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A first step in fragment-based drug discovery (FBDD) often entails a fragment-based screen (FBS) to identify fragment “hits.” However, the integration of conflicting results from orthogonal screens remains a challenge. Here we present a meta-analysis of 35 fragment-based campaigns at Novartis, which employed a generic 1400-fragment library against diverse target families using various biophysical and biochemical techniques. By statistically interrogating the multidimensional FBS data, we sought to investigate three questions: (1) What makes a fragment amenable for FBS? (2) How do hits from different fragment screening technologies and target classes compare with each other? (3) What is the best way to pair FBS assay technologies? In doing so, we identified substructures that were privileged for specific target classes, as well as fragments that were privileged for authentic activity against many targets. We also revealed some of the discrepancies between technologies. Finally, we uncovered a simple rule of thumb in screening strategy: when choosing two technologies for a campaign, pairing a biochemical and biophysical screen tends to yield the greatest coverage of authentic hits. [ABSTRACT FROM PUBLISHER]

The article presents a study concerning the effect of topical lidocaine during flexible endoscopic evaluation of swallowing (FEES) examinations in patients with dysphagia. Details on the methods used for the study are given. Results suggest that topical lidocaine during FEES impair swallowing ability in dysphagic patients and that subjective pain and discomfort are significantly reduced by topical nasal anesthesia.

Dengue virus (DENV) is the most significant mosquito-borne viral pathogen in the world and is the cause of dengue fever. The DENV RNA-dependent RNA polymerase (RdRp) is conserved among the four viral serotypes and is an attractive target for antiviral drug development. During initiation of viral RNA synthesis, the polymerase switches from a “closed” to “open” conformation to accommodate the viral RNA template. Inhibitors that lock the “closed” or block the “open” conformation would prevent viral RNA synthesis. Herein, we describe a screening campaign that employed two biochemical assays to identify inhibitors of RdRp initiation and elongation. Using a DENV subgenomic RNA template that promotes RdRp de novo initiation, the first assay measures cytosine nucleotide analogue (Atto-CTP) incorporation. Liberated Atto fluorophore allows for quantification of RdRp activity via fluorescence. The second assay uses the same RNA template but is label free and directly detects RdRp-mediated liberation of pyrophosphates of native ribonucleotides via liquid chromatography–mass spectrometry. The ability of inhibitors to bind and stabilize a “closed” conformation of the DENV RdRp was further assessed in a differential scanning fluorimetry assay. Last, active compounds were evaluated in a renilla luciferase–based DENV replicon cell-based assay to monitor cellular efficacy. All assays described herein are medium to high throughput, are robust and reproducible, and allow identification of inhibitors of the open and closed forms of DENV RNA polymerase. [ABSTRACT FROM PUBLISHER]

We assessed whether quantitative analysis of Doppler flow velocity waveforms is able to identify subclinical microvascular abnormalities in SLE and whether eigenvector analysis can detect changes not detectable using the resistive index (RI). Fifty-four SLE patients with no conventional cardiovascular risk factors, major organ involvement or retinopathy were compared to 32 controls. Flow velocity waveforms were obtained from the ophthalmic artery (OA), central retinal artery (CRA) and common carotid artery (CA). The waveforms were analysed using eigenvector decomposition and compared between groups at each arterial site. The RI was also determined. The RI was comparable between groups. In the OA and CRA, there were significant differences in the lower frequency sinusoidal components (P < 0.05 for each component). No differences were apparent in the CA between groups. Eigenvector analysis of Doppler flow waveforms, recorded in proximity of the terminal vascular bed, identified altered ocular microvascular haemodynamics in SLE. Altered waveform structure could not be identified by changes in RI, the traditional measure of downstream vascular resistance. This analytical approach to waveform analysis is more sensitive in detecting preclinical microvascular abnormalities in SLE. It may hold potential as a useful tool for assessing disease activity, response to treatment, and predicting future vascular complications. [ABSTRACT FROM AUTHOR]

Mine water management is often an afterthought in mine planning processes and can introduce significant risks to projects when studied as a stand alone component at a later stage in the mine design. Incorporation of a mine dewatering and pore pressure dissipation strategy in the early stages of mine planning is imperative in order to minimise constraints on the production schedule, to match designed pit slopes and maximise project value for an open cut mine option such as Olympic Dam. A risk-based mine planning approach was adopted during the project selection phase study whereby water management was introduced into mine planning, scheduling and the development of an operational strategy. Hydrological and hydrogeological studies and outputs were successfully integrated into the various iterations of the mine planning cycle during early selection phase to manage the potential water management risks associated with pit slope depressurisation and access to dry working conditions during rapid advancement of mining phases. An extensive network of vibrating wire piezometer sets and long-term depressurisation testing characterised aquifer conditions and demonstrated that hydraulic connectivity exists within the geological profile due to the presence of structures and resource drill holes which enhance vertical connectivity. This connectivity, along with underdrainage from mining activities contributes up to 100 m of depressurisation in low permeability units. A pit dewatering strategy incorporates the mine planning schedules and accounts for operational constraints as to the location and development of the dewatering wells, storages and pipelines. Numerical modelling generated a range of likely pit inflows and dewatering requirements with the average initial dewatering discharge likely to be 150 L/s and reduce quickly to 50 L/s after five years, depending on the premine schedule. Coupled hydrogeological and geotechnical assessments were also carried out as part of the mine planning cycle and indicate that successful dewatering will go a long way to reduce the pore pressures within key geotechnical units during the rapid mining phase where around 300 m of cover sequence is stripped in five years. However, the residual storage in the primary aquifer and the residual pore pressure in underlying low permeability units will need to be dissipated (in-pit horizontal holes) as the pit floor advances. Pit slope design angles are sensitive to depressurisation and dewatering and up to 70 per cent depressurisation of key geotechnical rock units are required. Whilst an accelerated program of aquifer dewatering supported by lithostatic unloading should drive rapid depressurisation in the lower permeability units, intervention is anticipated in key geotechnical units such as the Tregolana Shale and volcaniclastics. The extent of induced drainage will ultimately depend in part upon the mining rate and geotechnical stability requirements. Practical operability testing addressed the potential for operational constraints to mine depressurisation activities such as congestion and mining schedule development within the pit and identified that depressurisation drilling can be achieved even with reduced access availability. Mine operations and planning groups established design criteria and considered the likely inoperable periods following rainfall events of seven to 14 days to manage the base surge and minimise impact on production. In-pit surface water management options to minimise operational disruptions during and after significant rainfall events were estimated used a stochastic approach. [ABSTRACT FROM AUTHOR]

Automated electron backscatter diffraction (EBSD) or orientation imaging microscopy (OIM) has become a common analytical tool for the statistical characterisation of grain boundaries in polycrystalline materials. However, as such studies have become more tractable with the advances in EBSD technology some critical complexities of grain boundary analysis have been neglected. This includes the multidimensionality of grain boundaries, correlated versus uncorrelated misorientation distributions, OIM scanning artefacts specifically critical to boundary analysis. The present work describes some of these shortfalls as well as approaches for mitigating problems in grain boundary analysis via EBSD. [ABSTRACT FROM AUTHOR]

This study was designed to investigate anabolic steroid users' experiences of, and motivations for, use. Five men and six women users took part in in-depth interviews. Four themes emerged: Steroid Use vs Abuse; Side-effects; Trusted Information Sources; and Social Pressure. Many users believed that steroids used in moderation were safe. Serious side-effects (liver and kidney damage, hypertension) were not significant disincentives. Information from health professionals tended to be mistrusted because it was not based on first-hand experience of use. Social support, especially from within the body building community, was an important motivator. It is concluded that intervention programmes need the support of the body building community in order to be effective. Copyright © 2006 SAGE Publications Ltd. [ABSTRACT FROM AUTHOR]

The article discusses the factors which should be considered in the diagnosis of HIV. It is important to look for signs of immunosuppression which include documenting weight loss and careful examination of the oral cavity for candida, or palatal Kaposi's sarcoma. It outlines several structures which may increase the confidence of patients toward HIV testing such as ensuring confidentiality.

The equilibrium distribution of Cu, Fe and Ni between Cu–Ni–Fe mattes and Pt alloy was examined as functions of the sulphur partial pressure (pS2), oxygen partial pressure (pO2), temperature and Fe content of the matte. The distribution ratios of Cu, Fe and Ni between matte and alloy were independent of oxygen pressure when the pS2 was fixed at 25 × 10-5 atm and pO2 was varied between 10-15 atm and 10-12 atm. The distribution ratio of Cu, Fe and Ni increased as the sulphur partial pressure increased. The Cu and Ni distribution ratios decreased with increasing temperature and the Fe distribution ratio increased slightly over the temperature range of 1350–1500°C. For mattes where the proportions of Cu and Ni were kept constant, the distribution ratio of Cu increased as the Fe content in the matte increased. The Fe and Ni distribution appeared to be independent of the iron content in the matte and had a value of 1·2 and 1·6, respectively. The activity of Cu, Fe, Ni in the matte was calculated using a regular solution model for solid Pt–Fe–Ni–Cu alloy. The activity coefficient of Cu, Fe and Ni decreased as pO2 and pS2 increased. The activity coefficients also appeared to be independent of the Fe content and temperature over the range of 36–54 wt% iron and 1350–1500°C, respectively. [ABSTRACT FROM AUTHOR]

Within the setting of trauma, there are many indications for intubation and ventilation, but the ultimate aims are always the same. These are to ensure airway patency and security, provide an acceptable level of arterial oxygenation at the lowest possible inspired oxygen concentration, control arterial carbon dioxide tension and optimize pulmonary and systemic blood flow. The clinical situation, developing trends, and the experience of the individual concerned will all influence the decision to intubate and ventilate the patient who has suffered trauma. This paper considers the `rule-of-thumb' indications for intubation in the emergency room and discusses the factors which may influence their interpretation. [ABSTRACT FROM AUTHOR]

Fifty-one men charged with or convicted of sexual assault on an adult female were compared with thirty-six controls consisting of nonviolent, nonsex offenders using the Luria-Nebraska Neuropsychological Test Battery, WAIS and CT scans. The sexual assaulters were classified as twenty-two sadists and twenty-one nonsadists on the basis of clinical interview, criminal history and a standardized sex history questionnaire. There was 92% agreement on psychiatric and neuroradiological diagnoses. IQ scores did not differ significantly among the groups. Right-sided temporal horn dilatation was found on CT scans significantly more often in sadists than in the nonsadistic assaulters and controls. On the Luria-Nebraska Neuropsychological Test Battery, nonsadists showed more global impairment than the other two groups. The results were unchanged when history of alcohol abuse was taken into consideration. The study was a replication and refinement of an earlier report published by the authors and, despite problems of interpretation as a result of the different instruments used to assess cerebral damage and dysfunction, it provides additional support for the hypothesis that some types of sexual anomalies are associated with subtle forms of brain damage. [ABSTRACT FROM PUBLISHER]

Evaluations of the effect of interventions on the terminally ill focus on outcomes such as patient satisfaction and quality of life. Due to the theoretical nature of these measures, researchers must rely on patients and family members as primary data sources. Family members of terminally ill patients wee queried concerning their motives for participation in the National Hospice Study and their reactions to an intensive interview schedule. Of those contacted, 94% agreed to the interview. The most frequently cited reasons for participating in the study were the desire to help other families facing a serious illness and the desire to help the hospice movement. Responses indicated a real enthusiasm for study participation in spite of the stressful nature of the terminally ill patient's situation. [ABSTRACT FROM AUTHOR]

This study examines temporal trends in the use and outcomes of cardiac procedures for patients hospitalized with acute myocardial infarction in Department of Veterans Affairs (VA) hospitals with and without invasive cardiac services. Between 1988 and 1994, there was striking overall growth in the use of cardiac procedures in the VA. Over this time period, the authors found persistent variation in the use of cardiac procedures but diminished differences in patient survival among patients admitted to different types of hospitals. Growth of cardiac procedure use and improvements in patient survival were most significant in hospitals without on-site invasive cardiac services. We were unable to determine whether survival gains were associated with increased procedure use or unmeasured improvements in the process of care. These trends raise intriguing questions about access to and outcomes of cardiac procedures in health systems composed of hospitals with and without a full complement of on-site invasive cardiac services. [ABSTRACT FROM AUTHOR]

The linear electrochemical polarization method was used to provide quantitative in vitro measurements of corrosion rates as a function of exposure time for Cu-Ni-Mn, Cu-Ni-Mn-Au, Cu-Ni-Mn-Ag, and Cu-Ni-Mn-Au-Ag alloys in artificial saliva. Both Au and Ag additives to dental-cast Cu-Ni-Mn alloys lowered the corrosion rate significantly. [ABSTRACT FROM AUTHOR]

The article discusses the association of intestinal dysfunction and inflammatory changes in the small intestine or tropical enteritis in other diseases. One important viral enteritis in the tropics is that associated with severe measles. Though clinical evidence of measles is obtained from examination of the skin and mucous membranes of the mouth, the gastrointestinal tract may be involved with the same pathological process producing inflammation.

We have investigated prospectively the diagnostic accuracy, specialist satisfaction and patient-specialist rapport of a low-cost audio-visual link between a junior doctor with a patient and a consultant rheumatologist. Using a telephone link and subsequently a video-phone link, 20 patients, with various rheumatological problems, were presented by a junior doctor to the consultant rheumatologist for provisional diagnosis. All patients were then seen face to face by the consultant, when a final diagnosis was made. An independent consultant rheumatologist made a 'gold standard' diagnosis. Thirty-five per cent of diagnoses were made correctly over the telephone and 40% over the video-phone - there was no significant difference in the diagnostic accuracy between these two methods of communication. Rapport over the video-phone was universally poor. Where it was important, clinical signs could not be visualized over the video-phone and in more than 85% of cases small joint swellings could not be seen clearly. [ABSTRACT FROM AUTHOR]

Examines the connection between Spread and Pearson. Type of study using a playing card to reflect the score; Effect of variability changes; Computation of standard deviations.

A retrospective note audit was carried out across two genitourinary (GU) medicine services in Central London to review a radical change in policy one year after its implementation that allows patients assessed as low risk for HIV infection to receive their HIV result by post. Sixteen patients tested positive across the two clinics but had arranged to receive their results by post. Their recall management and outcomes are discussed. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 61 year old man with myeloid leukemia, who has been admitted for solid food dysphagia. It mentions that the transnasal esophagoscopy depicts the narrowing of the esophagus, proximal esophageal stricture and irregular squamocolumnar junction. It mentions that systemic therapy with immunosuppressants are involved in graft-versus-host disease (GVHD) .

The article presents a case of a 25-year-old woman who experienced headache and blurred vision and was diagnosed with acute isolated sphenoid sinusitis