An integrated clinical program and crowdsourcing strategy for genomic sequencing and Mendelian disease gene discovery.

Despite major progress in defining the genetic basis of Mendelian disorders, the molecular etiology of many cases remains unknown. Patients with these undiagnosed disorders often have complex presentations and require treatment by multiple health care specialists. Here, we describe an integrated clinical diagnostic and research program using whole-exome and whole-genome sequencing (WES/WGS) for Mendelian disease gene discovery. This program employs specific case ascertainment parameters, a WES/WGS computational analysis pipeline that is optimized for Mendelian disease gene discovery with variant callers tuned to specific inheritance modes, an interdisciplinary crowdsourcing strategy for genomic sequence analysis, matchmaking for additional cases, and integration of the findings regarding gene causality with the clinical management plan. The interdisciplinary gene discovery team includes clinical, computational, and experimental biomedical specialists who interact to identify the genetic etiology of the disease, and when so warranted, to devise improved or novel treatments for affected patients. This program effectively integrates the clinical and research missions of an academic medical center and affords both diagnostic and therapeutic options for patients suffering from genetic disease. It may therefore be germane to other academic medical institutions engaged in implementing genomic medicine programs

Comparison of the diagnostic accuracy of commercial NS1-based diagnostic tests for early dengue infection

<p>Abstract</p> <p>Background</p> <p>We compared the diagnostic accuracy and reproducibility of commercially available NS1-based dengue tests and explored factors influencing their sensitivities.</p> <p>Methods</p> <p>Paired analysis of 310 samples previously characterized as positive (n = 218) and negative (n = 92) for viral isolation and/or RT-PCR and/or IgM seroconversion. Masked samples were tested by two observers with Platelia™ Dengue NS1 Ag, second generation Pan-E™ Dengue Early ELISA, SD Dengue NS1 Ag ELISA, Dengue NS1 Ag STRIP™, and SD BIOLINE™ Dengue Duo (NS1/IgM/IgG).</p> <p>Results</p> <p>SD BIOLINE™ NS1/IgM/IgG had the highest sensitivity (80.7% 95%CI 75-85.7) with likelihood ratios of 7.4 (95%CI 4.1-13.8) and 0.21 (95%CI 0.16-0.28). The ELISA-format tests showed comparable sensitivities; all below 75%. STRIP™ and SD NS1 had even lower sensitivities (<65%). The sensitivities significantly decreased in samples taken after 3 days of fever onset, in secondary infections, viral serotypes 2 and 4, and severe dengue. Adding IgM or IgG to SD NS1 increased its sensitivity in all these situations.</p> <p>Conclusions</p> <p>The simultaneous detection of NS1/IgM/IgG would be potentially useful for dengue diagnosis in both endemic and non endemic areas. A negative result does not rule out dengue. Further studies are required to assess the performance and impact of early laboratory diagnosis of dengue in the routine clinical setting.</p

Applications of raman spectroscopy in dentistry part II: Soft tissue analysis

Raman spectroscopy is rapidly moving from an experimental technique for the analysis of biological molecules to a tool for the real-time clinical diagnosis and in situ evaluation of the oral tissue in medical and dental research. The purpose of this study is to identify various applications of Raman spectroscopy, to evaluate the contemporary status and to explore future directions in the field of dentistry. Several in-depth applications are presented to illustrate Raman spectroscopy in early diagnosis of soft tissue abnormalities. Raman spectroscopy allows to analyze histological and biochemical composition of biological tissues. The technique not only demonstrates its role in the disclosure of dysplasia and malignancy but also in performing guided biopsies, diagnosing sialoliths, and assessment of surgical margins. Raman spectroscopy is used to identify the molecular structures and its components to give substantial information about the chemical structure properties of these molecules. In this paper, we acquaint the utilization of Raman spectroscopy in analyzing the soft tissues in relation to dentistry

Directional Limits on Persistent Gravitational Waves from Advanced LIGO’s First Observing Run

We employ gravitational-wave radiometry to map the stochastic gravitational wave background expected from a variety of contributing mechanisms and test the assumption of isotropy using data from the Advanced Laser Interferometer Gravitational Wave Observatory’s (aLIGO) first observing run. We also search for persistent gravitational waves from point sources with only minimal assumptions over the 20–1726 Hz frequency band. Finding no evidence of gravitational waves from either point sources or a stochastic background, we set limits at 90% confidence. For broadband point sources, we report upper limits on the gravitational wave energy flux per unit frequency in the range Fα;ΘðfÞ < ð0.1–56Þ × 10−8 erg cm−2 s−1 Hz−1ðf=25 HzÞα−1 depending on the sky location Θ and the spectral power index α. For extended sources, we report upper limits on the fractional gravitational wave energy density required to close the Universe of Ωðf; ΘÞ < ð0.39–7.6Þ × 10−8 sr−1ðf=25 HzÞα depending on Θ and α. Directed searches for narrowband gravitational waves from astrophysically interesting objects (Scorpius X-1, Supernova 1987 A, and the Galactic Center) yield median frequency-dependent limits on strain amplitude of h0 < ð6.7; 5.5; and 7.0Þ × 10−25, respectively, at the most sensitive detector frequencies between 130–175 Hz. This represents a mean improvement of a factor of 2 across the band compared to previous searches of this kind for these sky locations, considering the different quantities of strain constrained in each case

Prospects for observing and localizing gravitational-wave transients with Advanced LIGO, Advanced Virgo and KAGRA

We present possible observing scenarios for the Advanced LIGO, Advanced Virgo and KAGRA gravitational-wave detectors over the next decade, with the intention of providing information to the astronomy community to facilitate planning for multi-messenger astronomy with gravitational waves. We estimate the sensitivity of the network to transient gravitational-wave signals, and study the capability of the network to determine the sky location of the source. We report our findings for gravitational-wave transients, with particular focus on gravitational-wave signals from the inspiral of binary neutron star systems, which are the most promising targets for multi-messenger astronomy. The ability to localize the sources of the detected signals depends on the geographical distribution of the detectors and their relative sensitivity, and 90% credible regions can be as large as thousands of square degrees when only two sensitive detectors are operational. Determining the sky position of a significant fraction of detected signals to areas of 5– 20 deg2 requires at least three detectors of sensitivity within a factor of ∼2 of each other and with a broad frequency bandwidth. When all detectors, including KAGRA and the third LIGO detector in India, reach design sensitivity, a significant fraction of gravitational-wave signals will be localized to a few square degrees by gravitational-wave observations alone

Analyzing the Economic Sustainability of Tourism Development: Evidence from Hong Kong

Despite increased concerns about the negative economic impacts of tourism on host communities, insufficient attention has been paid to assess tourism economic sustainability. This paper aims to develop and validate a framework for assessing economic sustainability from the perspective of local stakeholders. In-depth interviews with 12 major stakeholders and a telephone survey with 1839 Hong Kong citizens were conducted. The tourism economic sustainability construct consisted of three dimensions: economic positivity, development control and individual welfare. The reliability and validity of the dimensions were confirmed by the data of sub-samples. The links between socio-demographic characteristics and attitudes toward tourism economic sustainability were evaluated. This paper enhanced our understanding of tourism economic sustainability by expanding the measurement from the macro level to micro level. Using the study setting in Hong Kong, it transcends previous analysis by providing a context to learn from ongoing controversies about the effects of tourism on host community

3D inkjet printing of tablets exploiting bespoke complex geometries for controlled and tuneable drug release

A hot melt 3D inkjet printing method with the potential to manufacture formulations in complex and adaptable geometries for the controlled loading and release of medicines is presented. This first use of a precisely controlled solvent free inkjet printing to produce drug loaded solid dosage forms is demonstrated using a naturally derived FDA approved material (beeswax) as the drug carrier and fenofibrate as the drug. Tablets with bespoke geometries (honeycomb architecture) were fabricated. The honeycomb architecture was modified by control of the honeycomb cell size, and hence surface area to enable control of drug release profiles without the need to alter the formulation. Analysis of the formed tablets showed the drug to be evenly distributed within the beeswax at the bulk scale with evidence of some localization at the micron scale. An analytical model utilizing a Fickian description of diffusion was developed to allow the prediction of drug release. A comparison of experimental and predicted drug release data revealed that in addition to surface area, other factors such as the cell diameter in the case of the honeycomb geometry and material wettability must be considered in practical dosage form design. This information when combined with the range of achievable geometries could allow the bespoke production of optimized personalised medicines for a variety of delivery vehicles in addition to tablets, such as medical devices for example

The use of mobile phone data for the estimation of the travel patterns and imported Plasmodium falciparum rates among Zanzibar residents

Background: malaria endemicity in Zanzibar has reached historically low levels, and the epidemiology of malaria transmission is in transition. To capitalize on these gains, Zanzibar has commissioned a feasibility assessment to help inform on whether to move to an elimination campaign. Declining local transmission has refocused attention on imported malaria. Recent studies have shown that anonimized mobile phone records provide a valuable data source for characterizing human movements without compromising the privacy of phone users. Such movement data in combination with spatial data on P. falciparum endemicity provide a way of characterizing the patterns of parasite carrier movements and the rates of malaria importation, which have been used as part of the malaria elimination feasibility assessment for the islands of Zanzibar. Data and methods: records encompassing three months of complete mobile phone usage for the period October-December 2008 were obtained from the Zanzibar Telecom (Zantel) mobile phone network company, the principal provider on the islands of Zanzibar. The data included the dates of all phone usage by 770,369 individual anonymous users. Each individual call and message was spatially referenced to one of six areas: Zanzibar and five mainland Tanzania regions. Information on the numbers of Zanzibar residents travelling to the mainland, locations visited and lengths of stay were extracted. Spatial and temporal data on P. falciparum transmission intensity and seasonality enabled linkage of this information to endemicity exposure and, motivated by malaria transmission models, estimates of the expected patterns of parasite importation to be made. Results: over the three month period studied, 88% of users made calls that were routed only through masts on Zanzibar, suggesting that no long distance travel was undertaken by this group. Of those who made calls routed through mainland masts the vast majority of trips were estimated to be of less than five days in length, and to the Dar Es Salaam Zantel-defined region. Though this region covered a wide range of transmission intensities, data on total infection numbers in Zanzibar combined with mathematical models enabled informed estimation of transmission exposure and imported infection numbers. These showed that the majority of trips made posed a relatively low risk for parasite importation, but risk groups visiting higher transmission regions for extended periods of time could be identified. Conclusion: anonymous mobile phone records provide valuable information on human movement patterns in areas that are typically data-sparse. Estimates of human movement patterns from Zanzibar to mainland Tanzania suggest that imported malaria risk from this group is heterogeneously distributed; a few people account for most of the risk for imported malaria. In combination with spatial data on malaria endemicity and transmission models, movement patterns derived from phone records can inform on the likely sources and rates of malaria importation. Such information is important for assessing the feasibility of malaria elimination and planning an elimination campaign

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes