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1.  Drivers of Emerging Infectious Disease Events as a Framework for Digital Detection 
Emerging Infectious Diseases  2015;21(8):1285-1292.
Improved and expanded data collection is required to fulfil the promise of an early-warning digital system.
The growing field of digital disease detection, or epidemic intelligence, attempts to improve timely detection and awareness of infectious disease (ID) events. Early detection remains an important priority; thus, the next frontier for ID surveillance is to improve the recognition and monitoring of drivers (antecedent conditions) of ID emergence for signals that precede disease events. These data could help alert public health officials to indicators of elevated ID risk, thereby triggering targeted active surveillance and interventions. We believe that ID emergence risks can be anticipated through surveillance of their drivers, just as successful warning systems of climate-based, meteorologically sensitive diseases are supported by improved temperature and precipitation data. We present approaches to driver surveillance, gaps in the current literature, and a scientific framework for the creation of a digital warning system. Fulfilling the promise of driver surveillance will require concerted action to expand the collection of appropriate digital driver data.
PMCID: PMC4517741  PMID: 26196106
epidemiology; communicable diseases; emerging; public health; data collection; awareness; disease outbreaks; risk; the Internet; surveillance; detection; digital disease detection; disease drivers; antecedent conditions; disease events; epidemic intelligence
2.  The separation of ADHD inattention and hyperactivity-impulsivity symptoms: pathways from genetic effects to cognitive impairments and symptoms 
Both shared and unique genetic risk factors underlie the two symptom domains of attention deficit hyperactivity disorder (ADHD): inattention and hyperactivity-impulsivity. The developmental course and relationship to co-occurring disorders differs across the two symptom domains, highlighting the importance of their partially distinct etiologies. Familial cognitive impairment factors have been identified in ADHD, but whether they show specificity in relation to the two ADHD symptom domains remains poorly understood. We aimed to investigate whether different cognitive impairments are genetically linked to the ADHD symptom domains of inattention versus hyperactivity-impulsivity. We conducted multivariate genetic model fitting analyses on ADHD symptom scores and cognitive data, from go/no-go and fast tasks, collected on a population twin sample of 1312 children aged 7-10. Reaction time variability (RTV) showed substantial genetic overlap with inattention, as observed in an additive genetic correlation of 0.64, compared to an additive genetic correlation of 0.31 with hyperactivity-impulsivity. Commission errors (CE) showed low additive genetic correlations with both hyperactivity-impulsivity and inattention (genetic correlations of 0.17 and 0.11, respectively). The additive genetic correlation between RTV and CE was also low and non-significant at −0.10, consistent with the etiological separation between the two indices of cognitive impairments. Overall, two key cognitive impairments phenotypically associated with ADHD symptoms, captured by RTV and CE, showed different genetic relationships to the two ADHD symptom domains. The findings extend a previous model of two familial cognitive impairment factors in combined subtype ADHD by separating pathways underlying inattention and hyperactivity-impulsivity symptoms.
PMCID: PMC4520068  PMID: 23839718
ADHD; Genetics; Reaction time variability; Commission errors; Inattention; Hyperactivity/impulsivity
Neuro-Oncology  2014;16(Suppl 3):iii3.
BACKGROUND: The mechanisms driving glioblastoma (GBM) relapse remain elusive. To investigate evolutionary patterns in recurrence and therapy-resistance of GBM, we analyzed the genomic profiles from 252 primary GBM and 60 biopsy samples taken from 23 pairs of pre- and post-treatment GBM tumors. METHODS: We integrated mutation allele fraction, DNA copy number and genotype information to determine the cellular frequencies of all mutations and found that 70.5% of mutations were classified as clonal and 30.5% as subclonal. We validated our classification approach through multi-sector sequencing of 13 GBM tumors. RESULTS: Separating patients into discrete age groups by an interval of 10 years, we observed a significant linear correlation between clonal mutations and age (P < 3.69x10−7), but no correlation between age and subclonal mutations (P = 0.62). This result suggested that clonal mutations predominantly accumulated over the life span of the cell population that gave rise to the cell of origin before neoplastic onset, whereas_ENREF_22 subclonal mutations were acquired during tumorigenesis and may reflect intratumor heterogeneity. Interestingly, mutation or aneuploidy of p53 pathway members strongly correlated with increased fraction of subclonal mutations (P = 6 × 10−5, Wilcoxon rank test), unrelated to patient age. To further evaluate the association between TP53 mutation status, intratumoral heterogeneity and clonal evolution, we analyzed exome sequencing and DNA copy number data from 23 pairs of first and recurrent GBM tumors. We found that TP53 mutant GBM showed a significant increase in subclonal mutation frequency relative to the matched primary tumor (P = 0.0015). The clonal mutation frequency was unaffected (P = 0.23). These data suggested that TP53 mutant GBM became increasingly clonally complex at time of recurrence, whereas TP53 wildtype GBM showed a reduced level of intratumoral heterogeneity. To comprehensively investigate tumor recurrence we performed whole genome sequencing of seven primary-recurrent tumor pairs. We found that major clones in the tumor recurrence resembled major clones in the matching primary, and were both derived from an ancestral cell population. The same applied to minor clones, suggesting that multiple types of ancestral cells existed. CONCLUSIONS: We showed that mutations in the p53 pathway resulted in increased intratumoral heterogeneity at time of diagnosis and after tumor recurrence. Disease relapse was fueled by ancestral cell populations. Further research is needed to determine the impact of intratumoral heterogeneity on treatment response. Our study provides a molecular snapshot of tumor evolution in glioblastoma. SECONDARY CATEGORY: Neuropathology and Tumor Biomarkers.
PMCID: PMC4144474
4.  Accurate genetic diagnosis of Finnish pulmonary arterial hypertension patients using oligonucleotide-selective sequencing 
The genetic basis of pulmonary arterial hypertension (PAH) among Finnish PAH patients is poorly understood. We adopted a novel-targeted next-generation sequencing (NGS) approach called Oligonucleotide-Selective Sequencing (OS-Seq) and developed a custom data analysis and interpretation pipeline to identify pathogenic base substitutions, insertions, and deletions in seven genes associated with PAH (BMPR2, BMPR1B, ACVRL1, ENG, SMAD9, CAV1, and KCNK3) from Finnish PAH patients. This study represents the first clinical study with OS-Seq technology on patients suffering from a rare genetic disorder. We analyzed DNA samples from 21 Finnish PAH patients, whose BMPR2 and ACVRL1 mutation status had been previously studied using Sanger sequencing. Our sequencing panel covered 100% of the targeted base pairs with >15× sequencing depth. Pathogenic base substitutions were identified in the BMPR2 gene in 29% of the Finnish PAH cases. Two of the pathogenic variant-positive patients had been previously tested negative using Sanger sequencing. No clinically significant variants were identified in the six other PAH genes. Our study validates the use of targeted OS-Seq for genetic diagnostics of PAH and revealed pathogenic variants that had been previously missed using Sanger sequencing.
PMCID: PMC4521970  PMID: 26247051
BMPR2; genetic diagnostics; genetics; OS-Seq; pulmonary arterial hypertension
5.  MP-12 virus containing the clone 13 deletion in the NSs gene prevents lethal disease when administered after Rift Valley fever virus infection in hamsters 
Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) causes a range of illnesses that include retinitis, fulminant hepatitis, neurologic disease, and hemorrhagic fever. In hospitalized individuals, case fatality rates can be as high as 10–20%. There are no vaccines or antivirals approved for human use to prevent or treat severe RVFV infections. We previously tested the efficacy of the MP-12 vaccine strain and related variants with NSs truncations as a post-exposure prophylaxis in mice infected with wild-type pathogenic RVFV strain ZH501. Post-exposure efficacy of the rMP12-C13type, a recombinant MP-12 vaccine virus which encodes an in-frame truncation removing 69% of the NSs protein, resulted in 30% survival when administering the virus within 30 min of subcutaneous ZH501 challenge in mice, while the parental MP-12 virus conferred no protection by post-exposure vaccination. Here, we demonstrate uniform protection of hamsters by post-exposure vaccination with rMP12-C13type administered 6 h post-ZH501 infection while no efficacy was observed with the parental MP-12 virus. Notably, both the MP-12 and rMP12-C13type viruses were highly effective (100% protection) when administered 21 days prior to challenge. In a subsequent study delaying vaccination until 8, 12, and 24 h post-RVFV exposure, we observed 80, 70, and 30% survival, respectively. Our findings indicate that the rapid protective innate immune response elicited by rMP12-C13type may be due to the truncated NSs protein, suggesting that the resulting functional inactivation of NSs plays an important role in the observed post-exposure efficacy. Taken together, the data demonstrate that post-exposure vaccination with rMP12-C13type is effective in limiting ZH501 replication and associated disease in standard pre-exposure vaccination and post-challenge treatment models of RVFV infection, and suggest an extended post-exposure prophylaxis window beyond that initially observed in mice.
PMCID: PMC4484224  PMID: 26175722
Rift Valley fever virus; phlebovirus; viral hemorrhagic fever; vaccine; post-exposure
6.  Genetics and genotype–phenotype correlations in Finnish patients with dilated cardiomyopathy 
European Heart Journal  2015;36(34):2327-2337.
Genetic analysis among patients with dilated cardiomyopathy (DCM) is becoming an important part of clinical assessment, as it is in hypertrophic cardiomyopathy (HCM). The genetics of DCM is complex and therefore next-generation sequencing strategies are essential when providing genetic diagnostics. To achieve maximum yield, the diagnostic approach should include comprehensive clinical phenotyping combined with high-quality, high-coverage deep sequencing of DCM-associated genes and clinical variant classification as a basis for defining true yield in genetic testing. Our study has combined a novel sequencing strategy and clinical interpretation to analyse the yield and genotype–phenotype correlations among well-phenotyped Finnish DCM patients.
Despite our increased understanding of the genetic basis of dilated cardiomyopathy (DCM), the clinical utility and yield of clinically meaningful findings of comprehensive next-generation sequencing (NGS)-based genetic diagnostics in DCM has been poorly described. We utilized a high-quality oligonucleotide-selective sequencing (OS-Seq)-based targeted sequencing panel to investigate the genetic landscape of DCM in Finnish population and to evaluate the utility of OS-Seq technology as a novel comprehensive diagnostic tool.
Methods and results
Using OS-Seq, we targeted and sequenced the coding regions and splice junctions of 101 genes associated with cardiomyopathies in 145 unrelated Finnish patients with DCM. We developed effective bioinformatic variant filtering strategy and implemented strict variant classification scheme to reveal diagnostic yield and genotype–phenotype correlations. Implemented OS-Seq technology provided high coverage of the target region (median coverage 410× and 99.42% of the nucleotides were sequenced at least 15× read depth). Diagnostic yield was 35.2% (familial 47.6% and sporadic 25.6%, P = 0.004) when both pathogenic and likely pathogenic variants are considered as disease causing. Of these, 20 (53%) were titin (TTN) truncations (non-sense and frameshift) affecting all TTN transcripts. TTN truncations accounted for 20.6% and 14.6% of the familial and sporadic DCM cases, respectively.
Panel-based, high-quality NGS enables high diagnostic yield especially in the familial form of DCM, and bioinformatic variant filtering is a reliable step in the process of interpretation of genomic data in a clinical setting.
PMCID: PMC4561350  PMID: 26084686
Dilated cardiomyopathy; Genetics; Diagnosis
7.  Mitogenomic Meta-Analysis Identifies Two Phases of Migration in the History of Eastern Eurasian Sheep 
Molecular Biology and Evolution  2015;32(10):2515-2533.
Despite much attention, history of sheep (Ovis aries) evolution, including its dating, demographic trajectory and geographic spread, remains controversial. To address these questions, we generated 45 complete and 875 partial mitogenomic sequences, and performed a meta-analysis of these and published ovine mitochondrial DNA sequences (n = 3,229) across Eurasia. We inferred that O. orientalis and O. musimon share the most recent female ancestor with O. aries at approximately 0.790 Ma (95% CI: 0.637–0.934 Ma) during the Middle Pleistocene, substantially predating the domestication event (∼8–11 ka). By reconstructing historical variations in effective population size, we found evidence of a rapid population increase approximately 20–60 ka, immediately before the Last Glacial Maximum. Analyses of lineage expansions showed two sheep migratory waves at approximately 4.5–6.8 ka (lineages A and B: ∼6.4–6.8 ka; C: ∼4.5 ka) across eastern Eurasia, which could have been influenced by prehistoric West–East commercial trade and deliberate mating of domestic and wild sheep, respectively. A continent-scale examination of lineage diversity and approximate Bayesian computation analyses indicated that the Mongolian Plateau region was a secondary center of dispersal, acting as a “transportation hub” in eastern Eurasia: Sheep from the Middle Eastern domestication center were inferred to have migrated through the Caucasus and Central Asia, and arrived in North and Southwest China (lineages A, B, and C) and the Indian subcontinent (lineages B and C) through this region. Our results provide new insights into sheep domestication, particularly with respect to origins and migrations to and from eastern Eurasia.
PMCID: PMC4576706  PMID: 26085518
wild ancestor; domestication; gene flow; mitogenome; Ovis aries; meta-analysis; colonization simulation
8.  Optimization of a Novel Non-invasive Oral Sampling Technique for Zoonotic Pathogen Surveillance in Nonhuman Primates 
PLoS Neglected Tropical Diseases  2015;9(6):e0003813.
Free-ranging nonhuman primates are frequent sources of zoonotic pathogens due to their physiologic similarity and in many tropical regions, close contact with humans. Many high-risk disease transmission interfaces have not been monitored for zoonotic pathogens due to difficulties inherent to invasive sampling of free-ranging wildlife. Non-invasive surveillance of nonhuman primates for pathogens with high potential for spillover into humans is therefore critical for understanding disease ecology of existing zoonotic pathogen burdens and identifying communities where zoonotic diseases are likely to emerge in the future. We developed a non-invasive oral sampling technique using ropes distributed to nonhuman primates to target viruses shed in the oral cavity, which through bite wounds and discarded food, could be transmitted to people. Optimization was performed by testing paired rope and oral swabs from laboratory colony rhesus macaques for rhesus cytomegalovirus (RhCMV) and simian foamy virus (SFV) and implementing the technique with free-ranging terrestrial and arboreal nonhuman primate species in Uganda and Nepal. Both ubiquitous DNA and RNA viruses, RhCMV and SFV, were detected in oral samples collected from ropes distributed to laboratory colony macaques and SFV was detected in free-ranging macaques and olive baboons. Our study describes a technique that can be used for disease surveillance in free-ranging nonhuman primates and, potentially, other wildlife species when invasive sampling techniques may not be feasible.
Author Summary
Wild nonhuman primates are frequent sources of pathogens that could be transmitted to humans because they are closely genetically related and have intimate contact with humans in many parts of the world. Sampling primates to screen for zoonotic pathogens is logistically challenging because standard invasive sampling techniques, such as the collection of a blood sample or an oral swab, requires field anesthesia. This research describes a non-invasive oral sampling technique that involves distributing a rope for primates to chew on that can be retrieved and screened for pathogens. Oral samples were successfully collected from multiple wild primate species in remote field settings and viruses were detected in those samples. This non-invasive sampling method has the potential for future applications in disease studies examining primates as sources of diseases that could affect humans in remote tropical settings.
PMCID: PMC4457869  PMID: 26046911
9.  A Less Saline Baltic Sea Promotes Cyanobacterial Growth, Hampers Intracellular Microcystin Production, and Leads to Strain-Specific Differences in Allelopathy 
PLoS ONE  2015;10(6):e0128904.
Salinity is one of the main factors that explain the distribution of species in the Baltic Sea. Increased precipitation and consequent increase in freshwater inflow is predicted to decrease salinity in some areas of the Baltic Sea. Clearly such changes may have profound effects on the organisms living there. Here we investigate the response of the commonly occurring cyanobacterium Dolichospermum spp. to three salinities, 0, 3 and 6. For the three strains tested we recorded growth, intracellular toxicity (microcystin) and allelopathic properties. We show that Dolichospermum can grow in all the three salinities tested with highest growth rates in the lowest salinity. All strains showed allelopathic potential and it differed significantly between strains and salinities, but was highest in the intermediate salinity and lowest in freshwater. Intracellular toxin concentration was highest in salinity 6. In addition, based on monitoring data from the northern Baltic Proper and the Gulf of Finland, we show that salinity has decreased, while Dolichospermum spp. biomass has increased between 1979 and 2013. Thus, based on our experimental findings it is evident that salinity plays a large role in Dolichospermum growth, allelopathic properties and toxicity. In combination with our long-term data analyses, we conclude that decreasing salinity is likely to result in a more favourable environment for Dolichospermum spp. in some areas of the Baltic Sea.
PMCID: PMC4456099  PMID: 26042598
10.  Evidence for Henipavirus spillover into human populations in Africa 
Nature communications  2014;5:5342.
Zoonotic transmission of lethal Henipaviruses (HNV) from their natural fruit bat reservoirs to humans has only been reported in Australia and South/Southeast Asia. However, a recent study discovered numerous HNV clades in African bat samples. To determine the potential for HNV spillover events among humans in Africa, here we examine well-curated sets of bat (Eidolon helvum, n=44) and human (n=497) serum samples from Cameroon for Nipah virus (NiV) cross-neutralizing antibodies (NiV-X-Nabs). Using a VSV-based pseudoparticle seroneutralization assay, we detect NiV-X-Nabs in 48% and 3-4% of the bat and human samples, respectively. Seropositive human samples are found almost exclusively in individuals that reported butchering bats for bushmeat. Seropositive human sera also neutralize Hendra virus and Gh-M74a (an African HNV) pseudoparticles, as well as live NiV. Butchering bat meat and living in areas undergoing deforestation are the most significant risk factors associated with seropositivity. Evidence for HNV spillover events warrants increased surveillance efforts.
PMCID: PMC4237230  PMID: 25405640
11.  Safety and tolerability of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor antidepressants for patients with major depressive disorder 
Drugs in Context  2015;4:212279.
The aim of this analysis was to assess the safety profile of edivoxetine as adjunctive treatment to selective serotonin reuptake inhibitor (SSRI) antidepressants.
A pooled analysis was conducted on data obtained from the integrated safety database of edivoxetine as adjunctive treatment to SSRIs. Safety and tolerability assessments included discontinuation rates, spontaneously reported treatment-emergent adverse events (TEAEs), clinical laboratory tests, blood pressure (BP) and pulse, and electrocardiograms (ECGs).
The analysis included 1260 patients treated with adjunctive edivoxetine and 806 treated with adjunctive placebo. Study completion rates were 85.2% and 84.5% (p=0.994), respectively. Discontinuations due to adverse events were 4.9% and 3.5% (p=0.07), respectively. Significantly more patients in the adjunctive edivoxetine group compared with adjunctive placebo group reported at least one TEAE (56.8 vs 43.7%, p<0.001). The most common TEAEs (occurred ≥5% frequency) were hyperhidrosis, nausea, and tachycardia. Mean changes in sitting BP and pulse at the last visit were increased significantly in patients treated with adjunctive edivoxetine compared with adjunctive placebo (SBP: 2.7 vs 0.5 mm Hg, p<0.001; DBP: 4.1 vs 0.8 mm Hg, p<0.001; pulse: 8.8 vs −1.3 bpm, p<0.001). There were no clinically significant changes in laboratory measures.
The tolerability and safety profile of edivoxetine as adjunctive treatment to SSRI antidepressants was consistent with its norepinephrine reuptake inhibitor mechanism of action, and was comparable with edivoxetine monotherapy treatment in patients with major depressive disorder.
PMCID: PMC4434861  PMID: 26005493
norepinephrine reuptake inhibitor; serotonin reuptake inhibitor; second-generation antidepressive agent; major depressive disorder; adjunctive therapy; drug safety; drug tolerability
12.  Duplicated Leptin Receptors in Two Species of Eel Bring New Insights into the Evolution of the Leptin System in Vertebrates 
PLoS ONE  2015;10(5):e0126008.
Since its discovery in mammals as a key-hormone in reproduction and metabolism, leptin has been identified in an increasing number of tetrapods and teleosts. Tetrapods possess only one leptin gene, while most teleosts possess two leptin genes, as a result of the teleost third whole genome duplication event (3R). Leptin acts through a specific receptor (LEPR). In the European and Japanese eels, we identified two leptin genes, and for the first time in vertebrates, two LEPR genes. Synteny analyses indicated that eel LEPRa and LEPRb result from teleost 3R. LEPRb seems to have been lost in the teleost lineage shortly after the elopomorph divergence. Quantitative PCRs revealed a wide distribution of leptins and LEPRs in the European eel, including tissues involved in metabolism and reproduction. Noticeably, leptin1 was expressed in fat tissue, while leptin2 in the liver, reflecting subfunctionalization. Four-month fasting had no impact on the expression of leptins and LEPRs in control European eels. This might be related to the remarkable adaptation of silver eel metabolism to long-term fasting throughout the reproductive oceanic migration. In contrast, sexual maturation induced differential increases in the expression of leptins and LEPRs in the BPG-liver axis. Leptin2 was strikingly upregulated in the liver, the central organ of the reproductive metabolic challenge in teleosts. LEPRs were differentially regulated during sexual maturation, which may have contributed to the conservation of the duplicated LEPRs in this species. This suggests an ancient and positive role of the leptin system in the vertebrate reproductive function. This study brings new insights on the evolutionary history of the leptin system in vertebrates. Among extant vertebrates, the eel represents a unique case of duplicated leptins and leptin receptors as a result of 3R.
PMCID: PMC4422726  PMID: 25946034
13.  A Longitudinal Twin Study of the Direction of Effects between ADHD Symptoms and IQ 
PLoS ONE  2015;10(4):e0124357.
While the negative association between ADHD symptoms and IQ is well documented, our knowledge about the direction and aetiology of this association is limited. Here, we examine the association of ADHD symptoms with verbal and performance IQ longitudinally in a population-based sample of twins. In a population-based sample of 4,771 twin pairs, DSM-IV ADHD symptoms were obtained from the Conners’ Parent Rating Scale-Revised. Verbal (vocabulary) and performance (Raven’s Progressive Matrices) IQ were assessed online. ADHD symptom ratings and IQ scores were obtained at ages 12, 14 and 16 years. Making use of the genetic sensitivity and time-ordered nature of our data, we use a cross-lagged model to examine the direction of effects, while modelling the aetiologies of the association between ADHD symptoms with vocabulary and Raven’s scores over time. Although time-specific aetiological influences emerged for each trait at ages 14 and 16 years, the aetiological factors involved in the association between ADHD symptoms and IQ were stable over time. ADHD symptoms and IQ scores significantly predicted each other over time. ADHD symptoms at age 12 years were a significantly stronger predictor of vocabulary and Raven’s scores at age 14 years than vice versa, whereas no differential predictive effects emerged from age 14 to 16 years. The results suggest that ADHD symptoms may put adolescents at risk for decreased IQ scores. Persistent genetic influences seem to underlie the association of ADHD symptoms and IQ over time. Early intervention is likely to be key to reducing ADHD symptoms and the associated risk for lower IQ.
PMCID: PMC4398424  PMID: 25875897
14.  Medically Unexplained and Explained Physical Symptoms in the General Population: Association with Prevalent and Incident Mental Disorders 
PLoS ONE  2015;10(4):e0123274.
Clinical studies have shown that Medically Unexplained Symptoms (MUS) are related to common mental disorders. It is unknown how often common mental disorders occur in subjects who have explained physical symptoms (PHY), MUS or both, in the general population, what the incidence rates are, and whether there is a difference between PHY and MUS in this respect.
To study the prevalence and incidence rates of mood, anxiety and substance use disorders in groups with PHY, MUS and combined MUS and PHY compared to a no-symptoms reference group in the general population.
Data were derived from the Netherlands Mental Health Survey and Incidence Study-2 (NEMESIS-2), a nationally representative face-to-face survey of the general population aged 18-64 years. We selected subjects with explained physical symptoms only (n=1952), with MUS only (n=177), with both MUS and PHY (n=209), and a reference group with no physical symptoms (n=4168). The assessment of common mental disorders was through the Composite International Diagnostic Interview 3.0. Multivariate logistic regression analyses were used to examine the association between group membership and the prevalence and first-incidence rates of comorbid mental disorders, adjusted for socio-demographic characteristics.
MUS were associated with the highest prevalence rates of mood and anxiety disorders, and combined MUS and PHY with the highest prevalence rates of substance disorder. Combined MUS and PHY were associated with a higher incidence rate of mood disorder only (OR 2.9 (95%CI:1.27,6.74)).
In the general population, PHY, MUS and the combination of both are related to mood and anxiety disorder, but odds are highest for combined MUS and PHY in relation to substance use disorder. Combined MUS and PHY are related to a greater incidence of mood disorder. These findings warrant further research into possibilities to improve recognition and early intervention in subjects with combined MUS and PHY.
PMCID: PMC4390312  PMID: 25853676
15.  Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment 
Antiviral research  2014;104:84-92.
Rift Valley Fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, we challenged hamsters with the highly pathogenic ZH501 strain of RVFV to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2–3 days after infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater in hamsters challenged with RVFV when administered within 1 or 6 h post-exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden in the brain observed in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin.
PMCID: PMC3975078  PMID: 24486952
16.  Global Avian Influenza Surveillance in Wild Birds: A Strategy to Capture Viral Diversity 
Emerging Infectious Diseases  2015;21(4):e141415.
Wild birds play a major role in the evolution, maintenance, and spread of avian influenza viruses. However, surveillance for these viruses in wild birds is sporadic, geographically biased, and often limited to the last outbreak virus. To identify opportunities to optimize wild bird surveillance for understanding viral diversity, we reviewed responses to a World Organisation for Animal Health–administered survey, government reports to this organization, articles on Web of Knowledge, and the Influenza Research Database. At least 119 countries conducted avian influenza virus surveillance in wild birds during 2008–2013, but coordination and standardization was lacking among surveillance efforts, and most focused on limited subsets of influenza viruses. Given high financial and public health burdens of recent avian influenza outbreaks, we call for sustained, cost-effective investments in locations with high avian influenza diversity in wild birds and efforts to promote standardized sampling, testing, and reporting methods, including full-genome sequencing and sharing of isolates with the scientific community.
PMCID: PMC4378471  PMID: 25811221
influenza; influenza virus; viruses; wild birds; global avian influenza surveillance; viral diversity; epidemiologic monitoring; molecular evolution; genetic variation; genomic library; animal diseases; zoonoses; genetic databases; disease reservoirs; Organisation for Animal Health; OIE; One Health
17.  Treatment received and treatment adequacy of depressive disorders among young adults in Finland 
BMC Psychiatry  2015;15:47.
Under-treated depression may be especially harmful in early adulthood. The aims of this study are to describe treatments received for depressive disorders, to define factors associated with treatment adequacy and dropouts from treatment in a Finnish general population sample of young adults.
A nationally representative two-stage cluster sample of 1894 Finns aged 19 to 34 years was sent a questionnaire containing several mental health screens. All screen positives and a random sample of screen negatives were invited to participate in a mental health assessment including a SCID interview. Case records from mental health treatments for the same sample were obtained for the final diagnostic assessment. Based on all available information, receiving antidepressant pharmacotherapy for at least two months with at least four visits with any type of physician or at least eight sessions of psychotherapy within 12 months or at least four days of hospitalization were regarded as minimally adequate treatment. Treatment dropout was rated if the treatment strategy was assessed to be adequate according to the case records but the patient discontinued the visits.
Of participants with depressive disorders (n = 142), 40.9% received minimally adequate treatment. In multiple logistic regression models, substance use disorder and female gender were associated with at least one visit with a physician, while having major depressive disorder was associated with visits with a physician at least 4 times a year. Women had higher odds of having received any psychotherapy and psychotherapy lasting for at least 8 sessions in a year. Low education and a history of suicide attempt were associated with increased odds of treatment dropout. None of the factors explained the final outcome of minimally adequate treatment.
Treatment adequacy in the present study was better than previously seen, but more efforts are needed to provide adequate treatment for young adults, especially those with low education and suicidality.
Electronic supplementary material
The online version of this article (doi:10.1186/s12888-015-0427-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4364633  PMID: 25881327
Depressive disorders; Treatment; Young adults
18.  Child behaviors associated with childhood obesity and parents’ self-efficacy to handle them: Confirmatory factor analysis of the Lifestyle Behavior Checklist 
The development of family-based programs for child weight management requires an understanding of parents’ difficulties in managing children’s eating and physical activity behaviors; however, knowledge about the specific behaviors that parents find most difficult to address is still limited. The Lifestyle Behavior Checklist (LBC) is an Australian instrument that assesses parents’ perceptions of children’s obesity-related behaviors (the Problem scale), and parents’ self-efficacy in dealing with these behaviors (the Confidence scale). Our aims were 1) to examine the psychometric properties (the factor structure, internal reliability, construct and discriminative validity) of the LBC in parents of preschoolers in Sweden, using the Child Feeding Questionnaire (CFQ) as a criterion measure, 2) to study associations between the LBC and socio-demographic factors.
The LBC and the CFQ (measuring parental feeding practices) were distributed to parents from 25 schools/preschools and to parents starting a childhood obesity intervention. To test the fit of the original four-factor model (misbehavior in relation to food, overeating, emotional correlates of being overweight, physical activity (24 items)) to the data, confirmatory factor analysis (CFA) was performed. Structural equation modelling was used to examine associations between the LBC and the CFQ and socio-demographic factors.
In a sample of 478 parents, a five-factor structure proved best fit to data, after excluding 6 items and allowing two pairs of error terms to correlate (TLI = 0.899; CFI = 0.918; RMSEA = 0.042; SRMR = 0.055). The Confidence scale indicated unidimensionality, therefore a hierarchical CFA with 5 first order factors and one second order factor was tested showing good fit. The validity of the LBC was proven by relevant associations with the CFQ and child weight status; parental responses differed depending on child weight status. The Confidence scale was not associated with any child or parent variables.
In a large sample of Swedish parents of preschoolers, the LBC showed good psychometric properties, with relevant correlations to similar constructs. A five-factor structure showed best fit to data with moderate to high internal reliability. The LBC was shown to discriminate effectively between parents of normal weight children and parents of overweight/obese children.
PMCID: PMC4403705  PMID: 25889819
Lifestyle behavior checklist; Children; Eating; Obesity; Parenting; Validation; Confidence
19.  Integrin traffic – the update 
Journal of Cell Science  2015;128(5):839-852.
Integrins are a family of transmembrane cell surface molecules that constitute the principal adhesion receptors for the extracellular matrix (ECM) and are indispensable for the existence of multicellular organisms. In vertebrates, 24 different integrin heterodimers exist with differing substrate specificity and tissue expression. Integrin–extracellular-ligand interaction provides a physical anchor for the cell and triggers a vast array of intracellular signalling events that determine cell fate. Dynamic remodelling of adhesions, through rapid endocytic and exocytic trafficking of integrin receptors, is an important mechanism employed by cells to regulate integrin–ECM interactions, and thus cellular signalling, during processes such as cell migration, invasion and cytokinesis. The initial concept of integrin traffic as a means to translocate adhesion receptors within the cell has now been expanded with the growing appreciation that traffic is intimately linked to the cell signalling apparatus. Furthermore, endosomal pathways are emerging as crucial regulators of integrin stability and expression in cells. Thus, integrin traffic is relevant in a number of pathological conditions, especially in cancer. Nearly a decade ago we wrote a Commentary in Journal of Cell Science entitled ‘Integrin traffic’. With the advances in the field, we felt it would be appropriate to provide the growing number of researchers interested in integrin traffic with an update.
PMCID: PMC4342575  PMID: 25663697
Integrin; Trafficking; Rab GTPases; Migration; Invasion; Signalling crosstalk
20.  Cognitive Performance and BMI in Childhood: Shared Genetic Influences Between Reaction Time But Not Response Inhibition 
Obesity (Silver Spring, Md.)  2014;22(11):2312-2318.
The aim of this work is to understand whether shared genetic influences can explain the association between obesity and cognitive performance, including slower and more variable reaction times (RTs) and worse response inhibition.
RT on a four-choice RT task and the go/no-go task, and commission errors on the go/no-go task for 1,312 twins ages 7-10 years were measured. BMI was measured at 9-12 years. Biometric twin models were run to give an estimate of the genetic correlation (rG) between body mass index (BMI) and three cognitive measures: mean RT (MRT), RT variability (RTV; the standard deviation of RTs), and commission errors (a measure of response inhibition).
Genetic correlations indicated that 20%-30% of the genes underlying BMI were shared with both RT measures. However, only small phenotypic correlations between MRT and RTV with later BMI (rPh = ~0.1) were observed. Commission errors were unassociated with later BMI (rPh = −0.03, ns).
Our results are the first to demonstrate significant shared genetic effects between RT performance and BMI. Our findings add biological support to the notion that obesity is associated with slower and more variable RTs. However, our results also emphasize the small nature of the association, which may explain previous negative findings.
PMCID: PMC4313367  PMID: 25376398
21.  Activity of a phenolic dibenzylsulfide against New World arenavirus infections 
Junín virus (JUNV) and several other Clade B New World arenaviruses cause human disease ranging from mild febrile illness to severe viral hemorrhagic fever (HF). These viruses pose a significant threat to national security and safe and effective therapies are limited outside of Argentina, where immune plasma is the standard of care for treating JUNV infection in cases of Argentine HF.
An in vitro screen of the Chemtura library identified several compounds with activity against Tacaribe virus (TCRV), a Clade B arenavirus closely related to JUNV. Of these compounds, D746, a phenolic dibenzylsulfide, was further pursued for additional in vitro studies and evaluated in the AG129 mouse TCRV infection model.
D746 was found to act during an early to intermediate stage of the TCRV replication cycle and micromolar range activity was confirmed by virus yield reduction assays with both TCRV and JUNV. Although intraperitoneal twice daily treatment regimens were found to be highly effective when started 2 hours prior to TCRV challenge in AG129 mice, post-exposure treatment initiated 3 days after infection was not efficacious. Interestingly, despite the pre-exposure treatment success, D746 did not reduce serum or tissue virus titers during the acute infection. Moreover, D746 elicited ascites fluid accumulation in mice during, as well as independent of, infection.
Our findings suggest that D746 may be altering the host response to TCRV infection in AG129 mice in a way that limits pathogenesis and thereby protects mice from otherwise lethal infection in the absence of measurable reductions in viral burden.
PMCID: PMC3664662  PMID: 23337126
22.  Rift Valley Fever Virus Infection in Golden Syrian Hamsters 
PLoS ONE  2015;10(1):e0116722.
Rift Valley fever virus (RVFV) is a formidable pathogen that causes severe disease and abortion in a variety of livestock species and a range of disease in humans that includes hemorrhagic fever, fulminant hepatitis, encephalitis and blindness. The natural transmission cycle involves mosquito vectors, but exposure can also occur through contact with infected fluids and tissues. The lack of approved antiviral therapies and vaccines for human use underlies the importance of small animal models for proof-of-concept efficacy studies. Several mouse and rat models of RVFV infection have been well characterized and provide useful systems for the study of certain aspects of pathogenesis, as well as antiviral drug and vaccine development. However, certain host-directed therapeutics may not act on mouse or rat pathways. Here, we describe the natural history of disease in golden Syrian hamsters challenged subcutaneously with the pathogenic ZH501 strain of RVFV. Peracute disease resulted in rapid lethality within 2 to 3 days of RVFV challenge. High titer viremia and substantial viral loads were observed in most tissues examined; however, histopathology and immunostaining for RVFV antigen were largely restricted to the liver. Acute hepatocellular necrosis associated with a strong presence of viral antigen in the hepatocytes indicates that fulminant hepatitis is the likely cause of mortality. Further studies to assess the susceptibility and disease progression following respiratory route exposure are warranted. The use of the hamsters to model RVFV infection is suitable for early stage antiviral drug and vaccine development studies.
PMCID: PMC4301868  PMID: 25607955
23.  Evaluation of repeated [18F]EF5 PET/CT scans and tumor growth rate in experimental head and neck carcinomas 
EJNMMI Research  2014;4:65.
Tumor hypoxia is linked to invasion and metastasis but whether this associates with tumor growth rate is not well understood. We aimed to study the relationship between hypoxia evaluated with the positron emission tomography (PET) tracer [18F]EF5 and tumor growth. Our second goal was to assess the variability in the uptake of [18F]EF5 in tumor between two scans.
Four human head and neck squamous cell carcinoma (UT-SCC) cell lines were xenografted in flank or neck of nude mice, and tumor size was closely monitored over the study period. The tumors were clearly visible when the first [18F]EF5 scan was acquired. After an exponential growth phase, the tumors were imaged again with [18F]EF5 and also with 18F-fluorodeoxyglucose ([18F]FDG).
There was a clear correlation between the percentage of tumor growth rate per day and the [18F]EF5 uptake in the latter scan (r = 0.766, p = 0.01). The uptake of [18F]EF5 in the first scan and the uptake of [18F]FDG did not significantly correlate with the tumor growth rate. We also observed considerable variations in the uptake of [18F]EF5 between the two scans.
The uptake of [18F]EF5 in the late phase of exponential tumor growth is associated with the tumor growth rate in mice bearing HNC xenografts.
PMCID: PMC4412195  PMID: 25977879
[18F]EF5; [18F]FDG; PET/CT; Hypoxia; Tumor growth rate; HNSCC; Xenograft
24.  Autologous bone marrow derived mesenchymal stromal cell therapy in combination with everolimus to preserve renal structure and function in renal transplant recipients 
Kidney transplantation has improved survival and quality of life for patients with end-stage renal disease. Despite excellent short-term results due to better and more potent immunosuppressive drugs, long-term survival of transplanted kidneys has not improved accordingly in the last decades. Consequently there is a strong interest in immunosuppressive regimens that maintain efficacy for the prevention of rejection, whilst preserving renal structure and function. In this respect the infusion of mesenchymal stromal cells (MSCs) may be an interesting immune suppressive strategy. MSCs have immune suppressive properties and actively contribute to tissue repair. In experimental animal studies the combination of mammalian target of rapamycin (mTOR) inhibitor and MSCs was shown to attenuate allo immune responses and to promote allograft tolerance. The current study will test the hypothesis that MSC treatment, in combination with the mTOR inhibitor everolimus, facilitates tacrolimus withdrawal, reduces fibrosis and decreases the incidence of opportunistic infections compared to standard tacrolimus dose.
70 renal allograft recipients, 18–75 years old, will be included in this Phase II, open label, randomized, non-blinded, prospective, single centre clinical study. Patients in the MSC treated group will receive two doses of autologous bone marrow derived MSCs IV (target 1,5x106, Range 1-2x106 million MSCs per/kg body weight), 7 days apart, 6 and 7 weeks transplantation in combination with everolimus and prednisolone. At the time of the second MSC infusion tacrolimus will be reduced to 50% and completely withdrawn 1 week later. Patients in the control group will receive everolimus, prednisolone and standard dose tacrolimus. The primary end point is to compare fibrosis by quantitative Sirius Red scoring of MSC treated and untreated groups at 6 months compared to 4 weeks post-transplant. Secondary end points include: composite end point efficacy failure (Biopsy Proven Acute Rejection, graft loss or death); renal function and proteinuria; opportunistic infections; immune monitoring and “subclinical” cardiovascular disease groups by assessing echocardiography in the different treatment groups.
This study will provide information whether MSCs in combination with everolimus can be used for tacrolimus withdrawal, and whether this strategy leads to preservation of renal structure and function in renal recipients.
Trial registration
PMCID: PMC4273432  PMID: 25491391
Mesenchymal stromal cells; Renal transplantation; Fibrosis; Immune modulation; Repair
25.  New Approach for Interpreting Changes in Circulating Tumour Cells (CTC) for Evaluation of Treatment Effect in Metastatic Breast Cancer 
Translational Oncology  2014;7(6):694-701.
Aim: Attempts have been made to use CTC values for interpretation of treatment response and to guide change of chemotherapy by using a static cut-off of 5 CTC to stratify patients in favourable or unfavourable responders. We propose a new approach to interpret treatment effect using significant changes in CTC values (SCV-limits1) as grouping parameter for responders and non-responders to chemotherapy among metastatic breast cancer (mBC) patients. Method: CTC were analysed using the CellSearch System in blood from 47 mBC patients before the start of new chemotherapy and before the third cycle of therapy. The new and old approach to interpret changes in CTC values were compared in relation to progression free survival (PFS). Results: The new approach using significant CTC change (P = .032) and the old approach using static cut-off (P > .001) correlated significantly with PFS using a cohort of 47 patients. Conclusion: We propose a new approach to interpret significant changes between baseline and follow-up CTC values as a tool for assessing treatment effect in mBC. Our approach stratified patients in new risk groups that were stratified significantly with respect to PFS. More patients are needed to balance the size of the risk groups for better comparison to the existing approach based on a 5 CTC cut-off.
PMCID: PMC4311024  PMID: 25500078

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