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Vice President, Global Sales & Service
Responsible for global sales and service organization in China, Taiwan, Korea, Europe, South East Asia, US, and Japan.
Ten years of experience in capital equipment business development.Proven record in managing complex country, and regional multi-culture organization.Demonstrated capability in establishing alliances with strategic accounts, resulting in new and sustainable business in Taiwan, China and Korea.Experienced in leading strategic business unit with P/L responsibility.
Responsible for global sales and service organization in China, Taiwan, Korea, Europe, South East Asia, US, and Japan.
Vice President, Strategic Business Unit (SBU) Wire Bonder
Responsible for Strategic Business Unit Wire Bonder.
§Re-established product strategy with emphasis on long-term production management instead of short term opportunistic approach.
§Reduced overall working capital by 25% in 9 months.Results achieved through strict management of re-cycle usage of equipment assets; and control of inventory level.
§Implemented account strategy to focus on key high volume accounts rather than a large quantity of low volume accounts.
§Successfully launched of new platform wire bonder at Semicon Taiwan 2007.
§Doubled revenue growth rate to 14%, tripled shipment growth rate to 22%.
Managing Director, South East Asia
Legal entity representative and board member covering sales and service organizations in Singapore, Malaysia, Philippines, and Thailand.Responsible for local legal and finance compliance, manufacturing facilities ISO compliance, and coordinator of Singapore Economic Development Board (EDB) subsidized research and development projects.
§Built up and stabilized local management team by filling functions in finance, human resources, operations, and sales and service.
§Manage R&D projects with Economic Development Board of Singapore and fulfill agreement.
ESEC Pacific North (Taiwan) Inc.,Chu Pei City, Taiwan
General Manager and Key Account Manager (2001 – 2006)
Managed Taiwan organization and regional key account sales team to achieve yearly defined sales targets and strategic goals; responsibility for 25% of overall company sales budget.Account owner and strategic planner for three of the top ten customers (ASE, Greatek, and Spil).Managed regional team of 31, with members in Taiwan, Malaysia, China and Korea.
§Positioned strategically with the biggest player in the industry (ASE) to form partnership.Worked closely with corporate offices to align common goals and execute defined plan.Resulted in successful penetration of one of the two core products (Wire Bonder) to multiple sites of customer's factories in Asia (improved share of wallet from 0% to 20% in 2005).
§Retained and grew the largest account (Greatek) over 9 years with 100% share of wallet in all addressable product markets (average annual turnover of USD 10 million)
§Achieved country operation cost reduction via effective management, transparent communication and ownership culture.Resulted in achieving lowest DSO (60 Day Sales Overdue) among all subsidiary companies for two years.


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subset: commoncrawl


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by jeffdjevdet Dollar Savings Direct Account offers an interest rate of 4.00 pc, which is among the highest you will see this season, according to the latest personal finance tips gurus. The guys behind Dollar Savings Direct are the same as the creators of Emigrant Direct, which was not a very popular service and there were inklings of security issues. The high interest rate … [Read more...]
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Fears a cat killer could be at large in Wirksworth have arisen after an unsuspecting moggy fell prey to poisoning.
When Jenna Taylor's cat Trixie showed signs of being ill on Sunday, December 7, she thought it might just be a cold. However when the two–year–old white and ginger cat hadn't perked up by the following Wednesday, she took her to the vet.
"They told me they suspected poisoning so they kept her in overnight," the office administrator said. "They then told me they believed she had been poisoned with anti-freeze that had affected her brain and they had no option but to put her to sleep."
She added: "The vet did say 'unfortunately this is not the first case we have had this week from your area'.
"It's very upsetting that someone could have done this, but also the vets bills are massive."
Jenna, who lives in Slater Crescent, Wirksworth, said a friend of hers who lives in neighbouring Bournebrook Avenue said her cat had recently come home with something in its mouth that was found to have antifreeze on it.
In February last year, the Mercury reported that six cats living in nearby King Edward Street, Wirksworth, had been poisoned within a month.
Jenna is now concerned for the safety of her remaining cat, Roxy.
"If it's been done deliberately I don't know how someone could be so cruel," she said.


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Consider the moduli space $\mathcal{M}$ of equivariant holomorphic embeddings of closed oriented Riemann surfaces into a generic quintic three-fold $X$ in $\mathbb{P}^4,$ of given degree $d \in H_2(X,L;\mathbb{Z})$ (i.e. $f_*([\Sigma])=d$) and genus $\hat g.$
Here equivariance means the following: we can write every surface (2 real dimensions) (with boundaries, possibly non-oriented) as $\Sigma = \hat\Sigma / \Omega$ where $\hat\Sigma$ is closed oriented of genus $\hat g$ and $\Omega$ is an orientation reversing involution; moreover we define $\sigma:\mathbb{P}^4 \to \mathbb{P}^4$ given by $(x_1:x_2:x_3:x_4:x_5) \mapsto (\overline{x}_2:\overline{x}_1:\overline{x}_4:\overline{x}_3:\overline{x}_5)$ and call $L$ the pointwise fixed subset of $X$ under $\sigma.$ Equivariance means $\hat f \circ \Omega = \sigma \circ \hat f$ (assuming that $f:\Sigma \to X/\sigma$ always admits a lift $\hat f:\hat \Sigma \to X$)
I'd like to know whether, for every map containing a crosscap (i.e. $\mathbb{RP}^2$) which develops a node on top of the lagrangian $L,$ this map admits another smoothing to a disk, and viceversa, thus giving a bijection between the two kinds of behavior.
A local model should be $\mathbb{P}^1\ni(u:v) \mapsto (x:y:z) \in \mathbb{P}^2$ given by $$ x= au^2, \quad y=av^2, \quad z=uv$$ which is mapped to the conic $xy-a^2z^2,$ which is real if $a^2 \in \mathbb{R}.$ This admits two different equivariant smoothings $$ \begin{aligned}[3] &a \in \mathbb{R} \quad &(u:v)& \sim (\overline{v}:\overline{u}) \quad &\text{disk} \\ &a \in \mathrm{i}\mathbb{R} \quad &(u:v)& \sim (\overline{v}:-\overline{u}) \quad &\text{crosscap}\end{aligned}$$
Does this extend to a local model for higher genera?
This is expected to hold only if $d$ contains an even ''piece'' $d_i,$ because only this can come from a trivial element in $H_1(L;\mathbb{Z})$ due to exactness in $$ H_2(X;\mathbb{Z}) \to H_2(X,L;\mathbb{Z}) \to H_1(L;\mathbb{Z})$$


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My brother Yodhi and I have registered to play doubles at the Singapore Tennis Association's SONY ERICSSON Open 2008 on 3-11 May.
The last time we played in tournament together was perhaps in the 1980s where we toured around Java for junior tournaments. As for me, the last competitive tennis I played was when Ben Metzger and I won the State of Maine 1993 high-school doubles title.
With aging and heavier (and slower!) bodies, we don't plan to win the trophy. We just want to have fun and give younger players a hard time!
After sending our DNA sample to National Geographic's Genographic Project, I found out that, based on our Y-chromosome lab analysis, my body carries a true African blood.
But why Y-chromosome? It is something which is passed directly from father to son, unchanged, from generation to generation.


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Cesarean Scar: Katie
My scar is never visible to me and is almost completly faded. My last cesarean was almost four years ago. I have a flap of skin from the 1st cesarean that covers it only to see if I look at it in the mirror. The physical scar doesn't bother me, I can touch it and look at it with no problems. It's the emotional scar that weighs heavy on my heart.
The second picture of me and my second son I can't bear to look at without crying. I have oxygen on because I was throwing up from the spinal. I can hardly see him because I was laying flat and not able to move my arms without them getting heavy and falling on me. I had to have help holding him, it wasn't a natural process. I can say though at least I have pictures. My first delivery wouldn't allow a camera into the OR so we have no pictures of his first cry, his weight check or anything else in those first moments.
Even though those emotional scars hurt I am so happy to be who I am today because of them. I would have never been an ICAN Leader had this not happened and never been able to teach so many women about birth and the amazing process it CAN be! Never would have been so happy to have a baby vaginally...naturally, I will never take that for granted.
My first picture is of my scar and of my pregnant belly too, this baby will be brought up to Mama by Mama and not by surgical staff or a doctor.


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Friday, 10 August 2012
Soul Companionate 3D Activity Software over life general
Dissimulation Mage is a 3D Activeness aggregation that was put together by Man Avery.


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- Research
- Open Access
The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases
- Brigitta E Miyamoto1 and
- Emil D Kakkis1Email author
© Miyamoto and Kakkis; licensee BioMed Central Ltd. 2011
- Received: 19 May 2011
- Accepted: 6 July 2011
- Published: 6 July 2011
Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases.
To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments.
We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment.
Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases.
- Accelerated approval
- Rare diseases
- Drug development
- Surrogate endpoint
- Clinical trials
Patients with rare diseases have had difficulty obtaining disease-specific treatments due to inadequate biotechnology investment despite the existence of promising science. The 1983 Orphan Drug Act was passed to address this problem, offering financial incentives to companies developing rare disease drugs. During the first 25 years since the passage of the Act, 1,892 drugs were given orphan designation, 326 of which have been approved [1]. While this astounding success has significantly impacted rare disease-affected patients, 95% of over 6,000 rare diseases still have no specific treatment.
Although there are numerous challenges in development of a disease treatment, the most critical is the clinical study process. By law, all drugs must undergo clinical trial testing to demonstrate safety and substantial efficacy before FDA approval. This process usually requires a Phase 3, double-blind, placebo-controlled trial, widely regarded as the "gold standard." Phase 3 trials typically assess efficacy using a measure of clinical benefit such as how a patient feels, functions, or survives [2]. For disorders with very few and variable patients or lengthy time courses or irreversible disease progression, the use of clinical measures as endpoints can make specific treatment development intractable for practical and ethical reasons.
The Accelerated Approval (AA) regulations were promulgated by FDA in 1992 to drive the development of new treatments for serious and life-threatening disorders, primarily motivated by the AIDS crisis and the slow pace of treatment development for HIV infection [3]. In HIV, monitoring death rate or complex endpoints such as hospitalization for opportunistic infections was difficult or unethical. Consequently, AA regulations allowed for drug approval based on the use of surrogate endpoints "reasonably likely to predict clinical benefit" [3] - a surrogate endpoint being a measure, such as a blood test or urine marker, believed to be indicative of a disease state and treatment effect, but not demonstrative of a direct health gain to the patient.
AA has been enormously successful at driving innovation in the development of cancer and HIV therapies during the first 16 years: 26 new chemical entity (NCE) cancer drugs have been approved, using either tumor load or progression-free survival as surrogate endpoints, and 29 HIV drugs (25 NCEs and 4 combination drugs) have gained approval using either CD4 count or viral load as endpoints [4]. In the case of HIV, using survival as an endpoint would have made drug trials too time-consuming due to the lengthy disease course, too costly due to the high number of required patients, and unethical due to the use of placebo in a lethal condition. Even more critical for the development of HIV treatment was the ability to test the complex combinations of drugs responsible for the substantial improvement in long-term outcome. Drug combination studies would have been impossible using a clinical endpoint given large patient numbers and extended study lengths, despite the fact that drug combinations are now essential to the HIV treatment process. Current HIV therapies are a prime example whereby great scientific ideas would nonetheless have led to little or no treatment success without AA access. These successes show that the AA regulatory pathway is having a profound impact on innovation in treatment development.
Rare and ultra-rare diseases have not shared in cancer and HIV's successes. Only one drug among the 73 NCEs approved under AA, agalsidase beta (Fabrazyme ®), has been used to specifically treat a rare genetic disease, Fabry [4]. Although treatments for biochemical genetic diseases, such as urea cycle disorders and phenylketonuria (PKU), have been approved through traditional FDA pathways using blood test endpoint-driven trials, the existence of regulatory precedents for approval (urea cycle drugs), substantial routine disease management history, and published study data (PKU drugs), supported the use of blood test-based endpoints [5, 6]. Most ultra-rare diseases do not have the same pre-existing body of clinical management or historical study data currently required to utilize the AA pathway. For example, during the clinical development of Aldurazyme to treat mucopolysaccharidosis I (MPS I), there was insufficient independent clinical data to support the use of the surrogate endpoint of urine glycosaminoglycan excretion to predict clinical benefit despite substantial scientific, animal, and clinical data supporting its relevance acquired in clinical trials. A second study using clinical endpoints was required for approval [7, 8]. With this essential requirement for independent clinical data, the AA pathway is virtually unavailable for novel drugs developed for untreated ultra-rare diseases.
The European Medicines Agency grants Conditional Marketing Authorization (CMA), similar to AA, to disease treatments addressing unmet medical need, including orphan diseases. Under CMA guidelines, treatments are conditionally approved on the basis of a presumed positive benefit-risk profile, and further confirmatory studies are agreed upon to establish clinical benefit. While the use of surrogate endpoints to obtain a CMA is not explicitly mentioned in legislation, industry has demonstrated a willingness to cooperate with government to make this a reality, and the necessity of collaboration between academia, government, and industry has been foreseen [9, 10]. Therefore, the use of surrogate endpoints to achieve drug approval is a pressing issue in more than one continent.
Three factors influencing the likelihood of initiation of a development program for rare disease treatment have been evaluated recently: prevalence, disease class, and scientific output. It is less than one-third as likely that a drug treating an ultra-rare disease with a very low prevalence of 0.1 to 9 per 100,000 enters the development process, as compared to a rare disease having a prevalence of 10 to 50 per 100,000 [11]. The authors interpreted their finding as an indication that additional economic incentives and initiatives are necessary to promote ultra-rare disease treatment development.
We believe improving access to the AA pathway could potentially fulfill this need. By studying the effect of increased access to AA for ultra-rare diseases of a specified disease class and having ample scientific output, our analysis isolates one of the three factors studied by the authors: prevalence. We believe that all rare diseases, even those with more limited research activity or more poorly understood, would also benefit from this increased access to the AA pathway, given that a clearer path to approval will then drive more research in more productive directions.
To identify scientifically promising disease treatments that have not translated to human approved use and which might benefit from access to the AA pathway, we searched for ultra-rare disease therapies that consistently reversed disease pathology in animal models, but had stalled in development. We uncovered numerous examples of successful treatments, and investigated the probable effect that access to AA would have on investment potential for their development. After reviewing the diseases and their underlying science, we established reasonable clinical and surrogate endpoints and devised development programs dependent on both endpoint types. We demonstrate that improved AA access could enhance ultra-rare disease treatment feasibility and investment potential by decreasing the development cost to approval, shortening the time to approval, and increasing potential investment return. We are not verifying or implying that these surrogates have been proven to be valid, nor at this time are we suggesting methods to qualify surrogates more efficiently. By highlighting and quantifying the substantial benefit to development that we observe, we hope to spur experts in this field to discuss practical and rational solutions to the challenges of qualifying surrogates as primary endpoints for pivotal clinical trials in ultra-rare diseases.
Literature search
Fifteen rare diseases with potential treatments.
Disease class
Approx. patient number
Pub. year
Lysosomal storage
i.v. α-mannosidase
i.v. glycosyl- asparaginase
i.v. PPCA
Mucopolysaccharidosis IV A (MPS IVA)
i.v. GALNS
Mucopolysaccharidosis VII (MPS VII)
i.v. β-glucuronidase
GM1 Gangliosidosis
oral chaperone N-octyl-4-epi-β-valienamine
Late Infatile Neuronal Ceroid Lipofuscinosis (LINCL)
intraventricular TPP1
Metachromatic Leukodystrophy (MLD)
intrathecal ASA
Mucopolysaccharidosis IIIA (MPS IIIA)
intra-CSF sulfamidase
Niemann-Pick B
i.v. ASM
Lysosomal Acid Lipase Deficiency
(LAL Deficiency)
i.v. mannose-6-phosphate terminated LAL
Enzyme deficiencies affecting:
Primary Hyperoxaluria
oral crystalline oxalate-decarboxylase
Skin and connective tissue
Recessive Dystrophic Epidermolysis Bullosa (RDEB)
i.d. C7
X-Linked Hypohidrotic Ectodermal Dysplasia
(X-Linked HED)
i.v. EDA1
Carb. metabolism
Congenital Disorder of Glycosylation Ib
oral mannose
Parameters used in NPV and cost to approval calculations.
Estimated cost of treatment
Sample size
Time to see effect
Sample size
Time to see effect
6 Minute Walk Test (6MWT) (meters)
6 mos
6 mos
Urinary Man2GlcNAc (mmol/mol creatinine) measured by HPLC
3 mos
6 mos
Aspartyl- glycosaminuria
6MWT (meters)
6 mos
6 mos
Urinary aspartylglucosamine (μmol/mmol creatinine)
3 mos
6 mos
6MWT (meters)
6 mos
6 mos
Urinary oligosaccharides (nmol/mg creatinine)
3 mos
6 mos
6MWT (meters)
6 mos
6 mos
Urinary keratan sulfate (ng/g creatinine)
3 mos
6 mos
6MWT (meters)
6 mos
6 mos
Urinary GAG (μg/mg creatinine)
3 mos
6 mos
GM1 Gangliosidosis
Mullen Scales of Early Learning (MSEL)
6 mos
1 yr
CSF GM1 ganglioside (pmol/ml)
3 mos
6 mos
Modified Hamburg LINCL clinical rating scale
6 mos
1 yr
CSF neurofilament protein (ng/L)
3 mos
6 mos
6 mos
1 yr
CSF sulfatide (nmol/L)
3 mos
6 mos
6 mos
1 yr
CSF MPS (heparan sulfate)
3 mos
6 mos
Niemann-Pick B
Forced vital capacity (FVC %)
6 mos
6 mos
Liver size (% change in liver size by MRI)
6 mos
6 mos
LAL Deficiency
6 mos
1.5 yrs
Liver size (% change in liver size by MRI)
6 mos
6 mos
Primary Hyperoxaluria
Renal failure
6 mos
2 yrs
Urinary oxalate (mg/1.73 m²/day)
3 mos
6 mos
6 mos
1 yr
Number of anchoring fibrils over 2 × 25 μm of lamina densa
3 mos
6 mos
X-Linked HED
Episodes of severe illness
6 mos
1 yr
First molar tooth bud presence
6 mos
6 mos
6 mos
1 yr
Antithrombin III (%)
6 mos
6 mos
Conversely, because urinary and CSF marker information is more readily available even in diseases without treatment, an attempt was made to obtain disease-specific surrogate endpoint values. Urinary and CSF markers are often presented as a "value in patients," and a "value in healthy controls." In this case, when a value in treated patients is unavailable, we estimated the ERT treatment effect to be 60% of total possible improvement. In addition, standard deviations were reduced such that the ratio of standard deviation to surrogate value was maintained as the value of the surrogate decreased. This was done because standard deviations of surrogate markers tend to decrease as heterogeneous patients are treated [13, 14]. We obtained information in this manner for α-mannosidosis [15, 16], aspartylglucosaminuria [17], galactosialidosis [18], MPS IV A [19], and GM1 gangliosidosis [20]. Urinary GAG values from the Phase 3 MPS I laronidase study [13] were used to estimate the possible effect of ERT in MPS VII. Unpublished data was used to estimate brain injury and sulfatide levels in both late infantile neuronal ceroid lipofuscinosis and metachromatic leukodystrophy. Unpublished values of mean serum pathologic substrate measured during the laronidase Phase 1/2 study obtained from Zacharon Pharmaceuticals were used to estimate treatment effect in MPS IIIA.
To test drug efficacy for Niemann-Pick B, we used % Predicted Forced Vital Capacity [13] as a clinical endpoint since impaired lung function and frequent lung infections are common in this disease. Niemann-Pick B patients experience hepatosplenomegaly which can affect breathing because the large organs infringe upon space normally inhabited by the lungs. Liver size [21] was therefore chosen as a potential surrogate endpoint.
In some diseases, clinical endpoints were chosen to reflect a severe problem faced by patients, namely, survival (LAL Deficiency [22]), renal failure (Primary Hyperoxaluria [23]), hospitalizations (RDEB [24] and X-Linked HED [25]), and episodes of thrombosis (CDG-Ib [26–30]). Surrogate endpoints were almost always chosen to relate directly to disease mechanism, and were often connected to the clinical endpoint: in Primary Hyperoxaluria, urinary oxalate [31, 32] increases risk of renal stones, which in turn raises risk of renal failure; and in Congenital Disorder of Glycosylation Ib, episodes of thrombosis are brought about by a deficiency in antithrombin III [33–36] levels. Liver size [21] was chosen as surrogate endpoint for LAL Deficiency. Number of anchoring fibrils in biopsy was chosen as surrogate endpoint for RDEB [37].
In X-linked Hypohidrotic Ectodermal Dysplasia [38], the presence of the first molar tooth bud was chosen as a surrogate endpoint. In the treated canine model [39], the appearance and number of primary teeth were unchanged from the untreated model. However, permanent teeth showed dramatic improvement. We postulated that the same phenomenon might hold true in the treatment of the human disease and chose to measure the appearance of permanent teeth. Evidence of permanent first molar tooth buds, the earliest of human permanent teeth, can be detected by X-ray as early as 6 months after birth.
Minimum and maximum sample sizes and trial lengths
In order to assure the clinical programs had sufficient safety exposure, a minimum number of patients exposed was set, particularly in the case of very low patient prevalence, or if the treatment effect is expected to be dramatic and need too few study patients. Length and sample size during Phase 3 were primarily determined by time needed to detect efficacy and sample size calculations.
Being an exploratory study, Phase 1/2 trial patient numbers were all set between 6 and 20. The small number of 6 patients was only assigned in the surrogate endpoint Phase 1/2 trial for diseases with extremely low prevalence (Aspartylglycosaminuria, MPS VII, and CDG 1b). The larger number of 20 patients was assigned to those diseases in which the clinical endpoint required over 60 patients in order to detect efficacy in the Phase 3 trial. Ample time was allotted to establish dosing and get a better sense of efficacy.
Patient numbers in Phase 3 trials were primarily determined by sample size calculations. When sample size needed was low, a minimum of 12 patients for a urinary marker, and 30 for any other surrogate or clinical marker, was set. Again, the small number of 12 was reserved for the rarest of diseases. A minimum of 6 months was chosen for a Phase 3 trial to provide adequate safety and exposure information. See Table 2 for trial times and numbers of patients.
NPV and cost to approval calculation
NPV was calculated by using a template obtained from Nature Biotechnology [40], which was then modified to account for a Phase 4 trial in surrogate endpoint development models. For simplicity, the orphan drug tax credit was omitted and no adjustment for risk was applied. Some key elements of the NPV Calculation are described below.
Preclinical cost was set at $10 M over 2 years. This figure includes the cost of development after a product is identified, and covers pharmacokinetics and toxicology studies, pilot formulation work, and minimal drug production required for an IND filing. Clinical costs were based on size and length of studies. Common per patient per year costs were based on study types. The cost of product manufacturing was built into the cost per patient number.
Since the NPV spreadsheet was designed to work in whole years, clinical trial times were averaged to the nearest whole year, rounding up at the halfway point. In order to preserve accuracy of cost prediction over rounded years, the cost estimates during actual trial lengths were spread out over the rounded trial length. Annual overhead was set at $2 M, independent of market size. It should be noted that during Phase 3 and Approval phases, annual overhead includes the cost of continuing to treat patients from previous trials in extension studies. This continued treatment is routinely done in most if not all rare disease studies. In the post-marketing phase, patents would certainly stretch out sales beyond that for orphan drug protection and change the economics. However, at the decision-making stage for investment in rare disease treatments, often no patents are available and compounds are in the public domain so the decision to invest assumes no patents were in existence. During the commercial phase, manufacturing, distribution and marketing costs were estimated at 60% of revenue, and this figure includes post-marketing commitment costs such as product support and patient registries other than the AA- related Phase 4 commitment.
Treatment cost selection
Intravenous ERT in the case of severe rare diseases was estimated at $300,000 while the cost of intrathecal ERT would approximate $200,000/year, based on current ERT costs (Table 2). Small-molecule therapy for severe diseases was estimated to be $120,000, a similar order of magnitude to miglustat for Gaucher disease type 1 treatment, at about $80,000/year. Mannose for CDG-Ib was estimated at $50,000/year. Companies were not consulted in these pricing estimates, and they are rough estimates provided only for relative comparisons.
Revenue determination
The estimated number of patients was multiplied by price of therapy in order to calculate estimated revenue. Number of patients was calculated by multiplying incidence rates and average life span. Alternatively, when patients had been directly counted, this value was multiplied by 3, and when there existed a published number of patients described in the literature, the number of reported patients was multiplied by 5 to account for underrepresentation in the literature. To estimate these values, the OMMBID and Orpha.net were searched. There is no precise and accurate way to determine market size in rare diseases.
Statistical analysis
For all determinations of sample size, a p-value of 0.05 and a power of 80% were used. When endpoint values with standard deviations for both untreated and treated patients, or untreated and control patients, were available, a two sample t-test analysis was performed [41] to calculate sample size. If the percentage of patients experiencing an event or symptom before and after treatment were given, a comparison of event rates between two independent cohorts was done [42]. The result used was the one "assuming outcome data will be analyzed prospectively by Fisher's exact-test or with a continuity corrected chi-squared test [42]." This assumption was chosen based on small clinical trial size. For some programs with surrogate endpoints, the study size estimate based on power calculations would have been too small for reasonable expectations of safety exposure, and in these cases, a minimum study size was applied.
Numerous rare diseases exist with successfully treated animal models and stalled clinical development
We searched PubMed to locate publications describing successfully treated animal models with rare disease treatments not yet approved in the US or EU. These treatments were either completely stalled in development, or are currently in the process of development, though delayed. Stem cell and gene therapy treatments were not considered due to the potential complexity of translation to humans, and instead we focused on protein or small molecule therapies. Our experiences, as well as the relative ease of treatment, led us to primarily focus on inherited disorders of metabolism. Endocrine, nutritional, and metabolic disease treatments were found to be among the most likely to have development programs initiated [11]. We identified 15 diseases having a relevant corresponding animal model, a treatment with a known mechanism, and a treatment effect which appeared to be potentially clinically relevant [26, 43–56] (Table 1). This disease selection is not intended to be an exhaustive listing of all possible successful treatments in animal models, but represents a sufficient set of examples for study.
Comparing cost of development using clinical or surrogate endpoints
In order to rigorously investigate the differences between the use of clinical and surrogate endpoints, we first identified reasonable endpoints for our 15 diseases (Table 2). We sought and obtained input from experts to help guide our choice in the determination of both types of endpoints. All endpoints, their values, expected treatment effects, and timeframe needed to detect change can be located in Table 2. Additional details on endpoint selection are in the online Methods section. Although we believe that these endpoints are reasonable, we do not imply that we have singled out the optimal ones, nor that these endpoints currently meet the qualification criteria a regulatory authority might require for use in pivotal clinical study. Our aim is to illustrate the benefit of surrogate endpoint use to demonstrate the potential value and stimulate discussion of appropriate qualification criteria.
The first clinical endpoint-based program contains a Phase 1/2 study in which pharmacokinetics and dosing are established and a first look at clinical efficacy occurs, followed by a Phase 3 study; realistic sample sizes and durations for Phase 3 trials were determined based on chosen endpoint properties and historical study sizes. Surrogate-based clinical development programs come in two forms: one surrogate-based program uses a similar 2-study sequence, and a second program uses a single study. Because a surrogate endpoint-based study requires fewer patients and less time to observe treatment effects, the time to enroll patients, treat them, and conduct analyses is shortened. In this analysis, we required a minimum study length and minimum patient enrollment to ensure the collection of sufficient safety data. The 1-study surrogate endpoint-based program has a greater risk of failure because there is less prior clinical experience, less insight into optimal drug dosing, and a lack of data to inform on the choice of endpoints and potential treatment effect size, information which would have been acquired during a Phase 1/2 trial. However, in the case of a disease with an exceptionally small patient population and a dramatic clinical or biochemical effect in the treated corresponding animal model, a single study may be the only financially or clinically viable option. Both surrogate endpoint programs include the cost of an additional 2-year post-marketing study comparable in size and cost to Phase 3, as expected under AA, whereas the clinical endpoint-based program does not. Post-marketing studies are often required even when a drug has been approved under a clinical endpoint-based program. We elected to omit this requirement in our model in order to avoid skewing financial results too favorably toward the surrogate endpoint-based programs. The net present value of a development program, an investment calculation explained below, is reduced by the addition of the cost of a post-marketing study. Our three programs represent increasingly aggressive approaches to drug development and provide us with three points on the cost spectrum.
Financial impact of surrogate versus clinical endpoint-based clinical development
Cost to approval and NPV calculations and analysis for all three clinical development programs.
Cost to approval
% Decrease in cost to approval
Net present value
Clinical (all values in millions)
Two-study surrogate
One-study surrogate
From clinical to two-study surrogate
From clinical to one-study surrogate
Two-study surrogate
One-study surrogate
Difference between clinical and one-study surrogate
GM1 Gangliosidosis
Niemann-Pick B
LAL Deficiency
Primary Hyperoxaluria
X-Linked HED
Investment value of surrogate endpoint-based programs
Net Present Value (NPV) is the dollar amount that encompasses the overall investment and return for a program, and is commonly used in industry as a tool to assess the value of investing in a program. We did not include an adjustment for the risk of failure, which would have likely skewed results even more favorably toward surrogate endpoint use, which have a greater likelihood for detecting a consistent effect and reducing NPVs in general.
NPVs increase from a mean of $23 M using a clinical endpoint design to $53 M and $72 M using a 2- and 1-study surrogate endpoint design, respectively (Table 3). The most significant gains were observed with a 1-study surrogate compared to a clinical surrogate program. Fourteen out of 15 NPVs increased by $19 M or more. Four out of nine which displayed negative values in a clinical endpoint program changed to positive. Of the remaining six NPVs, three increased by two-fold or better with the AA pathway.
Case examples
MPS VII is a lysosomal storage disease and one of the rarest of our 15 disorders, with only an estimated 200 patients in industrialized nations. The first successful demonstration of ERT in MPS VII mice showed a significant reduction in accumulation of lysosomal storage in 1994 [52] and many additional papers have since appeared demonstrating successful enzyme therapy in MPS VII animals. Three similar MPS disorders, MPS I, II, and VI, all have approved ERTs, confirming the likely success of a program for MPS VII. The diseases α-mannosidosis, aspartylglucosaminuria, and galactosialidosis are similar cases. Switching from the 6MWT to a urinary storage marker, the needed number of Phase 3 patients is reduced by at least half, a key consideration given the rarity of these diseases, and the total time for development is likely shortened since a broader spectrum of patients qualifies for enrollment. The NPV for ERT in MPS VII is negative for all three models. However, it approaches a positive value in the 1-study surrogate endpoint model.
Primary hyperoxaluria results from overproduction of urine oxalate, leading to kidney stones, loss of kidney function, and oxalosis, the deposition of calcium oxalate crystals in the organs. Mice displaying symptoms similar to primary hyperoxaluria type 1 were treated with an oxalate-degrading enzyme and exhibited histologically normal kidneys with no oxalate crystals and normal kidney filtration [57]. In order to detect efficacy by measuring rates of renal failure, the disease's most damaging feature, a two-year study enrolling approximately 183 patients selected for their particular stage of disease where renal failure is progressing would likely take a long time to enroll and conduct. In contrast, reduction of urinary oxalate is a straightforward measurement that could take as little as three months and 20 patients to detect. Far from being an unreliable marker, excessively high oxalate levels are known to directly damage kidneys. In this case, an NPV of $68 M jumps to $242 M when switching from a clinical endpoint to a 2-study surrogate endpoint model.
Recessive dystrophic epidermolysis bullosa (RDEB) is a disease caused by defects in type VII collagen protein which binds the dermis to the epidermis. Blistering and sores readily occur, open wounds are slow to heal and susceptible to infection, esophageal scarring can cause eating difficulties, and chronic inflammation increases risk of squamous cell carcinoma. Injection of type VII collagen in DEB mice corrected the disease phenotype by decreasing skin fragility, blistering, and prolonging lifespan [58]. Clinical endpoints might include the rate of hospitalizations or skin infections, though these endpoints may be confounded by varying clinical practice or quantities of supportive home care. In contrast, using a measure of skin adhesion, such as number of anchoring fibrils, or a tension test that would measure adhesion strength between dermis and epidermis, would be a more direct measure of drug effect. The NPV for type VII collagen treatment increases from -$14 M to $18 M and $33 M using the 2-study and 1-study surrogate endpoint model, respectively.
The potential benefit of surrogate markers is particularly critical in neurologic disorders. To detect efficacy of ERT in the neurological lysosomal storage diseases, LINCL, MLD, and MPS IIIA, we selected CSF markers for abnormal brain substrate storage and/or brain injury as surrogate endpoints since they should represent the direct adverse impact of storage on brain pathology. Variability in disease expression, the plasticity and complexity of the nervous system, and the indeterminate degree of irreversibility make using neurological clinical endpoints, such as development quotient, challenging. A surrogate marker of neurologic injury or substrate accumulation may provide better evidence of the biochemical effect of treatment in neurologically heterogeneous patients and be a more reliable way to assess treatment benefit.
We have located a number of potential treatments for rare genetic diseases that have yet to be translated to clinical use due to a number of barriers in development. By assessing development costs in model development programs using clinical or surrogate endpoints, we have demonstrated the potential benefit of increased accessibility to the AA pathway in obtaining rare disease drug approval. The use of surrogate endpoints brings about profound changes in cost to approval and NPV. AA accessibility potentially increases the number of drugs developed for rare diseases 3-fold for the same investment, resulting in many more diseases and patients treated in a more innovative and productive development system.
Although concern has been raised that orphan product costs are very high, and that increasing the approval rate of drugs might increase health care costs, we believe that many of these treatments could reduce some clinical care costs as well and reduce the economic impact on families. In addition, as long as development costs are extremely high, the costs of drugs will be driven to stay equally high. By controlling high development costs through improved access to AA, orphan drug cost management is more plausible, without shutting down the incentive for investment in development. In no case should it be said that blocking the development of life-saving, life-changing treatments is an ethical option to save money on healthcare.
This paper does not aim to prove the merit of the proposed surrogates, but only shows how the use of surrogate endpoints could impact investment potential. Improved access to AA depends on whether the surrogate can be shown to be "reasonably likely to predict clinical benefit" [3] by FDA standards. Biotechnology companies have encountered development difficulties because of the lack of clear qualification criteria for surrogate endpoints due to the belief that each must be evaluated on a case-by-case basis. This unpredictable process significantly hinders the initiation of development of many programs that might require a novel surrogate endpoint. As an example, the use of the surrogate endpoint of kidney biopsy to gain approval for the treatment of Fabry was initially resisted by FDA, which sought greater assurance that the pathologic surrogate was predictive of clinically meaningful benefit. The renal pathology marker for Fabry was eventually affirmed by the Metabolic and Endocrine Advisory Committee Meeting in January 2003 [59] and over time, has been shown to predict clinical outcome in a confirmatory study. Other examples exist of surrogate endpoints in rare diseases that have substantial animal model data to support them, but are rejected due to regulatory uncertainty of their ability to predict clinical outcome [7, 8]. Some uncertainty for surrogates will always exist in rare diseases with limited patient-based clinical data. The creation of a precise guidance or established criteria to support researchers, those involved in treatment development for rare diseases, and investors would help foster the effective use of appropriate surrogates and improve access to the AA pathway.
The use of surrogate endpoints poses a risk for the approval of ineffective or unexpectedly harmful treatments. This concern has heightened due to recent high profile failures of large market drugs. Some surrogates were unable to provide accurate assessments of clinical benefit or failed to capture adverse effects unrelated to the drug's mechanism of action, as in the case of cardiac arrhythmias or many other diseases [60]. For instance, encainide and fleicanide were successful in suppressing arrhythmia, with the intent of decreasing risk of sudden cardiac death, but were later found to bring about a 3-fold increase in sudden cardiac death [61]. However, such cases may not provide an applicable cautionary example of surrogate use for many life-threatening rare diseases because many rare biochemical disorders have far more relevant and direct biochemical or pathologic markers. These biomarkers are directly related to the disease pathophysiology and also to the mechanism of drug action, and so should more accurately assess whether a drug has a beneficial treatment effect. This holds true even if the ability of the endpoint to predict clinical outcome is yet unproven. It is plausible that some of these drugs may not demonstrate clinical efficacy in Phase 4, but given that the drugs should be reasonably safe through the required clinical evaluation, we believe that families will accept the possibility that the drugs' efficacy may be less than expected. To date, no rare disease drugs approved on biochemical endpoints have been withdrawn for lack of efficacy or safety issues. Our analyses do require minimum patient exposure in clinical trials to ensure a reasonable degree of safety, even if efficacy using the surrogate endpoint could be proven with smaller patient numbers.
Surrogate endpoints are not simply a convenience, but are a necessary part of the development path for some ultra-rare disorders. Surrogate endpoints may be indispensable for clinical trials when too few patients exist to conduct a large clinical endpoint-driven, double-blind trial. Diseases with substantial heterogeneity or variable irreversibility of disease symptoms, such as bone or neurologic disease, may also require surrogate endpoint-driven trials to ever have the chance to be treated. It is difficult to detect drug efficacy in treating diseases manifested by a variety of symptoms when not every patient expresses each symptom; those who are not affected in one aspect of a disease cannot, with therapy, show substantial improvement in that aspect, even if overall improvement in health is significant. It is also difficult to detect drug efficacy in treating diseases with varying levels of irreversibility, which results when a disease is diagnosed and treated after chronic tissue damage has occurred. If a patient has been permanently changed by disease, a small clinical improvement may appear to be a failure, even if the degree of improvement was the maximum possible for that patient. Surrogate endpoints may be more effective than clinical endpoints in detecting efficacy in these situations because they can indicate that the drug is having the correct metabolic reversal effect regardless of the reversibility of the accumulated clinical disease symptoms. Since patients with some diseases such as neurologic disorders are commonly diagnosed too late in their disease course for effective disease reversal, the biochemical treatment effect may be the only readily measurable benefit. Once a drug is approved, there will be a strong incentive to diagnose patients earlier in their disease course as a result of the availability of treatment [62]. Clinical benefit must then be verified over time by studying early-treated patients in post-marketing studies over several years. With these development steps using the AA pathway, a drug can be developed and the natural history of the rare disease is forever changed by the approved treatment. This development course to early rare disease management can never be initiated if the first step to treatment approval via the AA pathway is not taken.
We cannot and should not expect surrogates to accurately and quantitatively predict all clinical outcomes. The relationship between a blood or urine test and a clinical outcome will rarely be a perfect linear proportional relationship, nor can a surrogate endpoint quantitatively predict the complex interplay of severity, progression, and other clinical factors on a given clinical outcome. The surrogate can provide a clear indication that the treatment effect is occurring and that the probabilistic outcome of clinical benefit is substantially improved. A reasonable degree of predictive value and risk must be determined, based on sound science, to allow therapies to begin the path to development. Discussion between patient groups, biotechnology leaders, drug developers, and regulatory authorities is essential to develop clear criteria for rare or ultra-rare diseases, detailing necessary features of a usable surrogate endpoint that will protect patients and guide early research toward providing the needed information. Clear criteria are also essential to biotechnology companies and investors since only a high degree of certainty regarding the feasibility of a surrogate-endpoint driven pivotal study will increase the incentive to initiate development programs in many rare diseases. If a reasonable guidance were provided which defines scientifically-sound surrogates and achievable qualification criteria for the AA pathway to biotechnology companies, investors, and patients alike, rare disease drug development could potentially grow many fold as renewed biotechnology investment becomes plausible. Difficult and tragic diseases will then finally have a chance to be treated based on cutting-edge science.
By highlighting fifteen ultra-rare disease examples, we have demonstrated the existence of promising, scientifically-sound animal model therapies that have not yet been translated to the clinic. We evaluated clinical- or surrogate-based clinical development programs for these fifteen diseases and showed that the use of the AA pathway led to a decrease in cost to approval of 62%, and an increase in NPV from a mean of $23 M to $72 M. For the same biotechnology company investment, three times as many ultra-rare disease drugs could be developed with AA. Collaboration between academia, government, and industry is essential in order to set clear and practical regulatory criteria for use of AA in ultra-rare disease treatment development, accelerating the translation of science into treatments for ultra-rare disease patients.
The authors would like to thank Dr. Remco de Vrueh and Ms. Patti Engel for reviewing versions of the manuscript.
Authors' Affiliations
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- Roces DP, Lullmann-Rauch R, Peng JH, Balducci C, Andersson C, Tollersrud O, Fogh J, Orlacchio A, Beccari T, Saftig P, von Figura K: Efficacy of enzyme replacement therapy in alpha-mannosidosis mice: a preclinical animal study. Hum Mol Genet. 2004, 13: 1979-1988. 10.1093/hmg/ddh220.View ArticlePubMedGoogle Scholar
- Sands MS, Vogler C, Kyle JW, Grubb JH, Levy B, Galvin N, Sly WS, Birkenmeier EH: Enzyme Replacement Therapy for Murine Mucopolysaccharidosis Type-Vii. J Clin Invest. 1994, 93: 2324-2331. 10.1172/JCI117237.PubMed CentralView ArticlePubMedGoogle Scholar
- Savas PS, Hemsley KM, Hopwood JJ: Intracerebral injection of sulfamidase delays neuropathology in murine MPS-IIIA. Mol Genet Metab. 2004, 82: 273-285. 10.1016/j.ymgme.2004.05.005.View ArticlePubMedGoogle Scholar
- Sidhu H, Schmidt ME, Cornelius JG, Thamilselvan S, Khan SR, Hesse A, Peck AB: Direct correlation between hyperoxaluria/oxalate stone disease-and the absence of the gastrointestinal tract-dwelling bacterium Oxalobacter formigenes: Possible prevention by gut recolonization or enzyme replacement therapy. J Amer Soc Nephrol. 1999, 10: S334-S340.Google Scholar
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This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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2013 Forest River WILDCAT 293REX
Amazing rear living, lightweight camper! The 2013 Forest River Wildcat 293REX is a 31' 5th wheel that weighs in under 12,000 lbs GVWR but has all the high-end amenities - leather furniture, electric fireplace, outdoor kitchen, electric awning and tons of storage! This unit has been well-maintained - no odors, stains or tears. Super clean camper that is ideal for full-time living, highway travel or back country camping being only 31' total length.
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Constructing meaning from mentoring : the experiences of mentors and mentees.
Permanent Linkhttp://hdl.handle.net/10092/2569
Thesis DisciplineEducation
Degree GrantorUniversity of Canterbury
Degree LevelMasters
Degree NameMaster of Arts
In this thesis I explored the experiences of four pairs of mentors and mentees who were part of a mentoring programme aimed at reducing truancy. I used in-depth interviews to gain insight into the complexity of mentoring relationships within this particular setting. The central focus of this work was to understand more about the processes of the relationship that occurred between mentors and mentees and the way the experience is made sense of by them. The findings suggest that factors such as the inherent assumptions of the programme, the expectations of the mentors and the responses of the mentees impact on feelings of satisfaction for mentors and the potential for developmental growth for mentees. I used the results of this study along with the current literature as a starting point to critique the underlying assumptions of this particular programme, to question the nature of successful mentoring and to explore the usefulness of socio-cultural theory as a perspective to add to our understanding of relationship dynamics within mentoring relationships. I suggest that this programme's use of 'friendship' as a method of encouraging developmental relationships that impacted on truancy left mentors under prepared for their role and feeling confused. I draw on socio-cultural perspectives to suggest that relationship dynamics like negotiation, joint engagement and participation in activity are useful ways to encourage developmental mentoring relationships within programme settings.


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Gayle Forman
Series: Just One Day, #1
Release Date: January 8th, 2013
Publisher: Dutton Juvenile
Number of Pages: 368
Source: Bought
Rating: 4.5 stars
A breathtaking journey toward self-discovery and true love, from the author of If I Stay.Quite a few months ago, in my early reviewing days, when I was just a new face in the world of reviewing and book blogging, I read a book called Die for Me. Although it had an interesting and original premise (which, ultimately, was revealed to be poorly executed), a pretty cover, and some mixed to positive reviews from friends of mine, the main reason I really wanted to read Die for Me was because it took place in Paris, and I'd hoped that the author would take advantage of such a wonderful and rich setting. Unfortunately, the most background of Paris the author provided us readers with in Die for Me was the Metro and a few coffee shops. Maybe a lake or two. Some really great details of Paris in that book, you guys.
When sheltered American good girl Allyson "LuLu" Healey first meets laid-back Dutch actor Willem De Ruiter at an underground performance of Twelfth Night in England, there's an undeniable spark. After just one day together, that spark bursts into a flame, or so it seems to Allyson, until the following morning, when she wakes up after a whirlwind day in Paris to discover that Willem has left. Over the next year, Allyson embarks on a journey to come to terms with the narrow confines of her life, and through Shakespeare, travel, and a quest for her almost-true-love, to break free of those confines.
Just One Day is the first in a sweepingly romantic duet of novels. Willem's story—Just One Year—is coming soon!
Since then, I've been wary of books taking place in Paris. Until, however, Just One Day appeared on my feed. Written by an incredibly hyped author and receiving rave early reviews, I figured that Forman could do no wrong with the beautiful Paris.
And I was right.
I'd gone into Just One Day with expectations of heartbreak, high levels of swoon, awe-worthy prose and a strong, overwhelming desire to hop on a plane to Paris immediately. And while all of those expectations were met, and in fact exceeded, I came across quite a few surprises along the way - such as the fact that Just One Day is filled with truly hysterical passages and moments - which I don't say very often about books, especially not about books in the YA genre, considering the fact that I have the sense of humor that will have me inevitably burning in hell, and most YA novels don't cross that particular boundary to meet my sense of humor - and the fact that I'd be so engaged with Allyson and Willem's travels in such a short amount of time.
Allyson was, for the most part, an awesome and incredibly witty character, and in the end, I am definitely able to say that I enjoyed reading in her perspective and seeing her character meet such a large amount of growth throughout the course of the novel. While she did, at times, get on my nerves - most notably how she got jealous whenever a girl looked at Willem, or whenever a girl talked to Willem after knowing him for just one day
Charming, often hysterical, with some great characters, equally as great relationship dynamics, and a clever incorporation of Shakespeare, Just One Day is not a novel to be missed for anyone looking for a quick and incredibly fun read that makes you feel like you're roaming the streets of Paris. If you had asked me before reading this novel if two people can fall in love in just one day, I probably would have lectured you about the vast difference between lust and love, but after reading this novel and experiencing the relationship that is Allyson and Willem's firsthand, my opinion may have been swayed.


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Music schools » Learning Music » Learning to read music » Key Signatures
Key Signatures
Is a series of sharp symbols or flat symbols situated on the staff, specify notes that are to be frequently played. Key signature are normally written after the clef at the Starting of a line of musical notation.
The Table Below outlines the several Key Signatures you may encounter. There are several others but these are simply the basic or most common key signatures.
Common Key Signatures


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The Ancient King is an unmarked location in the Forgotten Vale in The Elder Scrolls V: Dawnguard.
Directly to the left of the Inner Sanctum is a large archway on the cliffside. Past the archway, skeletal remains can be found trapped within the rock. A crown is worn on the skeleton's head, adorned with several precious gems which can be taken. An Elven Greatsword can also be found on top of it, just out of reach of the skeleton's hand.
Notable itemsEdit
- If the scale of the crown is increased using console commands it can be seen that it is actually a soul gem holder.


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Date advertised: 19 Jan 2018
Location: Lanyon Plaza (Towers 1 & 2 (floors Ground and 5 to 11), 8 Lanyon Place
Proposal: 8 additional apartments on top 2 floors (in lieu of approved duplexes) with rooftop plant rooms and minor amendments to elevational finishes
Advertisement type: Initial
View application on NI Planning portal: http://epicpublic.planningni.gov.uk/publicaccess/applicationDetails.do?activeTab=summary&keyVal=P289E3SV30000


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Samsung unveils Tocco Ultra Edition
Mobile phone manufacturer Samsung has lifted the lid on its latest handset, the Tocco Ultra Edition.
The new phone, which will be Samsung's flagship product for 2009, carries the model number S8300 and features an eight mega-pixel camera, a wide range of video support and editing features and high-speed internet access.
It also has the space for a 16Gb external memory card and has a full touchscreen.
Samsung claimed it was looking to build on the success of the original Tocco, which was the best selling contract handset in the UK during the second half of last year.
"After the monumental achievements in 2008, we're looking forward to the Tocco Ultra Edition driving our business forward and showcasing our leading credentials for style and innovation," commented Mark Mitchinson, SamsungMobile UK and Ireland's vice-president.
Samsung is the world's second most popular mobile phone manufacturer, according to ABI Research, with a 16.2 per cent share of the marketplace.


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Libraries NI has announced plans to consult on reducing opening hours in its 14 busiest libraries, including Central Library at Foyle Street.
A public consultation is being held until July 17 to identify the most suitable pattern of hours in the libraries concerned. It is proposed that opening hours will be reduced from 54 and 50 hours to 45 hours accordingly,to help meet current budget demands. The new hours will be implemented in November.
For the consultation, people are invited to complete a questionnaire which can be accessed at any of the 14 libraries affected or online at www.librariesni.org.uk
Chief Executive Irene Knox said it was not an ideal situation, but plans had to be made to budget for the year ahead.


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Celebrity tastes, their choices, and preferences have always the eyes of the fans. Many aspire to live just the way their favorite celebs live and would love to experience the same lifestyle as their favorite superstar.
In this case, celebrity outfits and accessories are always on the leading edge of fashion fads. One of the most powerful female trendsetters is Madonna with her unique style and accessory choices. Let's look closely at Madonna's favorite handbag designers and which purses she favors and why.
Madonna's Gucci Handbag
Madonna's number one favorite handbag choice is Gucci. Lately, she has been seen with a large handbag from Gucci's Fall 2016 runway collection. It's a cool combination of comfy/cozy material with a touch of graffiti font to accent the purse. She had this piece before it appeared in stores. This bag is great for women – you can throw every necessity in there. However, this is not the only Gucci handbag she dons while out and about.
Madonna's Louis Vuitton Handbag
Another popular handbag designer among stylish women is Louis Vuitton. Madonna likes to rock a posh Louis Vuitton handbag. Not that we blame her – who wouldn't? And why do celebrities appreciate this brand so much? It's probably because Louis Vuitton is the epitome of quality and elegance. Madonna's Louis Vuitton handbag below is comprised of red and gray shades, which create an eye-catching look with the signature "LV" logo.
Madonna's 'Dealer' Handbag
Everybody's been speaking about Madonna's passion towards one of her newer purses. It's the sophisticated 'dealer' handbag that captures so many hearts with its classy look and feel. A swanky black crocodile handbag, this one stands out with its metallic elements and the word 'dealer' placed in the very center of the bag. It's been seen with many other celebrities too.
Madonna's Ralph Lauren Ricky Handbag
Another large and convenient handbag from Madonna's fancy wardrobe is the Ralph Lauren Ricky bag. She recently carried this oversized version of the Ricky through JFK airport. Her personal style seems to sway between "cozy" and "classy" designer bags.
Madonna's Louis Vuitton Mahina Handbag
The Mahina handbag is another cool accessory by Louis Vuitton's posh collection. This is a classic hobo-style bag which matches with her blonde hair and light complexion. This black handbag suits her style, complexion and overall appearance.
Madonna's Miss Sicily Handbag
Keeping up with the 'black is elegant' concept, Madonna carries the black crochet Miss Sicily bag. It's an elegant and polished option with gold-shaded elements which break down the monotone effect of the black color. It flatters her classy outfits and the rest of her accessories.
Madonna's Chanel Bag
The list would be incomplete without a luxurious and opulent handbag from Chanel's collection. Here you see Madonna's picture where she auctions off her cute Chanel Purse. It's really one of her best handbags with such dainty chains and soft alligator leather. It's known as Chanel diamond forever handbag studded with 334 diamonds was the purse she carried to the event. The final winning bid was 300,000 euros.


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How incredibly fantastic is that? It's so amazing that there aren't enough words to describe it.
For you, this could be happening like I said before in a creative sense or just in way that is completely out of the ordinary, yet also quite amazing.
I myself, find myself creating & co-creating new concoctions on an on-going basis, lately. Who knew a dark roast coffee could be mixed with a de-caff and be just as low in caffeine as a straight de-caff?!
I know it's a mind-blower.
Or that when you buy something for yourself but it ends up someone else needs it more than you do, so you give it to them and on it goes. This is due to the fact that the moon is going to be sitting in the artistic, community minded sign of Aquarius.
Life at the moment seems, like it is really one big spontaneous accident played out to be like a well thought out plot, with every detail thoroughly well investigated.
This is what gives the creative person their drive, what motivates them to move beyond the status quo of what is the general consensus or the norm. Because they know that it isn't like that, it really is how you want to make it. To have the ability to create things no one would ever dream in a million years, and have the imagination and ability to do so. That is the goal. To bring lasting change for the better in whatever outlet prevails.
This is what I want for my country to realize, too. When the door closes and it's time to decide in the fall, are they going to be too afraid to upset the apple cart for fear of trying something new. Only to postpone the inevitable. I certainly hope not. Life is too precious.


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Scrap Car West Heath, Scrap your car for free
Scrap Car West Heath will collect your car for free in West Heath, London. Got an old scrap car then you will still be expected to keep the vehicle taxed if your vehicle is still on the road, even if you are not actually driving the vehicle. Don't pay to have your old vehicle collected We will collect your old scrap car at no cost to you at all in West Heath.
West Heath - Breaking News
As well as offering a completely free collection, we are also currently able to offer cash for scrap cars in West Heath depending upon the weight of the vehicle!
If you'd like us to make you an offer just ask when calling or add 'CASH QUOTE PLEASE' in the 'Additional Info' box when submitting our online form.
- Environment agency approved recycling facilities
- Nationwide coverage
- Convenient collection times
- DVLA notification
- Completely free collection!
Why not simply fill out the form to the right or ring a member of the team 0800 043 5100!
Choose Scrap Car West Heath
Here at Scrap Car West Heath we have many happy customers and considering we have been trading for a while now we are still going strong. We know the area so well we can be out to you within 30 minutes. At Scrap Car West Heath, our service also includes a very fast response and we will always be with you in your specified time slot. We are able to collect vehicles day or night, seven days a week, even on bank holidays, and we will work round you.
Scrap Car West Heath service is second to none we always dispose of cars in the right way. A lot of companies out there will sell on your scrap car and not even notify the DVLA that the vehicle is no longer yours. This can result and usually does in you being fined. We will take away your old car in West Heath and ensure that the DVLA are aware that the vehicle has been scrapped and you are no longer the owner. Whenever we scrap a car we always recycle or reuse whatever we can, meaning we are doing our bit for the environment.
Ensuring that your car is disposed of correctly will in time make a difference to London in terms of keeping it clean and tidy. If your area looks unsightly due to abandoned cars, we can help, call Scrap Car West Heath, we will help keep our streets clean and tidy. Scrap that old car, call today!
The car scrappage scheme
The car scrappage scheme may seem like a splendid idea at first. However, you might be surprised to learn that this discount is not available on every car. You can't just go out and purchase any vehicle you want This can cause people a lot of misery as you might have your heart set on a particular car only to be told that, "the vehicle is not in the scrappage scheme".
How to scrap your car
It is very easy to scrap your car in West Heath. Just by picking up the phone you can be told the process by our members of staff. Otherwise please feel free to browse our website and find as much information as you can before you call.
Reasons to scrap your car
There are a lot of different reasons for wanting to dispose of an old car. The main reason in our experience is that the car is beyond repair, it will be cheaper to buy a new one. If you have a car that is unusable you need to either declare it off road or scrap it, otherwise your will continue to need to pay road tax on the vehicle.
Just call us on 0800 043 5100 or fill out the following form:


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Chicken, shrimp and pineapple kebabs2014-09-12
- Cuisine: Portuguese
- Skill Level: Easy
- Servings : 4
- Prep Time : 15m
- Cook Time : 20m
- Ready In : 1:05 h
This is a simple and perfect recipe for a Summer lunch among friends! Chicken kebabs with the delicious shrimp and pineapple combination… Try it your friends will love it…
Units: Metric (Units: US)
- 2 chicken breasts (about 700 grams (1 1/2 pounds))
- Juice of half a lemon
- Pepper (to taste)
- 1 tablespoon honey
- 12 shrimps
- 4 pineapple slices (about 200 grams (7 ounces))
- A drizzle of olive oil
- 1 small onion
- 1 bunch of coriander
- Thyme (to taste)
- Salt (to taste)
Step 1
- Put the shrimps in a saucepan with water seasoned with a bunch of coriander and the peeled onion. Boil over high heat. When starts boiling, reduce to low heat and coke the shrimps about 4 to 5 minutes. When the shrimps are cooked, drain them with a skimmer and let cool slightly. Peel them and set aside.
Step 2
- Cut the chicken breasts into pieces and put them on a plate together with the shrimps. Season with a little salt, lemon juice, pepper, thyme and honey. Let marinate about 30 minutes.
Step 3
- Put alternately the chicken pieces, the shrimp and the pineapple cut into chunks on wooden skewers. Heat over low heat a skillet with a drizzle of olive oil. When the oil is hot enough, add the kebabs and fry them until they start to turn golden brown.
Step 4
- Sprinkle the kebabs with some thyme and serve immediately.


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1. Food is always on her mind.
2. Seriously.
3. She's got her priorities straight.
4. She's a fangirl just like you.
5. She freaks out when she meets other celebs.
6. She's a total goofball.
7. She takes the best selfies.
8. She knows her Mean Girls.
9. She gives great advice.
10. She's a classy lady.
11. She's a master of photobombing.
12. Sometimes she doesn't have a word filter.
13. And when she does it's adorable.
14. She makes the best facial expressions.
15. And they probably match yours.
16. She gets easily distracted.
17. She's a total homebody.
18. She's refreshingly honest and real.
19. And she isn't afraid to admit her flaws.
20. She's pretty much the best person ever.
This post was created by a member of BuzzFeed Community, where anyone can post awesome lists and creations. Learn more or post your buzz!


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The Women's Organisation is the largest developer and deliverer of instruction and help for women in the UK. We deliver services locally in Merseyside and Greater Manchester, with a reach across the North West and provide projects across the planet. Description: The women's services and resource center provides education to the BYU campus and community on women's problems to develop a safe, inviting place for women to come where they can locate assistance, expertise, and strength to meet the challenges facing girls these days and to provide ladies with opportunities to serve other girls.
Our vision is to inspire females to lead and we seek to empower those ladies through education to accomplish their greatest leadership prospective and enrich their communities. Notable applications include a little company incubator system in Senegal, a national obesity abatement initiative, and a partnership with women's organizations in Benin. Description: Aspiring Mormon Women's broad objective is to encourage, assistance, and celebrate the educational and skilled aspirations of LDS women. Their main aim is to enable ladies and girls to attain social and economic empowerment.
While earning a living for their families women started to understand that two incomes in the residence allowed for further spending and economic freedom. Females could join through undergraduate chapters at a college or university or they could also join by way of a graduate chapter right after acquiring an undergraduate or advanced college degree. Catalyst is a nonprofit organization that expands possibilities for ladies in business.
AWNY 's mission is to empower ladies in the advertising business to obtain private and specialist fulfillment at every single stage of their careers. We are here to assistance regional organization females and give them the chance to network with other folks in the community. Description: The WBN mission is to empower professional females by advertising enterprise connections, encouraging diverse personal and skilled networks, and offering improvement possibilities. SWE permits ladies to come into get in touch with with distinct businesses, expand their network and establish connections with other females. Description: Produce awareness and offer education relating to girls in company.
Description: The mission of the South Utah County Ladies in Enterprise is devoted to advancing the good results of enterprising girls by providing a platform on which their distinct concerns and challenges can be address proactively. Description: The Females in Organization of Murray was formed to empower specialist women by promoting organization connections, encouraging diverse private and professional networks, and supplying improvement possibilities. Description: The mission of Females in Enterprise is to help the functions and activities of the Ogden/Weber Region Chamber of Commerce. An organization for women whose businesses annually gross more than $two million.


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That's what I discovered when I first started learning the program. Since then I've made it a point to demystify the coloring process for students who have little to no experience with it. Take this demonstration for example. It was created last year while teaching at California State University Northridge.
From the initial digitized concept sketch drawn in black line and embellished with blue pencil I punched the overlapping shadows with a transparent gray.
Next I rendered the image in layers of transparent grays to establish tonal relationships.
While working in transparent layers I tinted the composition with color.
In no time at all I made pretty good progress. I had the option to continue but decided to leave it at this state of development. I was able to communicate I simple method of digital illustration to the class resulting in something that I could share on my blog a year and half later.


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I spent much of today either in class or having incredibly enjoyable competitions with a variety of board games. Because of this unfortunately I don't have the time or energy to really discuss anything. Tomorrow will either be a very rousing discussion of dinosaurs or the renaissance. Either way it is sexy stuff and I hope to see you all there (or here depending on when you read this).
Though on a closing thought, board games remind me of a time when game design was functional and pleasant. It's a shame that video games have lost that dichotomy.


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Get it all at Hall's
Hall's Carpet Inc. specializes in helping the end user of any application get the right product, install it properly and at the best price. We carry that approach in all of our divisions.
We have helped make thousands of homes like yours, look even more beautiful. Our Flooring Department continues to offer the price and service that have kept us in business for over 30 years!
Our work can also be seen on current Broadway show stages and several off- Broadway productions as well. Hall's installers are mill certified and proud of their skills.
Our Event Services Division continues to lead the way in providing world class commitment to a perfect party every time.
We offer free product consulting, as well as free maintenance and installation information.