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Pharmacy Author: Omudhome Ogbru, PharmD
Medical Editor: Jim Morelli, MS, RPh
Reviewed on 9/7/2021
multiple sclerosis (ms) medications article
What Are MS Medications?
Introduction to drugs for the treatment of multiple sclerosis
What are steroids, and which ones are available?
DMRs
What are disease modifying drugs, and which ones are available?
Rebif (interferon beta-1a)
Betaseron and Extavia
Betaseron and Extavia (interferon beta-1b)
Copaxone (glatiramer acetate)
Novantrone (mitoxantrone)
Tysabri (natalizumab)
Aubagio
Gilenya (fingolimod)
Lemtrada
Lemtrada (alemtuzumab)
Plegridy (peginterferon beta-1a)
Tecfidera
Tecfidera (dimethyl fumarate or DMF)
Ampyra (dalfampridine)
Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that leads to the degeneration of nerves in the brain and spinal cord. The immune or infection-fighting system in MS patients attacks the body's own cells, causing progressive damage in the brain and spinal cord.
Symptoms of MS include
vision problems,
muscle weakness,
trouble walking or speaking,
numbness and tingling,
problems related to bowel or bladder control, and
Although MS was first identified over a century ago, a cure still remains to be found. Available therapies help improve patients' overall quality of life and minimize long-term disability (by reducing inflammation, delaying the progression of the disease, reducing the frequency and severity of acute attacks, and improving walking speed). Physical, occupational, speech, and cognitive therapy also are used for improving function.
What Is Multiple Sclerosis? MS Symptoms, Causes, Diagnosis See Slideshow
Steroids available for the treatment of MS include:
Betamethasone
Steroids are mainly used for treating acute episodes of MS. Steroids help to reduce the body's autoimmune response. In doing so, steroids help to shorten the length of an attack, and rapidly reduce inflammation. Since their use is associated with significant long-term side effects, steroids are used only for short periods of time. Side effects of steroids include
psychosis,
insomnia (sleeping problems),
bone loss,
suppression of the immune system,
moon (rounded) face,
stomach ulcers, and
increases in blood sugar.
Disease-modifying drugs (DMDs) can decrease the frequency and severity of acute attacks, delay the progression of MS, and slow down the progression of disease-related disability and cognitive decline. DMDs are most effective when started early in the course of the disease.
Interferon-beta-1a, the active chemical in Avonex and Rebif, is a naturally occurring protein found in the body. Avonex and Rebif are synthesized using recombinant DNA technology, and the synthetic chemicals are identical to the natural protein. Although the mechanism of action of interferon-beta-1a in MS is unknown, interferon beta-1a is thought to inhibit the expression of chemicals that trigger the autoimmune response which causes inflammation and neurodegeneration associated with MS. Avonex and Rebif are used for the treatment of patients with relapsing forms of MS to slow the progression of physical disability and decrease the frequency of flare-ups. Interferons, type beta-1a, and 1b are associated with significant side effects. The most common side effects are injection site reactions. Flu-like symptoms are also common but can be managed with acetaminophen (Tylenol), ibuprofen (Motrin), and glucocorticoids. Additionally, interferons may cause liver damage and depression. Depression and flu-like symptoms are transient and usually decrease or go away with time.
Avonex (interferon-beta-1a)
Avonex is administered by intramuscular injection once a week. Once weekly Avonex is preferred over Rebif (administered 3 times weekly) by some patients because of fewer injections and injection-site reactions. In clinical studies, disease progression was slower in Avonex-treated patients. Compared to patients treated with a placebo, the risk of progressive physical disability was reduced by 37% in patients treated with Avonex.
Side effects associated with Avonex include
flu-like symptoms,
abnormal liver tests, and a drop in red and white blood cells and platelets.
Allergic reactions, seizures, and heart failure also have been associated with Avonex.
Due to the risk of miscarriage or harm to the fetus, Avonex should only be used during pregnancy if the potential benefit justifies the potential harm to the fetus. Females of reproductive potential should be made aware of the risk and use appropriate birth control while receiving treatment. Avonex is classified FDA pregnancy risk category C.
Rebif is the second formulation of interferon beta-1a which was approved by the FDA for relapsing-remitting MS in March 2002. Rebif was approved after the EVIDENCE study showed that Rebif was more effective than Avonex. Study findings show that approximately 75% of patients treated with Rebif did not relapse at 24 weeks of treatment versus 63% for Avonex. Additionally, at the end of 48 weeks, 62% of Rebif-treated patients were relapse-free compared to 52% for Avonex.
Rebif is administered by subcutaneous injection three times weekly. Common side effects associated with Rebif are injection site reactions, flu-like symptoms, abdominal pain, depression, abnormal liver tests, and abnormalities of the cells in the blood. Less common and transient side effects include thyroid dysfunction, shortness of breath, tachycardia, and neutralizing antibodies. Due to the risk of miscarriage or harm to the fetus, Rebif should only be used during pregnancy if the potential benefit justifies the potential harm to the fetus. Rebif is classified FDA pregnancy risk category C.
Interferon beta-1b, the active chemical in Betaseron, is a naturally occurring protein found in the body. Betaseron is synthesized using recombinant DNA technology and is identical to the natural protein. Although the exact mechanism of action of interferon-beta in MS is unknown, it is thought that interferon beta-1b inhibits the expression of chemicals such as interleukin-1 beta, tumor necrosis factor, interleukin 6, and others which cause the inflammation and neurodegeneration associated with MS. Betaseron is used for the treatment of patients with relapsing forms of MS to decrease the frequency of acute flare-ups. Betaseron was approved by the FDA on July 23th 1993 for the treatment of relapsing-remitting MS. Betaseron is injected subcutaneously every other day. In clinical trials patients treated with Betaseron experienced fewer flare-ups. Side effects associated with Betaseron include flu-like symptoms, depression, abnormal liver tests, skin reactions, thyroid dysfunction, and a drop in red and white blood cells and platelets. Allergic reactions and necrosis (cell death) of the skin have also been associated with Betaseron. Betaseron is classified FDA pregnancy risk category C and should only be used during pregnancy if clearly needed. Four women participating in the Betaseron RRMS clinical trial experienced spontaneous abortions. Although it is not clear if the abortions were related to Betaseron therapy, the manufacturer recommended limiting its use to patients who clearly need it. Patients exposed to Betaseron during pregnancy are encouraged to enroll in the Betaseron Pregnancy Registry by either calling 1-800-478-7049 or visiting the Betaseron Pregnancy Registry website.
Extavia (interferon beta-1b)
Extavia, the second formulation of interferon beta-1b, was approved by the FDA for the treatment of relapsing-remitting MS in August 2009. Importantly, Extavia is identical to Betaseron and therefore shares the same pharmacological benefits and risks for side effects. As with Betaseron, Extavia is administered via subcutaneous injection every other day.
What kind of disease is multiple sclerosis? See Answer
Copaxone (glatiramer acetate) is used for reducing the frequency of acute flare-ups in patients with Relapsing-Remitting Multiple Sclerosis (RRMS).
Glatiramer acetate is a synthetic protein that modifies the immune reactions which may be responsible for MS, but its exact mechanism of action is unknown.
Glatiramer acetate can now be administered via subcutaneous injection either once daily or 3 times per week.
The new formulation (40 mg/ml) approved in January 2014 has allowed greater patient convenience with administration three times per week compared to daily dosing with the original 20 mg/ml product.
Glatiramer acetate comes in prefilled syringes which should be stored in the refrigerator but can be kept at room temperature for up to a week.
In clinical trials, glatiramer acetate reduced the frequency of relapses and damages to nerves in patients with RRMS.
In one such trial, glatiramer acetate was compared to a placebo for a period of 2 years using a randomized double-blind study design.
At 2 years, the relapse rate was significantly lower in the glatiramer treated group at 1.19 versus 1.68 for the placebo group.
Furthermore, patients in the placebo group experienced increased disability at 41% versus 22% for the glatiramer group.
Also in a separate study, the use of glatiramer acetate was associated with a significant reduction in the formation of new disease-related lesions in the brain on imaging. The most common side effects associated with glatiramer acetate are
vasodilation,
shortness of breath,
chest pain, and
injection site reactions including pain, redness, itching, or lump.
Some patients report flushing, chest tightness or pain, heart palpitations, anxiety, and trouble breathing after injection of glatiramer acetate.
These symptoms generally appear within minutes after injection, last a few minutes, and then subside.
One advantage of glatiramer acetate treatment is that it has somewhat of a milder side effect profile and does not produce flu-like symptoms, fatigue, or depression which is a significant concern with many of the currently available MS therapies including interferons and steroids.
Due to the risk of potential harm to the fetus, glatiramer acetate should be used in pregnancy only if clearly needed.
Mitoxantrone or brand name Novantrone is used for reducing neurologic disability and the frequency of acute flare-ups in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting MS.
Due to the risk for cardiac toxicity (heart problems) and limited evidence demonstrating clear benefits, the American Academy of Neurology recommends that the use of mitoxantrone be reserved for patients who have rapidly progressing disease and who have failed to respond to other treatment options.
Mitoxantrone is a synthetic (man-made) injectable drug that interacts with deoxyribonucleic acid (DNA). It interferes with immune reactions by inhibiting the proliferation or growth of B cells, T cells, and macrophages, all of which are important cells of the immune system. It also impairs the presentation of antigens to cells of the immune system and the secretion of interferon-gamma, TNFα, and IL-2, chemicals that promote inflammation. The mechanism of action of mitoxantrone in MS is not known but may be related to the modification of the immune system as discussed. In clinical trials, mitoxantrone improved disability, ambulation, frequency of relapse, and neurologic status better than placebo.
Mitoxantrone is administered as an intravenous infusion dosed at 12 mg/m2 every 3 months. As mitoxantrone may have toxic effects on the heart, it is not recommended for use in patients with left ventricular ejection fraction (LVEF) <50%, patients with a clinically significant reduction in LVEF, or in those who have received a cumulative lifetime dose of mitoxantrone of 140 mg/m2. Furthermore, mitoxantrone should not be administered to patients with white blood cell counts less than 1500 cells/mm3, abnormal liver tests, or who are pregnant.
Side effects of treatment include
hair thinning,
loss of menstrual periods,
bladder infections, and
mouth sores.
Heart failure and drops in white blood cell or platelet counts may also occur.
Low white blood cell counts may lead to infections while low platelets may cause bleeding.
Mitoxantrone is dark blue in color and may turn the urine or the sclera of the eyes a blue-green color.
Mitoxantrone was approved by the FDA to treat RRMS or secondary progressive MS in October 2000.
Mitoxantrone is also approved to treat various types of cancers or tumors and has been used medically since 1987.
Mitoxantrone is classified as FDA pregnancy category D and should not be used during pregnancy as it may cause harm to the unborn fetus.
Females who may become pregnant must be made aware of the risk and use appropriate forms of birth control (contraception).
Females who are of childbearing potential should have a pregnancy test prior to each dose of mitoxantrone.
Tysabri is used to delay the progression of physical disability and reduce the frequency of clinically important flare-ups in patients with relapsing MS. Because natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal viral infection of the brain, it is reserved for patients with active RRMS who have failed to adequately respond or are intolerant to the beta interferons or glatiramer acetate.
Due to the risk of PML, natalizumab is available only through a restricted distribution program called the TOUCH Prescribing Program. Also, due to the risk for PML, natalizumab should not be co-administrated with immunosuppressants. The mechanism of action of natalizumab in MS is not well understood. Natalizumab is a humanized monoclonal antibody and is an alpha-4 integrin antagonist or blocker. It binds to integrins expressed on the surface of white blood cells (except neutrophils) and inhibits the adhesion of the white blood cells to their receptors.
Natalizumab is thought to exert its benefits in MS by preventing the migration of white blood cells into the brain and spinal cord. As white blood cells play an important role in promoting the inflammation of MS and the degeneration of nerves, natalizumab reduces relapse and appearance of brain lesions by reducing their numbers in the brain and spinal cord. In clinical studies, natalizumab delayed the onset of a sustained increase in disability. In a phase II clinical study that compared natalizumab to placebo, natalizumab was showed to significantly decrease the number of new gadolinium-enhancing lesions by more than 90%. Additionally, in the AFFIRM trial (A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis), natalizumab reduced the annual relapse rate by more than 60%, reduced gadolinium-enhancing lesions by more than 90%, and significantly delayed the progression of disability.
Natalizumab is infused intravenously every 4 weeks. The most common side effects in MS include
stomach pain,
joint pain,
urinary tract infection,
lower respiratory tract infection,
pain in the extremities,
diarrhea, and
rash.
Rare but serious side effects include progressive multifocal leukoencephalopathy (PML), liver dysfunction, and potentially life-threatening infections such as meningitis and encephalitis.
Natalizumab is classified as FDA pregnancy risk category C and should only be used in pregnancy if clearly needed. Natalizumab was approved by the FDA for the treatment of MS in November 2004. Besides being effective in treating MS, natalizumab is also used to treat moderate to severe Crohn's disease.
Aubagio is an oral immunomodulator. It works by altering the immune signals without causing significant cell toxicity or bone marrow suppression. More specifically, teriflunomide inhibits dihydroorotate dehydrogenase, an enzyme used to make pyrimidine -- which is required to make DNA.
Teriflunomide is used for the treatment of relapsing forms of MS. It was approved by the FDA in September 2013.
Although the exact mechanism of teriflunomide in the treatment of MS is unknown, it is thought to play an important role in reducing the over-activation of the immune system by decreasing the number of white blood cells in the brain and spinal cord.
In the clinical study which demonstrated the effectiveness of teriflunomide, patients treated with teriflunomide were reported to experience a 31% relative risk reduction in their annual MS relapse rate. Furthermore, the percent of patients who remained relapse-free at week 108 for the 14 mg teriflunomide, 7 mg teriflunomide, and placebo was 56.5%, 53.7%, and 45.6% respectively.
The usual recommended dose of teriflunomide is 7 mg or 14 mg orally once a day without regard to food.
The most common side effects associated with teriflunomide treatment are
alopecia (hair loss or thinning),
diarrhea, influenza (flu),
paresthesia (tingling, burning, prickling, or pricking sensations of the skin), and
a decrease in liver enzymes.
Less common but potentially serious side effects include
serious liver injury,
kidney failure,
increased risk of serious infections such as tuberculosis,
increase in blood potassium levels,
high blood pressure,
breathing problems,
serious skin problems, and
a drop in white blood cell count.
Teriflunomide may impair the development of the fetus or cause fetal death, and therefore should not be used during pregnancy. Pregnant women, women who wish to get pregnant, or men who wish to father a child should discontinue the use of teriflunomide.
Gilenya is the first oral medication approved for the treatment of relapsing-remitting MS.
Fingolimod helps to decrease the frequency of acute attacks and delays the accumulation of physical disability.
Fingolimod is a sphingosine 1-phosphate receptor modulator and is thought to help reduce the number of lymphocytes (white blood cells) in the peripheral blood.
Although the exact mechanism by which fingolimod helps to treat MS is unknown, it may be related to its involvement in reducing the migration of white blood cells into the brain and spinal cord.
The effectiveness of treatment with fingolimod was demonstrated in the TRANSFORMS trial that compared oral fingolimod (0.5 mg orally once a day) to intramuscular interferon beta-1a (30 mcg once weekly) for a period of 12 months.
The annualized relapse rate was significantly lower in the fingolimod recipients at 0.16 versus 0.33 for the interferon beta-1a recipients.
The usual recommended dose of fingolimod is 0.5 mg orally once a day without regard to food.
Initiation of treatment with fingolimod may cause a decrease in the heart rate. Therefore, the first dose of fingolimod must be administered in a clinical setting where the patient is observed by healthcare providers for at least 6 hours.
The most common side effects of treatment include
an increase in liver enzymes and
cough.
Other significant side effects which have been reported in clinical trials and require monitoring Include,
a drop in white blood cell counts,
macular retinal edema (eye problems),
AV block (abnormal conduction in the heart), and
the risk for infections. Also, when given oral ketoconazole (an azole antifungal), there is a concern for increased blood levels of fingolimod and the consequent risk for side effects. Because fingolimod may reduce the immune response to vaccines, administration of live attenuated vaccines should be avoided during and for 2 months after stopping treatment with fingolimod.
Use of fingolimod during pregnancy should be avoided if possible due to concerns about causing harm to the fetus.
Additionally, women of childbearing potential are advised to use effective contraceptive methods during and for at least 2 months after stopping fingolimod.
Fingolimod was approved by the FDA in September 2010.
Lemtrada is a humanized monoclonal antibody directed against the CD52 antigen. The CD52 antigen is found on the surface of numerous cells in the body including white blood cells, NK cells, monocytes, macrophages, platelets, and others.
Alemtuzumab is used to treat relapsing forms of MS and is generally reserved for patients who have failed to adequately respond to two or more MS treatments. In the CARE-MS clinical trial, alemtuzumab proved to be more effective than interferon beta-1a in reducing the relapse rate in patients with relapsing-remitting MS (RRMS).
The annualized relapse rate was 0.18 for the alemtuzumab group versus 0.39 for the interferon beta-1a group. Similar findings were also demonstrated in the CARE-MS II study which evaluated adult patients with RRMS who had experienced at least one relapse while being treated with interferon beta-1a or glatiramer. At 2 years, alemtuzumab was superior in reducing relapse and the progression of disability.
Alemtuzumab is administered by intravenous infusion at 12 mg/day over 4 hours for two treatment courses.
The first treatment course is given once daily for 5 consecutive days (60 mg total dose),
followed by the second treatment course 12 months later for 3 consecutive days (36 mg total dose).
Due to the significant risk of infusion reactions (infusion reactions occurred in approximately 90% of patients),
patients are premedicated with high-dose corticosteroids (1000 mg of methylprednisolone or equivalent) immediately prior to infusion and for the first 3 days of each treatment course.
Additionally, patients must also receive prophylaxis for herpes and pneumocystis jirovecii pneumonia (PCP) during treatment and for several weeks after. HIV-infected patients should not use alemtuzumab.
The most common side effects of alemtuzumab treatment are
nasopharyngitis (common cold),
insomnia (difficulty sleeping),
upper respiratory tract infection,
herpes viral infection,
urticaria (hives),
pruritus (itching),
thyroid gland disorders,
fungal infection,
arthralgia (joint pain),
pain in the extremity,
sinusitis,
oropharyngeal pain (mouth pain or sore throat),
paresthesia (tingling, pricking, burning sensations in the skin),
flushing and vomiting.
Due to the potential risk of causing harm to the fetus, alemtuzumab should be avoided in pregnancy if possible.
Alemtuzumab was approved by the FDA in November 2014 for the treatment of RRMS.
In addition to treating MS, alemtuzumab is also used to treat chronic lymphocytic leukemia (CLL), a type of blood cancer.
Plegridgy is the newest formulation of interferon beta-1a which is designed to have a longer half-life and therefore requires less frequent dosing. As peginterferon beta-1a requires fewer injections, it may be better tolerated than the nonpeglyated interferon formulations.
The exact mechanism by which peginterferon beta-1a exerts its therapeutic benefits in MS is unknown but is thought to be similar to that of the other interferons. As such, peginterferon is thought to decrease inflammation and have neuroprotective effects.
Approval of peginterferon beta-1a was based on the results of the ADVANCE clinical trial which compared peginterferon (125 mcg every 2 weeks or every 4 weeks) to placebo.
The annualized relapse rate at 48 weeks was 0.256 for the peginterferon every 2-week group, 0.288 for the every 4-week group, and 0.397 for the placebo group.
Additionally, peginterferon treatment was associated with statistically significant improvements in reducing disability progression and brain lesions.
Peginterferon beta-1a is administered subcutaneously every 14 days. The recommended dose is 125 mcg every 14 days, with most patients titrated as follows; 63 mcg on day 1, then 94 mcg on day 15, and finally 125 mcg (full dose) on day 29.
The most common side effects of treatment are
injection site reactions (pain, redness, or itching),
muscle pain,
joint pain, and
weakness.
Other reported side effects include
liver disease,
allergic or anaphylactic reactions,
decrease in blood counts, and
worsening of heart disease.
Peginterferon beta-1a is not recommended for use during pregnancy due to the potential risk of causing harm to the fetus. Peginterferon beta-1a was approved by the FDA in August 2014.
Tecfidera is an oral medication used to treat relapsing forms of MS. The exact mechanism by which dimethyl fumarate provides therapeutic benefits in MS is not known but it appears to have neuroprotective and anti-inflammatory properties.
Evidence of clinical effectiveness of dimethyl fumarate treatment was provided in the "Efficacy and Safety Study of Oral Dimethyl Fumarate (BG-12) with Active Reference in Relapsing-Remitting Multiple Sclerosis (CONFIRM)" study that showed that dimethyl fumarate decreased the annualized relapse rate by 44% at twice daily dosing and 51% at three times daily dosing.
Similarly, in the "Determination of the Efficacy and Safety of Oral BG-12 in Relapsing-Remitting MS" study, dimethyl fumarate decreased the annualized relapse rate by 47% with 240 mg twice daily dosing and 52% with 240 mg three times daily dosing.
Treatment with dimethyl fumarate is usually started with 120 mg orally twice a day for 7 days followed by 240 mg twice daily thereafter.
Dimethyl fumarate is available in 120 mg and 240 mg delayed-release capsules which should not be crushed, chewed, or broken. Capsules may be taken with or without food; however, taking with food may decrease the incidence of flushing.
flushing,
These side effects usually decrease over the first month of treatment. Other reported side effects include
an increase in liver enzymes, and
loss of protein in the urine.
Due to the potential risk of causing harm to the fetus, dimethyl fumarate should be avoided in pregnancy if possible. Dimethyl fumarate was approved by the FDA in March 2013.
Ampyra is used for improving walking in patients with MS. Benefits of dalfampridine in MS are demonstrated by an increase in walking speed.
Although its mechanism of action in MS is not fully understood, dalfampridine is a potassium channel blocker.
In animal studies, dalfampridine improved the conduction of impulses in damaged nerves by blocking potassium channels. In clinical trials, dalfampridine improved walking speed more than placebo.
In one clinical study, 34.8% of dalfampridine-treated patients experienced improved walking as compared with 8.3% of placebo recipients. In a separate study, 42.9% of dalfampridine recipients showed improved walking speed versus 9.3% for the placebo group.
Dalfampridine is administered orally twice daily without regard to food.
Dalfampridine is available in 10 mg tablets which must be swallowed whole.
Patients with a history of seizures, or moderate or severe renal failure should not use dalfampridine.
Common side effects of dalfampridine include
constipation,
balance disorder,
MS relapse,
nasopharyngitis,
throat pain and burning, and
tingling or itchiness of the skin.
Dalfampridine has not been adequately evaluated in pregnancy and is classified as FDA pregnancy risk category C.
Due to the lack of conclusive safety data,
Dalfampridine should only be used during pregnancy if the potential benefit justifies the potential harm to the fetus. Dalfampridine was approved by the FDA for MS treatment in January 2010.
Combat MS Fatigue With Exercise
Fighting MS Fatigue With Physical Activity
Getting the Care You Need for Your MS
Joseph Carcione, DO
American board of Psychiatry and Neurology
Prescribing Information for Avonex (interferon beta-1a); Betaseron (interferon beta-1b); Copaxone (glatiramer acetate); Rebif (interferon beta-1a); Novantrone (mitoxantrone); Tysabri (natalizumab); AMPYRA (dalfampridine); Aubagio (teriflunomide); Gilenya (fingolimod); Lemtrada (alemtuzumab), Plegridy (peginterferon beta-1a), Tecfidera (dimethyl fumarate); Extavia (interferon beta-1b)Litzinger MH, Litzinger M. Multiple Sclerosis: A therapeutic overview. US Pharmacist 2009;34(1):HS3-HS9 Olek MJ. Treatment of relapsing-remitting multiple sclerosis in adults. UpToDate. Last updated Dec 11, 2014.
Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2009. http://www.clinicalpharmacology.com.
Drug information for Avonex (interferon beta-1a); Betaseron (interferon beta-1b); Copaxone (glatiramer acetate); Rebif (interferon beta-1a); Novantrone (mitoxantrone); Tysabri (natalizumab); AMPYRA (dalfampridine); Aubagio (teriflunomide); Gilenya (fingolimod); Plegridy (peginterferon beta-1a); Tecfidera (dimethyl fumarate); Lemtrada (alemtuzumab), Ampyra (dalfampridine); Extavia (interferon beta-1b) Lexicomp: Drug Information [online database]. Drug information for Avonex (interferon beta-1a); Betaseron (interferon beta-1b); Copaxone (glatiramer acetate); Rebif (interferon beta-1a); Novantrone (mitoxantrone); Tysabri (natalizumab); AMPYRA (dalfampridine); Aubagio (teriflunomide); Gilenya (fingolimod); Plegridy (peginterferon beta-1a); Tecfidera (dimethyl fumarate); Lemtrada (alemtuzumab); Extavia (interferon beta-1b)
DiPiro et al. Pharmacotherapy: A Pathophysiologic Approach, 9th edition. Chapter 39: Multiple Sclerosis. Access Pharmacy [online].


To turn on simply press the button situated in the inside upper of the shoe - Toggle through the settings to reach you required light colour or mode.
Turn off by simply holding the button in for a few seconds.
3 Flash Settings which include: slow blinking, fast blinking and colour fade mode.
Dual USB Charger Lead (charges both shoes at the same time).
Charger bag to keep your lead safe and free of damage.


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redpajama_set_name: RedPajamaCommonCrawl


In the beginning it seems it will never come to an end … but finally time is racing to the last days. I would have had time to travel around – but actually I was tired of traveling – especially traveling alone. But for the last weekend I got invited by friends – Samantha and Mladen – to Karadere, a beautiful wild beach on the Black Sea coast between Varna and Burgas. I didn't take me a lot of thought to decide to join – you shouldn't miss such opportunities.
We went there with a fully stuffed car – us, our equipment and half a band equipment (amplifieres, speakers and wires) – which took us twelve hours (double the estimated time), because we stopped in several places to pick up stuff or meet people.
The beach was just great – no hotels, not even houses, no electricity, no water, no mobile phone; just a bunch of people camping and having a good time. The water of the Black Sea is very nice – clear, warm and not very salty. We enjoyed the days hanging on the beach, reading, playing, swimming and talking, the evening doing barbecue, eating salad and drinking rakia – the nights doing a jam session – live music, powered by the battery of our car.
If you want to experience this too … my friends will organize a little festival on that beach for beginning of August (and later to a street festival in Istanbul). I want to go there again next year.
Sun rise after a long night – what's better to go for a swim?
* Don't dig for your favorite book, the cool book, or the intellectual one: pick the CLOSEST.
This book was just lying on the table next to my laptop because I found it in my (new) room, and apparently it belongs to nobody – a good reason to read it.
I just had a heavenly apparition. As I was waiting at the traffic lights to turn green, the lettering "58 Mariagrün" was appearing in front of my eyes. First I couldn't believe what my eyes tried to tell me so I looked closer and it was really a bus from Graz.
For those who don't know, Mariagrün is the place in Graz where I grew up and where I still visit my mother regularily. And the bus 58 is the bus from the Train Station to home. To see it at such a remote place was really a surprise.


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About a week ago, my fortune cookie read, "Something once lost will return to you." I thought, "Ha! My keys?" I'd lost them last May 2 in the Seabury parking lot as I was packing up for a long trip to Iowa to attend our first clergy conference. We already were running late, I had a splitting headache, and losing the keys made me uncharacteristically frantic.
Today the keys turned up in a coat pocket, as I was headed out to walk the dog in my jester's hat (she declined to go in costume, Halloween or not). So, Heidi, take heart: your keys may reappear, too. Maybe you should go out for some Chinese food, though.
For those who know that I arranged my sock drawer in seminary according to the colors of the liturgical calendar, I'd like to point out that I'm wearing red socks today in order to shout, "Yay, Boston!" and not to note the feast of St. Simon and St. Jude a day early.
I knew it would be fun to show Laurel the places I love in Iowa City, but it was even better introducing her to some of my favorite people at church: Meg and Andrew, Ellyn and Carol. It was my day off, so I surprised Vickie by appearing in the sacristy. She said, "You're here! I'll make you a bouquet for your office." As Laurel and I toured the building, we saw Vickie out in the courtyard, cutting deep red roses, English ivy and some small blue flowers. My whole office smells like an English garden.
After stoppping for some sushi, we went to the historic building on campus where my Campus ministry program offers Taize Evensong each Sunday. Outside the door was a man with a big red vacuum, into which he'd just sucked a baby bat in order to remove it from the building. There on the lawn was the bat, visibly trembling after its journey inside the big scary vacuum. Laurel and I watched as the man encouraged the bat to hang onto a large stick. Then he transferred the little thing to the top of a bird house -- which of course is no longer a bird house, at least till the bat is brave enough to fly off into the Iowa night.
It's been great to discuss leadership issues while eating our way through the day. Our last stop tonight was the best ice cream shop in eastern Iowa, which serves pumpkin ice cream every October. But we're still thinking about the bat, and I still remember the smell of those freshly cut roses, wet from the garden.
We are awaiting the arrival, any moment now, of our former neighbor in Evanston. Tomorrow I'll drive her down the interstate, bless some trucks, wave to the corn, and show her my office. The largest piece of framed art on my wall is one of her original works, so I hope she'll enjoy finding it there.
And then we'll eat, drink, and catch up. Friends matter so much to me, and often I wonder if that's especially true because I never had siblings. Hmm.
Yes, there really is a corncob at the top of this page from the Iowa Independent! And yes, it's still strange to be quoted by the press.
Never would I have imagined that while I'm home with the dog as she recovers from surgery, I'd visit YouTube and watch clips of myself preaching! It's a 10-minute video (a bit long!) with a jumpy camera, but does show the shape of the church, the crowd, and the altar frontal and vestments made for this service.
Y'all know how much I'm not a likely YouTube type! But here's the link.
Early this morning, our 9 yr. old poodle Maggie sat in the doorway to our bedroom with a look that said, "Do something." She had been restless all night and not feeling well in the evening. We took her to the vet because her behavior seemed so odd.
Two hours later, Maggie had emergency surgery for an intestinal mass. She came through the surgery (her fourth since she was 2 yrs. old) well, and might come home tomorrow or Monday. The vet invited us in to watch as he performed an ultrasound -- fascinating stuff. We were able to see her liver, spleen, pancreas, kidneys and intestines (sorry if this makes anyone queasy), and there it was: the dark spot causing the vet to say, "I don't like the looks of that." Our vet, by the way, was married in our home parish, with his dog as ring bearer!
After surgery, we viewed the tumor itself via camera. Things might have been worse, so we're fortunate (but $2000 poorer). I still marvel at dogs' capacity to communicate distress. Many humans communicate less effectively and less directly.
At least for tonight, Maggie seems to have gotten through another health crisis. But the house is too quiet, and this day certainly challenged our emotions.
Send up a prayer for Maggie's recovery, if you will. Thanks.
The Campus Ministry team at St. Ambrose University (where John has professed botany for 25 years) invited him to officiate and preach at a special vespers service today, to formally recognize his priesthood and ministry. There's a lovely reception planned afterwards, too.
Labels: Campus Ministry, St. Ambrose Univ.
Last night's U2charist filled the pews and brought in many new friends. Our children danced in the aisles when a bubble machine sent hundreds and hundreds of bubbles into the air during the final song. So here I am the next morning (serious snobby musician who doubted rock music in church!) to tell you that I don't know when I've had such a joyful, marvelous and holy experience leading worship. Even the cameras from two TV stations, pointed right at me, didn't seem too intrusive. People from the ONE Campaign in Des Moines joined us, handing out tee shirts and wristbands. As I looked out from the altar, faces looking back were visibly moved, and we surely praised God.
The exuberant youth of our parish helped to design the altar frontal, stoles, candlesticks, patens and chalices. I thank God for these young people!
Before long we'll be sending Luke off for a rest, and welcoming Matthew. At clergy conference a few days ago, Dr. Katherine Grieb from Virginia Seminary led four sessions on the upcoming lessons for Advent, and talked about common themes in Matthew's gospels. She presented admirably, but...I did take a ten week course on Matthew not so long ago.
To awaken curiosity and in preparation for Sunday's U2charist, the youth of Trinity Church wrapped the entire building with 600 feet of white plastic tablecloth. White band wrapping of public objects has been popular for while now, but this is the first live wrap that I've seen. Large black letters on each side of the building read, "MAKE POVERTY HISTORY."
As I drove away from the building at dusk, passersby were stopping, staring, and pointing. The youth had a blast wrapping the building! So I'd best deliver a sermon that meets that kind of energy. We're expecting hundreds of people, last I heard. So, am I anxious? Don't even ask!
At least I'm not in charge of serving all these people chili afterwards!


text:
'Supernatural': But that's not me
February 12, 2018 by whitney hall, posted in supernatural, supernatural: season 13
"What the cuss?!? A vampire??"
Oshkosh, Nebraska. A car pulls in to Mann-burned out Y-'s Truck Stop Cafe to fill up. The driver's credit card is declined at the pump, so the young woman goes inside to pay. The room stills and all eyes turn to her when she walks in. The energy is not friendly. The cashier is downright slimy. After gassing up and declining a gaunt Manson looking dude's offer to wash her windows, the woman drives away.
Some distance down the road she pulls over with a flat tire. I would drive on the rims before I stopped on a dark murder road. I HAVE driven on the rims rather than stopping on a dark murder road. She tries to flag down a passing semi, but the truck roars past.
She crouches down to inspect the tire and discovers a large three-pointed spike is embedded in the rubber. And that's when she's attacked from behind by the leather-masked man who put it there.
Never stop on the murder road.
6:00 AM. Sam is laying in bed, wide awake. 8:22 AM. Sam, still in bed. He seems stuck in his own head. Dean knocks on the door. He's making pancakes. Sam doesn't respond. 10:00 AM. Sam is finally roused out of bed by the insistent buzzing of his phone.
Dean is just finishing tidying the kitchen when Sam walks in. He remarks on the time and says he saved Sam a short stack. Bless his heart. I love domestic Dean.
Sam puts his call on speaker. Donna is on the line. She's sitting alone in her truck on the side of the murder road. All the sunshine is drained out of her voice. She's scared and fighting back tears. Her niece Wendy has gone missing and Donna knows it's not their normal thing, but … Dean immediately tells her to text the address. They're on the way.
Donna is waiting for the boys at the impound yard. Her mind is a million miles away, but her face brightens when she sees them. There is hugging. Yay! Hugging! She admits that she's not doing well. She seems wracked with guilt for inspiring Wendy's road trip with stories of her own gap year adventures.
She says she's sorry for calling them, but Jody has her hands full with the girls … Dean tells her never to apologize for sending up a flare. The boys try to keep her focused and positive. Just work the case.
New Doug is inside talking to local law. Dean gives Wendy's car a quick look and is aggressively challenged by another suit. New Doug rushes over to diffuse the confrontation, introducing Agent Clegg to Agent Savage. Clegg asks which field office he should call about Dean walking through his crime scene.
Dean quickly downshifts and says he's not there on official business. The victim is family – his cousin, which just seems like an unnecessary detail, especially when a confused New Doug starts asking questions about the family reunion a few weeks ago in Sioux Falls. SIMMER DOWN NEW DOUG.
The story is enough to satisfy Clegg, who offers to fill Dean in on what they know. That seems … unusual. I can't decide at this point if Clegg is legit or if he's working for the monster.
Sam, Donna, and New Doug join them in a makeshift office. Clegg says Wendy's disappearance matches the pattern of a serial abductor he calls the Butterfly. Victims are never seen again. "We've never even found a body." Donna is stone-faced. Clegg tells them he's been chasing the Butterfly for 12 years, and if they want to help, he can use all the help he can get.
Dean looks at Sam who shakes him off with a worried expression. Dean says they're in. Sam's bitch-face is like, WE LIVE TO SERVE.
That night, Dean pulls out the CB radio and is poo-poo'd by Sam, who says no one uses them anymore. "No one except truckers." Dean says it will work. John used it all the time. Dean's handle, naturally, is 67 Midnight Rider. He gets a lot of chatter but no leads on his "Alice in Wonderland".
Sam says the whole thing is stupid. The case isn't even their kind of thing! Not to mention the risk of exposure with the real Feds there. He reminds Dean that they're still fugitives. Does he really want to get on the FBI's radar again?
Dean says the Feds think they're dead. And what exactly does Sam want to do? Peace out on Donna so they can go back to the Bunker and Sam can mope some more?
After complaining that Sam turned down pancake – PANCAKES! – Dean changes tack. He acknowledges that Sam is in a dark place after losing Jack and Mary, but says that he can't let it eat him up. The only way out is through. And right now, Donna needs their help.
A voice crackles through the CB. Felix the Cat says she might have some info to share. Dean throws a puffy vest on over his flannel and meets her for coffee the next day. Felix tells him she saw Wendy once at Manny's and then again on the murder road. Felix was the driver who passed Wendy by and her decision not to stop seems to be eating at her.
New Doug joins Dean at Manny's and gives him every incident report ever recorded at the truck stop. There's nothing in the file that screams "secret hunting ground for a kidnapper." New Doug turns the conversation to Donna. He asks Dean if she's going to be okay. He says he's never seen her like this and worries that it's more than Wendy's disappearance. He thinks she's hiding something from him.
Oh, New Doug.
Clegg brings in a suspect. Wendy's credit card activity also led him to Manny's and Pastor Diamond Don Hinkey. He was in the diner the night Wendy disappeared, sitting at a booth with Felix. Clegg says he's liked Hinkey for years but never had enough to bring him in. Until now.
Sam and Clegg take a run at Hinkey while Donna watches through the glass. Clegg shows him Wendy's photo along with a picture of Luis Fernando, also missing. Hinkey asks for a lawyer … "Then you can ask me anything you like about your illegal and your whore."
Donna walks into the room with a "not today, Satan" set to her jaw.
Son, you're about to get hit by the D Train.
Donna wonders if Hinkey is sure about that lawyer. She says the Bible doesn't have much good to say about them. She joshes that even the good book's got lawyer jokes and quotes from memory Luke 7:30.
When Hinkey persists in his request, Donna pulls up a chair and real talks him. It's a small town and it's Friday night. A public defender might be assigned to him by Monday. That's at least two long nights fending for himself in county lock up.
So he can deal with that, or he can answer a few questions and be on his way.
Clegg remarks to Sam that Donna is good. Sam grins in appreciation and agrees that she is – for anyone in the back who hasn't already picked up from context that Donna is HBIC.
She asks Hinkey about his life on the road and his family. She wonders if his wife and two children know about the girl he flashed outside of Cheyenne. Or the teenaged boy he picked up hitchhiking. Hinkey begins to squirm but says he's weak. He's made of flesh. God knows he's a sinner, and he's working through things with his wife, so.
Donna reaches for the manilla envelope sitting on the table. She pulls out an evidence bag containing a bloody t-shirt. Does Mrs. Hinkey know about that? Donna says the shirt is Wendy's and they found it in Hinkey's van. She increases the pressure on Hinkey as his composure crumbles and he begins to panic. She hisses at him not to lie to her before abruptly standing and leaning over the table shouting, "DON'T LIE TO GOD!"
Donna leaves Hinkey sobbing in the interview room. She says she believes him – he didn't do it. Sam agrees. He says the t-shirt doesn't make any sense. It's too easy. Donna suggests someone could have planted it, but who?
Windshield Jesus approaches Dean and New Doug as they get out of the car. Dean offers him a little folding money to jog his memory about Wendy. Windshield Jesus says he saw her and that Marlon the cashier saw her, too. He closed up after she left and drove off after her. He didn't come back until dawn.
Marlon plays dumb about Wendy and immediately finds his face smashed into the counter. Dean tells New Doug that's how they do things in the FBI. Marlon quickly relents. He pulls out his laptop and pulls up an auction site on the deep web. Luis Fernando is shown on a webcam bound and gagged. The current bid on his left arm is $230 and rising.
The auction ends and Luis struggles against his restraints as a gloved hand and whirring saw come into view of the camera. Dean says they're selling the man off, piece by piece.
Sam and Donna join them at the truck stop a short time later. Sam recoils at the video and hits pause. Marlon wonders if Sam is vegan and gets a smack in the back of the head from New Doug. He shrugs with his voice. "That's how they do it in the FBI." Donna gives Dean a look – stop corrupting her boyfriend.
She wonders if the point of the sale is for trophies, but Sam points out the auction comments. He says it's for food. Dean calls it take out. It's the 'oh shit' look on Dean's face when Donna fills in the blank and says, " … for monsters", that makes it poetry. New Doug is like, what in the who now?
Donna tells him they'll talk about it later. Dean makes a mental note to be someplace else when that happens.
Marlon blithely says he doesn't know anything about the site or who runs it. When he sees someone he thinks nobody is going to miss he sends a message and gets paid. As they're talking the site refreshes and Wendy appears on the screen as the next item up for bid.
Sam says it would take him days to hack the site. He can't do it – but the FBI can. They have 58 minutes to find Wendy. Clegg gets them the location of the video feed in less than 15.
Sam goes around back while Dean and Donna go in the front. New Doug follows with Marlon, which seemed weird to me, but given that the boys are shit at securing prisoners, it's as good a call as any. He hangs back with Marlon while Dean and Donna press deeper into the building.
Clegg arrives on scene to Sam's surprise and consternation. He says he's been hunting the Butterfly a long time and he needs to see it through. He arrives alone with no additional backup, which doesn't seem strange at all …
20 minutes until bidding closes. The leather-masked man who abducted Wendy sharpens his blade while she watches. The camera captures her terrified screams for its slavering viewers.
Y'all, this episode has moments in it that are straight up Criminal Minds. It's the creepiest that Show has been in a long time.
Dean and Donna stalk through the darkened halls following the sound of music. They find an empty room and a transistor radio. When they get back to New Doug he's on the floor. His chin is covered in blood. Marlon is gone. New Doug says he's not hurt, but he doesn't think he's okay, as his new baby vampire fangs descend.
Dean calmly drops his bag and pulls out a syringe of dead man's blood. He injects New Doug before he can feed on Donna. Dean talks her off the ledge of panic, reassuring her that there is a cure and New Doug will be fine. They just need a little sage, a little garlic … and the blood of the vampire who turned him. Marlon ambles back into the room.
He taunts that Dean never even saw it coming. Clegg played them. And he's got Sam. Dean goes to his dead-eyed special place. If only Dean hadn't been so rough with Marlon, he might be willing to spill where Sam is. But the vampire holds a grudge, so. Dean unsheathes the machete. "Bring it Twilight."
Donna is like, TICK TOCK, and shoots Marlon in the knee. While the vampire writhes in pain on the floor, Donna tersely tells Dean to get the blood and mix the cure. She puts the muzzle of her shotgun in Marlon's face. The vampire gasps that if he tells her where Clegg is, she'll kill him.
Donna stares him down. Oh, she's killing him either way. "You just gotta decide if you want it fast or slow."
Sam comes to in the bloody abattoir strapped down to a metal table. Clegg is next to him stage directing his faceless minion. I'm going to call him Larry. Clegg tells Larry to set the camera further back. Sam is a big boy. They need him on a wide lens.
Also, he's Sam Winchester. He and Dean are famous.
Clegg rolls up his sleeves and says he knew who they were as soon as he saw the car and oh my god THANK YOU writer Davy Perez. I was sure in "The Scorpion and the Frog" that Shrike was going to recognize Baby – and try to add her to his collection.
Clegg admits that he set up the preacher, but since Donna and Sam saw right through that, it's on to Plan B. He tells Sam there are tens of thousands of monsters out there. That the freaks that he and Dean chase are just the ones who are too mean or too stupid to pass. He says most monsters have assimilated – but they still need to eat.
The way that Clegg sees it, by providing this service, he's saving lives. Sam and Dean wouldn't be able to stop the carnage if Clegg's customers were left to their own devices. No one could. "You should be thanking me."
To quote "The Benders" from Season 1: "Demons I get. People are crazy."
Donna administers the cure to New Doug as Dean races to Sam. She asks again some more if it's going to work. Dean says it worked on him.
And let's just push pause to remember one of Show's greatest moments.
The auction is going hot and heavy on Sam. His liver sells for $5,000 before Clegg opens the bidding on his heart.
Dean and Donna arrive at another abandoned building and split up. Donna finds Wendy but is soon set upon by Larry. She brains him with a crowbar and puts his own knife through his heart.
Sam's heart meanwhile tops out at $500,000. It's his expression when Clegg announces the winning bid that makes the moment sing. Like, he's about to die but yet also quietly pleased at his market value. Also, the comments that accompany the auction – people complaining about other bidders driving up the price at the last minute – is like every Creation Entertainment Meet & Greet auction ever.
Clegg tells Sam that he usually does the next part slow – so the victim can feel it and the online audience can enjoy it – but with Dean still in play, he's opting for quick and dirty instead. Not quick enough. Dean shoots him first. "Show's over."
Donna sits at the motel keeping watch over New Doug. He swims back to consciousness with a loud gasp. Donna calls him Dougie-bear. Dean confirms that New Doug doesn't want to bite any of them and Donna unlocks the handcuffs. He immediately asks about Wendy and Donna tells him she's safe and in the hospital. She's going to be fine, just like Doug.
"Fine? I was a vampire."
Donna tries to force a bright smile. Just for a couple of hours …
New Doug is not comforted.
Dean welcomes him to the family. He says he knows New Doug has had a lot of day. But now he knows what's out there, it would be nice to have another good guy on their side.
New Doug is like,
The smile slides off Donna's face. She takes his hand. New Doug pulls away. He says that maybe they can live this life, but he can't. Donna apologizes for lying to him but says she can't give up hunting. New Doug says he knows. He is full of nothing but pride and admiration for her. But it's not enough.
"Donna, you kill monsters. You're a damn hero. But that's not me."
He says he's sorry. He says he loves her. He walks away.
Sam tells her to let him go. It's for the best. "When you choose this life, anyone who gets too close, eventually they get hurt. Or worse. So let him go. He'll be safer that way."
Dean puts a comforting hand on Donna's shoulder as the tears start to fall. I'd also like to think he offered her the comfort of his pantaloons in the back seat of the car. But that's just me writing fanfic in my head again.
As the boys drive through the night, Dean observes that Sam was not at his caring and sharing best with Donna. Sam is like, was I wrong? He asks when knowing them has ever worked out – for anyone? He acknowledges that they save people, but they also get them killed. He brings up Kaia. He says she helped them and she died for it. He does not mention that they only needed her help because Dean THREATENED TO SHOOT HER IN THE FACE AND KIDNAPPED HER. That really needs to be addressed at some point.
I also think it's interesting to contrast this conversation to a similar one the boys had in "Baby". When Sam asked Dean if he didn't ever want something more with someone who understood the life. Sam still had a spark of hope then. Dammit, Bob Seger, he wanted tomorrow, not just tonight! But after losing Eileen last season (which is still some bullshit, never forget) and Mary and Jack now, that spark seems to have been crushed.
Oh, Sam!
He angrily pushes back when Dean says he's just in a dark place. To Sam that suggests a temporary state, but he says the dark place IS their lives. The dark place is why they can't have nice things. "This ends one way for us, Dean. It ends bloody. It ends bad."
Dean can't exactly argue when he's been saying the same thing FOR TEN YEARS.
So he says nothing and keeps his eyes on the road.
Supernatural airs Thursday at 8:00 p.m. (Eastern) on The CW. Whitney also watches Timeless and (sometimes) Outlander. Follow her on Twitter @Watcher_Whitney.
Tagged Brianna Buckmaster, castiel, dean winchester, donna hanscum, jared padalecki, jensen ackles, misha collins, New Doug, sam winchester, spn, supernatural, the cw, vampires
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3 thoughts on "'Supernatural': But that's not me"
Maureen Gallagher says:
"Like, he's about to die but yet also quietly pleased at his market value."
This might be the most Sam Winchester thing in since the invention of Sam Winchester.
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Joe Polish with Tim Paulson
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Joe Polish is the President of Piranha Marketing, Inc., a publishing/training/coaching business based in Tempe, Arizona. A self-made millionaire, Polish has organized products, people, intelligence, and hundreds of joint ventures and strategic alliances in a unique way that has led not only to great personal success, but to success for thousands of others affiliated with him or influenced by him. Most of that success is the result of his discovery and application of direct-response marketing.
His integrated advertising, marketing, and business development system has been licensed and adapted for use in over ten industries. Polish is much in demand as a speaker, and he has been featured in numerous niche magazines and on television as an advocate against unethical advertising, most recently on ABC's 20/20. Outside of his business, he occasionally consults for clients who want to dramatically improve and reinvent their business.
Tim Paulson is one of the most valuable teachers or speakers you'll ever be exposed to! He is the former Vice President of the gigantic Hair Club for Men where he helped Hair Club grow from 8 offices to 69 offices during the time he was with the company. Tim is the founder and president of Prime-Time Business Institute, Inc., a marketing company based in Pleasant Grove, Utah, which specializes in helping business owners and doctors earn more money, in easier ways, while working less by "firing up" their marketing and sales. He also served as Vice President of Piranha Marketing where he helped teach "E.L.F." Strategies ("Easy, Lucrative, and Fun") to business owners worldwide. Known as 'The Head Coach of Marketing'
Piranha Marketing
by Joe Polish & Tim Paulson
In Piranha Marketing, famed marketing renegades Joe Polish and Tim Paulson reveal their radically different, consistently proven system for turning any business into a profit-generating machine that operates at full tilt 24 hours a day, seven days a week. This program system has helped thousands of entrepreneurs add millions of dollars to their bottom lines. Learn More


text:
Q: c++ templates generation times Hi everyone I've a question about templates in c++.
I would like to explain what I wonder via an example. Lets max() will be our template function:
template <typename Type>
Type max(Type tX, Type tY)
{
    return (tX > tY) ? tX : tY;
}

Now, when i call this max in my main, for each call does the compiler generate the function
and replaces the templates type with actual types ?
I mean;
int main()
{
int result1,result2;
float result3;

result1=max(3,5);
result2=max(10,12);
result3=max(4.5,12.2);
return 0;
}

In here  max will be copied 3 times and replaced its parameters or something else ? Is there anyone who can help me ? Thanks in advance.

A: My understanding is that a compiler typically resolves templates once per data type per compilation unit. And the linker does clever stuff to stop code bloat: i.e. multiple copies of the same function across all compilation units are condensed into 1. The early Microsoft C++ linkers didn't bother doing any such thing and the generated code was large.
In your example I would expect two functions to be generated; one with two arguments and one with four.
Ah - I see you've edited the post to have two floating point parameters in the last case rather than four integral types.

redpajama_set_name: RedPajamaStackExchange


In his last radio interview with Patricia Marx in 1968, Thomas Wilfred reiterated his vision of Lumia as "a unique art form to be performed." Trent Kim as a practice based researcher is currently working towards realising Wilfred's last vision of Lumia through his Heuristic research. In this presentation, Trent Kim proposes the concept of fold to close-read and advance Wilfred's theories and practices of Lumia.
Trent Kim is a Glasgow based artist. He works with a range of media from theatre lighting, video art to ink print and Lumia. Currently he teaches full time in BA(Hons) Technical Theatre and Production and BA(Hons) Digital Art and Design at University of the West of Scotland, and studies part time as a research student at the Royal College of Art in London. Trent teaches in MRes Creative Practices at the Glasgow School of Art as a visiting lecturer and supervisor and has guest lectured at the University of Glasgow, Royal Conservatoire of Scotland, Kyunsung University and Yale University. In his research, Trent revisits the performed Lumia by Thomas Wilfred and argues the importance of developing the 'embodiable language of Lumia' and borrows the notion of fold from Deleuzian reading of Leibniz.


My journey at Camp Living Stones began in January of 2011. I am continually amazed how God has prepared me for this season in my life. From working with my dad as a young boy and teenager in his restaurant, being in the housing industry, spending time in manufacturing, supervision and management, and being blessed continually by raising foster children. The list could go on and on. I see every aspect of my life having been put together for what God is doing now. It is a tremendous blessing to be able to live at CLS, to work with staff that desires Christ above all, and to see God working and moving in students, adults, and counselors lives.
I originally came to CLS to serve as maintenance and grounds supervisor. That grew into leading students and adults in mission activities at camp and in our community- out of which God birthed "Livin' the Mission" which encourages participants to live out Acts 1:8 in a practical everyday walk of life. Then, when Mom and Pops retired from their ministry serving in the kitchen I stepped into that role. As CLS continues to evolve, I've moved into an administrative position as President/Camp Director.
God has blessed me with a beautiful wife (married in 1982) and wonderful children and grandchildren. It is my desire to live life following Jesus and I am thankful He has allowed me to follow Him here to CLS.
A little about myself: I am currently 25 years old, married to my wife Kathy for 2 years now. I am finishing up my seminary education, Lord willing. I grew up in Fredericksburg, Virginia and lived there for the majority of my life before going to college at Messiah College in Pennsylvania and lived most recently in Wake Forest, North Carolina. I was originally introduced to Camp Living Stones as a counselor in the summers of 2012 and 2013. It was during these summers that I felt called into full time ministry and directed my education accordingly. After I graduated college I attended seminary as Southeastern Baptist Theological Seminary. I was seeking employment at a church during this time but nothing ever came to fruition. I never anticipated that the rejection I was receiving was a blessing from God to allow me to apply for a dream job at Camp Living Stones.


The 26th annual Sacred Heart Cathedral School's National Junior Honor Society induction ceremony was held on Wednesday, February 15th. Seven eighth-graders and thirty-one seventh graders were individually presented NJHS certificates and pins by Mrs. Maki and Mr. Breen. The new inductees were also congratulated by Father David Boettner, Father Joe Reed, and Father Author Torres. In order to be eligible for NJHS, students must have an "A" average in academic courses and in conduct as well as at least eight service hours. Candles were lit as students, parents, and grandparents heard about the five areas highly esteemed by the Society: scholarship, leadership, service, character, and citizenship. Congratulations to all of our new NJHS members!


text:
Q: Create Node.js app that gets data from api and creates table in html file with that data We are working with this API:
https://jsonplaceholder.typicode.com/users
And I need to create a node.js app, that will
get users list from api and create an html file content from 0 with a table inside it about that users.
I have written down this task with html/css/js with fetch and it works and now I do not know how to do it with node.js.
For now, I only have this code:
const axios = require('axios');
const url = 'https://jsonplaceholder.typicode.com/posts';
axios.get(url)
.then(function (response) {
    //console.log(response.data);
    let arr = [];
    arr = response.data;
    fillTheTable(arr);
  })
.catch((error) => console.log(error));

A: I would recommend you to use a minimal MVC Express App:
At app.js you start the server:
var express = require('express');
var app = express();
var index = require('../controllers/index');

app.set('views', path.join(__dirname, 'views'));
app.set('view engine', 'pug');

app.get('/', function (req, res) { // index url of your web app. Will call to index controller
  index
});

app.listen(3000, function () {
  console.log('Example app listening on port 3000!');
});

At controlles/index.js you specify the logic of your main url (get the data of your API and render it to a view to transform to HTML):
const axios = require('axios');

const asyncUtil = fn =>
    function asyncUtilWrap (req, res, next, ...args) {
        const fnReturn = fn(req, res, next, ...args)
        return Promise.resolve(fnReturn).catch(next)
    }

module.exports = {
  index: asyncUtil(async (req, res, next) => {
      let users = await axios(url)
      res.render('index', {users})
  })
}

You will specify the HTML in a pug view at views/index.pug, that will transform it to HTML:
table
  thead
    tr
      th Id
      th Name
      th Username

  tbody
    each user in users // iterate through users json
      tr
        td #{user.id}
        td #{user.name}
        td #{user.username}


text:
Home / Movies / Shadowzone (1990)
Shadowzone (1990)
August 16, 2010 Alex
Full MoonMonstersSci-fi
This is one of the earlier Full Moon productions. You can tell they were really trying to be series at this stage, so there isn't much camp involved. Shadowzone is played as a straight sci-fi movie and in that respect is works. Despite a few odd characters the only silliness comes from seeing the monster at the end, but overall it's solid.
When a movie is neither so bad nor so good, I'm really forced to go through with a plot oriented review. I don't like these as much, as I have to avoid spoilers while still trying to at least say something about the movie. Plus they're a little drier. If possible, I prefer to ramble on in a stream on consciousness and vaguely touch upon the movie from time to time. [break]
So here we go. At an underground research bunker, experiments are taking place to study dreams. It's currently getting government funding, so when one of the subjects dies during one of the tests, an official is sent down to see exactly what's going on, both from a financial and ethical standpoint.
His initial findings show some eccentric characters running the show, but nothing out of the ordinary. He sees male and female test subjects in some tubes, who appear to be sedated, but he is assured that everything is fine. Finally they decide to show him one of the tests to prove that everything is on the up and up. But as fate would have things don't go right. In fact they go so wrong that the man's head explodes. I imagine they tested on the guy first in order to provide a stronger subject for the test, but more likely in the interest to not have a nude man wander around for the rest of the movie.
This brings down the majority of the power to the facility, so we end up with an 'Aliens' feel for the next half hour as people are randomly killed. By the time the power comes back on, there are only a few people left which is convenient. Backing up a bit, it turns out that when we dream, we actually jump into another dimension. But by trying to control that connection, a hole was ripped and the other side started coming to us. And that other side wasn't pretty.
So we assume funding won't continue for the project, but that matters little since there really isn't anyone left to run it and most of the equipment is trashed. There really isn't much resolution either aside from some near misses with ruining the world, and a freeze frame leading into credits has always been one of my less favorite ways to end a movie. But overall this movie was pretty solid. It bridges the insanity that I hope for, and a traditional serious release, so it's not all that bad.


text:
Kaiserin Yin (, Geburtsname unbekannt; † wohl 102) war eine Kaiserin der Han-Dynastie. Sie war die erste Gemahlin des Kaisers He.

Sie war die Tochter von Yin Gang, dem Enkel des Bruders von Kaiser Guangwus Gemahlin Kaiserin Yin Lihua, Yin Shi. Yin wurde 92 zur kaiserlichen Konkubine erkoren und wurde eine von Kaiser Hes Lieblingsfrauen. Sie wird als schön, aber schroff und unbeholfen beschrieben. Sie soll oft nicht in der Lage gewesen sein, die kaiserlichen Zeremonien mit der gehörigen Grazie auszuführen. Sie soll außerdem wegen ihrer edlen Abstammung sehr arrogant gewesen sein.

Im Jahre 96 erhob Kaiser He sie zur Kaiserin. 97 machte er ihren Vater Yin Gang zum Marquis von Wufang.

Mit den Jahren verlor Kaiserin Yin die Zuneigung ihres Gemahls, weil sie auf seine Konkubine Deng Sui heftig eifersüchtig war, die ihrerseits eine edle Abstammung hatte. Anders als die Kaiserin wird Deng Sui als untertänig und friedfertig beschrieben.

Als Kaiser He einmal erkrankte, ließ Kaiserin Yin die Bemerkung fallen, dass sie als Kaiserinwitwe einst die Deng-Sippe auslöschen würde. Als Deng Sui das hörte, wollte sie sich das Leben nehmen, aber eine ihrer Dienerinnen erzählte ihr, der Kaiser habe sich bereits erholt, auch wenn das zu diesem Zeitpunkt eine Lüge war. Bald trat dies auch wirklich ein und Deng Sui entkam mit ihrer Familie einem grausamen Schicksal.

Im Jahre 102 wurden Kaiserin Yin und ihre Großmutter, Deng Zhu, der Hexerei gegen die Konkubinen angeklagt. Deng Zhu und Kaiserin Yins Bruder Yin Fu starben unter Verhören und Folter. Kaiserin Yin wurde abgesetzt, und ihr Vater Yin Gang tötete sich selbst. Der Rest ihrer Sippe wurde verbannt. Sie starb wahrscheinlich noch im selben Jahr an Kummer. Nach ihrer Absetzung wurde Deng Sui zur Kaiserin erhoben.

Kaiserin der Östlichen Han-Dynastie
Han-Dynastie
Geboren im 1. Jahrhundert
Gestorben im 2. Jahrhundert
Frau

redpajama_set_name: RedPajamaWikipedia


How would you feel if you stop your car at a traffic light, and suddenly a stranger hopped in? He gives you orders — "Turn left… slow down… that way.." You would naturally feel confused and perhaps frightened. That is probably was how St. Peter felt when Jesus suddenly hopped into his boat and began giving him orders. Fortunately, St. Peter chose to obey Jesus' orders and enjoyed the blessings he received for following him. Based on the readings of Isaiah 6: 1-8; 1 Corinthians 15: 1-11; & Luke 5: 1-11.


I really like him as a later round prospect. one of our 5ths?
I love his length and feet. I keep seeing people pumping up Tytus Howard, but when I see the two side-by-side, Oli is the better tackle.
I don't think he makes it out of the 3rd.
The best value for OL will be in rounds 2 and 3 this year. There's probably 6-8 OL that'll be great.
They are both very good developmental prospects. They are darn near the same prospect in what they offer and how far they need to improve. Watching them both at the Senior Bowl there were reps that Howard looked far better than Udoh and then he had reps where he looked far inferior. Oli Udoh has been steady eddie since the offseason began and its been steady improvement which is a great thing. Tells you that he is coachable. Overall I think Howard can be just as good. I wouldn't be mad at either pick.
I love combine season. A bunch of guys getting excited talking about liking how long other guys are and how much they want guys with big hands.
Add D.K. Metcalf to the list of guys the Browns have talked to at the combine.
WR is not even in our top 4 in our positions of need imo. Maybe if we don't resign Perriman but even then it is not a bigger need then DT, DE, LB, and 2nd CB. Plus on top of that, in all of Dorsey's time being a GM he has picked exactly 1 WR in the 1st round and if I remember correctly it was his 2nd year calling the shots. I think (especially in this draft) that we can get way better value in or around the 3rd round with a lot of great talent sitting there not to mention D.K.'s very troubling injury history. I don't hate the guy at all (you know cause I've never met him), I just think the Browns should fill a gaping hole of a need in the 1st round instead of a drip. Just my opinion and how I see the situation and I am by no means an expert as many in this forum can attest too.
I am by no means an expert as many in this forum can attest too.
And as fewer, if any, can claim they are.
If he is clearly BPA you go get him. Drafting for need is a ****ty way to manage a football team.
Btw I'm still not caught up on prospects in the draft. Just saying I'm a BPA guy, especially with a danged bonafide franchise freaking qb.
Marquise Brown indicated he had a meeting with the Browns scheduled for Friday night. He is not working out as he recovers from Lisfranc surgery on his foot. Weighing in at just 166 pounds and with the injury issue, his draft stock is probably not as high as the second-round projections from before the combine.
That is only because they had already made a promise to Bob Wylie to get some diet tips from him, before he was let go, and they felt compelled to follow through on that committment.
Yeah, no need to spend 17 on a T imo, but if they can grab one day 2 and redshirt him, we'll start to have the makings of a truly fantastic line with both elite talent and depth.


text:
by Dan Weiss
listen on Pitchfork
"Beggar's Bowl"
Between the fawning over the new Dinosaur Jr. and attention paid to Trent Reznor's personal dealings, it's conceivable that Polvo might have just thawed out and haven't yet realized what year this is. They hit the snooze and went to the studio in business-as-usual, time-to-release-our-next-record-cuz-it's-1995 mode. That's when their Chapel Hill brethren were clamoring to be on labels like Merge, and labels like Merge weren't making commemorative DVDs. And aghast, rock was still getting held back in math class year after year. But these early warriors of let-x-equal-x reappear in a time where something called doom metal not only exists but is maxing out its credit options over choir-vs.-orchestra dilemmas formerly reserved for like, Live. Polvo used to sound like Drive Like Jehu or Les Savy Fav or least one of those groups whose riffs zing-zang into a wall and then crawl up the ceiling rather than banging into it over and over. These days, they'll apparently settle for banging. With higher production values now easier to attain, Ash Bowie and Dave Brylawski up the dynamics and reach for a new metallic crunch. The punishing "Beggar's Bowl" has clean, echoing tones laid on top of the heaviness, and here, vocals are less essential than the drums or guitar overdubs. They may not give a reunion like Mission of Burma a run for its money, but if Polvo occupy a weird space nowadays, it's because they still sound so much like themselves.


text:
Ó Caoláin - Irish government has bowed to Unionist veto
Commenting on the British government's postponement of the Assembly elections, Sinn Féin Dáil leader Caoimhghín Ó Caoláin TD, said the Irish Government has "bowed to the unionist veto" and he called for a special Dáil debate and Question and Answer session next week. He said:
"The British government's postponement of the Assembly elections is an insult to democracy in Ireland. They are denying the electorate their right to make a judgement on the conduct of the political parties in the peace process and they are reinforcing a unionist veto on progress.
"It is disgraceful that the Irish Government has also bowed to the Unionist veto. In chorus with Tony Blair, the Taoiseach Bertie Ahern has claimed that the clarifications sought and received from republicans are not enough for him. But the Taoiseach knows well that republicans are totally committed to the peace process and to the Good Friday Agreement. In reality all this is a desperate effort to protect David Trimble, despite the fact that he now leads a party that effectively rejected the Agreement.
"The weakness of the Irish Government in the face of British government support for unionist intransigence is a major flaw
"Sinn Féin is also calling for a special Dáil Debate and Question and Answer session with the Taoiseach and Minister for Foreign Affairs next week." ENDS


Patio enclosures Etobicoke is one of the smartest (and strategic) maneuvers a homeowner can make, to capture useable space and to extend the square footage of the interior of their home! Our company and team of enclosure specialists know just how much enjoyment our Canadian homeowners have via their patios (extension of entertainment space, sun-tanning, outdoor cooking, etc.), and when they are enclosed, homeowners see even bigger benefits and perks! The patio space that is a big part of your home is your direct space that connects you to the world outside. Many homeowners want to 'bring the outside inside' for its health benefits and year long enjoyment. Creating your own space that is tranquil & personalized is exciting, creating a space that extends your entertaining capacity, or, a great place to just sit and enjoy the outdoors…the possibilities available to you are endless.
A great first step is to ascertain if your new patio enclosures Etobicoke will be used in all seasons, some seasons, as a privacy shield, or just as a protective and enjoyable guard against the hot sun and pesky insects. There are traditional patio enclosures that are sometimes called sunrooms, there are patio covers only, three season patio enclosures, four season patio enclosures, solariums and screened patio enclosures (our helpful team of enclosure specialists can help you to narrow down your choices and keep you within your budget). Patio enclosure materials individually perform with different pros and cons, and some of the resulting patio enclosure materials will be dictated by the exterior façade of the home, roof structure, dimensions of the enclosure and its overall anticipated use.
The interior and exterior finished patio enclosures Etobicoke will not only enhance your new, expansive views to the outside world, but patio enclosures also add fresh air ventilation perks, allow loads of natural sunlight and block unwanted drafts, adding energy efficiency. Patio enclosure extras you can optionally add into your design are tempered glass, insulated knee-walls or kick plates, in-swing doors, customized sills, sliding doors to save on space in smaller areas, transoms & sidelites and modern hardware & security options, just to name a few. We offer our customers other options like DIY kits for homeowners that prefer to install their patio enclosure themselves, or with the assistance of a professional.


The VLS-128 is in a preliminary R&D stage and is not released for sale yet. Information and A-Samples are available on request.
The Velodyne VLS-128 is the world's most advanced and capable 3D LiDAR sensor for autonomous vehicles. As a culmination of ten years of LiDAR development and learning from millions of road miles, the VLS-128 is a sensor specifically made for autonomous driving and advanced vehicle safety at highway speeds. It provides real-time 3D data up to 0.1-degree vertical and horizontal resolution with up to 300-metre range and 360° surround view. The VLS-128 provides the range, resolution and accuracy required by the most advanced autonomous vehicle programmes in the world.


text:
A powerhouse on the Pee Dee River
Producing power for more than a century, Blewett Falls Hydro Station in Lilesville, N.C., recently was inducted into Hydro Hall of Fame
Kim Crawford illumination Contributor
Located on the Pee Dee River in south-central North Carolina, Duke Energy's Blewett Falls Hydro Station has been providing clean, renewable energy since 1912. The plant in June was inducted into the Hydro Hall of Fame at the HydroVision International convention in Charlotte, N.C. The hall of fame recognizes hydropower projects from around the world that have been in continuous operation for more than a century.
It all started in the 1700s when William Blewett applied for land grants to operate a fishery and ferry on the river. Later, the expansion of the textile industry created interest in using the river to provide power to build and operate cotton mills, power companies, railways, and telephone and telegraph systems.
Hugh MacRae, a land developer from Wilmington, N.C., saw the potential at Blewett Falls and in 1905 obtained a charter for the Great Pee Dee Electric and Power Co., which later became Rockingham Power Co. Work on Blewett Falls dam began in 1905, with the help of as many as 1,200 men, the dam was completed in December 1911, and the plant started producing power in February 1912.
Duke Energy's conventional hydro stations help add other renewables, like solar, to the energy grid since these units can be brought online quickly to help manage rapid shifts in power demand.
Dam construction
Work on the Blewett Falls dam began in 1905. An economic panic in 1907 and floods the following year caused Rockingham Power Co. to fall into receivership. The property, which was 80 percent complete, was sold at auction in 1909 for $1 million to the Yadkin River Power Co., which merged in 1926 with Carolina Power & Light.
The dam today
Blewett Falls' concrete gravity dam has a maximum height of about 50 feet above the riverbed and forms Blewett Falls Lake. After flooding in 1917 and 1945, earthen embankments were added, the intake dam was raised and 4-foot flashboards were installed along the dam.
Water wheel construction in 1911
The plant's water wheels, or turbines, installed in 1911, move water through the powerhouse to create electrical energy.
Inside the power house
The station still operates the original six horizontal generating units and has a total generating capacity of 24.6 megawatts, enough to power about 20,000 homes.
The historic building
A four-story brick structure, the Blewett Falls powerhouse was deemed eligible for listing on the National Register of Historic Places in 2006. A fishing platform added in the 1990s abuts the downstream side of the building over the intake structures.
The building reflects the style of other powerhouses of the period, with arched windows, a spiral staircase and a covered passageway with arches in the basement.
Concrete flood plug
Changes over the years include adding two large concrete flood plugs in the powerhouse basement. As a last resort in extreme flooding, the plugs can be hoisted from an opening in the floor to allow water to flood the plant. The ballast counteracts the buoyancy of the plant, preventing the powerhouse from floating away. The flood plugs were opened only once: in 1945.
Blewett Falls Hydro Station
Blewett Falls Lake extends 10 miles upstream from the dam, encompassing 2,866 acres. At full pond elevation, the lake contains about 34 linear miles of shoreline and provides numerous recreation opportunities.
Tags: hydro, North Carolina
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