Assessing the pandemic risk posed by specific non-human influenza A viruses is an important goal in public health research. As influenza virus genome sequencing becomes cheaper, faster, and more ...readily available, the ability to predict pandemic potential from sequence data could transform pandemic influenza risk assessment capabilities. However, the complexities of the relationships between virus genotype and phenotype make such predictions extremely difficult. The integration of experimental work, computational tool development, and analysis of evolutionary pathways, together with refinements to influenza surveillance, has the potential to transform our ability to assess the risks posed to humans by non-human influenza viruses and lead to improved pandemic preparedness and response.
Nonadherence is a major challenge in schizophrenia treatment. While long-acting (depot) antipsychotic medications are often recommended to address adherence problems, evidence on the comparative ...effectiveness of depot versus oral antipsychotics is inconsistent. We hypothesize that this inconsistency could be due to systematic differences in study design. This review evaluates the effect of study design on the comparative effectiveness of antipsychotic formulations. The optimal use of different antipsychotic formulations in a general clinical setting depends on better understanding of the underlying reasons for differences in effectiveness across research designs.
A PubMed literature review targeted English-language studies (2000-2011) with information on relapse, hospitalization, or all-cause discontinuation for depot and oral antipsychotic treatment arms in schizophrenia. The time frame was chosen to reflect research focused on the newer generation of antipsychotic agents. The search required at least 1 term from each of the following categories: (1) schizophrenia; (2) inject, injection, injectable, injectables, injected, depot, long-acting; and (3) iloperidone, fluphenazine, haloperidol, paliperidone, risperidone, olanzapine, asenapine, flupentixol, flupenthixol, lurasidone, clopenthixol, fluspirilene, zuclopentixol, zuclopenthixol.
Thirteen relevant studies were identified by 2 independent reviewers; these studies included information on 19 depot-oral comparisons.
Age- and gender-adjusted risk ratios (RRs) (depot/oral) were calculated for the identified endpoints and pooled by study design (randomized controlled trial RCT, prospective observational, and retrospective observational). Meta-analysis with random effects was used to estimate the pooled RRs, by study design. Average conversion factors between study designs were calculated as the ratios of pooled RRs.
Meta-analysis of adjusted endpoints showed no apparent benefit of depot over oral formulations in RCTs, with an RR of 0.89 (P = .416). In contrast, there was a significant advantage for depot formulations in other study designs (prospective RR = 0.62 P < .001; retrospective RR = 0.56 P < .001). These imply conversion factors of 1.43 and 1.59 between RCTs and prospective and retrospective designs, respectively.
The comparative effectiveness of antipsychotic formulations is sensitive to research design. Depot formulations displayed significant advantages in nonrandomized observational studies, whereas in RCTs no difference was observed. The estimated conversion factors may facilitate comparison across studies.
Objectives
Sudden death is a recognized consequence of epilepsy. Little is known about the practice of confirming the cause of sudden death from most nations. We sought to determine how often autopsy ...is undertaken, clinician confidence in cause of death and identify the factors which may influence autopsy utilization.
Materials & Methods
An online questionnaire survey was sent to all International League Against Epilepsy (ILAE) chapters chairpersons, asking them to complete the survey based on their perceptions in their country. Questions included: confidence in cause of death in people with epilepsy, frequency of autopsy uptake, and perceived barriers to an accurate diagnosis and ongoing research work. Data were analyzed by chi‐squared, Kruskal‐Wallis and Spearman rank analysis.
Results
Responses were obtained from 77 of 114 individual chapter leaders (68%). Legal, coronial, family attitudes, including cultural and religious factors, to autopsy were considered the major barriers to obtaining an accurate diagnosis. Only 13% had a high level of confidence in the accuracy of the cause of death. There was greater confidence in the diagnosis of the causes of sudden death in epilepsy in the countries with higher autopsy rates. Sixty‐six percent of responders were not aware of published or unpublished research or audits on sudden death in epilepsy in their country in the last decade.
Conclusions
Significant disparities exist in the investigation of sudden death in epilepsy across countries and identified factors in this study provide an opportunity to formulate a global public health strategy to help overcome this gap.
European seas are encountering an upsurge in competing marine activities and infrastructures. Traditional exploitation such as fisheries, tourism, transportation, and oil production are accompanied ...by new sustainable economic activities such as offshore windfarms, aquaculture, and tidal and wave energy. One proposed solution to overcome possible competing claims at sea lies in combining these economic activities as part of Multi-Use Platforms at Sea (MUPS). MUPS can be understood as areas at sea, designated for a combination of activities, either completely integrated in a platform or in shared marine space. MUPS can potentially benefit from each other in terms of infrastructure, maintenance, etc. Developing MUPS in the marine environment demands adequate governance. In this article, we investigate four European sites to find out how governance arrangements may facilitate or complicate MUPs. In particular, we apply a framework specifying policy, economic, social, technical, environmental, and legal (PESTEL) factors to explore governance arrangements in four case study sites in different sea basins around Europe (the Mediterranean Sea, the Atlantic Ocean, the North Sea, and the Baltic Sea). The article concludes with policy recommendations on a governance regime for facilitating the development of MUPS in the future.
NF-κB is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core ...complex genes within the NF-κB pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes IκBε, a negative regulator of NF-κB in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced IκBε protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that IκBε loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-κB deregulation during lymphomagenesis.
Objective
To collect and prioritize the frequently asked questions (FAQs) that patients with hip or knee osteoarthritis (OA) and health care professionals consider to be the most important; to ...identify informational needs that go beyond guideline recommendations.
Methods
FAQs were collected among health care professionals and from the arthritis helpline of the Dutch Arthritis Foundation. After deleting overlapping FAQs, the remaining FAQs were prioritized by patients and health care professionals using a maximum difference scaling method. A hierarchical Bayesian method was used to calculate relative importance scores. Differences between health care professionals and patients were analyzed using independent t‐tests.
Results
A total of 28 health care professionals and the arthritis helpline provided 192 FAQs. After deleting overlapping FAQs, 60 FAQs were prioritized by 94 patients (57 60.6% women, mean age 67.3 years) and 122 health care professionals (67 54.9% women, mean age 45.7 years). The FAQ “What can I do myself to decrease symptoms and to prevent the OA from getting worse?” was prioritized as the most important by both patients and professionals. FAQs that were highly prioritized by patients but significantly different from professionals were more directed toward treatment options offered by health care professionals, whereas highly prioritized FAQs of professionals were more often focused on treatment options involving self‐management.
Conclusion
The health care professionals’ perspective on informational needs differs from that of OA patients. These differences are important to address in order to achieve more active involvement of patients in their own treatment process.
We report results from the Cryogenic Dark Matter Search at the Soudan Underground Laboratory (CDMS II) featuring the full complement of 30 detectors. A blind analysis of data taken between October ...2006 and July 2007 sets an upper limit on the weakly interacting massive particle (WIMP) nucleon spin-independent cross section of 6.6x10;{-44} cm;{2} (4.6x10;{-44} cm;{2} when combined with previous CDMS II data) at the 90% confidence level for a WIMP mass of 60 GeV/c;{2}. This achieves the best sensitivity for dark matter WIMPs with masses above 44 GeV/c;{2}, and significantly restricts the parameter space for some favored supersymmetric models.
Therapies targeting glioma cells that diffusely infiltrate normal brain are highly sought after. Our aim was to identify novel approaches to this problem using glioma spheroid migration assays. ...Lithium, a currently approved drug for the treatment of bipolar illnesses, has not been previously examined in the context of glioma migration. We found that lithium treatment potently blocked glioma cell migration in spheroid, wound-healing, and brain slice assays. The effects observed were dose dependent and reversible, and worked using every glioma cell line tested. In addition, there was little effect on cell viability at lithium concentrations that inhibit migration, showing that this is a specific effect. Lithium treatment was associated with a marked change in cell morphology, with cells retracting the long extensions at their leading edge. Examination of known targets of lithium showed that inositol monophosphatase inhibition had no effect on glioma migration, whereas inhibition of glycogen synthase kinase-3 (GSK-3) did. This suggested that the effects of lithium on glioma cell migration could possibly be mediated through GSK-3. Specific pharmacologic GSK-3 inhibitors and siRNA knockdown of GSK-3alpha or GSK-3beta isoforms both reduced cell motility. These data outline previously unidentified pathways and inhibitors that may be useful for the development of novel anti-invasive therapeutics for the treatment of brain tumors.
SuperCDMS SNOLAB will be a next-generation experiment aimed at directly detecting low-mass particles (with masses ≤10 GeV/c2) that may constitute dark matter by using cryogenic detectors of two types ...(HV and iZIP) and two target materials (germanium and silicon). The experiment is being designed with an initial sensitivity to nuclear recoil cross sections ∼1×10−43 cm2 for a dark matter particle mass of 1 GeV/c2, and with capacity to continue exploration to both smaller masses and better sensitivities. The phonon sensitivity of the HV detectors will be sufficient to detect nuclear recoils from sub-GeV dark matter. A detailed calibration of the detector response to low-energy recoils will be needed to optimize running conditions of the HV detectors and to interpret their data for dark matter searches. Low-activity shielding, and the depth of SNOLAB, will reduce most backgrounds, but cosmogenically produced H3 and naturally occurring Si32 will be present in the detectors at some level. Even if these backgrounds are 10 times higher than expected, the science reach of the HV detectors would be over 3 orders of magnitude beyond current results for a dark matter mass of 1 GeV/c2. The iZIP detectors are relatively insensitive to variations in detector response and backgrounds, and will provide better sensitivity for dark matter particles with masses ≳5 GeV/c2. The mix of detector types (HV and iZIP), and targets (germanium and silicon), planned for the experiment, as well as flexibility in how the detectors are operated, will allow us to maximize the low-mass reach, and understand the backgrounds that the experiment will encounter. Upgrades to the experiment, perhaps with a variety of ultra-low-background cryogenic detectors, will extend dark matter sensitivity down to the “neutrino floor,” where coherent scatters of solar neutrinos become a limiting background.
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