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The Assessment of Disease Activity in Rheumatic DiseasesView this Special Issue
Review Article | Open Access
Nadia J. Luca, Brian M. Feldman, "Disease Activity Measures in Paediatric Rheumatic Diseases", International Journal of Rheumatology, vol. 2013, Article ID 715352, 10 pages, 2013. https://doi.org/10.1155/2013/715352
Disease Activity Measures in Paediatric Rheumatic Diseases
Disease activity refers to potentially reversible aspects of a disease. Measurement of disease activity in paediatric rheumatic diseases is a critical component of patient care and clinical research. Disease activity measures are developed systematically, often involving consensus methods. To be useful, a disease activity measure must be feasible, valid, and interpretable. There are several challenges in quantifying disease activity in paediatric rheumatology; namely, the conditions are multidimensional, the level of activity must be valuated in the context of treatment being received, there is no gold standard for disease activity, and it is often difficult to incorporate the patient's perspective of their disease activity. To date, core sets of response variables are defined for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, and juvenile dermatomyositis, as well as definitions for improvement in response to therapy. Several specific absolute disease activity measures also exist for each condition. Further work is required to determine the optimal disease activity measures in paediatric rheumatology.
1. Introduction
Measurement of a health state is the cornerstone of clinical practice and medical research. As stated in 1883 by Lord Kelvin, "when you can measure what you are speaking about, and express it in numbers, you know something about it; but when you cannot, your knowledge is of a meagre and unsatisfactory kind" [1]. When caring for children and youth with rheumatic diseases, standardized and validated definitions of disease activity, as well as of change in disease activity in response to treatment, are critical for making decisions in clinical practice as well as for conducting clinical research studies. Use of standardized measures can also facilitate comparisons between trials through meta-analyses.
Over the past several years, an international collaborative effort has been made to develop and validate measures of disease activity, treatment response, inactive disease, and flare of disease in several paediatric rheumatic conditions [2]. These measures are numerous, and several new ones are emerging on an annual basis. This paper will discuss the theoretical basis of disease activity measures, methods for their development and validation, and an overview of available measures within paediatric rheumatology.
2. Definition of Disease Activity in Paediatric Rheumatic Diseases
In order to measure disease activity, it is necessary to define it and to identify its measurable components. "Disease activity" may be defined as aspects of a patient's disease that are potentially reversible [3–5]. This is in contrast to "disease damage," which refers to the irreversible (i.e., due to scarring) manifestations of the disease or its treatment. Both disease activity and damage contribute to "disease severity," which is the total effect of the disease on the individual and often relates to prognosis [5]. Disease activity may fluctuate widely during a patient's disease course. In the context of rheumatic diseases, a disease activity measure typically attempts to quantify the inflammatory process of the disease [3]. Consolaro et al. define disease activity in juvenile idiopathic arthritis (JIA) as measuring "signs and symptoms related to inflammation," which "should separated from measures of disease severity, such as those that assess… structural damage" [6]. Evaluating disease activity may include measurement of biochemical markers of inflammation (e.g., erythrocyte sedimentation rate (ESR)), quantifying the amount of inflammatory tissue (e.g., number of swollen joints), and assessing the clinical consequences of inflammation (e.g., degree of morning stiffness). Generally, disease activity in most paediatric rheumatic diseases is multidimensional, and therefore this concept is measured in several domains [7]. For example, a measure of disease activity in juvenile dermatomyositis (JDM) incorporates muscle strength, skin disease, internal organ manifestations, and any other disease components in patients with JDM. Disease activity measures may take the form of observed values (e.g., muscle enzymes level), rating scales completed by health care providers, parent- or patient-reported outcomes (PROs), or any combination of these. When measuring disease activity, its impact on the biological, individual, and social perspectives of health is often considered, as described in the International Classification of Functioning, Disability, and Health (World Health Organization) [8, 9]. This system takes into account that disease activity interacts with internal and external factors to determine the levels of biological, physical, and social functioning. For example, a child with JIA who has swelling and reduced motion of a joint may have difficulty running and may not participate in gym class because of fear of injuring herself. Interventions can be aimed at each level: medical treatment to reduce joint inflammation, physiotherapy to improve running, and accommodations at school to allow the child to participate at their own pace.
3. Challenges in Measuring Disease Activity in Paediatric Rheumatic Diseases
Given the multidimensionality of disease activity in paediatric rheumatic disease, a challenge exists when some components suggest that the disease is more active, while others suggest that it is less active. Thus there is appeal to a pooled and appropriately weighted composite index that can give one answer. For example, the American College of Rheumatology (ACR) core outcome variables for JIA were combined into a definition to dichotomously divide patients into those who improve by a clinically important amount and those who do not [10]. Variables in the core set include: (1) physician global assessment of disease activity, (2) parent/patient assessment of overall wellbeing, (3) functional ability, (4) number of joints with active arthritis, (5) number of joints with limited range of motion (ROM), and (6) ESR. Consensus methods were used to define improvement; for example, an ACR Pedi30 response requires ≥30% improvement from baseline in 3 of 6 variables, with ≤1 remaining variable worsening by >30%. Similar core sets and definitions for improvement have also been developed for JDM and juvenile systemic lupus erythematosus (JSLE) [11–14].
The ACR Pedi response criteria are defined relative to each patient's baseline parameters but do not enable the quantification of absolute disease activity or comparison of absolute responses amongst patients. For instance, these response criteria cannot distinguish between a patient who has improved by 30% starting with 30 active joints (still has 21 active joints) and one who started with 3 active joints (still has 2 active joints). This prompted the development of a scale that quantifies the absolute level of disease activity, the Juvenile Arthritis Disease Activity Score (JADAS), which includes 4 items: (1) physician global assessment of disease activity, (2) parent/patient global assessment of wellbeing, (3) number of active joints, and (4) ESR [6]. The JADAS is scored on a numerical scale, which allows patients to be compared directly. Absolute disease activity measures have also been developed for JSLE (e.g., European consensus lupus activity measurement (ECLAM), systemic lupus erythematosus disease activity index (SLEDAI)) and JDM (e.g., disease activity score (DAS), myositis disease activity assessment tool (MDAAT)) and are discussed further in Section 6.
An additional factor to consider is how to value clinical improvement in the context of the treatment regimen of the patient. For example, if one polyarticular JIA patient is managed on a nonsteroidal anti-inflammatory drug and achieves inactive disease, is his/her "disease activity" equivalent to another patient whose disease is quiescent while taking methotrexate and an anti-tumor necrosis factor alpha agent? Criteria for inactive disease and clinical remission in JIA do distinguish between patients who are on or off medical therapy. Wallace et al. define "inactive disease" as when a patient on medical therapy achieves the following criteria: (1) no joints with active arthritis, (2) no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy, (3) no active uveitis, (4) normal ESR and/or C-reactive protein (CRP), and (5) physician global assessment indicates no disease activity [15]. If patients meet the inactive disease criteria for 6 continuous months while taking medication they are classified as being in "clinical remission on medication," and if they meet the criteria for 12 continuous months off medication they are considered to be in "clinical remission off medication" [15]. Each of these health states is considered to be a distinct outcome. However, these criteria do not take into consideration the relative intensity of the treatment required to control the disease.
Another significant challenge when measuring disease activity in pediatric rheumatic disease is that expert clinical judgment (i.e., opinion of a paediatric rheumatologist) is commonly used for validation of disease activity instruments [3], and this can be ambiguous and subjective. Thus, a limitation is that there is no truly objective "gold" standard with which to validate disease activity measures, although some promising biomarkers are being identified [16]. In addition, it is important that "circularity of reasoning" is avoided [17]. That is, if the group of clinicians that derives the criteria set is the same group that classifies disease activity, there will be a strong correlation between the criteria set and the so called "gold" standard. Lastly, the use of a physician-based measure alone for comparison entirely excludes the patient perspective of the disease burden.
Parent or patient global assessments are included in many paediatric rheumatic disease activity measures. Interestingly, studies show concordance with physician assessments of JIA disease activity in only about 40% of cases [18–20]. Sztajnbok et al. report that physicians tend to given higher global ratings compared to parents [18]. Conversely, parents gave scores of zero in only 65% of cases who met the Wallace definition of inactive disease in JIA (listed above) [19]. Parents are more likely to score higher disease activity if their child has a shorter disease duration, is taking second-line drug therapy, has increased reported pain, or has functional impairment. Alternatively, physicians consistently rate disease activity more highly than parents in the presence of any active joints [18, 19]. In JDM patients, Rider et al. found that physician and parent global ratings of disease activity were not collinear and that the nonredundancy may be the result of each evaluating different aspects of the disease [21]. This may also be because parents are often asked about overall "wellbeing" rather than specifically "disease activity." Thus, the parent or patient perspective adds information on the impact of disease activity on overall health.
For this reason, several new composite disease assessment measures have included more PROs. The juvenile arthritis parent assessment index (JAPAI) and the juvenile arthritis child assessment index (JACAI) include: (1) parent/child rating of overall wellbeing, (2) parent/child rating of pain intensity, (3) assessment of physical function, and (4) assessment of HRQOL [22]. Similarly, the juvenile arthritis multidimensional assessment report (JAMAR) incorporates parent- or patient-reported physical functioning, social participation, and HRQOL, among other items [23].
Although it can be challenging to validate PRO measures as they are inherently subjective, they provide rich information on the patient's perspective of their disease activity. However, it should be noted that paediatric rheumatologists developed these measures, and so they include items that health care providers judge as significant to patients but may not address all of the perceptions, values, and preferences important to patients.
4. Development of Disease Activity Measures
Measurement instruments are developed systematically, and the process is often iterative [7, 24, 25]. An approach for developing outcome measures in paediatric rheumatic diseases has been described in detail by Brunner and Ravelli [25]. Here we present a brief overview of the process (summarized in Table 1).
4.1. Purpose of the Measure
Along with defining what is to be measured and in which population, the purpose of the disease activity measure should be explicitly determined at the outset. Kirshner and Guyatt [45] describe three main purposes of health status measures. Firstly, "discriminative" measures are used to distinguish between individuals or groups with a certain attribute (e.g., criteria for inactive disease in JIA [15]). "Predictive" measures classify individuals into a set of predefined risk categories when a gold standard is available. This type of index is generally used as a screening or diagnostic instrument (e.g., dipstick proteinuria in lupus nephritis). Lastly, "evaluative" measures are used to assess the magnitude of longitudinal change in the dimension of interest (e.g., manual muscle testing (MMT) in JDM [46]). Disease activity measures typically fall into the evaluative category as they typically measure clinically significant changes in disease activity over time and in response to interventions.
4.2. Item Generation and Reduction
The process of item generation creates a list of all possible items for inclusion, generally thorough the literature review and opinions from important stakeholders [47]. Ideally, patients and parents should be included in the process of measure development [48]. Item generation is followed by item reduction, with the goal of including all the important items but minimizing redundancy. Consensus methods have commonly been used for this phase of measure development (see below). Ideally, it is also important to determine the number of different aspects of disease activity, or "factors," being measured. Principal component and factor analysis identify the number of factors within the scale and which of these explain the majority of the overall variance [26, 49]. At the item level, item-scale correlations and measures of internal consistency (Cronbach's alpha) can indicate which individual items within the factors may be redundant and possibly unnecessary [26].
4.3. Consensus Methods
In recent years, consensus methods such as Delphi surveys and nominal group techniques (NGTs) have commonly been used in the item generation and item reduction phases of measure development in paediatric rheumatology [50]. The definition of consensus should be stated a priori and utilized as criteria for termination of the process [51], although this is not always the case in practice [52]. The Delphi technique is an iterative multistage method that allows the use of anonymous written or online responses [53]. It involves a series of questionnaires, each of which is based on the results of the previous step, and the process stops when participants approach consensus. NGT utilizes a highly structured face-to-face meeting to gather information from relevant stakeholders [53]. Panelists rank, discuss, and then rerank a series of items related to the topic. The results are analyzed for agreement in prioritization, and generally 70–80% consensus is required [51]. These approaches have been used successfully to develop several disease activity measures in paediatric rheumatology such as the definition for improvement in JIA [10] and disease activity core set measures for JDM and JSLE [11].
4.4. Derivation Study
Once candidate sets of criteria are determined, they should be applied to a large and diverse group of patients with the disease from a variety of practices [17, 26]. A comparator group is chosen based on the intended use of the criteria and should represent patients from whom the criteria aim to distinguish. In order to avoid circularity of reasoning, the group of clinicians who create the list of candidate items should be separate from those who provide and classify the patients [17, 26]. The sample size required for derivation studies is approximately 100 per group [24].
4.5. Selection of Final Set of Items
The final set of items is often selected using statistical techniques such as comparing the sensitivity and specificity of candidate sets of items with receiver operating characteristic curve analysis. This was performed by Brunner et al. to determine the best definition for flare in patients with JIA [33]. Logistic regression may also be used to determine what variables best discriminate between more and less severely affected patients as was employed in the development of criteria for minimal disease activity (MDA) in JIA [42].
4.6. Assessment of Psychometric Properties
Prior to carrying out formal psychometric testing of a measurement tool, it should be pretested in a small group of users to ensure comprehensibility and relevance [47]. Evaluation of face and content validity ensures the items are reasonable and cover all the aspects of the disease. Feasibility should also be assessed, with consideration given to ease of use and minimal burden on the patient and health care provider. Without these characteristics, the tool is unlikely to be accepted by medical practitioners or adopted into clinical care.
Once a tool is developed and piloted, its measurement properties must be evaluated in the target population. Most disease activity measures should be assessed with regards to their reliability, validity, responsiveness, and interpretability (Table 2) [28]. As a final step, measures should be applied to an independent sample to ensure external validation [24, 27].
5. Disease Activity Measures in JIA, JSLE, and JDM
A summary of the most commonly cited disease activity measures in JIA, JSLE, and JDM is presented in Table 3.
|ACR: American College of Rheumatology, CHAQ: child health assessment questionnaire, ESR: erythrocyte sedimentation rate, SJIA: systemic juvenile idiopathic arthritis, PRINTO: Pediatric Rheumatology International Trials Organization, SLEDAI: systemic lupus erythematosus disease activity index, BILAG: British Isles lupus assessment group index, SLAM: systemic lupus activity measure, ECLAM: European consensus lupus activity measurement, HRQL: health-related quality of life, CHQ: child health questionnaire, IMACS: International Myositis Assessment and Clinical Studies group, JADAS: juvenile arthritis disease activity score, MMT: manual muscle testing, CMAS: childhood myositis assessment scale, DAS: disease activity score, MDAAT: myositis disease activity assessment tool, and CAT: cutaneous assessment tool.
5.1. Core Response Variables in JIA, JSLE, and JDM
Composite disease activity measures comprising 5 or 6 core response variables (CRV) have been defined for each disease by consensus methodologies involving members of the ACR, PRINTO, and/or International Myositis Assessment and Clinical Studies (IMACS) groups, as mentioned above. Note that there are 2 slightly different core sets for JDM developed by PRINTO and IMACS (Table 3). The common components for each disease include physician and parent or patient global assessments, which use 10 cm visual analogue scales (VAS) to evaluate the extent of active inflammation based on all information available [21]. A score of zero indicates inactive disease and 10 indicates extremely high activity. In addition, the JIA and JDM core sets include a measure of physical function (most typically the childhood health assessment questionnaire (CHAQ), which has been validated in both populations [54, 55]). The CHAQ is divided into disability and discomfort indices which assess function in 8 areas (score 0–3) and pain intensity and overall wellbeing, respectively [54]. The JSLE and JDM core sets include a generic measure of HRQL that has been validated in both populations, the child health questionnaire (CHQ). The CHQ contains 14 domains to evaluate the physical, emotional, and social components of health and provides physical and psychosocial summary scores [56]. A notable challenge is that measures of physical function and HRQL within the core sets may reflect disease damage in addition to disease activity. The remaining CRV are specific to each disease and are further discussed in the sections below.
Clinically meaningful improvement in the core set is often used in clinical research to define the primary endpoint. Criteria for improvement have been developed for each composite measure [10, 29–32], and a definition of disease flare has been proposed for JIA only [33]. As noted in Section 4, achieving improvement or flare is relative to the patient's baseline status, and thus the absolute degree of disease activity is different for each patient.
5.2. Disease Activity Measures in JIA
In addition to the items mentioned above, the ACR core set also includes a measure of systemic inflammation (usually ESR or CRP), the number of joints with active arthritis (defined as joint effusion or limitation of motion accompanied by heat, pain, or tenderness), and the number of joints with limited ROM [10]. A systematic review of outcome measures in JIA compares the psychometric properties of the measures within the ACR core set, although it did not identify any validation studies of the composite core set itself [57]. The CHAQ has strong reliability and moderate correlations with other measures of disease activity but poor responsiveness. Active joint count and physician global assessment have the strongest correlations with disease activity and are most responsive to change.
The JADAS is a measure of absolute disease activity in JIA. It is similar to the core set in that it incorporates physician and parent/patient global assessment of disease activity, number of active joints, and ESR; however, it does not include functional status or number of joints with reduced ROM because these may be more reflective of disease damage [6]. Depending upon the number of joints assessed, the JADAS is scored on a continuous scale from 0–101 (71 joints), 0–57 (27 joints), or 0–40 (10 joints) and has good construct validity and responsiveness [6]. Changes in JADAS score are able to classify patients according to ACR Pedi response and have excellent ability to predict flare and inactive disease [34]. Recently, the "JADAS3," which excludes ESR and avoids the necessity of a blood sample, was found to correlate with individual measures of disease activity as well as the original JADAS [58].
With improved success in the treatment of JIA, criteria for MDA, inactive disease, and remission have been defined. MDA is intended to define a state between high disease activity and remission that is acceptable to the physician and patient [42]; however, there is no data on the prognostic significance of maintaining this state. The MDA definitions have been validated in independent samples [42]. Similarly, the measurement properties of the Wallace criteria for inactive disease, remission on medication, and remission off medication have been assessed on data from 3 independent JIA clinics [43].
Systemic JIA (SJIA) differs from the other subtypes in that it is characterized by fever, rash, serositis, organomegaly, and lymphadenopathy, and these features must be considered in a disease activity measure. Batthish and colleagues have begun to develop an SJIA-specific disease activity measure using patient and parent interviews [48] and Delphi survey of health professionals to generate items [59]. The top items included fever, rash, increased CRP and ESR, and requirement for increasing medications. From here, the goal is to determine the best and most parsimonious list of items. At present, the ACR core set specifies the absence of spiking fever (≤38°C during past week) [2], and the definition of inactive disease requires absence of SJIA symptoms [15] as an additional requirement for SJIA children.
5.3. Disease Activity Measures in JSLE
Several disease activity measures initially developed in adult SLE patients have been found to be sensitive to change in JSLE [60]. The SLEDAI [35], British Isles lupus assessment group index (BILAG) [36], systemic lupus activity measure (SLAM) [37], and ECLAM [38] consist of many attributes grouped into 8–10 organ systems. The SLEDAI and SLAM are scored by weighting and summing of each attribute to give a total score. There are several rules for scoring the ECLAM to give an integer between 0 and 10. The BILAG uses an alphabetical rating system for each organ system, although numerical conversion schemes have been suggested [60]. Of the measures described, the SLEDAI and SLAM are the most user-friendly, and the ECLAM appears to be the most sensitive to change in JSLE [61]. The BILAG is complicated and takes longer to score.
5.4. Disease Activity Measures in JDM
Rider et al. have recently published a very comprehensive review of all the disease activity measures available for JDM, including their psychometric properties and utility for both clinical and research purposes [62]. The core sets for JDM include a measure of myositis activity assessed either with MMT or the childhood myositis assessment scale (CMAS). A modified MMT of 8 proximal, distal, and axial muscle groups tested unilaterally is scored from 0 to 80, and was found to closely approximate a total MMT score of 26 muscle groups tested bilaterally and is more feasible for use in the clinic setting as it takes less than 5 minutes to perform [63]. The CMAS uses 14 maneuvers (score 0–52) to measure muscle strength, physical function, and endurance and has excellent measurement properties [46]. The IMACS cores set considers the CMAS a measure of physical function, along with the CHAQ [12]. Levels of muscle enzymes are included in the IMACS core set as they are felt to be clinically useful but not in the PRINTO core set because they were found to correlate poorly with myositis activity in a clinical trial setting [14]. Global disease activity in JDM is measured with the DAS and the MDAAT. The DAS assesses muscle, cutaneous, and vasculopathic features of JDM [39], while the MDAAT includes extramuscular manifestations and assesses disease activity in 7 organ systems [40]. The cutaneous assessment tool (CAT) assesses the full range of cutaneous manifestations of JDM and provides both skin disease activity and skin damage scores [41].
Recently, criteria have been proposed for inactive disease in JDM (on or off therapy), requiring 3 or more of (1) CPK ≤ 150 U/I, (2) CMAS ≥ 48, (3) MMT ≥ 78, and (4) physician global assessment ≤0.2 [44]. These criteria should be externally validated prior to use in the clinical or research setting [64].
6. Conclusions
Over the last 20 years there has been an explosion of disease activity measures in paediatric rheumatology. The development of these tools is important as we aim to investigate and compare therapies for JIA, JSLE, and JDM. Challenges remain in determining which disease activity measures are optimal for use in the clinic and research settings. We are still working towards incorporating patient perspectives to obtain a comprehensive assessment of health in paediatric rheumatology patients.
|Juvenile idiopathic arthritis
|Juvenile systemic lupus erythematosus
|Juvenile dermatomyositis
|Nominal group technique
|Patient-reported outcome.
Conflict of Interests
The authors declare that they have no conflict of interest.
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Copyright © 2013 Nadia J. Luca and Brian M. Feldman. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


text:
Renewable energy
Triodos Bank and its investment funds, offered via Triodos Investment Management, finance and cofinance enterprises that augment the use of renewable resources in particular and supports projects that reduce the demand for energy and promote energy efficiency.
Triodos Bank describes and independently verifies the contribution it makes to the avoided carbon emissions that result from these energy projects. We are transparent about this approach in the annual report because we think it's important that our stakeholders understand the approach we take to these disclosures.
In reporting our impact as a sustainable bank, we include all the impact of the projects and clients that we finance. In technical jargon this is called the contribution approach. We also used the contribution approach in reporting the greenhouse gas emissions of our renewable energy portfolio up to 2017. This was previously both practical and, we believe, reasonable. From 2018 onwards we will also include the attribution approach in our carbon disclosures. This means that we will calculate the avoided emissions as they relate to the proportion of our finance in a project.
It's important to note that an attribution approach leads to lower carbon emissions figures than a contribution approach. That is because a contribution approach accounts for all of the emissions from a project rather than a proportion of them. This attribution approach is a more accurate reflection of Triodos Bank's responsibility for the greenhouse gas emissions of the projects it finances, and is consistent with the PCAF methodology.
By the end of 2018, Triodos Bank and its climate and energy investment funds were financing 513 projects in the energy sector: including 34 energy efficiency projects, 28 sustainable power projects in a construction phase and another 451 sustainable power projects (2017: 410) with a total generating capacity of 3,800 MW (2017: 3,100 MW), producing the equivalent of the electricity needs of 2.5 million households worldwide (2017: 1.4 million). Together these projects contributed to the avoidance of over 2.9 million tonnes of CO2 emissions (2017: 2.4 million tonnes). Of these avoided emissions about 0.9 million tonnes CO2 can be attributed to Triodos Bank's financing in the renewable energy projects.
These projects include 207 windpower projects, 230 solar photovoltaic projects, and 34 hydro projects. The rest include heat and cold storage, biomass and a diverse range of energy efficiency initiatives.
Organic farming and nature development
The organically managed land on the farms which Triodos Bank and Triodos Investment Management financed in 2018 could produce the equivalent of 32 million meals in 2018, or enough food to provide a sustainable diet for approximately 29,000 people (2017: 27,000). Together they financed approximately 35,000 hectares of organic farmland across Europe. This means one football-pitch sized piece of farmland for every 13 customers, each one producing enough for 550 meals per year.
We also financed 30,000 hectares of nature and conservation land (2017: 31,000 hectares), representing around 420m2 of nature and conservation land per customer. This land is important for the sequestration or absorption of CO2 from the atmosphere.
In 2018 over 104,000 smallholder farmers (2017: 146,000) in 13 emerging market countries worldwide were paid directly and fairly upon delivery of their harvest, as a result of the trade finance that Triodos Investment Management funds provides to farmers' cooperatives and agribusiness. These farmers' harvest that is brought to international markets, consists of 12 different fair trade and organic products, such as cocoa, coffee, oils and quinoa. In 2018 the clients of the funds had 56,000 hectares of certified organic farmland under cultivation (2017: 60,000). An additional 24,000 (2017: 17,000) hectares was in conversion – an important number because it takes time before conventional farmland is ready to be certified organic.
Sustainable property and private sustainable mortgages
As well as offering green mortgages that incentivise households to reduce their carbon footprint, Triodos Bank and Triodos Investment Management finance new building developments and renovation projects for properties to reach high sustainability standards. In 2018 Triodos Bank and Triodos Investment Management financed directly, and via sustainable property, approximately 11,800 homes and apartments (2017: 10,600) and about 440 commercial properties (2017: 540) comprising approximately 717,000m2 for office and other commercial space (2017: 540,000m2) and about 226,000m2 of buildings and brownfield sites (2017: 18,000m2).
Health care
As a result of its finance across Europe around 41,000 individuals (2017: 53,000) were residents of facilities at 502 elderly care homes financed by Triodos Bank and Triodos Investment Management in 2018, representing the equivalent of 21 days of care per Triodos Bank customer.
Community projects and social housing
In 2018 Triodos Bank and Triodos Investment Management financed 525 community projects (2017: 490), and 204 social housing projects, which directly and indirectly provide accommodation for approximately 56,000 people (2017: 94,000).
Triodos Investment Management's specialised emerging markets funds provided finance to 103 financial institutions working for inclusive finance in 43 countries (2017: 44). These organisations reached approximately 11.1 million individuals saving for their future (2017: 15.1 million) and 19.2 million customers borrowing for a better quality of life (2017: 20.3 million). Of these loan clients, 82% are female. Women are often in disadvantaged positions in many developing countries. Giving women the freedom to manage their income and to provide for their families empowers their position.
Arts and culture
During 2018 Triodos Bank and Triodos Investment Management helped make it possible for 22.6 million visitors (2017: 17.6 million) to enjoy cultural events including cinemas, theatres and museums across Europe, as a result of its lending and investments activity to cultural institutions. This represents the equivalent of 31 cultural experiences per Triodos Bank customer.
Triodos Bank and Triodos Investment Management finance helped approximately 3,300 artists and creative companies active in the cultural sector (2017: 3,400). Theatre, music and dance productions from creative companies were attended by 1.2 million people. New productions in 2018 from the film and media sector financed by Triodos Bank (most importantly in Spain) were seen by approximately 13 million people (2017: 9 million).
Triodos Bank and Triodos Investment Management also financed organisations that provided 4,000 affordable spaces for cultural activities such as workshops and music courses.
Approximately 680,000 individuals benefited from the work of 550 education initiatives financed by Triodos Bank in 2018 (2017: 650,000). For every Triodos Bank customer, the equivalent of 1 person was able to learn and grow because of education provided by an establishment we financed.

subset: commoncrawl


text:
Blue Flame
|Blue Flame
|Main appearance(s)
300 Rupees (OoT)
Ice Cavern (OoT)
Ganon's Castle (OoT)
|Comparable item(s)
Blue Flames,(BotW) also known as Blue Fire,(OoT)[1] are recurring items and objects in The Legend of Zelda series.
Location and Uses
Ocarina of Time
Navi's Comment
Blue Fire can be found in the Ice Cavern and Ganon's Castle in Ocarina of Time. It can also be bought at the Medicine Shop for 300 Rupees. In Master Quest, it can also be found in the Gerudo's Training Ground.
Blue Fire is used to melt Red Ice. Link must first scoop it from a pedestal by using a Bottle or buying it from the Medicine Shop. Blue Fire is required to progress through the Ice Cavern and obtain the Iron Boots and a Piece of Heart. It is also needed to get the Zora Tunic by melting the Red Ice in which King Zora is encased. Alternatively, Link can melt the Red Ice blocking the entrance to the Zora Shop in order to buy the Tunic.
When flying through Blue Fire, Keese will become Ice Keese.
Breath of the Wild
Blue Flame is a type of Fire that never burns out while in a Torch in Breath of the Wild. Certain Torches can only be lit with Blue Flames, such as inside the Divine Beast Vah Rudania, within Ancient Shrines, and the Ancient Furnaces outside of the Akkala Ancient Tech Lab and the Hateno Ancient Tech Lab. Link must bring Blue Flame to both Ancient Tech Labs from a nearby Blue Fire furnace in order to activate certain features of the Tech Lab. Link must use a wooden Weapon, such as a Torch or a Tree Branch, to transport Blue Flame. At the Hateno Ancient Tech Lab, this will allow Link to upgrade his Sheikah Slate. At the Akkala Ancient Tech Lab, this will allow Link to exchange Ancient Materials for many types of Ancient Soldier Gear and equipment. If Blue Flames are used to set flammable objects on fire, they will behave the same way as normal Fire.
- Blue Fire can be used to destroy bombable walls in Ocarina of Time.[2]
- All of the Hylian Hateno villagers have unique dialogue if Link speaks to them while holding a torch lit with the Blue Flame, save Pruce. The children will also follow Link indefinitely, even out to of Hateno Village, until he gets too far away from them or puts the torch out.
|Names in Other Regions
|青い炎 (Aoi Honō)
|Same as English.
|蓝色火焰 (Lánsè Huǒyàn)
|Same as English.
|Flamme Bleue
|Same as English.
|Blaues Feuer
|Same as English.
|Fuego Azul
|Same as English.
See Also
- ↑ Encyclopedia (Dark Horse Books) pg. 117 (OoT)
- ↑ VerySydney, How to get the market skulltula with no explosives, Twitch (Video), published December 19, 2016, retrieved January 2, 2017.


text:
Rowe: I wouldn't shoot Murray but I'd buy the bullet
Michael Jackson's ex-wife Debbie Rowe said she will 'buy the bullet' to end Conrad Murray's life after he insulted her during an interview.
Jackson speaks following suicide attempt
Paris Jackson's biological mother has revealed her daughter is 'fine' and in a treatment centre after she was allegedly rejected from a top rehab facility because they feared they would be plagued by paparazzi.
Jackson ex Rowe gave 'warning over doctor'
Michael Jackson's ex-wife, Debbie Rowe, reportedly told police she had concerns about the singer's doctor prior to his sudden death in June. According to sources, Rowe anonymously told officials she was aware the 'Thriller' star was actively using false names in order to obtain drugs fuelling an addiction. Rowe, who met Jackson while working for Arnold Klein, allegedly holds the doctor responsible for the death of Jackson.
Oliver star's Jacko daughter claims were 'twisted'
Childhood Oliver! star Mark Lester has played down an apparent claim that he is the real father of Michael Jackson's 12-year-old daughter Paris. Insiders close to Lester, 51, have tried to diffuse the storm sparked after he claimed he had provided the late King of Pop with a sperm donation for free in 1996, at a time when Jackson was married to nurse Debbie Rowe.
Jackson's ex to fight for custody
Debbie Rowe will fight for custody of the two children born during her marriage to Michael Jackson, according to US reports.


text:
Mr and Mrs Dursley sat in front of the television watching the Six O'Clock News, as Peter Sissons'
voice boomed out of the television. "And now the latest on notorious mass murderer Sirius Black,
who escaped from a top-security prison last night. We hand over to Nick Ross, Crimewatch
presenter. Nick, what can you tell us?"
"Well, the authorities are reporting that Sirius Black killed thirteen people in 1981, in a
spree killing on a busy shopping street. To be honest, though, Peter, we're finding this difficult to
understand, because we've looked in the BBC Archive, and we don't have any records of a spree
killing having taken place in 1981, much less by anyone by that name. We've found a record of a
gas explosion that killed that number of people at the time that Black supposedly carried out the
murder, but that's it, and Black wasn't named in connection with it, either as a culprit or as a
victim. Obviously we'll continue to look into this—"
At that moment, a harassed looking woman in long flowing robes ran onto the screen. She
pointed a piece of wood at the presenter, and shouted "Confundo!", before pointing at the camera
and shouting "Obliviate!". Then she ran off.
Watching at home, Mr and Mrs Dursley were slightly confused, having forgotten what
point Nick Ross was making. Nick, who looked slightly blank, just said, "So, yes, we're very
confused by this case, Peter, and I don't have anything to report. Apologies, and back to you in the
"Right," said the newsreader, looking nonplussed. "Well, anyway, the police have asked us
to inform viewers that if they spot Sirius Black anywhere, they should not approach him, and
should inform the police immediately by telephoning…"
"Nasty business," said Vernon, turning to his wife. "They should bring back hanging,
shouldn't they? Then we wouldn't have any of this scum walking the streets."
"Yes, well, I blame his parents," said Petunia. "Something must have gone wrong with his
upbringing. People don't raise their kids right these days. Potter, the washing machine's done;
empty it, you lazy boy!" she added as an aside.
Harry trudged down to the washing machine, tossing Neville's Remembrall idly. Neville
had left it in the dormitory at the end of term, and Harry had decided to keep it for safe-keeping.
It had turned red, which meant he'd forgotten something; he wondered for a while if the "thing"
was that he'd forgotten to throw the Remembrall at Aunt Petunia's head, perhaps causing a mild
concussion, or maybe even death if he threw it at the right point; and he could use Alohomora to get
out of prison, so he'd escape, and could go on the run… But no, he thought, he didn't want to
become a murderer; he liked his soul intact, he thought, presciently.
"Yes, Aunt Petunia," he said, remembering what the Remembrall was telling him to
remember, and simultaneously wondering what the advantage of one of these was over a notepad.
He'd had his permission form for Hogsmeade all summer, and he needed to ask one of the
Dursleys to sign it.
"And make us some tea while you're in there!"
"Yes, Aunt Petunia." He got out the teapot, wondering whether she'd notice if he poured
some washing powder into the tea pot with the tea leaves, but he realised the lethal dose would be
detectable by taste. A shame. He boiled the kettle, put some tea leaves into the pot, and placed the
tea cosy over the top. It was slightly too large for the pot, and slightly worn, and it split along two
of its seams. He had a sudden vision of Dobby wearing the tea cosy as a hat, for no reason other
than that it really needed to be clear that a House-Elf might wear it.
Harry put the teapot down in the living room while Petunia was still talking about Sirius
Black. "No, it's like your sister Marge says, it's all about the breeding. We should ask her about
that when she comes."
"Oh, bloody hell, Petunia, don't get her on about dogs, I don't think I could stand to listen
to another ruddy anecdote about Colonel ruddy Fubster."
"We should get them together sometime," muttered Petunia.
"I'm afraid last I heard he was spending a lot of time with Brigadier Lethbridge-Stewart,"
he said, a faint look of disgust on his face.
"Ah, well," said Petunia. "Potter, this tea is cold."
Harry had reached the end of his tether. Not thinking, he drew his wand, and sparks flew
out of it, pointing it, unfortunately, at the teapot.
With a small pop, the teapot disappeared, being replaced by the living embodiment of a
joke. Well, that's what Harry thought it was—he had to admit he'd never seen a joke in the flesh
before, but he was pretty sure that this was one looked like. And "in the flesh" was the phrase for
it, because the joke was undeniably naked. Thankfully for anyone attempting to write about this
moment, the scene was utterly indescribable.
"What in blazes?! Is this some sort of a joke?" bellowed Uncle Vernon.
"Yes, I think it is," said Harry, attempting to suppress a smile.
The joke, still wearing the tea cosy as a hat, was now standing on the table. It raised one
arm (was that an arm?), then another, in rhythm, before turning both arms over, then placing them
in turn on its—upper arms, maybe, or shoulders?—and then on its head.
At this point, Dudley walked into the room. "That's the Macarena," he said, dully.
Everyone stared at him. "It's a dance you can do to a Spanish song. It'll be big in three years or so,
I bet." The other three continued to stare. "Everyone's doing it at Smeltings."
"Since when have you paid attention to what happens in school?" asked Harry.
"Enough!" shouted Petunia. "Up to your room!"
"Not yet, he's not," replied Vernon. "He needs to get rid of this bloody—whatever it is!"
Harry sighed. "This is such a joke."
"Yes, it is. Now get rid of it!"
"But I don't know how! I don't know how I even created it!" The joke, meanwhile, had
now completed four quarter turns and seemed to have decided the inaudible music had stopped.
It had progressed, instead, to making horse like movements with its legs, in time to words it was
singing in Korean.
At this point, an official-looking owl flew in through the window. It dropped a letter on top
of the joke, which Harry had to wrestle off it (he wasn't sure how something without identifiable
hands could have such a good grip). He opened the letter as the owl flew away, and read it.
Dear Mr Potter,
We have received intelligence that you carried out a Transfiguration at eight minutes past six this evening in a Muggle-inhabited house and in the presence of a Muggle, turning a teapot into the corporeal representation of a joke.
Ordinarily, the severity of this breach of the Decree for the Reasonable Restriction of Underage Sorcery would result in your expulsion from Hogwarts School of Witchcraft and Wizardry. However, to be quite frank, we're not sure what you did to make that happen, and the Department of Mysteries has got quite enough on at the moment to be trying to explain how you transfigured an object into a sentient version of an abstract concept, and so we're going to let this one slide on this occasion. A Ministry Obliviator will be on their way to your address shortly to wipe your memories of this incident for canon-protecting purposes.
Enjoy the rest of this evening while you still remember it!
Yours sincerely,
Mafalda Hopkirk
Improper Use of Magic Office, Ministry for Magic
Harry sighed, but thought that, since none of them would remember this, he might as well ask
Uncle Vernon to sign his Hogsmeade letter.
"Um, I realise this might not be the best moment," said Harry, "but third-years are allowed
to go to the village near the school, but only with their guardians' permission, and I wondered if
"Are you having a laugh?" replied Vernon, as the doorbell rang to signal the arrival of the
"Well, in the presence of a joke, I thought I might as well," replied Harry.
The joke seemed to have sensed its imminent destruction. It started flailing around,
repeating itself over and over again, before the Obliviator made it vanish with a wave of his wand.
"Well, you killed that joke," said Harry.
"It died about five paragraphs ago," said the Obliviator.
"Fair enough," said Harry, and waited to forget this had ever happened.


text:
I'm excited to share Fabiola Francisco's new release, Sweet on Wilde. Add it to your TBR.
Sweet on Wilde by Fabiola Francisco
Eight months ago, I made a deal with my best friend. This wasn't your typical pact. No, we had to take a different route. The deal was that if we were still single by fall, we would join online dating. Yes…now I am that girl. Just me, though, because she met a guy and saved herself from the awkwardness of dating people you meet via the Internet.
Cheesy pick up lines.
Inappropriate messages.
Disaster dates.
I don't want to be "Savannah, profile 8713," but a pinky promise is a promise you keep. What I wasn't counting on was meeting a guy at the local bar.
So what happens when you decide to open yourself up to new opportunities? You might just cross paths with someone who makes you believe in love. Parker Wilde brought out the best in me and understood the worst, but when an amazing opportunity presents itself and our lives take different directions, is being sweet on Wilde enough for us?
The music blasting from the speakers draws me, and I move my body to the beat as I sit by the bar facing the dance floor. Although Southern is a more laid back bar, it has a small area designated for the patrons that want to dance without feeling like they're disrupting the flow of the service.
"Let's go dance." Parker is eyeing me mischievously, obviously enjoying as I move to the music. The stress he came in with has now totally eased out of his body. He is back to his relaxed, confident self.
"It's okay. I'm fine here, not much of a dancer," I lie because the thought of dancing with him throws me off.
"Really? You haven't stopped moving. Come on," he reaches his hand out to me. Taking a moment to watch him as he stands before me with his hand out, I can appreciate how good-looking he is. I take his hand and let him lead me towards the small crowd dancing in the center of the venue.
"Sweet Home Alabama" begins to come through the speakers, and as soon as everyone hears the familiar introduction, they get in position, ready to dance the steps taught to us from a young age. In perfect unison, we all begin the line dance, looking like something out of Footloose. As I'm turning with the beat, I notice Parker beside me, following along without missing a step. I look down at his feet, and smile, shaking my head.
Two more songs come on, each with its own line dance to accompany the music, and we all dance. The next song that comes on is a slower one, so I head back to the bar in need of a cold beer to cool down. Line dancing always gets me excited but it can be tiring. Before I make it out of the crowd, an arm jerks me back and turns me. I'm facing Parker, his smile causing my heart rate to speed out of control. "One more," he says, beginning the two-step to Billy Currington's lyrics. Leading me around the dance floor, Parker is confident, his grip on me firm as we move through the other people dancing.
"You know, for someone who mocks my boots, yours look quite worn and broken in."
He chuckles, his grip tightening around my waist. "I may not be from Tuscaloosa, but I am a southern boy, Savannah." His drawl heavier, making his point.
Fabiola Francisco is a contemporary romance author from Miami, FL. She has always enjoyed writing. When she was young she began writing creatively. It was always a therapeutic way for her to express herself. She began with poetry, and throughout the years went expanding to short narratives until she finally decided to write a novel.
Her love for books has inspired her to write her own stories. Her books range from emotional to lighthearted humor. She is a firm believer in happily ever afters and the sometimes jagged path to achieving it. She hopes to continue writing more stories to reach readers individually.
When she's not writing, Fabiola loves expressing herself through art and being out in nature. She loves to cuddle with a good book and a glass of wine.


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When it comes to listening to great quality music look no further than, Art Royalty byTT The Artist. This 9 track EP released by the Baltimore Club music phenom, TT The Artist has done it yet again with releasing tracks that are diverse yet dope at the same damn time! Starting off the fresh EP, TT goes in with a hot track produced by Gianni Lee and Mighty Mark titled Let Me See Ya, which is easily one of my favorite tracks on the entire project. It has dope lyrics, shotouts to K Swift and showcase TT's dynamic flow.
Although, this was already highly expected considering that Mighty Mark was the executive producer on the project. Moving forward, Fly Girl is a nicely put together track that has a 90's Space Jam, sound that'll definitely make the ladies move and want to dance. I remember when she mentioned this track when we interview her when Stereo Champions was first getting started and she gave word then that Fly Girls was a dope track and I have to say she was definitely speaking truth. Following this dope track you can hear a more grudge style beat introducing you to "Thug It Out".
"If you got a problem we can settle it tonight meet me outside you ain't bout that life"! —TT The Artist
My sister has been repeating this one line for like the past month and I have to say it matches TT's style considering she goes in on every beat and performance. The next track Lavish produced by Guess Who On The Track has a more playful sound and TT is dropping nothing but heavy ass bars even showing love to Diplo in one verse. Moving on you'll hear some ill beats from one of my favroite producers from Baltimore, Thunderbird Juicebox. Giddy Up is a club banger that you'll hear in any club playing hot music you can enjoy while drinking Ciroc or riding on a mary jane high. Easily this is followed up with Imma Shake which has an electric dance music sound mixed with a trap sound you might here at a lot of the summer music festivals this year.
Pum Pum produced by Histo comes after Imma Shake which features verse more around the theme of dance hall which will make any shorty out there looking for a hot track to twerk turn this joint on. It's almost like Pussy Ate grown up considering the premise of the track altogether. Which leads to the classic and original, Pussy Ate Remastered produced by Mighty Mark. To finalize the project TT The Artist ends the project with Freaky Life produced by Big Dope P, which has a dope beat and a more experimental flow that ends the EP on a dynamic note for all the TT The Artist lovers.
Overall this EP, is definitely one you need to have in you iTunes so be sure to Download Art Royalty and support the big homie TT The Artist. Needless to say the cover artwork for her EP is sick as well so shoutout to Donald Ely (Graphic Designer) and Nicole Fallek (Photographer) that created that as well.


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Community Amenities
- Online Payments Available
Free e-check option
Accepts credit card payments
Accepts cash payments via MoneyGram
- 24-Hour Emergency Maintenance
- Water and Sewer Included
- Barbecue Area
- 24-Hour Fitness Center
- Baltimore County School District
- Controlled Access Entrances
- Insulated Windows and Doors
- Large Private Balcony
- Olympic Size Pool and Wading Pool
- Tennis Court and Playground
Apartment Amenities
Certain floor plans may have different amenities depending on when they were updated, what building they're in, etc. To tour our floor plans and see what amenities may be available, please call us at (443) 519-2687.
- Multi-cycle Dishwasher
- Garbage Disposal
- Cable-ready
- Ice Makers*
- Cathedral Ceilings on Top Floor Apts.
- Cooling Fan
- Fireplace Available in some Two Bedroom Apartments
- Full Size Washer and Dryer in unit
- Hot Water and Cooking Gas Included
- Individual Heating & Air Conditioning Systems
- Microwave Oven
- Refrigerator with Frost Free Freezer
- Wall-to-wall Carpeting
*Select Apartment Homes Only


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North American Network Operators Group
Date Prev | Date Next | Date Index | Thread Index | Author Index | Historical
Re: dns - golog
On Thu, 19 Oct 2006 14:50:37 +0200, Luke Besson said: > Can you suggest me any objective reason in order to invalidate this > proposal? Others have pointed out that wildcarding *might* work when done to consenting HTTP traffic. It certainly doesn't work very well if applied to non-consenting HTTP, or non-HTTP. On the other hand, if your policy-makers want to get a piece of the big revenue stream and positive PR that Verisign and Earthlink got when they deployed similar schemes, there isn't much I can do other than channel Randy Bush at you....


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Sanofi Enters Deeper Into Emerging Markets With Awamedica Deal To Manufacture Drugs In Iraq
This article was originally published in PharmAsia News
Executive Summary
Sanofi signed an agreement with Awamedica, Iraqi Kurdistan's first private pharmaceutical company, for the production of seven products in Erbil, Northern Iraq.
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Turkey's $2.6Bn Hospital Medtech Debts Create Problems On Top Of COVID-19
Turkey's efforts to control rising rates of COVID-19 are compromising the ability of hospitals to pay their debts to medtech and pharmaceutical companies. The government has devised a payments plan, but there is catch.
COVID-19 Pushes Ongoing Concerns of Turkish Medtech Industry Down The Agenda
The Turkish medtech industry's ongoing hospital payments problems appeared likely to come back onto the government's agenda, with the national economy recovering somewhat in late 2019. But COVID-19 dashed those hopes.
Turkey: International Medtechs Demand Stable Pricing And On-Time Payments
Growth prospects for Turkey's medical technology market are significant, but local companies have complained about public policies that are harmful to business and about the ongoing crisis in the hospital system. Now, international medtechs are starting to react, with some downscaling local operations and portfolios. Association of Research Based Medical Technologies Manufacturers president Umut Gokalp laid out the problems being faced by industry, and what action he thinks the government should take.
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Formal Mentoring
Companies that are approved for participation in the formal mentoring program are provided with an advisory board for a certain amount of time or until an event occurs with the company, such as acquisition or IPO. Advisory boards provide the portfolio companies with specific advice and direction they need to attract financing, grow and succeed. These boards are drawn from the finance, entrepreneurial and professional sectors. Recommendations for participation in the formal HiBEAM mentoring program are made by the board and members based on established selection criteria.
Informal Mentoring
HiBEAM directors and members assist with informal mentoring through Springboard Forums, office hours, workshops and events. Springboard Forums – Many inventors, researchers and young entrepreneurs who have an idea need access to experienced people to talk about the "next steps" of commercialization and to identify potential avenues for assistance in these specific areas. The panel will also provide candid recommendations for the refinement of a business plan, if the presenter has one. Normally, the HiBEAM Springboard Forum provides free assistance for life sciences and technology companies in early stages of development. The Forum invites curious scientists, researchers, or even students, who are aspiring entrepreneurs, and who wish to educate themselves on potential opportunities for the future. In short, the informal mentoring program will offer much-needed support for these individuals to help them take their science from the 'good idea' phase to technology licensing to building a successful global company. Anyone interested in presenting at a Springboard Forum, please contact us.
Advancing Entrepreneurship Knowledge and Practice
HiBEAM aims to encourage the intersection of different disciplines of science and innovators with accomplished entrepreneurs and venture capitalists. We will cultivate this environment by hosting informal meeting and discussions, and sponsoring educational forums, like "The Hawaii Entrepreneurs Summit" in 2006, 2007, and 2008, the Hawaii Spinout Summit in 2009, and the annual Hawaii VC Summit to help entrepreneurs on getting follow-on funding. HiBEAM has partnered with HTDC and Enterprise Honolulu, organizations to hold the Hawaii Entrepreneur Investor Pitch Competition in past years. We support the efforts of Entrepreneurs Foundation of Hawaii to hold its popular pitch events. We support the University of Hawaii Business Plan Competition with a prize for the second runner up team. HiBEAM members have volunteered as coaches and judges.
Workshops on "go-to-market" and professional selling have been well attended. We hope to attract a cross-section of individuals interested in developing the high tech, biotech, and life sciences sectors in HI to meet and talk with budding entrepreneurs or give a presentation. We also have successful entrepreneurs in Hawaii that are willing to share their experiences with others. HiBEAM has organized symposiums on commercialization for the research community titled "Transitioning Technology into the Marketplace". For firms that are at the edge of growth, the symposium topic is "Growth Strategies".
Technology Showcase
The Technology Showcase is an event we anticipate holding for researchers and inventors to showcase their new technologies to entrepreneurs, funders, and other interested parties. At these showcases, our focus is to present the newest innovations from the technology and life science fields and allow interested parties a preview. These showcases bring inventors together with entrepreneurs and investors, to cultivate the commercialization of new technologies and inventions. We hope to continue to highlight the best and brightest in Hawaii's research community.


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Connect: Convening Community Partners Across Issues
The Women's Foundation of California was founded on the ideal of the power of the collective. The third pillar of our strategy connects nonprofit and grassroots leaders, WPI fellows and alums, donors and policy leaders, advocates, grant partners and grantmakers in a variety of convenings and learning opportunities that will collectively build and advance gender justice in California.
One of our important continued partnerships is with the California Budget and Policy Center, with which we launched the California Women's Well-Being Index in 2016. This first of-its-kind online resource provides data on women's health, safety, economic security, employment and earnings, and political empowerment for all of California's 58 counties. In the coming months, with support from JP Morgan Chase Foundation, we will host a series of gatherings to share and use the data to advance system-level change.
In 2018 we will partner with the cities of San Francisco, Oakland, and San Jose to host the next Bay Area Women's Summit in June. This action-oriented convening will gather 1,500 people to explore solutions to the most pressing challenges for women and girls in our local region.
Looking across a broader geographic scope, we enjoy a powerful role in the women's funding movement. This work builds on recent alliances including the United State of Women Summit in Washington, D.C., held in 2016, at which eight women's foundations came together to launch the National Collaborative of Young Women's Initiatives. This collaborative, modeled on the successful initiative led by the New York Women's Foundation, has already moved women's foundations in Dallas, New York, Memphis, Minnesota, Birmingham, western Massachusetts and Washington D.C. to develop innovative solutions with and for young women, girls, and trans youth of color.
In California, we recently forged a partnership with Alliance for Girls to launch a Bay Area Young Women's Initiative and are rapidly bringing on funding partners, including the Peggy and Jack Baskin Foundation to join us in increasing resources to young women, girls, and trans youth of color.
Our role as a public community foundation gives us a unique position between funders and activists. The Philanthropy and Public Policy Institute, modeled after the Women's Policy Institute, is an experiential learning opportunity that trains funders about the public policy process and helps them be more effective grantmakers in advocacy efforts. In partnership with the California Endowment, Blue Shield of California Foundation, and Fondation CHANEL, we will host the first-ever California Gender Justice Funders Convening. This diverse gathering of funders and donors will collaborate, coordinate, and leverage our respective investments for greater effect.


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Allergan to Buy Tobira Therapeutics in $1.7 Billion Deal
Allergan PLC on Tuesday said it agreed to acquire Tobira Therapeutics Inc., a biopharmaceutical company that develops therapies for liver diseases, in a deal worth as much as $1.7 billion, or 19 times Tobira's previous market value.
Tobira focuses on products that treat nonalcoholic steatohepatitis, or NASH, a common liver disease associated with obesity and type-2 diabetes. NASH occurs when the accumulation of liver fat is accompanied by inflammation and cellular damage, and it can lead to scarring of the liver and progress to cirrhosis, liver cancer and eventual liver failure.
"NASH is set to become one of the next epidemic-level chronic diseases we face as a society," Allergan Chief Executive Brent Saunders said in prepared remarks, citing the increasing rates of diabetes and obesity. NASH has no approved treatments available, the company said, and affects 5% of the U.S. population.
Separately on Tuesday, Allergan said it further bolstered its NASH pipeline by purchasing privately held biopharmaceutical company Akarna Therapeutics Ltd. for $50 million, plus potential milestone payments that weren't disclosed.
As for the Tobira deal, Allergan will make an upfront payment of $28.35 a share in cash, approximately six times Tobira's closing price Monday of $4.74 a share. Tobira holders also will each receive one contingent value right to receive as much as $49.84 a share linked to certain development and regulatory milestones.
Shares of Tobira surged 721% to $38.91 in trading Tuesday, while Allergan shares fell 2.7% to $238.67. Tobira now has a market value of about $725 million, up from $89.2 million on Monday.
Drug deals frequently carry high premiums. According to Dealogic, the average premium in biotech and pharmaceutical deals of more than $100 million has been 45% this year and was 37% in 2015.
In recent years, the U.S. pharmaceutical deal with the highest premium—at 256%—was Roche Holding AG 's $230 million acquisition of U.S.-based Anadys Pharmaceuticals Inc. in October 2011, Dealogic said. That deal boosted the Swiss company's hepatitis franchise and broadened its business outside its main cancer drug operations.
Tobira's lead product candidate, cenicriviroc, suffered a setback this summer when the company said the treatment missed its primary endpoint in a midstage trial. The drug did meet one of two secondary endpoints in treating liver scarring associated with NASH, as patients treated for a year saw their scarring improve without a worsening of NASH.
As a result, Tobira said in July that it planned to meet with regulators to discuss the design of a late-stage study, which it expected to begin next year.
In January 2015, cenicriviroc was granted fast-track status by the U.S. Food and Drug Administration, a designation that aims to bring medicines for difficult conditions to market more quickly.
Allergan also will gain another investigational NASH treatment, evogliptin, which is in early-stage studies. Both investigational treatments can make a significant impact in treating NASH, Allergan said.
In the Akarna purchase, Allergan gains Akarna's investigational treatment for NASH, called AKN-083, which targets a certain hormone receptor in the liver and is in early stage studies. Allergan said AKN-083 is highly complementary to the investigational NASH therapies added in the Tobira deal.
For the first six months of 2016, Tobira reported license and collaboration revenue of $1.2 million and posted a loss of $25.6 million. Allergan, through the first six months, had revenue of $7.08 billion but lost $246 million amid acquisition-related charges, asset sales, write-downs and other items.
Allergan has been an active buyer. Last week, it agreed to acquire clinical-stage biotechnology company Vitae Pharmaceuticals Inc. for $639 million, more than double its market value, in a move aimed at strengthening the drugmaker's skin-care pipeline.
The company has built up its spending power, in part, through the recent sale of its generics business to Teva Pharmaceutical Industries Ltd. for $40.5 billion.
Jefferies analysts said the high premium that Allergan is paying for Tobira suggested there were multiple bidders for the company, and it points to the industry's interest in companies developing NASH treatments. Others developing NASH treatments include Intercept Pharmaceuticals Inc., Galmed Pharmaceuticals Ltd. , Conatus Pharmaceuticals Inc. and the French company Genfit SA .
Genfit's treatment, elafibranor, and Intercept's therapy, obeticholic acid, are considered among the current leaders in the NASH race. Both are in late-stage trials, and Intercept's drug in April received the backing of an FDA panel for approval in treating a separate rare liver condition called primary biliary cirrhosis.
Credit Suisse earlier this year predicted that sales of Intercept's obeticholic acid could reach $159 million in 2018 if it is approved for primary biliary cirrhosis this year, but it eventually could rise to annual sales of $6.5 billion if cleared for NASH.
The four drug companies with NASH products saw sharp gains Tuesday following news of the Tobira deal. Intercept added 8.5% to $170.01; Galmed rose 25% to $4.61; and Conatus gained 19% to $2.09. Genfit increased 16% in Paris trading.
Gilead Sciences Inc. and Bristol-Myers Squibb Co. are among the heavyweights seeking to bring a NASH drug to market. Shares of Gilead rose 3.5% Tuesday, while Bristol-Myers added 0.9%.
Sept. 20, 2016
Source: http://www.wsj.com/


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Siren Publishing.
Beautiful, curvy, Ravyn Templeton saw Zane Ramsey in a BDSM club in Houston three years ago. He's haunted her dreams ever since.
Zane is an Assistant District Attorney but he's also a co-owner of Club Mystique, the BDSM club he and his brothers built on their Texas ranch. When Ravyn's ex-husband is arrested for hiring an assassin to kill her the case is assigned to Zane.
The moment Zane meets Ravyn he wants her and even though he knows having an affair with her will jeopardize his career he can't resist her. When Ravyn's ex-husband accuses her of laundering money for a drug cartel, and she refuses to answer Zane's questions, he leaves her.
Fate steps in and brings them together again. Zane has the power to save Ravyn but only if he loves her enough to fight for her.
What Reviewers Say...
The Book Fairy Reviews - 5 stars - This series just keeps getting better and better! Although I still love the dynamic between Addison and Cade(they are my fave's) I love how conflicted Zane is in this book. The Ramsey family just keeps growing adding more subs with each book, which means more women who really rule in the Ramsey Ranch... see the rest of the review at goodreads.
Beverly Ovalle - 5 stars - Okay, let me just say that I finished Zane's Choice and read it again! Once again Addison is matchmaking, trouble making, the view depends on who she has in her sights. Zane is torn by his job as ADA and Ravyn. Ravyn has secrets she can't afford to tell Zane. Bullied and blackmailed Ravyn does what she has to do, regardless of her feelings for Zane... see the rest of the review at goodreads.
A moment later, Zane Ramsey appeared. His black hair was mussed as if he'd shoved his hands through it a dozen times, and his black suit jacket was rumpled and hung open. His leaf-green eyes blazed with rage and she wanted to slip behind Thor or Mac, or even Ben for protection. Instead, she lifted her chin and dared him to do his worst. He took one step into the room before his eyes zeroed in on her.About Mardi Maxwell
"You can't be here, Ravyn. This puts me in an impossible position."
Ravyn rested a graceful hand on her hip. "Well, hello to you, too, lover."
Zane cursed, then stalked toward her. Without pausing, he clenched his fist in the hair at her nape, then curved her into him until their noses were almost touching.
The heat from his body sent a shiver of arousal through her. "Let go, Zane."
"You need to leave, Ravyn. Now."
"No. I'm hiding from the press and everyone else who wants to put me behind bars—people like you."
"Dammit, Ravyn. I told you I would protect you."
"No, you didn't. You said you would get me the best deal you could if I would turn state's evidence." She tried to move away, but he tightened his hand and pulled her head farther back while curving her pelvis against his. His erection pressed into her belly and she breathed a swift sigh of relief at the proof that he still wanted her.
"I told you from the beginning if you were guilty, I wouldn't lie for you," Zane said, the words gritted out between clenched teeth.
"Then you shouldn't have fucked me." Ravyn reached up and tried to pry his fingers from her hair. "Let go, Zane."
"This time you've gone too far. Be still or I'll beat your ass."
"You can't. You're the one who set the limits of our relationship." She gave up trying to pry his hand loose then lowered her voice. "You said fucking only. Nothing else."
"Tell me the truth, then—tell me what you know and I'll help you."
"Nothing. I don't know anything."
"You lie to me and then you question why I won't—" He pulled her head back until the tendons in her neck stood out. "Just don't lie to me again. It really pisses me off."
Ravyn glanced to her right and saw that everyone's attention was focused on them. "Zane, let go. Everyone's watching."
"Don't mind us," Cade said. "You'd be surprised how often something like this happens around here lately."
Zane shot a dirty look toward the room's occupants, then focused on her again. "Everyone out."
Cade picked Addison up, then settled in the chair behind his desk and smiled. Addison grinned at Zane, then snuggled into Cade, letting him know they were staying.
"We may have some information you might be interested in knowing, little brother." Cade smoothed his hand down the length of Addison's braid.
Ravyn glanced at the wall behind Cade's desk and saw a large portrait of him and Addison. In it, Addison was over Cade's shoulder. One of her hands grasped the waistband of his leather pants as she looked down at the camera with a huge smile on her beautiful face. Cade's large hand nearly covered her entire bottom as he held her in place and looked over his shoulder at someone below them. The dark look of passion on their faces was mesmerizing.
That was the way she wanted to be loved. Passionately, as if her death would totally destroy the man who loved her.
"I'm addicted to books. I love reading them and I love writing them. My earliest memories are of my oldest brother reading one chapter a night of The Wizard of Oz to me and my siblings. He had to read it because he was the only one who could read at the time! lol I've loved books ever since.
When I don't have my nose in a book or my laptop I'm spending time with my family and friends, gardening, cooking, traveling, swimming and daydreaming about my next hero."


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Go to https://sarawakid.sarawak.gov.my.
Log in to view your member page.
Under 'Profile', click 'Mobile Phone'.
The Mobile Phone screen will look like this.
To update your phone number, you simply have to key in your new phone number in the "New Phone Number" text field such as below.
Once you have key in your new phone number, click on the "REQUEST OTP" button.
System will send a one-time-password (OTP) to your new mobile phone for you to verify your new number.
Key in the OTP obtained from the sms sent to the field labelled "One Time Password".
You need to make sure that the security code that is shown on screen is the same with the ones sent to you.
Click on the "SUBMIT" button to submit the OTP and system will verify the OTP submitted.
Once verification is succesful, system will show the succes message as below :
To update your phone number now, please click on this link.
Scan the above QR code to access this portal through mobile
Disclaimer: The Government of Sarawak shall not be liable for any loss or damage caused by the usage of any information obtained from this portal. Services provided through this portal are subject to the terms and conditions of the respective service providers.
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