text:
A coroner is a judicial officer, usually a qualified doctor or lawyer, who is responsible for investigating the circumstances surrounding any death which occurs under unusual or unnatural circumstances, or is thought to be due to certain industrial diseases. A coroner also becomes involved in the investigation of deaths which occur during surgical procedures, whilst under an anaesthetic, whilst in the custody of the police or in prison, or in circumstances where the cause of death is in some way unclear.
The coroner may request that a pathologist perform a post-mortem examination of the deceased (an autopsy) in order to look for signs of disease or injury that may account for the death. Additionally, a coroner may consider it necessary to hold a formal enquiry into the individual case, called an inquest.
Who is it that has died?
When and where did the death occur?
How did the determined cause of death come about? What was the nature of the death, and what was the nature of the contributory events preceding it?
An inquest is usually opened in the first few days following the death, in order to record the fact of death, and is then subsequently adjourned. The inquest is re-opened and completed once all necessary police enquiries and coroner's investigations have been completed.
An inquest is not a criminal trial. It is an inquiry into the facts surrounding a death. It is not the job of the coroner to place blame or responsibility for the death, as a trial would do. However, the coroner does have the power to investigate not just the main cause of death, but also "any acts or omissions which directly led to the cause of death".
What are the possible verdicts of an inquest?
Are witnesses called to an inquest?
The coroner decides who to ask and the order in which they give evidence. Any person who wants to give evidence can come forward at an inquest without being summoned by the coroner, but the evidence must be relevant to the inquest. A person who wants to give evidence should contact the coroner as soon as possible after the death.
The evidence of a witness may be vital in preventing injustice, and they may have to pay a penalty if they do not attend. A witness will normally receive a formal summons to attend the inquest. In certain circumstances, a signed statement or other document may be given in evidence.
Anyone who has "a proper interest" may question a witness at the inquest. They may be represented by lawyers or, if they prefer, ask questions themselves. The questions must be sensible and relevant. This is something the coroner will decide. There are no speeches.
Any other person the coroner determines to have a "proper interest"
Can a funeral be held before the completion of an inquest?
Under normal circumstances, it is possible to hold a funeral, with either a burial or a cremation, before the formal completion of the inquest. The coroner will issue the relevant documentation permitting the funeral director to undertake proper disposal of the body.
However, there may be some delays and restrictions in certain types of cases, particularly those relating to cases of unlawful killing, homicide, road traffic accidents etc. A coroner's officer and your funeral director will be able to advise you on the individual circumstances of your particular case.


text:
60%67°46°Cloudy with a high of 67 °F (19.4 °C). Winds from WNW to W at 8 to 9 mph (12.9 to 14.5 kph).Night - Showers with a 60% chance of precipitation. Winds variable at 9 to 17 mph (14.5 to 27.4 kph). The overnight low will be 46 °F (7.8 °C).
25%62°45°Rain today with a high of 62 °F (16.7 °C) and a low of 45 °F (7.2 °C). There is a 25% chance of precipitation.
10%60°46°Mostly cloudy today with a high of 60 °F (15.6 °C) and a low of 46 °F (7.8 °C).
0%63°48°Partly cloudy today with a high of 63 °F (17.2 °C) and a low of 48 °F (8.9 °C).
Today - Cloudy with a high of 67 °F (19.4 °C). Winds from WNW to W at 8 to 9 mph (12.9 to 14.5 kph).
Tonight - Showers with a 60% chance of precipitation. Winds variable at 9 to 17 mph (14.5 to 27.4 kph). The overnight low will be 46 °F (7.8 °C).

industry_corpus2: Media & Journalism


text:
I cleaned up and updated my To-Do List and renamed it to “Entertainment To-Do List.” It only had to do with entertainment anyways. I don’t know if I’ll keep it updated, but I removed the crap I don’t want to do. There’s a link to it on the left.
This entry was posted in Featured Content on August 1, 2004 by TheUser.

industry_corpus2: Film & Entertainment


text:
When we got home from our night away at Ross Bridge, I jumped in the shower to get cleaned up for the Cub Scout popsicle party.
The eagle-eyed among you will notice some of the as-yet-unshared details of her redecorated room (curtains, bright-white board-and-batten wall treatment, BRAND-NEW GREEN RUG COVERED IN BABY POWDER).
And he hadn't stopped there. He'd also shaken it all over the inside of the drawer from whence the baby powder had come.
I was fit to be tied. I did what some might call "raise my voice." And what SOME might call "yell at the top of my lungs."
It was abundantly clear that Jake was the culprit.
I have no idea what possessed him to do it, other than curiosity and the fact that it seemed fun at the time. Oh, and he ALSO peed on the gliding rocker in the corner of the room, which ran into the carpet. He's never done anything like either of these two things before, not even as a much younger baby.
He says it has nothing to do with Amelia. We'll see.
For now, I was able to clean up the mess, and the room just smells a whole lot like a really clean baby's bottom. There are worse things, I suppose.
Awwwwww, Mama, how could you mad at that precious little face? LOL I'm sure I would have lost it and yelled a little too!
Wow! Oh my! Just...wow! How pitiful and oh how angry I would have been. I still get mad when my kids pull stunts like this. And, love the curtains.
You will find this funny one day, I promise!!!
If it wasn't so obvious who did it from the powder covering him as well as the room, the "I am SO guilty" look on his face would've surely given him away. Sorry but I just guffawed loudly at this post. I am still giggling in fact. He's just marking his territory, Mom. Don't forget. He was here FIRST. Next time it might be the baby herself covered in powder. Lest she forget as well. :) Love you, Kat. Hang in there.
I am not sure how absolutely crazed I would have been at the moment of the door opening. I think the drawer filled with powder would have sent me over the edge. So sorry that you had to face that when you were in a hurry AND tired. It's called Motherhood!
Nice. So glad I'm not the only one who has these moments.. . . If you could only meet my youngest.
my niece climbed on the TOP of the chest of drawers with the largest container of powder. the ceiling fan was on. Looked like a blizzard. I think I heard the screetch all the way over here. If I remember she got into a little trouble over this. Her Dad apoligized to his Mom since everyone said the little one was just like him.
Oh, my! I have never been able to take photos of the 'scene of the crime' - although it would've been pretty cool to get one of my J the day he decided to buzz the center front of his head and then act like nothing happened. (It was the Saturday evening before Mother's Day, and I was nearly in tears - from shock/sadness.) Also, I am sure I would have lost my temper - especially over the powder in. the. drawer.
By the way - love the curtains and rug! Can't wait to see how the nursery has come together!
When my oldest daughter was around 2 (about 25 years ago). She proudly came out of the playroom with a bottle of babypowder in her hand and proclaimed "I dusted Mama!" She sure did. Thanks for the memory and you too will add this to the story of Jake as years unfold.

industry_corpus2: Others


text:
The real estate market in Germany still offers opportunities compared to other European member states. Hence, investment into the German market can be quite beneficial.
Who should the acquirer be?
Will the investment be a long-term or a short-term one?
In principle, with each direct or indirect transaction of German real estate, German real estate transfer tax (RETT) will be triggered. Depending on the location of the real estate in Germany, RETT rates range between 3.5% - 6.5%. RETT arises irrespective of whether the real estate itself is sold or a company which owns the real estate is transferred (share deal). Hence, in case the real estate needs to be moved within a group, return on investment may be reduced by unnecessary German RETT. By choosing the optimal position of the real estate from the beginning, this can be avoided. It is even more important when considering that RETT exemption rules apply only to a limited range of scenarios.
The decision where to place the real estate determines the effcient yearly taxation as well as the effect of a potential exit taxation of the German real estate. With a good and forward planning, for example, the yearly taxation can be reduced by half (e.g. 15.825% instead of approx. 30%) or the exit taxation can be entirely avoided. Another benefit may be reducing the administration cost in Ger- many when choosing a carefully planned structure.
The information given above shows that before investing in German real estate, the structure should be considered carefully in the context of RETT and potential exit taxation. Furthermore, crossborder scenarios might even provide an opportunity to save taxes.
Ingo Prang is a German certified tax advisor and Partner of KPP. In addition, he lectures on comparative business taxation at the Rhine-Waal University of Applied Sciences.
During the past 20 years, KPP has become one of the leading tax consultancy offices in Lower Rhine region of Germany. The company offers taxation, legal and consulting services. As KPP is close to the Netherlands, the company has acquired considerable expertise in advising on cross-border matters, especially for foreign companies investing in Germany.

industry_corpus2: Real Estate & Construction


text:
Full-service architectural design and documentation services, from conceptual design through to construction administration and acquisition of a certificate of occupancy.
Coordination and management of project design teams across disciplines.
Sustainable design and adaptability studies for refurbishment and renovation projects.
Site planning and master planning.
Programming of both new and existing developments.
Development of design guidelines for existing and future developments.
Tracking, verification and implementation of LEED requirements.
Mechanical, electrical, and plumbing engineering.
Specialized energy and sustainable systems design.
Start the conversation about your next project and how we can help.


text: Enter your comments about your experience at Maple Pool Campsite in Courtenay, British Columbia. Please do not include requests for booking or reservation information or ask for other contact details in relations to the property owners. Any such requests will be removed from the review system.

industry_corpus2: Hospitality & Catering


text:
La Polla Records Plaza de Toros de Valencia, Valencia, Spain Cheapest in Valencia! This event has the cheapest La Polla Records tickets in Valencia available on our site.
Cheapest in Madrid! This event has the cheapest La Polla Records tickets in Madrid available on our site.
Cheapest in Ansio-Barakaldo! This event has the cheapest La Polla Records tickets in Ansio-Barakaldo available on our site.
Cheapest in Barcelona! This event has the cheapest La Polla Records tickets in Barcelona available on our site.


text:
Each vial of powder for concentrate for solution for infusion contains 5 mg gemtuzumab ozogamicin.
After reconstitution (see section 6.6), the concentrated solution contains 1 mg/mL gemtuzumab ozogamicin.
Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of the CD33-directed monoclonal antibody (hP67.6; recombinant humanised immunoglobulin [Ig] G4, kappa antibody produced by mammalian cell culture in NS0 cells) that is covalently linked to the cytotoxic agent N-acetyl gamma calicheamicin.
MYLOTARG is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukaemia (AML), except acute promyelocytic leukaemia (APL) (see sections 4.4 and 5.1).
MYLOTARG should be administered under the supervision of a physician experienced in the use of anticancer medicinal products and in an environment where full resuscitation facilities are immediately available.
MYLOTARG should be used only in patients eligible to receive intensive induction chemotherapy.
Premedication with a corticosteroid, antihistamine, and acetaminophen (or paracetamol) is recommended 1 hour prior to dosing to help ameliorate infusion-related symptoms (see section 4.4).
Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemic or other agents for treatment of hyperuricaemia should be taken (see section 4.4).
The recommended dose of MYLOTARG is 3 mg/m2/dose (up to a maximum of one 5 mg vial) infused over a 2-hour period on Days 1, 4, and 7 in combination with DNR 60 mg/m2/day infused over 30 minutes on Day 1 to Day 3, and AraC 200 mg/m2/day by continuous infusion on Day 1 to Day 7.
MYLOTARG should not be administered during second induction therapy.
For patients experiencing a complete remission (CR) following induction, defined as fewer than 5% blasts in a normocellular marrow and an absolute neutrophil count (ANC) of more than 1.0 × 109 cells/L with a platelet count of 100 × 109/L or more in the peripheral blood in the absence of transfusion, up to 2 consolidation courses of intravenous DNR (60 mg/m2 for 1 day [first course] or 2 days [second course]) in combination with intravenous AraC (1,000 mg/m2 per 12 hours, infused over 2 hours on Day 1 to Day 4) with intravenous MYLOTARG (3 mg/m2/dose infused over 2 hours up to a maximum dose of one 5 mg vial on Day 1) are recommended.
MYLOTARG should not be administered during second induction.
a. See Table 3 and Table 4 for dose modification information.
b. For patients experiencing a complete remission (CR) following induction.
In patients with hyperleukocytic (leukocyte count ≥ 30,000/mm3) AML, cytoreduction is recommended either with leukapheresis, oral hydroxyurea or AraC with or without hydroxyurea to reduce the peripheral white blood cell (WBC) count 48 hours prior to administration of MYLOTARG.
See Table 1 for dose recommendations for consolidation course.
a. See Table 3 and Table 4 for additional dose modification information.
Dose modification of MYLOTARG is recommended based on individual safety and tolerability (see section 4.4). Management of some adverse reactions may require dose interruptions or permanent discontinuation of MYLOTARG (see sections 4.4 and 4.8).
Tables 3 and 4 show the dose modification guidelines for haematological and non-haematological toxicities, respectively.
• Postpone start of consolidation course.
• If platelet count recovers to ≥ 100,000/mm3 within 14 days following the planned start date of the consolidation course: initiate consolidation therapy (see as described in Table 1).
• If platelet count recovers to < 100,000/mm3 and ≥ 50,000/mm3 and within 14 days following the planned start date of the consolidation course: MYLOTARG should not be re-introduced and consolidation therapy should consist of DNR and AraC only.
• If platelet count recovery remains < 50,000/mm3 for greater than 14 days, takes longer than 14 days, or if platelet count does not recover to ≥ 50,000/mm3 consolidation therapy should be re-evaluated and a BMA should be performed to re-assess the patients' status.
• If neutrophil count does not recover to greater than 500/mm3 within 14 days following the planned start date of the consolidation cycle (14 days after haematologic recovery following previous cycle), discontinue MYLOTARG (do not administer MYLOTARG in the consolidation cycles).
Abbreviations: AML=acute myeloid leukaemia; AraC=cytarabine; BMA=bone marrow aspirate, DNR=daunorubicin.
Discontinue MYLOTARG (see section 4.4).
Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to ≤ 2.5 × ULN prior to each dose.
Consider omitting scheduled dose if delayed more than 2 days between sequential infusions.
Interrupt the infusion and institute appropriate medical management based on the severity of symptoms. Patients should be monitored until signs and symptoms completely resolve and infusion may resume.
Consider permanent discontinuation of treatment for severe or life-threatening infusion reactions (see section 4.4).
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; SOS=sinusoidal obstruction syndrome; ULN=upper limit of normal; VOD=venoocclusive disease.
No adjustment of the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤ 2 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN. Postpone MYLOTARG until recovery of total bilirubin to ≤ 2 × ULN and AST and ALT to ≤ 2.5 × ULN prior to each dose (see Table 4, sections 4.4 and 5.2).
No dose adjustment is required in patients with mild to moderate renal impairment. MYLOTARG has not been studied in patients with severe renal impairment. MYLOTARG does not undergo renal clearance, the pharmacokinetics in patients with severe renal impairment is unknown (see section 5.2).
No dose adjustment is required in elderly patients (≥ 65 years) (see section 5.2).
The safety and efficacy of MYLOTARG in patients less than 15 years of age has not been established. Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.
MYLOTARG is for intravenous use and must be reconstituted and diluted before administration (see section 6.6). The reconstituted and diluted solution should be administered intravenously by infusion over a 2-hour period under close clinical monitoring, including pulse, blood pressure, and temperature. MYLOTARG should not be administered as an intravenous push or bolus (see section 6.6).
Hepatotoxicity, including life-threatening, and sometimes fatal hepatic failure and VOD/SOS have been reported in patients treated with MYLOTARG (see section 4.8).
Based on an analysis of potential risk factors, adult patients who received MYLOTARG as monotherapy, either before or after an haematopoietic stem cell transplant (HSCT), and patients with moderate or severe hepatic impairment are at increased risk for developing VOD (see section 4.8).
Due to the risk of VOD/SOS, signs and symptoms of VOD/SOS should be closely monitored; these may include elevations in ALT, AST, total bilirubin, and alkaline phosphatase, which should be monitored prior to each dose of MYLOTARG, hepatomegaly (which may be painful), rapid weight gain, and ascites. Monitoring only total bilirubin may not identify all patients at risk of VOD/SOS. For patients who develop abnormal liver tests, more frequent monitoring of liver tests and clinical signs and symptoms of hepatotoxicity is recommended. For patients who proceed to HSCT, close monitoring of liver tests is recommended during the post-HSCT period, as appropriate. No definitive relationship was found between VOD and time of HSCT relative to higher MYLOTARG monotherapy doses, however, the ALFA-0701 study recommended an interval of 2 months between the last dose of MYLOTARG and HSCT.
Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (see section 4.2). In patients who experience VOD/SOS, MYLOTARG should be discontinued and patients treated according to standard medical practice.
In clinical studies infusion related reactions, including anaphylaxis were reported (see section 4.8). There have been reports of fatal infusion reactions in the post-marketing setting. Signs and symptoms of infusion related reactions may include fever and chills, and less frequently hypotension, tachycardia, and respiratory symptoms, that may occur during the first 24 hours after administration. Infusion of MYLOTARG should be performed under close clinical monitoring, including pulse, blood pressure, and temperature. Premedication with a corticosteroid, antihistamine and acetaminophen (or paracetamol) is recommended 1 hour prior to MYLOTARG dosing (see section 4.2). Infusion should be interrupted immediately for patients who develop evidence of severe reactions, especially dyspnoea, bronchospasm, or clinically significant hypotension. Patients should be monitored until signs and symptoms completely resolve. Discontinuation of treatment should be strongly considered for patients who develop signs or symptoms of anaphylaxis, including severe respiratory symptoms or clinically significant hypotension (see section 4.2).
In clinical studies, neutropenia, thrombocytopenia, anaemia, leukopenia, febrile neutropenia, lymphopenia, and pancytopenia, some of which were life-threatening or fatal, were reported (see section 4.8). Complications associated with neutropenia and thrombocytopenia may include infections and bleeding/haemorrhagic reactions respectively. Infections and bleeding/haemorrhagic reactions were reported, some of which were life-threatening or fatal.
Complete blood counts should be monitored prior to each dose of MYLOTARG. During treatment, patients should be monitored for signs and symptoms of infection, bleeding/haemorrhage, or other effects of myelosuppression. Routine clinical and laboratory surveillance testing during and after treatment is indicated.
Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of MYLOTARG (see section 4.2).
In clinical studies, TLS was reported (see section 4.8). Fatal reports of TLS complicated by acute renal failure have been reported in the post-marketing setting. In patients with hyperleukocytic AML, leukoreduction should be considered with hydroxyurea or leukapheresis to reduce the peripheral WBC count to below 30,000/mm3 prior to administration of MYLOTARG to reduce the risk of inducing TLS (see section 4.2).
Patients should be monitored for signs and symptoms of TLS and treated according to standard medical practice. Appropriate measures to help prevent the development of tumour lysis-related hyperuricaemia, such as hydration, administration of antihyperuricemics (e.g., allopurinol) or other agents for treatment of hyperuricaemia (e.g., rasburicase) must be taken.
The efficacy of MYLOTARG has been shown in AML patients with favourable- and intermediate-risk cytogenetics, with uncertainty regarding the size of the effect in patients with adverse cytogenetics (see section 5.1). For patients being treated with MYLOTARG in combination with daunorubicin and cytarabine for newly diagnosed de novo AML, when cytogenetics testing results become available it should be considered whether the potential benefit of continuing treatment with MYLOTARG outweighs the risks for the individual patient (see section 5.1).
Women of childbearing potential, or partners of females of childbearing potential should be advised to use 2 methods of effective contraception during treatment with MYLOTARG for at least 7 months (females) or 4 months (males) after the last dose (see section 4.6).
No clinical drug interaction studies have been conducted with MYLOTARG. See section 5.2 for available data from in vitro studies.
Women of childbearing potential should be advised to avoid becoming pregnant while receiving MYLOTARG.
Women of childbearing potential, or partners of females of childbearing potential should be advised to use 2 methods of effective contraception during treatment with MYLOTARG for at least 7 months (females) or 4 months (males) after the last dose.
There are no or limited amount of data from the use of gemtuzumab ozogamicin in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3).
MYLOTARG must not be used during pregnancy unless the potential benefit to the mother outweighs the potential risks to the foetus. Pregnant women, or patients becoming pregnant whilst receiving gemtuzumab ozogamicin, or treated male patients as partners of pregnant women, must be apprised of the potential hazard to the foetus.
There is no information regarding the presence of gemtuzumab ozogamicin or its metabolites in human milk, the effects on the breast-fed child, or the effects on milk production. Because of the potential for adverse reactions in breast-fed children, women should not breast-feed during treatment with MYLOTARG and for at least 1 month after the final dose (see section 5.3).
There is no information on fertility in patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with gemtuzumab ozogamicin (see section 5.3). Both men and women should seek advice on fertility preservation before treatment.
MYLOTARG has moderate influence on the ability to drive and use machines. Patients should be advised they may experience fatigue, dizziness and headache during treatment with MYLOTARG (see section 4.8). Therefore, caution should be exercised when driving or operating machines.
The overall safety profile of MYLOTARG is based on data from patients with acute myeloid leukaemia from the combination therapy study ALFA-0701, monotherapy studies, and from post-marketing experience. In the combination therapy study, safety data consisting of selected treatment emergent adverse events (TEAEs) considered most important for understanding the safety profile of MYLOTARG consisted of all grades haemorrhages, all grades VOD, and severe infections. All of these TEAEs were determined to be adverse drug reactions. Because of this limited data collection, laboratory data from the combination therapy study are included in Table 5. Information about adverse drug reactions from monotherapy studies and post-marketing experience is presented Table 6 in order to provide full characterisation of adverse reactions.
In the combination therapy study ALFA-0701, clinically relevant serious adverse reactions were hepatotoxicity, including VOD/SOS (3.8%), haemorrhage (9.9%), severe infection (41.2%), and tumour lysis syndrome (1.5%). In monotherapy studies, clinically relevant serious adverse reactions also included infusion related reactions (2.5%), thrombocytopenia (21.7%), and neutropenia (34.3%).
The most common adverse reactions (> 30%) in the combination therapy study were haemorrhage and infection. In monotherapy studies the most common adverse reactions (> 30%) included pyrexia, nausea, infection, chills, haemorrhage, vomiting, thrombocytopenia, fatigue, headache, stomatitis, diarrhoea, abdominal pain, and neutropenia.
The most frequent (≥ 1%) adverse reactions that led to permanent discontinuation in the combination therapy study were thrombocytopenia, VOD, haemorrhage and infection. The most frequent (≥ 1%) adverse reactions that led to permanent discontinuation in monotherapy studies were infection, haemorrhage, multi-organ failure, and VOD.
Abbreviations: N=number of patients; PT=preferred term.
**Only selected safety data were collected in this study of newly diagnosed AML.
***Frequency is based on laboratory values (Grade per NCI CTCAE v4.03).
a. Infection includes Sepsis and Bacteraemia (53.4%), Fungal infection (15.3%), Lower respiratory tract infection (5.3%), Bacterial infection (9.2%), Gastrointestinal infection (8.4%), Skin infection (2.3%), and Other infections (28.4%).
b. Haemorrhage includes Central nervous system haemorrhage (3.1%), Upper gastrointestinal haemorrhage (33.6%), Lower gastrointestinal haemorrhage (17.6%), Subcutaneous haemorrhage (60.3%), Other haemorrhage (64.9%), and Epistaxis (62.6%).
c. Venoocclusive liver disease includes the following reported PTs: Venoocclusive disease and Venoocclusive liver disease*.
**Including fatal adverse reactions in the post-marketing setting.
***MYLOTARG in the treatment of relapsed AML (9 mg/m2).
a. Infection includes Sepsis and Bacteraemia (25.6%), Fungal infection (10.5%), Lower respiratory tract infection (13.0%), Upper respiratory tract infection (4.3%), Bacterial infection (3.6%), Viral infection (24.2%), Gastrointestinal infection (3.3%), Skin infection (7.9%), and Other infections (19.5%). Post-marketing (frequency category unknown) fungal lung infections including Pulmonary mycosis and Pneumocystis jirovecii pneumonia*; and bacterial infections including Stenotrophomonas infection were also reported.
b. Thrombocytopenia includes the following reported PTs: Platelet count decreased and Thrombocytopenia*.
c. Neutropenia includes the following reported PTs: Neutropenia, Granulocytopenia and Neutrophil count decreased.
d. Anaemia includes the following reported PTs: Anaemia and Haemoglobin decreased.
e. Leukopenia includes the following reported PTs: Leukopenia and White blood cell count decreased.
f. Pancytopenia includes the following reported PTs: Pancytopenia and Bone marrow failure.
g. Lymphopenia includes the following reported PTs: Lymphopenia and Lymphocyte count decreased.
h. Infusion related reaction includes the following reported PTs: Infusion related reaction, Urticaria, Hypersensitivity, Bronchospasm, Drug hypersensitivity, and Injection site urticaria#.
i. Hyperglycaemia includes the following reported PTs: Hyperglycaemia and Blood glucose increased#.
j. Tachycardia includes the following reported PTs: Tachycardia, Sinus tachycardia, Heart rate increased#, and Supraventricular tachycardia#.
k. Haemorrhages include Central nervous system haemorrhage (5.1%), Upper gastrointestinal haemorrhage (21.3%), Lower gastrointestinal haemorrhage (15.2%), Subcutaneous haemorrhage (28.5%), Other haemorrhage (32.9%), and Epistaxis (28.5%).
l. Hypotension includes the following reported PTs: Hypotension and Blood pressure decreased.
m. Hypertension includes the following reported PTs: Hypertension and Blood pressure increased.
n. Dyspnoea includes the following reported PTs: Dyspnoea and Dyspnoea exertional.
o. Abdominal pain includes the following reported PTs: Abdominal pain, Abdominal pain lower, Abdominal pain upper, Abdominal discomfort, and Abdominal tenderness.
p. Stomatitis includes the following reported PTs: Mucosal inflammation, Oropharyngeal pain, Stomatitis, Mouth ulceration, Oral pain, Oral mucosal blistering, Aphthous stomatitis, Tongue ulceration, Glossodynia, Oral mucosal erythema, Glossitis#, and Oropharyngeal blistering#.
q. Transaminases increased includes the following reported PTs: Transaminases increased, Hepatocellular injury, Alanine aminotransferase increased, Aspartate aminotransferase increased, and Hepatic enzyme increased.
r. Hyperbilirubinaemia includes the following reported PTs: Blood bilirubin increased and Hyperbilirubinaemia.
s. Venoocclusive liver disease includes the following reported PTs: Venoocclusive disease and Venoocclusive liver disease*#.
t. Hepatic function abnormal includes the following reported PTs: Liver function test abnormal and Hepatic function abnormal.
u. Rash includes the following reported PTs: Rash, Dermatitis#, Dermatitis allergic#, Dermatitis bullous, Dermatitis contact, Dermatitis exfoliative#, Drug eruption, Pruritus allergic# and Rash erythematous#, Rash macular#, Rash maculo papular, Rash papular, Rash pruritic, Rash vesicular#.
v. Erythema includes the following reported PTs: Catheter site erythema, Erythema and Infusion site erythema#.
w. Pyrexia includes the following reported PTs: Pyrexia, Body temperature increased, and Hyperthermia.
x. Oedema includes the following reported PTs: Oedema, Face oedema, Oedema peripheral, Swelling face, Generalised oedema, and Periorbital oedema.
y. Fatigue includes the following reported PTs: Fatigue, Asthenia, Lethargy, and Malaise.
In the combination therapy study, VOD and hepatic laboratory abnormalities were collected. Additional characterisation of hepatotoxicity adverse reactions is provided from the monotherapy studies.
In the combination therapy study (N=131), VOD was reported in 6 (4.6%) patients during or following treatment, 2 (1.5%) of these reactions were fatal (see Table 5). Five (3.8%) of these VOD reactions occurred within 28 days of any dose of gemtuzumab ozogamicin. One VOD event occurred more than 28 days of last dose of gemtuzumab ozogamicin; with 1 of these events occurring a few days after having started an HSCT conditioning regimen. The median time from the last gemtuzumab ozogamicin dose to onset of VOD was 9 days (range: 2-298 days). VOD was also reported in 2 patients who received MYLOTARG as a follow-up therapy following relapse of AML after chemotherapy treatment in the control arm of the combination therapy study. Both of these patients experienced VOD more than 28 days after the last dose of gemtuzumab ozogamicin. One of these patients experienced VOD 25 days after the subsequent HSCT.
Based on an analysis of potential risk factors, adult patients who received MYLOTARG as monotherapy, patients who had received an HSCT prior to gemtuzumab ozogamicin exposure were 2.6 times more likely (95% CI: 1.448, 4.769) to develop VOD compared to patients without HSCT prior to treatment with gemtuzumab ozogamicin; patients who had received an HSCT following treatment with gemtuzumab ozogamicin were 2.9 times more likely (95% CI: 1.502, 5.636) to develop VOD compared to patients without HSCT following treatment with gemtuzumab ozogamicin; and patients who had moderate/severe hepatic impairment at baseline were 8.7 times more likely (95% CI: 1.879, 39.862) to develop VOD compared to patients without moderate/severe hepatic impairment at baseline.
Patients should be monitored for hepatotoxicity as recommended in section 4.4. Management of signs or symptoms of hepatic toxicity may require a dose interruption, or discontinuation of MYLOTARG (see section 4.2).
In the combination therapy study in patients with previously untreated de novo AML treated with fractionated doses of gemtuzumab ozogamicin in combination with chemotherapy, Grade 3/4 decreases in leukocytes, neutrophils, and platelets were observed in 131 (100%), 124 (96.1%), and 131 (100%) patients, respectively.
During the induction phase, 109 (83.2%) and 99 (75.6%) patients had platelet recovery to counts of 50,000/mm3 and 100,000/mm3, respectively. The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 34 and 35 days, respectively. During the consolidation 1 phase, 92 (94.8%) and 71 (73.2%) patients had a platelet recovery to counts of 50,000/mm3 and 100,000/mm3, respectively. The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 32 and 35 days, respectively. During the consolidation 2 phase, 80 (97.6%) and 70 (85.4%) patients had a platelet recovery to counts of 50,000/mm3 and 100,000/mm3, respectively. The median times to platelet recovery to counts of 50,000/mm3 and 100,000/mm3 were 36.5 and 43 days, respectively.
Thrombocytopenia with platelet counts < 50,000/mm3 persisting 45 days after the start of therapy for responding patients (CR and incomplete platelet recovery [CRp]) occurred in 22 (20.4%) of patients. The number of patients with persistent thrombocytopenia remained similar across treatment courses (8 [7.4%] patients at the induction phase and 8 [8.5%] patients at the consolidation 1 phase and 10 [13.2%] patients at the consolidation 2 phase).
During the induction phase, 121 (92.4%) and 118 (90.1%) patients had a documented neutrophil recovery to ANC of 500/mm3 and 1,000/mm3, respectively. The median time to neutrophil recovery to ANC of 500/mm3 and 1,000/mm3 was 25 days. In the consolidation 1 phase of therapy, 94 (96.9%) patients had neutrophil recovery to counts of 500/mm3, and 91 (94%) patients recovered to counts of 1,000/mm3. The median times to neutrophil recovery to ANC of 500/mm3 and 1,000/mm3 were 21 and 25 days, respectively. In the consolidation 2 phase of therapy, 80 (97.6%) patients had neutrophil recovery to counts of 500/mm3, and 79 (96.3%) patients recovered to counts of 1,000/mm3. The median times to neutrophil recovery to ANC of 500/mm3 and 1,000/mm3 were 22 and 27 days, respectively.
In the combination therapy study, in patients with de novo AML treated with fractionated doses of gemtuzumab ozogamicin in combination with chemotherapy (N=131), 102 (77.9%) patients experienced all causality severe (Grade ≥ 3) infections. Treatment-related death due to septic shock was reported in 2 (1.5%) patients. Fatal severe infection was reported in 2 (1.53%) patients in the MYLOTARG arm and 4 (2.92%) patients in the control arm.
In the combination therapy study (N=131), all grades and Grade 3/4 bleeding/haemorrhagic reactions were reported in 118 (90.1%) and 27 (20.6%) patients, respectively. The most frequent Grade 3 bleeding/haemorrhagic reactions were epistaxis (1.5%), haemoptysis (3.1%), and haematuria (2.3%). Grade 4 bleeding/haemorrhagic reactions were reported in 4 (3.1%) patients (gastrointestinal haemorrhage, haemorrhage, and pulmonary alveolar haemorrhage [2 patients]). Fatal bleeding/haemorrhagic reactions were reported in 3 (2.3%) patients (cerebral haematoma, intracranial haematoma, and subdural haematoma).
Management of patients with severe infection, bleeding/haemorrhage, or other effects of myelosuppression, including severe neutropenia or persistent thrombocytopenia, may require a dose delay or permanent discontinuation of MYLOTARG (see sections 4.2 and 4.4).
In clinical studies of MYLOTARG in patients with relapsed or refractory AML, the immunogenicity of MYLOTARG was evaluated using 2 enzyme-linked immunosorbent assays (ELISAs).
Patients in the Phase 2 trials did not develop antidrug antibodies (ADAs) and only 2 patients in a Phase 1 trial developed antibodies against the calicheamicin-linker complex, 1 of whom had reduced hP67.6 plasma concentrations. Overall, the incidence rate of ADA development after MYLOTARG treatment was < 1% across the 4 clinical studies with ADA data. Definitive conclusions cannot be drawn between the presence of antibodies and potential impact on efficacy and safety due to the limited number of patients with positive ADAs.
The detection of ADAs is highly dependent on the sensitivity and specificity of the assay. The incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, circulating gemtuzumab ozogamicin concentrations, sample handling, timing of sample collection, concomitant treatments and underlying disease. For these reasons, comparison of incidence of antibodies to gemtuzumab ozogamicin with the incidence of antibodies to other products may be misleading.
The safety and efficacy of MYLOTARG in children and adolescents below the age of 15 years has not been established (see section 4.2).
In the completed randomised paediatric Phase 3 Study AAML0531 (see section 5.1) of gemtuzumab ozogamicin combined with intensive first-line therapy in newly diagnosed children, and young adults with de novo AML aged 0 to 29 years, the safety profile was similar with that observed in the other studies of gemtuzumab ozogamicin combined with intensive chemotherapy in adult patients with de novo AML. However, the optimal dose of gemtuzumab ozogamicin for paediatric patients was not established, since in Study AAML0531 during the second intensification period, a larger proportion of patients in the gemtuzumab ozogamicin arm experienced prolonged neutrophil recovery time (> 59 days) as compared with the comparator arm (12.0% versus 6.3%), and more patients died during remission (4.2% versus 2.4%).
No cases of overdose with MYLOTARG were reported in clinical experience. Single doses higher than 9 mg/m2 in adults were not tested. Treatment of MYLOTARG overdose should consist of general supportive measures.
Gemtuzumab ozogamicin is a CD33-targeted ADC. Gemtuzumab is a humanised immunoglobulin class G subtype 4 (IgG4) antibody which specifically recognises human CD33. The antibody portion binds specifically to the CD33 antigen, a sialic acid-dependent adhesion protein found on the surface of myeloid leukaemic blasts and immature normal cells of myelomonocytic lineage, but not on normal haematopoietic stem cells. The small molecule, N-acetyl gamma calicheamicin, is a cytotoxic semisynthetic natural product. N-acetyl gamma calicheamicin is covalently attached to the antibody via an AcBut (4-(4-acetylphenoxy) butanoic acid) linker. Non-clinical data suggest that the anticancer activity of gemtuzumab ozogamicin is due to the binding of the ADC to CD33-expressing tumour cells, followed by internalisation of the ADC-CD33 complex, and the intracellular release of N-acetyl gamma calicheamicin dimethyl hydrazide via hydrolytic cleavage of the linker. Activation of N-acetyl gamma calicheamicin dimethyl hydrazide induces double-stranded DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.
Saturation of a high percentage of CD33 antigenic sites is presumed to be required for maximum delivery of calicheamicin to leukaemic blast cells. Several single agent studies measured target (CD33) saturation post-MYLOTARG dose in patients with relapsed and refractory AML. Across all studies, near maximal peripheral CD33 saturation was observed post-MYLOTARG dose at all dose levels of 2 mg/m2 and above, suggesting that a low dose of gemtuzumab ozogamicin is sufficient to bind all available CD33 sites.
The efficacy and safety of MYLOTARG were evaluated in a multicentre, randomised, open-label Phase 3 study comparing the addition of MYLOTARG to a standard chemotherapy induction regimen of daunorubicin and cytarabine (DA) versus DA alone. Eligible patients were between 50 and 70 years of age with previously untreated de novo AML (Study ALFA-0701). Patients with acute promyelocytic leukaemia (APL, AML3) and patients with AML arising from myelodysplastic syndrome (MDS) or secondary AML were excluded from the study.
The primary endpoint was event-free survival (EFS). The secondary endpoints included CR and CRp rates, relapse-free survival (RFS), overall survival (OS), and safety of the combination DA with or without MYLOTARG.
In total, 271 patients were randomised in this study with 135 to induction treatment of 3+7 DA plus fractionated 3 mg/m2 × 3 doses of MYLOTARG and 136 to 3+7 DA alone (see section 4.2). A second course of induction therapy with DA but without MYLOTARG, regardless of the randomisation arm, was allowed. Patients in either arm who did not receive the second course of induction therapy and did not achieve a CR after induction could receive a salvage course comprised of idarubicin, AraC, and granulocyte colony-stimulating factor (G-CSF).
Patients with CR or CRp received consolidation therapy with 2 courses of treatment including DNR and AraC with or without MYLOTARG according to their initial randomisation. Patients who experienced remission were also eligible for allogeneic transplantation. An interval of at least 2 months between the last dose of MYLOTARG and transplantation was recommended.
Overall, the median age of patients was 62 years (range 50 to 70 years) and most patients (87.8%) had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 at baseline. Baseline characteristics were balanced between treatment arms with the exception of gender as a higher percentage of males were enrolled in the MYLOTARG arm (54.8%) than in the DA alone arm (44.1%). Overall, 59.0% and 65.3% of patients had documented favourable/intermediate risk disease by the National Comprehensive Cancer Network (NCCN) and European LeukaemiaNet (ELN) 2010 risk classifications, respectively. CD33 expression on AML blasts by flow cytometry harmonised from local laboratory results was determined in 194/271 (71.6%) patients overall. Few patients (13.7%) had low CD33 expression (less than 30% of blasts).
The trial met its primary objective of demonstrating that MYLOTARG added in fractionated doses (3 mg/m2 × 3) to standard induction chemotherapy for patients with previously untreated de novo AML resulted in a statistically significant and clinically meaningful improvement in EFS. Median EFS was 17.3 months (95% CI: 13.4, 30.0) in the MYLOTARG arm versus 9.5 months (95% CI: 8.1, 12.0) in the DA alone arm; hazard ratio (HR) 0.562 (95% CI: 0.415, 0.762); 2-sided p=0.0002 by log-rank test. Efficacy data from ALFA-0701 study are summarised in Table 7, and the Kaplan-Meier plot for EFS is shown in Figure 1.
Based on the primary definition of EFS: event dates (induction failure, relapse, or death) determined by investigator assessment.
The mITT population included all patients who were randomised, unless withdrawal of consent prior to start of treatment and were analysed according to initial randomisation arm.
Abbreviations: CR=complete remission; CRp=complete remission with incomplete platelet recovery; CI=confidence interval; EFS=event-free survival; mITT=modified intent-to-treat; n=number; N=number; NE= not estimable; OS=overall survival; RFS=relapse-free survival.
a. Median estimated by Kaplan-Meier method; CI based on the Brookmeyer-Crowley method with log-log transformation.
b. Estimated from Kaplan-Meier curve. Probability (%) calculated by the product-limit method; CI calculated from the log-log transformation of survival probability using a normal approximation and the Greenwood formula.
c. Based on the Cox proportional hazards model Versus daunorubicin + cytarabine.
d. 2-sided p-value from the log-rank test.
e. Response defined as CR+CRp.
f. Overall response difference; CI based on Santner and Snell method.
g. Based on Fisher's exact test.
Abbreviations: C=cytarabine; D=daunorubicin; GO=gemtuzumab ozogamicin; mITT=modified intent-to-treat.
In subgroup analyses in ALFA-0701, the addition of MYLOTARG to standard combination chemotherapy did not improve EFS in the subgroup of patients having adverse-risk cytogenetics (HR 1.11; 95% CI: 0.63, 1.95). EFS and OS analysed by cytogenetic risk classification and cytogenetic/molecular risk classification are presented in Table 8 and Table 9 below.
The ALFA-0701 trial was not designed to prospectively evaluate the benefit of MYLOTARG in subgroups; analysis are presented for descriptive purposes only.
Abbreviations: AML =acute myeloid leukaemia; CI=confidence interval; EFS=event-free survival; ELN=European LeukaemiaNet; mITT=modified intent-to-treat; n=number; N=number; NE=not estimable.
a. Median estimated by Kaplan-Meier method; CI based on the Brookmeyer and Crowley Method with log-log transformation.
b. Based on the Cox Proportional Hazards Model Versus daunorubicin+cytarabine.
c. 2-sided p-value from the log-rank test.
Hazard ratio [95% CI]Error! Reference source not found.
b. Based on the Cox Proportional Hazards Model Versus daunorubicin + cytarabine.
In a randomised study (COG AAML0531) that evaluated standard chemotherapy alone or combined with MYLOTARG in 1,022 newly diagnosed children (94.3% of patients < 18 years of age), and young adults (5.7% of patients); median age was 9.7 years (range: 0.003-29.8 years), patients with de novo AML were randomly assigned to either standard 5-course chemotherapy alone or to the same chemotherapy with 2 doses of MYLOTARG (3 mg/m2/dose) administered once in induction Course 1 and once in intensification Course 2. The study demonstrated that addition of MYLOTARG to intensive chemotherapy improved EFS (3 years: 53.1% versus 46.9%; HR 0.83; 95% CI: 0.70, 0.99; p=0.04) in de novo AML owing to a reduced relapse risk, with a trend towards longer OS in the MYLOTARG arm which was not statistically significant (3 years: 69.4% versus 65.4%; HR 0.91; 95% CI: 0.74, 1.13; p=0.39). However, it was also found that increased toxicity (post-remission toxic mortality) was observed in patients with low-risk AML which was attributed to the prolonged neutropenia that occurred after receiving gemtuzumab ozogamicin during intensification Course 2 (see sections 4.2 and 4.8). Thus, the optimal dose of gemtuzumab ozogamicin for paediatric patients was not established (see section 4.2).
Gemtuzumab ozogamicin is an antibody-drug conjugate (ADC) composed of CD33-directed monoclonal antibody (hP67.6) that is covalently linked to the cytotoxic agent N-acetyl-gamma calicheamicin. The pharmacokinetics (PK) of gemtuzumab ozogamicin is described by measuring PK characteristics of the antibody (hP67.6) as well as total and unconjugated calicheamicin derivatives. Given that the hP67.6 portion renders target selectivity on the intact molecule, and that gemtuzumab ozogamicin dosages are reported in terms of milligrams of protein (hP67.6), the hP67.6 concentration results are reported as the primary PK measures. After gemtuzumab ozogamicin binds to the target it is internalised and N-acetyl calicheamicin is released by hydrolytic cleavage. Determination of PK parameters for unconjugated calicheamicin was limited due to the low systemic concentration levels.
No clinical PK data have been collected using the fractionated regimen; however, the PK have been simulated using the population PK model. Although the total dose of the fractionated dosing regimen is half of that of the original dosing regimen (9 versus 18 mg/m2), the predicted total AUC of hP67.6 over the course of treatment is 25%, and Cmax is 24%, of the values for original 9 mg/m2 dosing regimen, since the PK is nonlinear. When gemtuzumab ozogamicin is administered at 3 mg/m2 on Days 1, 4, and 7, the Cmax of hP67.6, which would occur at the end of infusion, is predicted to be 0.38 mg/L following the first dose and increased to 0.63 mg/L after the third dose.
In vitro, the binding N-acetyl gamma calicheamicin dimethyl hydrazide to human plasma proteins is approximately 97%. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is a substrate of P-glycoprotein (P-gp). In patients, the total volume of distribution of hP67.6 antibody (sum of V1 [10 L] and V2 [15 L]) was found to be approximately 25 L.
The primary metabolic pathway of gemtuzumab ozogamicin is anticipated to be hydrolytic release of N acetyl gamma calicheamicin dimethyl hydrazide. In vitro studies demonstrated that N-acetyl gamma calicheamicin dimethyl hydrazide is extensively metabolised, primarily via nonenzymatic reduction of the disulphide moiety. The activity (cytotoxicity) of the resultant metabolites is expected to be significantly attenuated. In patients, unconjugated calicheamicin plasma levels were typically low, with a predicted mean Cmax of 1.5 ng/mL following the third dose.
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide is primarily metabolised via nonenzymatic reduction. Therefore, coadministration of gemtuzumab ozogamicin with inhibitors or inducers of cytochrome P450 (CYP) or uridine diphosphate glucuronosyltransferase (UGT) drug metabolising enzymes are unlikely to alter exposure to N-acetyl gamma calicheamicin dimethyl hydrazide.
Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with hydroxyurea, DNR, and AraC is not predicted to cause clinically meaningful changes in the PK of hP67.6 or unconjugated calicheamicin.
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to inhibit the activities of CYP1A2, CYP2A6 (tested only using gemtuzumab ozogamicin), CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 at clinically relevant concentrations. In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide and gemtuzumab ozogamicin had a low potential to induce the activities of CYP1A2, CYP2B6, and CYP3A4 at clinically relevant concentrations.
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of UGT1A1, UGT1A4, UGT1A6, UGT1A9, and UGT2B7 at clinically relevant concentrations.
In vitro, N-acetyl gamma calicheamicin dimethyl hydrazide had a low potential to inhibit the activities of P-gp, breast cancer resistance protein (BCRP), bile salt export pump (BSEP), multidrug resistance associated protein (MRP) 2, multidrug and toxin extrusion protein (MATE)1 and MATE2K, organic anion transporter (OAT)1 and OAT3, organic cation transporter (OCT)1 and OCT2, and organic anion transporting polypeptide (OATP)1B1 and OATP1B3 at clinically relevant concentrations.
Based on population pharmacokinetic (PK) analyses, the combination of gemtuzumab ozogamicin with DNR and AraC is not predicted to cause clinically meaningful changes in the PK of these agents.
Based on Population PK analyses, the predicted clearance (CL) value of hP67.6 from plasma was 3 L/h immediately after the first dose and then 0.3 L/h. The terminal plasma half-life (t½) for hP67.6 was predicted to be approximately 160 hours for a typical patient at the recommended dose level (3 mg/m2) of MYLOTARG.
Based on a population PK analysis, age, race, and gender did not significantly affect gemtuzumab ozogamicin disposition.
No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with hepatic impairment.
Based on a population PK analysis, the clearance of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is not expected to be affected by mild hepatic impairment status, as defined by National Cancer Institute Organ Dysfunction Working Group (NCI ODWG). The analysis included 406 patients in the following NCI ODWG impairment status categories: mild (B1, n=58 and B2, n=19), moderate (C, n=6), and normal hepatic function (n=322) (see section 4.2).
No formal PK studies of gemtuzumab ozogamicin have been conducted in patients with renal impairment.
Based on a population PK analysis in 406 patients, the clearance of gemtuzumab ozogamicin in patients with mild renal impairment (creatinine clearance [CLcr] 60-89 mL/min; n=149) or moderate renal impairment (CLcr 30-59 mL/min; n=47), was similar to patients with normal renal function (CLcr ≥ 90 mL/min; n=209). The PK of gemtuzumab ozogamicin has not been studied in patients with severe renal impairment.
The results of the population modelling showed that the PK behaviour of gemtuzumab ozogamicin (hP67.6 antibody and unconjugated calicheamicin) is similar between adult and paediatric AML patients following the 9 mg/m2 dosing regimen.
The main toxicities occurred in the liver, bone marrow and lymphoid organs, haematology parameters (decreased RBC mass and WBC counts, mainly lymphocytes), kidney, eye and male and female reproductive organs. Effects on liver, kidney and male reproductive organs in rats, and on lymphoid tissues in monkeys (approximately 18 times for rats, and 36 times for monkeys, the human clinical exposure after the third human dose of 3 mg/m2 based on AUC168) were not reversible. Effects on female reproductive organs and the eye in monkeys were adverse in the 12-week study (approximately 193 and 322 times, respectively, the human clinical exposure after the third human dose of 3 mg/m2 based on AUC168). The relevance of the irreversible animal findings to humans is uncertain. Nervous system effects have not been observed in animals after administration of MYLOTARG. Nervous system alterations were identified in rats with other antibody-calicheamicin conjugates.
Gemtuzumab ozogamicin was found to be clastogenic. This is consistent with the known induction of DNA breaks by calicheamicin and other enediyne antitumour antibiotics. N-acetyl gamma calicheamicin DMH (the released cytotoxin) was found to be mutagenic and clastogenic.
Formal carcinogenicity studies have not been conducted with gemtuzumab ozogamicin. In toxicity studies, rats developed preneoplastic lesions (minimal to slight oval cell hyperplasia) in the liver approximately 54 times, the human clinical exposure after the third human dose of 3 mg/m2 based on AUC168). There were no preneoplastic or neoplastic lesions observed in monkeys up to approximately 115 times the human clinical exposure after the third human dose of 3 mg/m2 based on AUC168). The relevance of these animal findings to humans is uncertain.
In a female rat fertility study slightly lower numbers of corpora lutea and increased embryolethality were observed in the presence of maternal toxicity (approximately 9.7 times, the human clinical exposure after the third human dose of 3 mg/m2 based on AUC168). Effects on the reproductive tract of female monkeys were observed in the 12-week study (atrophy of the ovary, oviduct, uterus, and cervix; approximately 193 times the human clinical exposure after the third dose of 3 mg/m2).
In a male fertility study, effects on male reproduction included lower spermatogonia and spermatocytes, decreases in testicular spermatids and epididymal sperm, vacuolation of the nucleus in spermatids, and/or appearance of giant cells. Additional findings included effects on the testes, epididymides and mammary gland as well as fertility. When male rats were mated again after a 9-week non-dosing period, effects on sperm and fertility were worse but there was partial recovery of the lower spermatogonia and spermatocytes in the testes. Effects on male rat reproductive organs were partially reversible or not reversible (see section 4.6). Male reproductive effects (testes, epididymides, seminal vesicles) in monkeys were observed at approximately 66 times the human clinical exposure after the third dose of 3 mg/m2).
In an embryo-foetal toxicity study lower foetal body weight, higher incidence of foetal wavy ribs, and lower incidence of foetal skeletal ossification were observed. Increased embryolethality and foetal morphological anomalies included digital malformations, absence of the aortic arch, anomalies in the long bones in the forelimbs, misshapen scapula, absence of a vertebral centrum, and fused sternebrae. Increased embryolethality was also observed in the presence of maternal toxicity. The lowest dose with embryo-foetal effects correlated with 9.7 times the human clinical exposure after the third human dose of 3 mg/m2, based on AUC168 (see section 4.6).
Following reconstitution and dilution, the solution should be protected from light and should be used immediately. If the product cannot be used immediately, the diluted solution may be stored up to 18 hours in a refrigerator (2°C–8°C) from the time of initial vial puncture with not more than 6 hours at room temperature (below 25°C). This includes the time required for reconstitution, dilution, and administration.
Store the vial in the original carton to protect from light.
Amber Type 1 glass vial, with butyl rubber stopper and crimp seal with flip-off cap containing 5 mg gemtuzumab ozogamicin.
Use appropriate aseptic technique for the reconstitution and dilution procedures. MYLOTARG is light sensitive and should be protected from ultraviolet light during reconstitution, dilution, and administration.
• Calculate the dose (mg) of MYLOTARG required.
• Prior to reconstitution, allow the vial to reach room temperature (below 25°C) for approximately 5 minutes. Reconstitute each 5 mg vial with 5 mL of water for injections to obtain a single-use solution of 1 mg/mL of gemtuzumab ozogamicin.
• Inspect the reconstituted solution for particulates and discolouration. The reconstituted solution may contain small white to off-white, opaque to translucent, and amorphous to fibre-like particles.
• MYLOTARG contains no bacteriostatic preservatives.
• If the reconstituted solution cannot be used immediately, it may be stored in the original vial for up to 6 hours in a refrigerator (2°C-8°C) with not more than 3 hours at room temperature (below 25°C). Protect from light and do not freeze.
• Calculate the required volume of the reconstituted solution needed to obtain the appropriate dose according to patient body surface area. Withdraw this amount from the vial using a syringe. Mylotarg vials contain 5 mg of drug product with no overfill. When reconstituted to a 1 mg/mL concentration as directed, the extractable content of the vial is 4.5 mg (4.5 mL). Protect from light. Discard any unused reconstituted solution left in the vial.
o Doses less than 3.9 mg must be prepared for administration by syringe. Add the reconstituted MYLOTARG solution to a syringe with sodium chloride 9 mg/mL (0.9%) solution for injection to a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
o Doses greater than or equal to 3.9 mg are to be diluted in a syringe or an IV bag in an appropriate volume of sodium chloride 9 mg/mL (0.9%) solution for injection to ensure a final concentration between 0.075 mg/mL to 0.234 mg/mL. Protect from light.
• Following dilution with sodium chloride 9 mg/mL (0.9%) solution for injection, MYLOTARG solution should be infused immediately. If not used immediately, store at room temperature (below 25°C) for up to 6 hours, which includes the 2-hour infusion time and 1 hour, if needed, to allow the refrigerated diluted solution to equilibrate to room temperature (below 25°C). The diluted solution can be refrigerated at 2°C-8°C for up to 12 hours. Protect from light and do not freeze.
• It is recommended that the infusion container be made of polyvinyl chloride (PVC) with DEHP, or polyolefin (polypropylene and/or polyethylene).
• Filtration of the diluted solution is required. An in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter must be used for infusion of MYLOTARG.
• Doses administered by syringe must utilize small bore infusion lines (microbore) with an in-line, low protein-binding 0.2 micron polyethersulphone (PES) filter.
• During the infusion, the intravenous bag or syringes needs to be protected from light using a light (including ultraviolet light) blocking cover. The infusion line does not need to be protected from light.
• Infuse the diluted solution for 2 hours. Infusion lines made of PVC (DEHP- or non DEHP-containing), or polyethylene are recommended.
See also section 6.3 for dilution, storage, and infusion information.
Toxic waste disposal procedures prescribed for anticancer medicinal products must be used.
Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.

industry_corpus2: Health & Medicine


text:
While I help people around the world with all kinds of life and career transitions, I’ve developed a special area of my practice focused on helping people have a smooth and successful transition when moving to Victoria.
I moved here over 25 years ago and I love this city, however it is a little different than many other cities and can sometime be challenging to settle into or find a job.
I decided that I wanted to do something to help newcomers and anyone thinking of moving to Victoria have a smooth and successful transition.
I help people in a variety of ways; through free information sessions live in Victoria, a free video about moving to Victoria, co-sponsored events in Victoria and other cities and paid workshops on topics such as Networking for Success in Victoria. Of course I also offer personalized one-on-one coaching to help you decide if this move is right for you. Want to explore your options?
Living Elsewhere and Thinking of Moving?
Many people visit Victoria year after year and dream of eventually moving here at some point in the future. My husband discovered this beautiful city while working on assignment with his company. He fell in love with the climate, the scenery and the city. We both decided that moving to Victoria as soon as possible was the right move for us instead of waiting until we retired. We came out in June of that same year on a mission to find work and by August we had sold our house in Ottawa and moved here. The job search helped us understand that we were moving to a smaller city with less opportunities, however we’d made a conscious choice to move here for an improved quality of life and we’ve never regretted our decision.
I’m often surprised at how little research some people do before moving here. This can lead to disappointment, frustration & stress, when assumptions about how easy it is to find work and a place to live don’t always hold true. Even making friends can be challenging if you don’t understand the culture of the city. I’ve heard too many stories of people moving here and not having the easiest time settling in, so I decided to do something about that. I developed a specific area of my coaching practice to support newcomers and people thinking of moving here, so that they can have a smooth and successful transition.
My Personal Relocation Discovery Coaching Package for people thinking of moving to Victoria is a stand-alone package to help you get clear on what you want from your move and includes a custom coaching session on a topic that best serves you. After completing this package you’ll have clarity about your goals for the future and you’ll have a much better idea of what you need to do to plan a successful move to Victoria.
Moving is often disruptive and expensive and there are always unexpected things to deal with. Having an experienced coach in your corner, someone who’s lived in this city for many years, is respected in the community, is a member of a number of local organizations and who specializes in helping others make a smooth transition, can be very reassuring and could be an excellent investment. I can also connect you with reputable local resources who can help you before and after you move.
I’ve also developed this FREE video summarizing the key points from my An Insider’s Guide to Moving to Victoria (formerly What You Need to Know About Moving to Victoria) information session for people who are thinking of moving here and can’t attend my live talks.
If you’re interested in more details and can’t attend my free workshop in person, you can request a .pdf of the handout I share with participants in An Insider’s Guide to Moving to Victoria by clicking the button below.
My free talk – An Insider’s Guide to Moving to Victoria is valued by newcomers and visitors. Whether you’ve been in Victoria for just a few months or even a few years, you’ll find my insider tips invaluable, so please consider blocking off time in your schedule to attend. I can’t tell you how many times I’ve heard participants say “I wish I’d met you years ago when I first arrived in Victoria”.
My Networking for Success in Victoria workshop is popular with both locals and newcomers. Networking is an essential skill in this town to uncover the hidden job market. It’s also a great way to meet people and make new friends. This workshop will help you reframe your view of networking. You’ll create a strategy for your networking and I’ll share my Ultimate Action Plan to support you showing up at networking events in a confident and authentic way. You’ll also get my simple yet powerful template for your 30 second introduction. You’ll even have a support call with me after the workshop to test drive your introduction and explore the best places for you to network in Victoria based on your goals.
My Personal Relocation Discovery Coaching Package for newcomers is a stand-alone package to help you get clear on what you want from your move and includes a custom coaching session on a topic that best serves you. After completing this package you’ll have clarity about your goals for the future and a plan to help you settle into your new home town.
Moving to Victoria can be challenging. Sharing your experience and goals for the future with an experienced coach who has lived in this city for more than 25 years can be helpful and reassuring. If you feel you’d like more personalized support now that you’ve moved to Victoria, this stand-alone coaching package could be an excellent investment.
Victoria is a beautiful and vibrant city and I wish you a smooth and successful transition.
Thinking of Moving Somewhere Other Than Victoria?
I’ve developed a couple of resources if you’re thinking of moving to a different city or part of town.
The first resource is a self-directed workshop called A Checklist for My Ideal Next Home. It will help you get clarity on the key features and location factors you’ll want to keep in mind when looking for your future home. You’ll have a list of a few mandatory features and some other nice to have features. You can then share this information with your relator if you’re buying a home, or just keep it in mind as you conduct your own search for your next home. This $15 investment can save a great deal of time in helping you determine which properties to look at and help to eliminate the risk that you’ll end up falling in love with and buying a property that really doesn’t meet your key criteria and finding you’re dealing with the added expense of moving yet again.
This resource is specifically directed at seniors and those who care about them. It’s a video of a presentation that I’ve delivered to hundreds of seniors. It really a call to action and some guideline for how to make a plan for where they’ll live in the future if in future, their current accommodation is no longer suitable for them. It’s difficult for most people to think about moving and it’s especially challenging for seniors. This video can be helpful for children of seniors who can watch it with an elderly relative and then use it as a starting point for a discussion about what the senior you care about might think about what they heard in the presentation. I don’t sugar-coat the message about the need to plan ahead and I firmly believe that the best people to drive the plan are seniors themselves. Seniors who heard me deliver this live, always left saying things like “It wasn’t easy to think about these things, but I guess we really do need to make a plan”. It just a $10 investment and can really help facilitate beginning this challenging discussion with an elderly relative who you know needs to begin to think about moving in the future.

industry_corpus2: Subject Education


text:
Last weeks meal plan mostly went to plan....On Friday the kids had their soup and Stu and I had a massive fry up.....It was so good!
This pretty sound exactly what my little one would choose too, especially hot dogs!
All sounds yummy - can I pop up!


text:
Discover the design-centered secrets behind the Museum's "floating" structure and the eco-friendly efforts of our plinth's native Texan wildlife in an eye-opening educational experience that will forever change how you look at our campus. Our guided walking tours last 1 to 1.5 hours.
To participate in our architecture tour, PURCHASE TICKETS for general admission on the day you'd like to attend, then select the option to reserve your spot on the tour once tickets have been added to your cart.


text:
There was a thread a while back that discussed them. It may have even been the "2 strokes" one, I don't recall.
Some people like 'em, some don't. I personally do. I wouldn't want to do a large garden with one though. If taken care and stored (for winter if you're in that kind of area) properly they work fine and they dig like crazy. You do have to hold on to 'em though as they can try to bounce if they strike a good sized root or something. You also pull them for digging rather than go foward.
I agree that they are really neat especially if you have narrow raised beds. I bought a Honda instead of the Mantis. It wasn't much more expensive. I don't like 2-strokes.

industry_corpus2: Agriculture & Fisheries


text:
Biggest fans list for A Pale Horse Named Death is empty.
A Pale Horse Named Death doesn't have any rated concert. If you were on any concert, you can add it to your concert list and rate it.
A Pale Horse Named Death doesn't have any concerts opinions. If you were on any concert, you can add it to your concert list and share your opinion.


text:
This product is just the way to begin transforming a water-sucking lawn into a garden that can feed you. Heirloom seeds are not genetically-modified by definition, & considered “choice” among gardeners as a quality seed. In case of emergency OR for beginning gardeners- this product is a smart way to begin.
Thanks for helping to support Richard Lonewolf’s Survival School!


text:
I’ve never read a novel like ‘The Stolen Bicycle’ before. The stories it contains circle each other, winding tighter and tighter around the central unnamed protagonist. Looking for his missing father’s bicycle, the narrator delves into the world of antique bicycle fanatics in Taiwan. The stories he encounters there traverse history. There’s the tale of the pregnant butterfly handicraft maker, the life of the oldest elephant who ever lived, the account of the Silverwheels unit who fought in the jungles of South-east Asia during World War II. At the centre of each of these stories are bicycles. Each is lost, stolen or gifted. The narrator follows their trails, hoping to be led to the story of his father’s.
I’m interested in where this central concept came from, a lost soul trying to find the bicycle that is so essential to his memories of his father. It’s one of the first questions I asked author Wu Ming-Yi when I met him in Melbourne last week during his visit for the Melbourne Writers Festival.
Can you start by telling me about where the concept for The Stolen Bicycle came from?
Ming-Yi: It relates to a previous novel I wrote in 2007 called Routes in a Dream. The father’s bicycle in that novel ends up going missing at this assembly hall, called the Chung-shan (Zhongshan) Hall. A reader wrote me an email saying, “well what happens to this bicycle? It’s a loose end.” So I decided to not tie up that loose end, but draw it out, and found I could draw it out so much that it could become the main narrative line of an entirely separate novel. It turned into The Stolen Bicycle.
This is his third novel, ‘Routes in a Dream’ was his debut. Wu Ming-Yi is known as one of the leading writers of his generation in his native Taiwan, as well as being a butterfly scholar, an environmental activist and an artist. For the cover of ‘The Stolen Bicycle’ he created a swirling illustration to tie together different components of the story. The finely drawn bikes in the “bicycle notes” sections that punctuate the book were also drawn by Ming-Yi.
His English translator, the Edmonton-born Darryl Sterk, also translated his last novel ‘The Man with The Compound Eyes.’ Sterk spent three months living in tents and youth hostels on the Taiwanese coast in order to have the details to fine-tune his translation.
I sat down with the two men in a loud cafe in the edge of Melbourne city. It was the first day of spring, and the sun beamed down through the window next to us. An instant intimacy was established as we sat with our heads close together to be heard over the tinny music and loud steam of the coffee machine. The conversation weaved between English and Mandarin, as Sterk translated parts of my questions and Ming-Yi answered in a combination of languages.
Darryl Sterk (left) and Wu Ming-Yi (right) in conversation. Photo by Beth Wilkinson for Lindsay.
From here, Ming-Yi focuses in on a small child who wakes up in the rice field of the village to discover the sky is turning black. Her only means of escape is a discarded police bicycle. Titled ‘Before Time,’ the opening section is self-contained. It reads very differently to the rest of the novel.
Can you tell me about the opening section ‘Before Time’?
Sterk: That section is untitled in the original. That was the editor’s idea, Elizabeth’s idea, to give it the title ‘Before Time’. Because it’s ambiguous I think.
It read like a prologue to me.
Sterk: Yeah, it’s a prologue. This is part of the backstory to the narrative.
It’s a beautiful and haunting depiction of a small village. It almost seems like a parable, was that the intention?
Ming Yi: My dad never talked about the past, it was always my mum. It seemed sort of legendary—the stories she used to tell, like parables. But she would say no, this is a real story, I lived through it. I didn’t put this in the novel, but in 1944 and 1945, the American’s were bombing Taiwan, which was then under Japanese rule. My mother said that she saw Mother Matsu, which is a goddess of the sea. The fisherman pray to her and there are temples to Mother Matsu all around the country. She would use her apron, her skirt, to catch the bomb so that it wouldn’t blow anything up. She said “I saw this with my very own eyes when I was a girl.” I said that’s impossible. It’s like a parable, but my mother believed it. My mother lived through a bombing like the mother of the narrator in the story. It’s a legend, or a parable, that she believes in.
Some of the stories that are told to the narrator in the book have a magical realism quality, and they are often set in the natural world. Even though the narrator spends most of the novel in the busy streets and markets of modern day Taipei, the stories he hears give us a sense of how much Taiwan has changed in recent history.
Can you tell us a bit about the theme of Taiwan’s urban growth in the novel?
Ming-Yi: It’s a story of material development and prosperity after the war. People in Taiwan talk about the economic miracle, and they mean industrialisation, rapid economic development. So that’s what the novel is about. It’s also about the price that Taiwanese people have had to pay for the miracle, ecologically. What paid for this miracle was natural resource extraction. It had an ecological cost.
I really got a sense of that through some of the stories in the novel—like Abbas’s and the elephant Lin Wang. There was quite a few different voices in the story—through emails, audio recordings or the narrator’s recollections of the stories told directly to him. Was the language different for each one?
Ming Yi: Taiwan is a multi-cultural society and China is too, but Taiwan has embraced multiculturalism more. Because multiculturalism is potentially dangerous if the individual cultures have their own ideas about whom they want to be. Language is the most obvious expression of multiculturalism. It’s a multi-linguistic society.
Can you tell us a bit more about the way you used language in the novel?
Ming-Yi: There’s a different kind of poetry that you can’t convey in English, because it’s particular to the languages that I speak and that my parents spoke. My parents grew up at the end of the Japanese era, so they would have learnt Japanese. So there’s a particular poetic beauty of Japanese that was in their consciousness. It entered their consciousness and shaped them somehow, was formative. My mother tongue is Taiwanese. The kind of Fujianese that’s spoken on Taiwan wasn’t respected to put it mildly. The government did everything it could to prevent people from speaking the language. When I went to school, if you were caught speaking Taiwanese, they’d punish you, make you wear tags. Even though it wasn’t respected Taiwanese, it has it’s own aesthetics. It’s in my consciousness and was formative for me and I wanted to express the poetry of Taiwanese in the novel.
Sterk: If you look at the original Chinese version there is more Taiwanese then there is in the English. I edited some of it out—especially in the chapters with the mother. Ming-Yi often uses Chinese characters to represent Taiwanese, but sometimes supplies the sound of the word in romanisation. A lot of people in Taiwan don’t speak Taiwanese very well, so this is to remind people how it sounds and its aesthetic. I think it’s beautiful to look at. If you know how to read it, it’s really beautiful to hear.
I really liked the part where the narrator finds an audio recording of his friend Abbas’s father, Pasuya, talking about his time as a soldier during World War II. In the recording, Pasuya uses a mix of languages and the narrator works to translate the story into Mandarin.
Sterk: Pasuya grew up speaking both an Indigenous language and Japanese; he’s bilingual. It’s sort of interesting how sometimes elites will speak more than one language. Sophisticated people will speak French and English and other languages. In Taiwanese history, it’s often subalterns, people who have to follow order, or just ordinary people who are bilingual—like Abbas’s father Pasuya.
Is this section different in the original version compared to the English?
Ming-Yi: I definitely wanted to keep the actual sounds of the words he was using in the actual recording, even though what you read of it is a translation into Mandarin.
Sterk: I made the English translation more paratactic; more like Hemingway, more like storytelling, less formal.
Did you add sections to the translation to explain parts that you thought English readers might not understand?
Sterk: When I’m translating something like a postscript, because it’s non-fiction, I somehow feel like I can do whatever I want. But with literary translation, more and more I feel I shouldn’t make any changes, I should be as literal as possible, as long as it’s acceptable to the reader and readable. If you re-write it, you might miss what’s really important or interesting in the original stylistically.
I add some things for the benefit of the reader, to make sure the reader can understand things like, what fate means. Ming-Yi notes that the two characters in the word for fate in Mandarin, ming-yun, are the other way around in Taiwanese, yun-ming, but doesn’t draw out the significance of that difference in order. I translated according to my interpretation of the significance.
I guess there would be things that would be assumed knowledge in Taiwan, things that might not translate culturally.
Sterk: Yeah, because the original reader would instantly know exactly what you mean, but you need lexical items—words you have to explain what they mean in context. With the editor, I even wanted to insist on words that she was concerned might seem offensive to the reader. Like there’s the Deciduous Ganyan tree, or Sparrow Banyan in Mandarin, which is a kind of fig tree (Banyan is in the Genus Ficus). In Taiwanese it’s “Bird Crap Banyan,” so I called it “Bird Crap Banyon” and the editor thought, oh this could be offensive. You call Indigenous people Indigenous people, you don’t call them savages or natives because it seems disrespectful, but that’s what it was in the original. Figure this, it’s anachronistic to say Indigenous that far back in history. That’s just how people talked. Sometimes the editor was worried it was going to be offensive or that the reader would find it disrespectful to say “Bird Crap Banyon,” but I ended up persuading her to let me have my way.
What was the process like translating this novel into English? I imagine it involves a lot of trust.
Sterk: I asked him about a thousand questions for the first novel, The Man with Compound Eyes, and maybe a hundred questions for this one. I didn’t want to bother him too much. He’s got better things to do than answer my questions. It’s my responsibility to make an educated decision about what he means, and I’m free to interpret too. He’s been the best.
The Stolen Bicycle by Wu Ming-Yi, 2017 [Text Publishing], 416 pp.

industry_corpus2: Literature & Emotions


text:
The controversial schemes to the police will be phased out. New politierekruten get from next year, less allowances, but more fixed salary.
A motard, a detective or someone to work for the general inspection: numerous police officers are entitled to an additional premium on the basis of the tasks they perform. In total dozens of functietoelagen, which, in some cases up to thousands of euros can deliver and, according to the court of audit and the audit Committee P the risk of abuse and premiejagerij.
But people that from next year, when the police go to work, will some of these three premiums will no longer be able to enjoy. In total disappear nineteen allowances. In exchange see police officers their base salary raised to the level of similar public functions. There signed minister of the Interior Jan Jambon (N-VA), the police and three of the four major trade unions, recently launched an agreement on. Only the socialist ACOD did not agree. To fees for night and weekend work or overtime is not hit.
In her most recent begrotingsbesprekingen, the federal government, 6.5 million euros aside to the new system from July next year, progressive roll-out. The politieleiding and the competent ministers bites for years their teeth on the file. “This is a very tough yard,” says Marc De Mesmaeker, the new commissioner-general of the federal police. ‘This adjustment is revolutionary.’ Eventually the police have to evolve to a wage that consists of three components: the fix, weekend, night, overtime, and meal vouchers.
“The agreement not only means that our policemen should be financially strengthened, but also that we finally do away with the jungle of outdated contributions to modernisation were,” says Jambon. ‘That was urgently needed.’ The measures in the attempt of the federal government to the politiestatuut to modernize. There is also a reform of the pension scheme and the abolition of the possibility for police officers to use their sick days to spare.
Against these two measures, in combination with the increased workload and the increased violence against them – protested politielui the last few weeks massively. Last week reported that hundreds of policemen are ill, what the security of the European summit very difficult. Earlier this month there were plenty of work-to-rule.
The agreement on the premium schemes points out that the social dialogue in the police, not yet dead, says The Mesmaeker. With the unions was a doubt has arisen as to whether the agreements on the grants, however, would continue, in the light of the social unrest of the past few weeks. “I honoreer our appointment integral,” says Jambon. ‘It is not true that this government tornt to the social status of our policemen, on the contrary. I am convinced that we also in terms of the pension plan and the ziektekapitaal will hit.’ That explanation take the trade unions not settle. Perhaps follow in the coming weeks even more actions.

industry_corpus2: Law & Justice


text:
we could supply good quality goods, aggressive cost and very best purchaser assistance. Our destination is "You come here with difficulty and we supply you with a smile to take away" for Toggle Switch Boot , toggle switch boot , Toggle Switch UL , and frequently create new machine is our company's organization objectives. We look forward for your cooperation.
"Our eternal pursuits are the attitude of ""regard the market, regard the custom, regard the science"" as well as theory of ""quality the basic, have faith in the initial and administration the advanced"" for Toggle Switch Boot , toggle switch boot , Toggle Switch UL , To have much more enterprise. ompanions we've got updated the item list and seek for optimistic co-operation. Our web-site shows the latest and complete information and facts about our merchandise list and company. For further acknowledge our consultant service group in Bulgaria will reply to all of the inquiries and complications immediately. They're intending to make their finest effort to meet buyers need to have. Also we support the delivery of absolutely free samples. Business visits to our business in Bulgaria and factory are generally welcome for a win-win negotiation. Hope to expertise a happy company co-operation perform with you.

industry_corpus2: Manufacturing


text:
James Bartholomew recently appeared at the Cato Institute. He argues that "the welfare state in Britain has resulted in a generation of badly educated and dependent citizens, leading to lives of deprivation for thousands and undermining the original intent behind its creation in the 1940s. Has the welfare state really led to more harm than good? What does this imply for the ever-expanding welfare state in the United States"?
And if so, what is to be done?
Because of welfare reform under Clinton, the U.S. technically no longer faces the problem of a permanent welfare class. You can be on it for so long until you get a job or are bounced from the rolls. I do believe that the UK has yet to make that adjustment to their system.
Obama is moving rapidly to undo this particular Clinton-era reform. Permanent dependency is a key part of creating the welfare state that he is striving to plunge the US into.

industry_corpus2: Politics & Administration


text:
These designs are the perfect solution for fabric décor in schools, restaurants, or even a pediatrics office. These styles are playful, fun, colorful, and people love them.
Customize your room with any design you'd like. Our novelty décor themes will brighten the room with colorful trucks, pets, and even shapes designs for applications like bedding, décor pillows, curtains or drapes.


text:
In October 1962, America and the Soviet Union brought the world to the brink of nuclear war. Cuba was the bone of contention. The small island nation is just 180 kilometers from the US state of Florida. At the time of the crisis, Cuba controlled the Gulf of Mexico. Cuba came under American influence after the US freed it from Spanish rule in 1898. With help from the US, Fulgencio Batista dominated Cuba from 1933 to 1958. Government corruption and ongoing use of violence provoked an uprising in 1958. Young lawyer Fidel Castro led the revolt. Cuba had sent him into exile for threatening to overthrow the government. Castro snuck back into Cuba with his friend and cohort Che Guevara. The pair led a series of guerrilla attacks that forced Batista to flee the country. On January 8, 1959, Castro entered in triumph. The new Cuban leader put most of the country’s industry under government control and strengthened ties with the Soviet Union. Alarmed at having a Communist-led country at short range, in 1961, US President John F. Kennedy backed a plan for Cuban exiles to invade the island. They landed in the Bay of Pigs, a cove on Cuba’s southwestern coast. The Cuban army easily defeated the anti-Castro invaders.
Openly threatened by the US, Castro asked the Soviets to provide Cuba with nuclear missiles. American spy planes saw the weapons en route to Cuba on October 14, 1962. Eight days later, Kennedy ordered US forces to blockade their neighbor, preventing delivery of the weapons. Over the next few days, the navies of the two superpowers came close to entering combat. Tensions were high. The possibility of nuclear warfare loomed. Soviet leader Nikita Khrushchev finally proposed a compromise to end the crisis. Kennedy accepted the deal on October 28. Soviet ships went home without delivering the weapons. America promised not to invade Cuba and dismantled missile bases in Turkey. After the crisis, the two nuclear powers worked on easing tensions between them. The process culminated in the Nuclear Test Ban Treaty signed August 5, 1963. From then on nuclear weapons were tested underground, reducing risks to civilians.


text:
If you want to remodel your home but aren't sure where to start, contact Mastertech Construction LLC. Our team handles home remodeling projects in Brighton, Michigan. We specialize in creating drop ceilings. Drop ceilings are great because they're stylish, soundproof and moisture-resistant. Our team will create a beautiful ceiling that will modernize your home.
Reach out to us today to get a free estimate on your home remodeling project.
Mastertech Construction builds home additions in Brighton, Michigan. We can build any type of room you want to increase your space and boost your home value. A contractor will tour your home with you and recommend which type of room would work best with your space. You can trust us to make your new room blend in seamlessly with the rest of your home.
See why other Brighton homeowners trust us to build their home additions. Call 810-623-4115 now to arrange for construction services.
Hire us to renovate your home from the ground up. We provide a variety of home improvement services.
Copyright © 2019 Mastertech Construction LLC, all rights reserved.


text:
During the old days, being presentable and looking decent is what our parents always tell us about, so as to look good and clean, and not being made fun of in public places. But times have changed, and there is a new fashion style trending nowadays.
Famous celebrities like Kim Kardashian-West, Kylie Jenner and Justin Bieber are just some of the celebrities that started this kind of weird fashion and are now trending in the fashion scene worldwide.
The latest addition to this trend from Korea.
It has come to a point that tattered clothes is the new trend and is becoming weird as time goes by.


text:
Flight will depart from New Delhi Indira Gandhi International Airport (DEL) and arrive at Suvarnabhumi Airport (BKK) in Bangkok, Thailand and vice versa for the return flight.
Fly to Bangkok DEL-BKK from April 2019 onwards with our instantly confirmed air tickets. Your diy free and easy package will be the most comprehensive, convenient, easy, super fast, real time air ticket/room availability, instant confirmation and most importantly save you time and money. Have a pleasant trip to Thailand from India. Taxes and fees inclusive. Terms and conditions apply.

industry_corpus2: Transportation


text:
EMOTION STAINLESS STEEL INDUCTION Emotion, get inspired !
Emotion, a trendy and elegant look, to enhance the pleasure of cooking. Thanks to its thick base and to its professional inspired design, Emotion is the best range for flavorful and evenly-cooked results. The range is made of premium quality 18/10 Stainless Steel, guaranteed for 10 years. Its titanium non-stick coating ensures an extreme resistance for a maximum durability.
This coating offers significant non-stick performance thanks to an extra-thick finish layer enhanced with titanium particles.
Thermo-Spot® (pans only) turns full red when the pan has reached the ideal temperature for perfect searing. It guarantees perfect texture, perfect color and perfect taste, for delicious full-flavored meals every day.
Prevents deformation over time and guarantees even heat diffusion for delicious, homogeneous cooking results.


text:
Rhodium plated bright silver tone finish.
Studded with clear Swarovski crystals and blue eye.
Height - 6.5cm. Widest point - 1.5cm.
Beautifully packaged in J&G ribbon tied box with tote gift bag.


text:
The idea that happy couples gain weight when they love each other sounds slightly far-fetched, but surprisingly, there is evidence that supports this statement. According to several studies, couples who reported to be happy and satisfied in their relationships/marriages are more likely to gain weight.
Here at Bright Side, we followed the studies that had been carried out and learned what was examined and what the result of the research was.
Research done by the University of North Carolina followed the weight measurements of more than 8,000 people and it was concluded that a married woman can gain, on average, 24 pounds during the first 5 to 6 years of her marriage. In addition, women who lived with their partners but weren’t married gained 22 pounds while women who were dating but weren’t living with their partner gained only 13 pounds.
The study also showed that men gained weight during the transition from being single to being in a relationship, and it showed that men who cohabited with their other half for more than 2 years were twice as likely to gain more than 25 pounds than men who did not live with their partner.
The study reached a conclusion that there is a strong association between romantic relationships and the number of obesity-related results. However, even though weight gain is evident in long-term romantic relationships, there was a significant decrease in smoking and alcohol abuse which shows a willingness of couples to pursue a healthier lifestyle.
More research was done by the National Institute of Health to examine whether weight gain in newly wedded couples was a positive or negative reflection of their happiness. The study followed couples who had been married for more than 4 years and it examined their emotional health and levels of stress. It was found that couples who had recently been happily married were twice more likely to put on weight whereas couples who reported being not as happy with their spouses were less likely to gain weight.
The study reached the conclusion that happy couples gain more weight because they don’t have the need to attract another partner and they feel happier the way they are. Whereas couples who feel unhappy in their relationships are unable to gain more weight due to stress. However, it is recommended for happily married couples who gained weight to think of their BMI because of health issues rather than their appearance.
A study done by the New England Journal of Medicine showed that weight gain is also contagious in married couples. If one partner is gaining weight, the other partner has a 37% chance of gaining more weight as well. This is because they adapt to each other's habits since they spend so much time together. Whereas couples that might be unhappy in their relationships avoid spending time together so it becomes more difficult to adapt to each other's eating habits.
People holding the study analyzed the social environment, habits and mutual activities of the couples and reached the conclusion that mutual weight gain derives from both individuals psychologically influencing each other with their eating habits.
It is important to keep in mind that even though these are studies done by health professionals, they only show a number of instances in the world and not the whole world in question, so it does not apply to everyone. There are always exceptions and it doesn't mean that when you don't gain weight when you are married that you are not happy with your partner. These studies were mainly done in order to understand the living situations of couples and to help fight obesity.
It is vital to influence each other in positive ways with healthy eating habits and lifestyles regardless of weight in order to enjoy each other's company for the rest of your lives.
What do you think about the results of these studies? Do you believe you can gain more weight when you are happily married? Please let us know your thoughts in the comments below!