beliefs in the efficacy of CAM resulted in widespread use of CAM. Most carers used CAM as ‘complementary’ to E-B medicine. Concerns about dependence on or side effects of E-B treatment influenced carers’ decisions to rely on CAM as an ‘alternative’, with an important minority of accounts describing potentially harmful CAM-use. Healthcare professionals should discuss beliefs about the necessity for and concerns about use of both E-B medicine and CAM, and provide balanced information about effectiveness and safety. The aim is to improve adherence to regular E-B preventer medication and prevent delays in seeking medical advice and harmful practices associated with CAM

Cassava brown streak disease: historical timeline, current knowledge and future prospects

Cassava is the second most important staple food crop in terms of per capita calories consumed in Africa and holds potential for climate change adaptation. Unfortunately, productivity in East and Central Africa is severely constrained by two viral diseases: cassava mosaic disease (CMD) and cassava brown streak disease (CBSD). CBSD was first reported in 1936 from northeast Tanzania. For approximately seventy years CBSD was restricted to coastal East Africa and so had a relatively low impact on food security compared to CMD. However, at the turn of the 21st century CBSD re-emerged further inland, in areas around Lake Victoria and it has since spread through many East and Central African countries, causing high yield losses and jeopardising the food security of subsistence farmers. This recent re-emergence has attracted intense scientific interest, with studies shedding light on CBSD viral epidemiology, sequence diversity, host interactions and potential sources of resistance within the cassava genome. This review reflects on 80 years of CBSD research history (1936 – 2016) with a timeline of key events. We provide insights into current CBSD knowledge, management efforts and future prospects for improved understanding needed to underpin effective control and mitigation of impacts on food security

In vitro influence of dietary protein and fructooligosaccharides on metabolism of canine fecal microbiota

BACKGROUND: The present in vitro study investigated whether the utilization of fructooligosaccharides (FOS) may influence canine fecal microbial population in presence of diets differing in their protein content and digestibility. Fresh fecal samples were collected from five adult dogs, pooled, and incubated for 24 h with the undigested residue of three diets: 1, Low protein high digestibility diet (LP HD, crude protein (CP) 229 g/kg); 2, High protein high digestibility diet (HP HD, CP 304 g/kg); 3, High protein low digestibility diet (HP LD, CP 303 g/kg) that had been previously subjected to enzymatic digestion. In the in vitro fermentation study, there were six treatments: 1) LP HD; 2) HP HD 3) HP LD; 4) LP HD + FOS; 5) HP HD + FOS; 6) HP LD + FOS. Fructooligosaccharides were added at the final concentration of 1.5 g/L. Samples of fermentation fluid were collected at 6 and 24 h of incubation. RESULTS: Values of pH were reduced by FOS at 6 and 24 h (P < 0.001); conversely, low protein digestibility and high dietary protein level resulted in higher pH at both sampling times (P < 0.001). At 24 h, FOS lowered ammonia (−10 %; P < 0.001) and resulted (P < 0.05) in higher concentrations of total volatile fatty acids (VFA) (+43 %), acetic acid (+14 %), propionic acid (+75 %) and n-butyric acid (+372 %). Conversely, at 24 h, low protein digestibility resulted (P < 0.01) in lower concentrations of acetic acid (−26 %), propionic acid (−37 %) and total VFA (−21 %). Putrescine concentrations were increased at 6 and 24 h of fermentation by low protein digestibility (+21 and 22 %, respectively; P < 0.05) and FOS (+18 and 24 %, respectively; P < 0.01). After 24 h of fermentation, high dietary protein level resulted in lower counts of lactobacilli and enterococci (−0.5 and −0.7 log cells/mL, respectively; P < 0.05) whereas low protein digestibility tended to increase counts of C. perfringens (+0.2 log cells/mL; P = 0.07). CONCLUSIONS: Results from the present study showed that diets rich in protein may exert negative influences on the canine intestinal ecosystem, slightly increasing the presence of ammonia and reducing counts of lactobacilli and enterococci. Moreover, the presence of poorly digestible protein resulted in lower concentrations of VFA. Conversely, administration of FOS may improve metabolism of canine intestinal microbiota, reducing ammonia concentrations and enhancing VFA production