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Q: Solid State Relay/High Voltage Switch unacceptable transient behavior I am using a whole array of IXYS CPC7524 high-voltage switches in one of my designs. Although the design of this specific switch is not made explicit, its characteristics and other products in the IXYS product line (such as the CPC1511) leads me to believe that the pass elements are quite probably pass NMOS devices with additional thermal protection circuitry.
The application requires fast switching of voltage/current across the switches (which remain constantly turned on) and we are getting very problematic behavior out of them. This conceptual schematic shows how the switches are being used:

simulate this circuit – Schematic created using CircuitLab
Q1 is used as a saturated switch and M1 as a current source. The slew rate in all nodes was measured and it never exceeds 100V/µs (the CPC7524 is specified in excess of 1500V/µs), however this is what we see on those nodes (everything is turned off after 600µs from the trigger):

Which clearly shows the switches enter a high-impedance state as soon as the NFET turns on, and takes as much as 250µs to reduce their impedance to the point the circuitry becomes properly biased (the chatter in the Drain node (CH1_R) shows instability due to the gain provided by the presence of the switch impedance).
In other scenarios (e.g., higher voltage or a shorter delay before NFET turn-on), the switches simply latch-up a temperature fault (an undocumented behavior) and open the circuitry requiring a power-cycle.

NOTE 1: this is a conceptual schematic. The details of the application are not very relevant. Suffice it to say that I need something that behaves just as a physical and slow mechanical switch or relay, connecting two sides of a circuit that has large fast-varying waveforms. Not a dynamically varying resistor, which is what I am getting with these switches.
NOTE 2: This is implemented in several interconnected PCBs with high-voltage edge-card connectors. We investigated all possibilities (including the possibility of inductive coupling between nearby traces) before narrowing down the problem to the switches. So yes, we are 100% certain the switches are the problem. And we understand the problem well enough to get the switches to predictably misbehave at will. The rest of the circuitry works exactly as designed.

Question
As these switches are clearly not acceptable for our application, before we undergo a redesign using large, cumbersome, and power hungry reed relays (note there are large numbers of these switches), does anyone know if a simpler Solid-State Relay, such as the Vishay VOR2142A8 would present the same kind of problems?
Can anyone suggest a better solution?

A: We went ahead with a test board to verify if the Vishay SSRs (Vishay VOR1142B4) would work for our application. The short answer is yes, they do. These do not show any of the problems of the IXYS CPC7524 which suggests that the problem with those switches is the protection circuitry removing the bias during relatively slow transient conditions.
As can be seen in the following figure, without a load, both sides of the switch are undistinguishable from each other (the two traces are on top of each other), which was not the case with the previous switches.

The following is a figure that shows a similar test condition as indicated in the question above (only the critical traces shown, as other tests confirm the 400pF parasitic capacitance on the nodes and the traces across the switch are nearly indistinguishable from each other with a quite consistent and constant 22Ω series resistance).

Note that the voltage at CH1 reaches the feedback condition almost instantaneously on turn-on with no chatter or other issues, however other circuit imperfections mostly due to parasitic capacitances across M1 have now come to light.
This comes to confirm that old adage of "simpler is better."


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The Chronicle's View: If you tell them, they will vote
Sophia Lingos saw a need and mobilized her troops to fill it.
Kudos to Lingos, director of the Associated Students of the University of Utah's Communications Board, and her "street force," who, together, worked tirelessly to publicize ASUU elections.
Lingos knew of poor voter turnout in past ASUU elections and set a goal to increase the number of voters by 5 percent, which amounts to approximately 1,400 students. This is a fairly significant goal, especially taking into consideration the U's tradition of student apathy when it comes to ASUU.
The efforts of the Communications Board are hard to miss. You've seen the T-shirts, the banners and balloons. Marriott Library even approved placing stickers on its computers to remind students to vote online.
It is refreshing to see someone who realizes there is a problem, but does not simply give in to the all-to-common excuses, such as, "This is a commuter campus-nobody cares about what goes on." It's easy to assume that, because students have not cared in the past, they will not care now or in the future.
But a new, innovative approach to publicizing student elections has proven effective. In the ASUU primary elections held this week, 5983 students cast their votes. The communications board did, indeed, meet its goal-and then some. Last year, 13 percent of the student body voted in the elections-a new voting record. The tally at the end of the primary elections alone amounts to more than 20 percent of registered students.
But the elections aren't over yet. Final elections take place next week. Students now have the responsibility to study the issues and determine which candidates most closely represent their needs and wants. A $1 million budget is significant-students ought to know how and where their money is spent, and voting in the ASUU final elections the first step in the process.
An increased voter turnout also empowers student leaders. To know that more of the student body is aware of your platform and voices their support breeds greater confidence, but also a greater responsibility to represent the needs of the U constituency.
Whatever happens at the end of the ASUU elections, Lingos and the rest of her board should know that they have set a new standard in reaching out to U students and encouraging them to choose their elected representatives.
And the winners should move ahead, ready to implement their platform, eager to represent both those who supported them during the elections and the rest of the student body who, unfortunately, don't seem to care.
Sundance 2023: 'Iron Butterfiles': A Thought-Provoking Look at Russian War Crimes
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Q: Simple endomorphisms and irreducibility of the minimal polynomial Let $E$ be a finite dimensional vector space over a field $K$. We say that an endomorphism $u:E\rightarrow E$ is simple if and only if the only subspaces of $E$ that are stable by $u$ are $\{0\}$ and $E$.
Let us denote by $\chi_u$ and by $\mu_u$ respectively the characteristic and the minimal polynomials of $u$.

1) Prove that if $u$ is simple, then $\mu_u = \chi_u$.
  2) Prove that $u$ is simple if and only if $\mu_u$ is irreducible over $K$.

I was able to prove 1) by considering the subspace $\operatorname{Span}(x,u(x),\ldots ,u^{d-1}(x))$ of $E$ where $d$ is the degree of $\mu_u$ and $x$ is any nonzero vector of $E$.
I could also prove the direct implication of 2). If $u$ is simple and $\mu_u$ is written as a product of two polynomials $AB$, then the kernels and images of $A(u)$ and of $B(u)$ are stable by $u$, so must be either $\{0\}$ either the whole space $E$. It follows that $A(u)$ and $B(u)$ either are $0$, either are invertible. Because $AB(u)=0$, we then see that $\mu_u$ must divide $A$ or $B$, so that it is irreducible.
However, I have some doubts about the reverse implication. I suspect it may not be true. Have a look at the following conter-example. Take $E = \mathbb R^4$ with its usual basis $e=(e_1,e_2,e_3,e_4)$. Consider the endomorphism $u$ having matrix representation
$$
\operatorname{Mat}_e(u)=
\left[ {\begin{array}{cccc}
0 & 0 & 0 & -1\\
0 & 0 & -1 & 0\\
0 & 1 & 0 & 0\\
1 & 0 & 0 & 0
\end{array} } \right]
$$
The minimal polynomial of $u$ is $X^2+1$ which is irreducible over $\mathbb R$. However, the subspace $\operatorname{Span}(e_1,e_4)$ is stable by $u$ since $u(e_1)=e_4$ and $u(e_4)=-e_1$.
Unless I am mistaken somewhere, there must be an error in this exercise. However, I couldn't come up with a correction for it. Would somebody know another characterization of simple endomorphisms ?
Thank you very much.

redpajama_set_name: RedPajamaStackExchange


Niemann-Pick disease Type C (NP-C) is a lysosomal lipid storage disorder characterized by progressive neurodegenerative symptomatology. The signs and symptoms of NP-C vary with age at disease onset, and available therapies are directed at alleviating symptoms and stabilizing disease progression. We report the characteristics and factors related to disease progression, and analyze the effect of miglustat treatment on disease progression and patient survival using NP-C disability scales.
This retrospective, observational chart review included patients with NP-C from five expert NP-C centers. Patient disability scores were recorded using three published NP-C disability scales, and a unified disability scale was developed to allow comparison of data from each scale. Disease progression was represented by scores on the unified NP-C disability scale. Patients were stratified as infantile (< 4 years), juvenile (≥ 4 − < 16 years), and adult (≥ 16 years) based on age at diagnosis, and treated ≥1 year and non-treated/treated < 1 year based on the duration of miglustat treatment.
The analysis included 63 patients; the majority (61.9%) were on miglustat therapy for ≥1 year. Ataxia and clumsiness/frequent fall were the most common neurologic symptoms across age groups, whereas, hypotonia and delayed developmental milestones were specific to infantile patients. In both infantile and juvenile patients, visceral signs preceded diagnosis and neurologic signs were noted at or shortly after diagnosis. Adult patients presented with a range of visceral, neurologic, and psychiatric signs in years preceding diagnosis. Patients on miglustat therapy for ≥1 year had a lower mean annual disease progression compared with those untreated/treated < 1 year (1.32 vs 3.54 points/year). A significant reduction in annual disease progression in infantile patients, and a trend towards reduced disease progression in juvenile patients after ≥1 year of miglustat treatment, translated into higher age at last contact or death in these groups.
The type and onset of symptoms varied across age groups and were consistent with descriptions of NP-C within the literature. Miglustat treatment was associated with a reduced rate of disability score worsening in infantile and juvenile patients, both in agreement with increased age at last contact.
Niemann-Pick disease Type C (NP-C) is a rare, fatal, autosomal recessive, lysosomal lipid storage disease characterized by progressive neurodegenerative symptomatology [1–3]. The incidence of NP-C is estimated to range between 1:100,000 and 1:150,000 live births or to be as low as 1:89,229 conceptions [3–5] and is caused by mutations in either the NPC1 gene, which accounts for 95% of cases, or the NPC2 gene [1, 6, 7].
The age of onset of NP-C can range from the perinatal period to adulthood, with symptomatology varying with age of onset. Early-onset NP-C tends to be more severe and rapidly progressive than adult-onset NP-C [3, 7]. Patients who develop NP-C during early infancy often present with visceral manifestations such as splenomegaly, hepatomegaly, and cholestasis, with varying degrees of neurologic signs and symptoms including delayed developmental milestones, hypotonia, and dystonia [8, 9]. In adolescence or adulthood, patients tend to present with varying combinations of progressive neurologic deficits such as ataxia, dystonia, and/or dementia or major psychiatric illness . Vertical supranuclear saccade palsy/vertical supranuclear gaze palsy (VSGP) is the most common neurologic symptom, and is often overlooked during the initial differential diagnosis .
The diagnosis of NP-C is often challenging, owing to the heterogeneous and nonspecific clinical presentation of patients with NP-C. This may result in substantial diagnostic delays, with a mean delay of 4.1 years from onset of neurologic symptoms reported [1, 10, 11]. Currently there is no cure for NP-C, and the therapies are directed to alleviate symptoms of the disease . Miglustat (Zavesca®, Actelion Pharmaceuticals Ltd.) is currently the only therapy available to treat the neurologic manifestations of NP-C and is approved in several countries in Asia, Europe, Middle East, North America, Oceania, and South America. Miglustat has been shown to delay or stabilize the disease course of NP-C [11–14]. Several observational studies have utilized disease-specific disability scales for patients with NP-C. These scales offer objective and semi-quantitative assessment of disease progression and responses to therapy, and provide additional evidence for the benefits of miglustat treatment [13–17].
Here we report data from an observational, retrospective chart review conducted to identify characteristics and factors related to disease progression and assess the effect of miglustat treatment on the rate of disease progression and patient survival using NP-C disability scales [14, 15, 17].
This was a retrospective, international, multicenter, observational chart review of data collected between February 2016 and December 2016 from five expert NP-C centers providing miglustat treatment, in the Czech Republic, Iran, Slovakia (two centers), and Spain. The participating site or physician was responsible for obtaining ethical approval. Informed consent was obtained from either the patient or their parents/legal guardians, according to local laws. Eligible patients had a confirmed diagnosis of NP-C by either classical filipin staining with or without two known pathogenic NPC mutations; variant filipin staining with two confirmed known pathogenic NPC mutations; or two confirmed known pathogenic NPC mutations. Patients with lysosomal storage diseases or enzyme deficiency diseases other than NP-C, and a variant filipin staining without confirmatory genetic diagnosis of NP-C by two confirmed known NPC mutations, were excluded from the study.
In this retrospective chart review, patient identification was anonymized for all persons involved in analysis and review of the data, including the participating investigators and the sponsor. Data were collected using a web-based electronic data capture (EDC) system, which was exported into SAS® (SAS Institute Inc., Cary, NC) for analysis. Data collection included demographics, disability scale and scores, medical history, NP-C diagnosis, onset date of signs and symptoms, and treatment history including miglustat treatment exposure. If necessary, and in agreement with the investigators, additional data were retrieved retrospectively from patient records.
Our primary objective was to analyze disease progression, represented by scores on a unified NP-C disability scale (or appropriately mapped scores), in patients diagnosed with NP-C, to assess the effect of miglustat treatment over time for different clinical forms of NP-C defined by age of diagnosis. Other objectives were to identify characteristics and factors related to disease progression and survival, and conduct a retrospective comparison of miglustat treatment with pre-miglustat, where data were available.
Patient disability scores were recorded using one of 3 NP-C disability scales: the Iturriaga et al. 4-domain NP-C disability scale , the Pineda et al. 6-domain NP-C disability scale , and the Fecarotta et al. 6-domain NP-C severity rating scale . For simplicity, we refer to each scale by its first named author. In order to allow comparison of data from each scale, a unified NP-C disability scale was produced for mapping domains and scores from the Iturriaga, Pineda, and Fecarotta scales (Additional file 1: Table S1). Harmonization of data was in concordance with authors and best clinical practice. The unified NP-C disability scale consists of the following 6-domains: Ambulation, Manipulation, Language, Swallowing, Seizures, and Ocular movements. The unique domains (Dystonia, Developmental delay/cognitive impairment) from either the Iturriaga or the Fecarotta scale were omitted. A score of 1 on the Iturriaga scale and not applicable (n/a) on the Pineda scale were recorded as '0' (normal, absence of abnormalities) on the unified scale. Two domains (Seizures and Ocular movements) that are part of the unified scale but not included in the Iturriaga scale were imputed from patient medical records using the Last Observation Carried Forward method and coherence rules. Imputation was also used to create additional timepoints for patients who had only one recorded visit where a disability scale had been used. Additional timepoints were imputed from medical records into disability scale scores, allowing disease progression to be monitored. A conservative approach to imputing symptoms (using the lowest quantitative score in the 6-domain disability scale) was selected to prevent overestimating the scores (Additional file 1: Table S2).
Disease progression (disability scale increase/year) was assessed using quantitative statistics. Patients were stratified by age at diagnosis according to previously published age categories: infantile (< 4 years), juvenile (≥ 4 − < 16 years), and adult (≥ 16 years) [8, 9]. Patients were also categorized based on the duration (defined by the sum of all) of miglustat treatment into non-treated and treated for < 1 year (herein referred to as control) and treated for ≥1 year (herein referred to as treated). One year was selected as the cut-off for the control cohort, as it may take up to 1 year to see a treatment effect following initiation of miglustat therapy [7, 18]. Two timepoints were defined. The baseline visit was defined as the first assessment post-diagnosis in both the control and treated groups. The last visit was defined as the last assessment post-diagnosis in the control group and the last assessment post-diagnosis and post-treatment initiation in the treated group.
The analysis population comprised all patients included in the database. Numerical variables in demographics and baseline characteristics were based on descriptive statistics. Annual progression was defined as the change from baseline to last visit divided by the number of years. Annual progression, absolute values, and changes from baseline values were analyzed by descriptive statistics. For patient disposition, descriptive statistics for first event, diagnosis, miglustat treatment initiation, last contact, and death were reported. First event was defined as the date of first sign or symptom (either neurologic, visceral, or psychiatric) included in the unified disability scale. Population survival was calculated as time from date of diagnosis to last contact or death. A linear regression model was used to assess the effect of miglustat treatment on the disease progression rate. The relationship between disability scores and time (time from the first sign or symptom) was determined, and the resulting linear equation estimates, standard error, 95% confidence interval (CI), and p-values were derived.
A total of 63 patients were included in this retrospective analysis. Based on age at diagnosis, patients were categorized into infantile (n = 18), juvenile (n = 22), and adult (n = 23) groups. The mean (standard deviation [SD]) time between first neurologic symptoms and miglustat therapy was 4.71 (6.05) years; mean (SD) time between diagnosis and miglustat treatment was 1.91 (3.19) years. The majority of patients (82.5%) received miglustat treatment, and 61.9% of patients received miglustat for more than 1 year (Table 1). The median (range) duration of miglustat treatment was 2.89 (0.01–9.7) years overall and 0.16 (0.01–1.0) years for patients who received miglustat treatment for < 1 year.
There was a lag between the mean (SD) age at neurologic onset (10.72 [8.83] years) and age at diagnosis (13.93 [11.23] years); this period was prolonged among adult-onset patients compared with infantile- and juvenile-onset groups (Table 1). Qualitative description of first event, NP-C diagnosis, miglustat treatment initiation, last contact, and death for individual patients is presented in Fig. 1. Overall, 13 patients died during the study period. Causes of death included respiratory infection (n = 6), aspiration pneumonia (n = 2), pneumonia and entering a vegetative state (n = 2), septicemia (n = 2), and failure of acid-base homeostasis (n = 1).
The time between onset of symptoms and diagnosis varied across the age groups. In the infantile group, the mean (SD) age of diagnosis was 2.15 (1.10) years and the most common (≥ 50%) visceral symptoms were splenomegaly and hepatomegaly, whereas the most common neurologic symptoms were clumsiness/frequent falls, ataxia, hypotonia, and delayed developmental milestones (Fig. 2). Patients in the juvenile group were diagnosed at a mean (SD) age of 10.97 (3.82) years; the most common neurologic symptoms were VSGP, clumsiness/frequent falls, ataxia, dysarthria/dysphagia, and seizures. Visceral symptoms were still apparent in many patients, and psychiatric symptoms (cognitive decline) were more common than in infantile patients (Fig. 2). Adult patients were diagnosed at a mean (SD) age of 25.98 (8.15) years, and presented with similar symptoms as observed in the juvenile group, but with a higher frequency of psychotic symptoms (Fig. 2).
In infantile patients, visceral signs that include hepatosplenomegaly, direct bilirubinemia, and jaundice typically preceded diagnosis, as well as delayed developmental milestones. However, other neurologic signs such as ataxia, clumsiness/frequent falls, or spasticity were typically noted around or shortly after the time of diagnosis (Fig. 3a and Additional file 1: Table S3). The pattern of presenting symptoms was similar in juvenile patients, albeit with a longer period between onset of visceral symptoms and eventual diagnosis. Neurologic signs were again noted at, or shortly after, the date of diagnosis, in addition to psychiatric manifestations in some patients (Fig. 3b and Additional file 1: Table S3). Patients with NP-C diagnosed in the adult period typically presented with a variety of visceral, neurologic, and psychiatric signs in the years/decades preceding diagnosis (Fig. 3c and Additional file 1: Table S3).
Mean (SD) annual disease progression from baseline to last visit was higher in control patients (3.54 [3.36] points/year) than in treated patients (1.32 [1.15] points/year), though this difference was not statistically significant (Fig. 4). The domains that showed the largest difference in mean progression (disability scale points/year) between treated and control patients were ambulation (0.64), swallowing (0.47), manipulation (0.46), and language (0.43). The progression of ocular movements (0.13) and seizures (0.09) was less affected by miglustat treatment.
Linear regression analysis was used to further assess miglustat treatment effect on disease progression (Fig. 5). Disease progression was significantly (p < 0.001) reduced with miglustat treatment in infantile patients compared with the age-matched control group (increase in annual disability score [95% CI]: 2.06 [1.70–2.43] and 4.97 [3.48–6.46], respectively; Fig. 5). In juvenile patients, a clear trend towards reduced disease progression with miglustat treatment compared with the control group was observed, although this was not significant (increase in annual disability score [95% CI]: 0.34 [0.16–0.51] and 0.78 [0.50–1.06], respectively; Fig. 5). In the adult group, the difference with miglustat treatment compared with control was not significant (increase in annual disability score [95% CI]: 0.371 [0.27–0.48] and 0.374 [0.14–0.61], respectively).
Population survival by age at last contact or death showed a reduction/delay in mortality in treated infantile patients (p = 0.031) and a trend towards reduction/delay in mortality in juvenile (p = 0.073) patients relative to the control group (Fig. 6).
This retrospective chart review explored the characteristic symptomology of patients with NP-C in different age groups. Overall, the type and onset of symptoms varied across the age groups and are in broad agreement with descriptions of NP-C within the literature [3, 9]. Symptoms that typically precede diagnosis include visceral symptoms in infantile patients, visceral and neurologic signs in juvenile patients, and a varying degree of visceral, psychiatric, and neurologic signs in adult patients. In the current study, patient categorization by age group was based on the date of diagnosis rather than the first symptom occurrence, because for many patients, first symptoms are generally mild and/or non-specific and may only be attributed to NP-C in hindsight upon diagnosis. The 4-year cut-off used in this study differed from the classical early and late infantile age groups, and was selected due to the shift in typical symptomology of NP-C that occurs at around 4 years of age [8, 9]. The pattern of onset of symptoms observed in this study is largely in agreement with the literature, where it is reported that patients who develop NP-C during early infancy often present with predominantly visceral manifestations followed by neurologic signs, whereas adolescent and adult patients present with varying combinations of progressive neurologic signs and psychiatric disturbances [3, 8, 19].
As NP-C is a rare disease, patient population sizes are limited and recruiting sufficient patient numbers for a prospective study is very challenging. This real-world, multicenter chart review of patient data from expert centers allowed a more detailed analysis of miglustat treatment and factors that affected disease progression and survival. Although data were pooled, two additional secondary outcomes that aimed to identify characteristics and factors related to survival (including the factors that differ between control and treated patients) and a retrospective comparison of miglustat treatment with pre-miglustat treatment, could not be assessed due to low numbers of patients with evaluable data. One notable limitation is the inexact agreement between the 3 NP-C disability scales that were used to map clinical data onto the unified NP-C disability scale. Data were obtained from medical records, and were imputed and mapped to obtain additional disability scale assessments. Also, there was a lack of complete medical history for older records. Nevertheless, it should be noted that the reduced rate of disease progression (Fig. 4) correlated with a higher age at last contact or death (Fig. 6), thus validating the use of disability scales to monitor disease evolution or worsening over time, and potentially as tools to predict life expectancy.
In the control group, approximately 20% of patients were prescribed miglustat, but these patients were considered non-treated (treated < 1 year) based on the assumption that the effects of miglustat treatment are not apparent for at least 12 months after treatment initiation [7, 18]. Disability scores from baseline deteriorated more slowly in patients who received miglustat for ≥1 year than in control patients who were not treated or treated < 1 year (Fig. 4). This finding was considered clinically significant but did not achieve statistical significance due to the large patient-to-patient variability and the rather low number of patients, particularly in the control group versus the treated group (n = 24 vs n = 39, respectively).
In patients treated for ≥1 year, linear regression modeling showed that miglustat treatment reduced disease progression in infantile patients and showed a trend towards reduced disease progression in juvenile patients in comparison with those who had no treatment or were treated for < 1 year. This trend was not seen in the adult group, possibly because the late onset of symptoms may lead to diagnosis when the disease is already at an advanced stage and therefore less amenable to treatment. Furthermore, patients in the infantile and juvenile groups are likely to follow a more severe and rapidly progressive disease course; in these patients the effects of treatment on disease progression are likely to be more pronounced than in adult-onset disease, which progresses more slowly.
Pooled data from five patient cohorts provide further clarification on the natural history of NP-C and are in agreement with the published literature. These data confirm that, in infantile and juvenile patients, visceral signs often predate diagnosis, whereas neurologic signs typically occur at the time of diagnosis; in adult patients, diagnosis is predated by a wide range of predominantly neurologic and psychiatric signs. Miglustat treatment is associated with a significant reduction in the rate of disability score worsening in infantile patients, and a trend towards reduced disability score worsening in juvenile patients. Both findings are in good agreement with an increased age at last contact or death, thereby supporting the use of miglustat for the treatment of NP-C.
Medical writing assistance was provided by Usha Gutti of Fishawack Communications GmbH, and was funded by Actelion Pharmaceuticals Ltd.
This study was funded by Actelion Pharmaceuticals Ltd., Allschwil, Switzerland. Statistical analysis was performed by Syntax for Science S.L. and funded by Actelion Pharmaceuticals Ltd. The sponsor participated in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript.
The dataset used and/or analyzed during the current study is available from the corresponding author on reasonable request.
All authors participated in the drafting of the manuscript, and have read and approved the final manuscript for submission.
Informed consent was obtained either from the patient, or their parents/legal guardians according to local laws. The participating site or physician was responsible for obtaining ethical approval.
MP, KJ, PK and MK have received honoraria for talks and travel reimbursement from Actelion Pharmaceuticals Ltd.
VM is has received consultancy fees, honoraria, and travel reimbursement from Actelion Pharmaceuticals Ltd., Alexion Pharma GmbH, Sanofi-Genzyme, and Shire.
JLI is an employee of Syntax for Science S.L.
CV and SAK are employees of Actelion Pharmaceuticals Ltd.


Paul has limited reproduction of his work to just 25 very high quality Giclee prints, the image measures 30cm x 40cm and comes with an additional 3cm border – These are printed by Whitewall of Germany on Hahnemühle Photo Rag and are hand signed and numbered.
With a weight of 308g/m² the Photo Rag is one of the most robust papers from Hahnemühle. It is made of 100% cotton and has a matte surface. With its soft, fine texture, this paper is very versatile and is well suited for Paul's work.
Whitewall use the Epson Inkjet 11880 printer for there special, 6-colour UltraChrome K3 pigment print. A total of nine ink cartridges – six colours and three shades of black – ensures the very finest tonality. In the deep blacks and light areas of your theThe image content is reproduced with a perfect grey balance and an ultra-high resolution of 1,440 dpi. Perhaps even more impressive, however, is that the colours of the Hahnemühle Fine Art Premium print will look just as good as the original, even after 100 years.
The Frames are provided by Brampton Framing in Derbyshire and come from their 'Urban' Range.
Categories: Paul Stowe, Artists, Artwork, Prints.


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AphioTx Pitches at Startup TNT's Life Sciences Investment Summit
AphioTx is excited to announce we have been chosen to advance to the top 10 at Start Up TNT's Life Sciences Investment Summit. Watch the recording of our pitch that landed us the next spot in the summit.
By AphioTx, 11 months February 24, 2022 ago
From One Scientific Breakthrough to the Next: The AphioTx Origin Story
Over a 15-year period, key scientific discoveries were made that changed our understanding of the important roles pannexin-1 channels play in opioid withdrawal, chronic pain, stroke, and cognitive impairment. These discoveries were led by three researchers from the Hotchkiss Brain Institute at the University of Calgary: Drs. Tuan Trang, Roger Thompson, and Darren Derksen.
By AphioTx, 12 months February 9, 2022 ago
Webinar, Innovation & Development: Addressing the Global Opioid Crisis
Researchers out of the Hotchkiss Brain Institute at the University of Calgary have discovered a treatment that shows potential in alleviating opioid withdrawal symptoms, which can help break the cycle of opioid use for millions worldwide. Join our leading scientist Dr. Tuan Trang and other scientific, medical and mental health and addictions experts for this community-run webinar with the Hotchkiss Brain Institute discussing the potential of this research, what this means for communities worldwide, and plans to fuel the development of the science from bench to bedside.
By AphioTx, 1 year January 27, 2022 ago
The Opioid Crisis is Growing Across North America
Governments across North America are taking urgent action to address the growing opioid crisis that is drastically gaining momentum. Current interventions have proven to be ineffective when trying to manage the growing overdose numbers and the number of patients experiencing debilitating withdrawal symptoms. We have compiled the latest articles on the subject, contextualizing the crisis, and emphasizing the global need for innovative treatments to help patients. AphioTx is eager to fill the need for effective therapies to help patients overcome their withdrawal symptoms and break the cycle of opioid use. Overdose Deaths Read more…
Calgary-based Company Launches with Potential Innovative Treatment to Help Tackle Global Opioid Crisis
AphioTx, a clinical research company from the University of Calgary developing a potential treatment for opioid withdrawal, is pleased to announce its formal launch today.
Trio of vet med researchers secures $2.6 million in national funding competition
The CIHR Project Grant program chose projects led by Drs. Sabine Gilch, PhD, Tuan Trang, PhD, and Patrick Whelan, PhD, all researchers in the University of Calgary Faculty of Veterinary Medicine (UCVM).
By AphioTx, 2 years October 1, 2020 ago
Researchers identify drug that alleviates opioid withdrawal
Opioid use and abuse is a significant social, health and economic issue in Canada. Researchers at the University of Calgary's Faculty of Veterinary Medicine (UCVM) and Hotchkiss Brain Institute (HBI) at the Cumming School of Medicine (CSM) have discovered that an existing anti-gout medication is effective in reducing the severity of withdrawal symptoms in opioid-dependent rodents.
By AphioTx, 6 years June 30, 2017 ago
Biochemists develop new way to control cell biology with light
Researchers at the University of Alberta have developed a new method of controlling biology at the cellular level using light.
By AphioTx, 6 years March 13, 2017 ago
Blocking microglial pannexin-1 channels alleviates morphine withdrawal in rodents.
The opium poppy is a natural source of opioids such as morphine. Although they are revered for their potent pain-relieving effects, when used chronically, opioids can lead to analgesic tolerance, hyperalgesia and withdrawal. Burma et al. (p 355) show that pannexin-1 (Panx1) channels on spinal microglia are essential for opioid withdrawal, and that blocking Panx1 can alleviate opioid withdrawal in rodents. Puig and Gutstein (p 272) discuss these findings alongside those recently reported by Corder et al. in the February issue of Nature Medicine. Read more…
By AphioTx, 6 years March 1, 2017 ago
Inhibition of Pannexin-1 Channels on Microglia Reduces Morphine Withdrawal in Rodents
Opioids are the mainstay of treatment strategies to reduce pain, but withdrawal can be a serious problem when patients stop taking these drugs. However, beyond the recognition that microglia play a role in this phenomenon, little is known about the cellular mechanisms involved. Now, new research shows how microglia contribute to withdrawal in rodents and identifies a potential path toward easing withdrawal in patients.
By AphioTx, 6 years February 21, 2017 ago


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Alexa has told over 100 million jokes, Amazon reveals in its year-end stats.
2018 was a good year for the Amazon Echo.
It seems like Alexa has had a busy 2018. On Wednesday, Amazon released some year-end stats about its Alexa smart assistant and Amazon Echo devices -- and the numbers are pretty impressive.
Amazon says that it sold tens of millions of Echo devices this year. While Amazon doesn't give an exact sales number, it shows other ways in which Alexa is booming.
According to Amazon, the number of people who use Alexa every day doubled in 2018. The number of people who own more than one Echo device has doubled too. The number of things Alexa can do for you has also skyrocketed -- developers have made more than 70,000 skills for Alexa.
Alexa is showing up in more places. There are now more than 28,000 Alexa-compatible smart home devices from 4,500 different brands. Alexa learned several new languages this year, and has new native experiences in Australia, New Zealand, France, Italy, Spain and Mexico.
Another impressive statistic: Alexa told over 100 million jokes in 2018 alone.
As more people buy Echo devices and more partners hop on board, the number of things you can do with Alexa grows. So that Echo smart speaker you bought years ago will continue to feel fresh.


The XLarge version of the Airdome is suitable for larger spots. Distinct and professional.
Available with various connectors and Voltages.
SelbyGuard® is a producer, wholesaler and lessor of rain protection for your lighting equipment.


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'Shrill' Season 2 Teaser: Annie and Ryan Encounter Boy Scouts at an Inopportune Time (Video)
Margeaux Sippell
The Wrap 4 December 2019
Hulu's original comedy series "Shrill" will return on Jan. 24, and this season, Annie is "shaking" her "s— up a little."
"I'm taking a chance on myself," Annie, who is played by Aidy Bryant, says in the first teaser for the new season. "I'm trying to be the person that I actually wanna be."
Apparently that involves going to the woods for a little rendez-vous with Ryan — until they're awkwardly interrupted by a wandering pack of Boy Scouts.
Also Read: Aidy Bryant's 'Shrill' Renewed by Hulu for Season 2
Here is Hulu's official synopsis of Season 2:
After facing her demons – her mom, her boss and, of course, her troll – Annie starts the season feeling pretty good with boyfriend Ryan by her side. That is, until she realizes that hastily quitting her job and jumping into a relationship with someone who is, well, a little less career-focused may not have been the best idea.
But Annie isn't the only one on a path to self-discovery… she'll be joined by both Fran and her mother, who are also figuring out what they really want out of life.
And while it's not easy to get what she always imagined she'd want, Annie is no longer the doormat she once was – and she's just getting started.
"Shrill" is executive produced by Lorne Michaels, Elizabeth Banks, Bryant, showrunner Ali Rushfield, Lindy West, Andrew Singer of Broadway Video and Max Handelman of Brownstone Productions. Rushfield, West, and Bryant are all co-writers. The series is produced by Warner Bros., Broadway Video, and Brownstone Productions, with Warner Bros. serving as the international distributor.
Watch the full teaser above.
Season 2 of "Shrill" premieres Jan. 24 on Hulu.
Read original story 'Shrill' Season 2 Teaser: Annie and Ryan Encounter Boy Scouts at an Inopportune Time (Video) At TheWrap
Hillary Clinton Has Some Words For Bernie Sanders In Her New Documentary
TV News Roundup: Marvel TV and Hulu Unveil Casting for 'Marvel's M.O.D.O.K'
Hulu in February: Here's Everything Coming and Going
What to Watch on TV This Week: 'Picard' Premieres and 'Shrill' Returns
Gerald Anderson not worried about competition for new series
Cinema Online
'A Soldier's Play' Broadway Review: Blair Underwood and David Alan Grier Stand and Salute


A live broadcast of the Google DeepMind Challenge Match in Seoul, South Korea.
Chalk one up for the machine.
Google's DeepMind AlphaGo AI brainiac defeated human Go champion Lee Se-dol on Wednesday in the first of five matches in Seoul, South Korea.
Go is an ancient Chinese board game that is seen as more difficult than chess for a computer to master because of the sheer number of options open at each step. Go is played on a 19-by-19 grid while a chess board is 8-by-8.
That win, along with the victory of IBM's (ibm) Deep Blue computer over chess grandmaster Gary Kasparov in 1997, show the scope of artificial intelligence, or machine learning. This technology enables computers to learn by ingesting a ton of information and from their own experience.
Google (goog) bought DeepMind Technologies, the British company behind this AI technology, two years ago.
It's not all fun and games. Smarter computers, capable of adjusting on the fly, will also find application in logistics and other business scenarios.
The prospect of "thinking" machines, excites many people, but sparks anxieties in others—you can insert your joke about welcoming our robot overlords here.


The Seven Havila is the most advanced diving support vessel (DSV) ever built by Havyard Group's shipyard Havyard Leirvik. Designed to fit the advanced saturated diving vessel system, it is specifically built for saturated diving operations.
Desso-Tarkett has delivered iQ Granit for the corridors on the vessel and Tarkett Standard Plus is used in the cabins.


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Auditor General Report confirms that there is a long way to go before reef is out of danger
MEDIA RELEASE 10/06/2015
Cairns and Far North Environment Centre (CAFNEC) is today drawing attention to a report by the Queensland Auditor-General 'Managing water quality in Great Barrier Reef catchments" tabled in Parliament today.
The report questions the effectiveness of Australian efforts to date to address water quality issues and implies that public statements by Minister Greg Hunt and representations to UNESCO regarding reef 'in danger' listing may have been misleading.
The report states that "The water quality and land management improvement targets set in the 2013 Reef Plan are unlikely to be achieved under the current level of practice change. Yet this outcome is not as evident as it should be, because of what is publicly reported and how it is reported."
In particular CAFNEC is drawing attention to the need to look after the relatively healthy Far North Queensland parts of the reef and to address land clearing and other practices emerging in the North that could see the mistakes made further South repeated up here.
The report also notes that "The recent relaxation of land clearing rules also increases the risk of adverse consequences from sedimentation run-off, and could work against the achievement of Reef Plan water quality targets."
Full report: https://www.qao.qld.gov.au/files/file/Reports%20and%20publications/Reports%20to%20Parliament%202014-15/RtP20GreatBarrierReef.pdf
CAFNEC Director Josh Coates said:
"Nobody wants to see our Great Barrier Reef in danger, what this report tells us is that we need more investment from our Government in addressing the problem and less focus on spin designed to make people think that the problems have already been addressed."
"Minister Hunt and others who are telling us that everything is fine are misrepresenting the facts and this report clearly confirms this."
"The recent UNESCO decision to defer 'in danger' listing for the reef cannot be a cause for complacency, when the Government reports back in 18 months we cannot afford to see 'in danger' listing back on the agenda."
"While we see activities like extensive land clearing at Olive Vale and elsewhere on the cape we would be kidding ourselves to think we are on track to achieve water quality improvement targets."
"We are calling on the Federal government to immediately put a stop to this land clearing using the EPBC Act, and on the State government to reinstate land clearing regulations relaxed under the former Queensland Government, as they promised to do prior to the election."
Media contact: Josh Coates, Director, (07) 4032 1586, director [at] cafnec.org.au
Disturbing footage of Olive vale clearing:
Topics: Great Barrier Reef, World Heritage


The Georgia Tax Laws for leasing a vehicle changed on January 1, 2018. Leasing a new vehicle can now be considered a viable option for consumers looking to drive a new car in the new year.
Pursuant to House Bill (HB) 340, the calculation of TAVT as it relates to new leased vehicles will change effective January 1, 2018. Beginning January 1, 2018, leased vehicles no longer will be taxed on the full value of the vehicle. Instead, TAVT will be calculated by multiplying the tax rate by "the total of base payments pursuant to the lease agreement."
The Georgia Department of Revenue (DOR) has finalized new Rules and Regulations designed to incorporate this change. View finalized DOR regulations. The final regulations by DOR state that, for new vehicles that are leased, TAVT will be calculated by multiplying the tax rate by "the total number of base payments, including down payments, pursuant to the lease agreement."
Please see your sales professional for more details.


There is nothing like the summer shred! If you have a zone that you can do it in, then do it! We hit Gorman Lake area on Saturday, and I have to say, it was pretty fun. With very minimal dirt to ride on, the access was super easy, and should be good for another few weeks really if you are looking for a zone. As we climbed the access road we found an inclosed trailer a little stuck on a switchback, but with a little help they were rolling in only a few minutes of shoveling. Something about unloading your sled with flip flops, shorts and a tee that makes these excursions so fun! Load up all the winter gear you normally rock, and set off! In only a few minutes we are sitting at 7400 ft. looking down onto the huge alpine lake below soaking in the rays!
We built a booter hit it a few times (make work project while sun tanning…), wondered around looking for some other jumps, and then went on a 'travel trip' mission. We headed over to East Quartz area and climbed to the top of towering peak. So cool up there. You really do feel like you are on top of the world!!
After messing around and having some social time with a few other riders who were over there, we packed it in and decided to head out, being that it was 7:30pm somehow. I don't think I have ever come out of that zone so quickly! We raced jockeying for position the entire ride out (the kind of ride that really makes me appreciate my ZBROZ Racing suspension! It was a blast, and a great way to end the season!


When the Romans persuade a Gaulish chief to challenge Vitalstatistix to single combat, no one worries much. But then a flying menhir hits Getaflix and he no longer remembers how to make his magic potion. Can Asterix help restore Getaflix's memory?


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Q: Piecewise function Pyomo I want to use piecewise function to modify values in my pyomo model :

*

*2 -> 1

*-3 -> 0

*5 -> 0.5

*0 -> 0

I have a variable called model.test taking values in [-3,0,2,5] :
h_change : Size=11, Index=vehicules
    Key : Lower : Value : Upper : Fixed : Stale : Domain
      0 :    -3 :   0.0 :     5 : False : False : Integers
      1 :    -3 :   2.0 :     5 : False : False : Integers
      2 :    -3 :   2.0 :     5 : False : False : Integers
      3 :    -3 :   2.0 :     5 : False : False : Integers
      4 :    -3 :   0.0 :     5 : False : False : Integers
      5 :    -3 :  -3.0 :     5 : False : False : Integers
      6 :    -3 :   0.0 :     5 : False : False : Integers
      7 :    -3 :   0.0 :     5 : False : False : Integers
      8 :    -3 :   0.0 :     5 : False : False : Integers
      9 :    -3 :   0.0 :     5 : False : False : Integers
     10 :    -3 :   5.0 :     5 : False : False : Integers

I used this next piecewise constraint :
model.test = Var(model.vehicules, initialize=0, bounds=(0,1))

DOMAIN_PTS = [-3.,0.,2.,5.]
RANGE_PTS  = [0.,0.,1.,0.5]

model.con = Piecewise(model.vehicules, #Indexation
                        model.test, # Var res
                        model.h_change, #Var observées
                          pw_pts=DOMAIN_PTS,
                          pw_constr_type='EQ',
                          f_rule=RANGE_PTS)

My variable model.test resulting is like this :
test : Size=11, Index=vehicules
    Key : Lower : Value               : Upper : Fixed : Stale : Domain
      0 :     0 :                 0.0 :     1 : False : False :  Reals
      1 :     0 : 0.20000000000000004 :     1 : False : False :  Reals
      2 :     0 : 0.20000000000000004 :     1 : False : False :  Reals
      3 :     0 : 0.20000000000000004 :     1 : False : False :  Reals
      4 :     0 :                 0.0 :     1 : False : False :  Reals
      5 :     0 :                 0.0 :     1 : False : False :  Reals
      6 :     0 :                 0.0 :     1 : False : False :  Reals
      7 :     0 :                 0.0 :     1 : False : False :  Reals
      8 :     0 :                 0.0 :     1 : False : False :  Reals
      9 :     0 :                 0.0 :     1 : False : False :  Reals
     10 :     0 :  0.5000000000000001 :     1 : False : False :  Reals

I don't understand why my 2 values (index 1, 2, 3) became 0.2 instead of 1.
Can you help me to understand what is wrong with my code ?

UPDATE :

I tried this code to test (from http://yetanothermathprogrammingconsultant.blogspot.com/2019/02/piecewise-linear-functions-and.html)
#
# expected solution X=5, Y=6
#

xdata = [1., 3., 6., 10.]
ydata  = [6.,2.,8.,7.]

from pyomo.core import *

model = ConcreteModel()

model.X = Var(bounds=(1,10))
model.Y = Var(bounds=(0,100))

model.con = Piecewise(model.Y,model.X,
                      pw_pts=xdata,
                      pw_constr_type='EQ',
                      f_rule=ydata,
                      pw_repn='SOS2')

# see what we get for Y when X=5
def con2_rule(model):
    return model.X==5

model.con2 = Constraint(rule=con2_rule)

model.obj = Objective(expr=model.Y, sense=maximize)

But with my solver (Couenne) I got

Y=7.600000072980164.

I think there is then a issue with my solver and not with the PieceWise code ...

A: I found a way to make my constraint working :
simply change pw_repn='SOS2'
to pw_repn='CC'

A: Try to use cplex solver.
I run the code with CPLEX solver and it gives me the same result.